Review

Use of Antipsychotics for the Treatment The Journal of Clinical Pharmacology

2016, 00(0) 1–10
of Behavioral Symptoms of Dementia C 2016, The American College of

Clinical Pharmacology
DOI: 10.1002/jcph.731

H. Karl Greenblatt, BA and David J. Greenblatt, MD

Abstract
Antipsychotic medications are widely used in the management of behavioral and psychological symptoms of dementia. While nonpharmacological
interventions should be the irst-line treatment for behavioral symptoms of dementia, these are often unfeasible and/or ineffective. Conventional
and atypical antipsychotic agents appear to have modest to moderate clinical eficacy in the treatment of these symptoms, though it is unclear
which individual agents are most effective. No conclusive evidence exists that any available alternative medications are safer and more effective than
antipsychotics. A number of studies have shown an increased risk of mortality associated with antipsychotics in patients with behavioral symptoms of
dementia, though the observed risk increase may be partially confounded by illness severity and/or preexisting health determinants. The mechanisms
of increased mortality risk are not fully established, but are likely to involve cardiovascular events. It is probable, though not certain, that conventional
antipsychotics are associated with a greater number of poor outcomes than atypical antipsychotics. In certain patients with refractory behavioral
symptoms, antipsychotics are a viable treatment option. Key considerations for antipsychotic prescribing for this population are published in regulatory
guidelines, and include minimization of dosage and duration of treatment, continuous reevaluation of symptoms, and involvement of caregivers.

Keywords
antipsychotics, behavioral symptoms, dementia, nursing homes

Dementia is characterized by a progressive loss of cog-
nitive and social function, with onset most commonly
after age 65. Several types of dementia are known,
including Alzheimer’s, vascular, Lewy body, and
frontotemporal; each has a different neuropathological
basis but a similar symptom presentation. Alzheimer’s
is the most prevalent. In the United States, Alzheimer’s
was implicated as the cause of 85 000 deaths in 2013,
and it is estimated to affect 5.2 million Americans.1
The principal symptom of any dementia is memory
impairment, but other cognitive symptoms can include
disorientation as well as dificulty speaking, planning,
or organizing thought. Another cluster of symptoms,
often referred to as “Alzheimer’s psychosis” or
behavioral and psychological symptoms of dementia,
commonly involves personality changes, inappropriate
behavior, agitation and aggression, and paranoia. In
some patients, this behavior manifests itself primarily
at night, in which case it is called “sundowning” or
“sundown syndrome,” and is usually managed similarly
to other forms of behavioral symptoms of dementia.2–4
The decline associated with dementia is irreversible, and
pharmacological treatments approved by the Food and
Drug Administration (FDA) provide at best temporary
symptom improvement. Cholinesterase inhibitors
(such as donepezil) and NMDA receptor blockers
(such as memantine) may modestly enhance cognition
in early-stage dementia patients, but their expense
and side effect proile pose signiicant challenges to
clinicians. There are currently no FDA-approved
treatments speciically for behavioral and psychological
symptoms of dementia, which are often the
most troubling and demanding from a caregiver’s
perspective. A number of psychotropic drugs are
widely used “off-label” to treat these symptoms.
These include selective serotonin reuptake inhibitor
(SSRI) antidepressants (eg, sertraline, citalopram),
mood stabilizers (eg, carbamazepine, valproate), and,
most commonly, antipsychotic medications. Both
irst-generation “conventional” antipsychotics (eg,
haloperidol, chlorpromazine) and second-generation
“atypical” antipsychotics (eg, risperidone, quetiapine)
are used for this purpose.
Many patients with dementia are treated in the
nursing home setting. In 2013, nearly 50% of US
nursing home residents had a diagnosis of dementia.5
Behavioral symptoms present a dilemma to nurs-
ing home staff and clinicians since disruptive or
Program in Pharmacology and Experimental Therapeutics, Sackler
School of Graduate Biomedical Sciences, Tufts University School of
Medicine, Boston, MA, USA
Submitted for publication 24 November 2015; accepted 29 February
2016.
Corresponding Author:
David J. Greenblatt, MD, Tufts University School of Medicine, 136
Harrison Avenue, Boston MA 02111
Email: DJ.Greenblatt@Tufts.edu

1
2 The Journal of Clinical Pharmacology / Vol 00 No 0 2016

dangerous behavior requires attention and resources
that are not always available. The use of antipsychotic
medications in nursing homes is extensive. The 2004
National Nursing Home survey found that 26% of
nursing home residents received an antipsychotic; 40%
of these were off-label.6
The prescribing of antipsychotic medications to
nursing home patients with dementia is a controversial
and polarizing issue. Reports in the lay press often
allege that antipsychotic use in nursing homes con-
stitutes elder abuse and unethical use of “chemical
restraints.”7–9 This has complicated critical, evidence-
based assessments of whether antipsychotics are a
viable option for the treatment of behavioral symp-
toms of dementia. The purpose of this review is to
evaluate the circumstances under which antipsychotics
could be useful in this population, and to pose clinical
considerations to ensure their appropriate use. Based
on a search of the PubMed database, the review will
draw from a representative (although not necessarily
completely comprehensive) sampling of literature that
addresses the eficacy, safety, and therapeutic role of
antipsychotics in dementia.
Controversy Surrounding Antipsychotics
for Behavioral and Psychological
Symptoms of Dementia
The allegation that antipsychotic prescribing for de-
mentia patients is categorically unnecessary, dangerous,
and even unethical is sometimes expressed by the lay
press, plaintiff’s attorneys, patient advocacy groups,
medicolegal experts, and health care professionals.10–18
These claims may be driven in part by valid though
anecdotal reports of dementia patients who experi-
enced poor outcomes attributable to antipsychotic drug
use. Proponents of this view generally raise issues relat-
ing to stafing of care facilities, “chemical restraints,”
inappropriate Medicare billing, pharmaceutical pro-
motion for off-label prescribing, and mortality risk
associated with antipsychotics (Table 1).
In response to these issues, government agencies,
patient advocacy groups, and professional societies in
the United States and elsewhere in the world have devel-
oped approaches to modifying and reducing the extent
of antipsychotic prescription in nursing homes.19–26
The problem of understafing of nursing homes is
an unfortunate reality, and inappropriate prescribing
and/or promotion of antipsychotics likely does occur.
There is no clear evidence as to the past or present in-
cidence of these infractions. Regarding the FDA Black
Box Warning, this in general is an objective statement
of observed risk that does not relect the potential ben-
eits of a drug, nor does it mean that an individual pa-
tient should or should not receive the drug.18 For exam-
ple, SSRI antidepressants carry a Black Box Warning
regarding suicidal ideation in children and adolescents,
yet these drugs are among the most widely prescribed—
often with considerable therapeutic beneit—for these
populations. Some expert and government groups have,
with a correct interpretation of the Black Box Warn-
ing in mind, taken a position on the appropriateness
of antipsychotics for dementia. A 2011 report from
the American Society of Consultant Pharmacists con-
cluded that an antipsychotic may be appropriate in
some dementia patients, provided the medication is
appropriately indicated (where an off-label prescription
is not equivalent to an inappropriate indication), a spe-
ciic and documented goal of treatment exists, the pa-
tient is closely monitored, and the medication is used as
sparingly as possible.25 In addition, guidelines released
by the Centers for Medicare and Medicaid Services in
2013 stated that an antipsychotic may be appropriate
only when used to treat speciic symptoms related to a
documented, diagnosed medical condition.26
Alternatives to Antipsychotics for
Behavioral Symptoms of Dementia
Both pharmacological and nonpharmacological alter-
natives to antipsychotic use have been studied, with
nonpharmacological interventions universally consid-
ered irst-line treatment.27–32 A 2014 panel formulated

Table 1. Points Commonly Discussed by Opponents of Antipsychotic Medication Use in Patients With Behavioral and Psychological Symptoms of
Dementia

1. Nursing homes are inadequately staffed and do not have the capacity to manage dificult behaviors nonpharmacologically. Thus, antipsychotics are
tantamount to “chemical restraints” used primarily for the convenience of the nursing home staff, not for the well-being of the patient. When such
“restraints” are used, informed consent is often withheld from families before an antipsychotic is prescribed.
2. Legal action has been initiated against individual nursing homes accused of billing Medicare for unnecessary medications or prescribing for unapproved
indications.13–15 One government report found that 51% of Medicare claims for atypical antipsychotics in 2007 were “erroneous.”17 Pharmaceutical
manufacturers have also been ined for “aggressively” marketing antipsychotics to nursing homes for non-FDA-approved indications.13–15 Events of this
type are used to support the view that a proit motive partially underlies the prescribing of antipsychotics in dementia.
3. The FDA has issued a Black Box Warning regarding an increased risk of mortality in elderly dementia patients prescribed an antipsychotic.18 Opponents
of antipsychotic prescribing interpret these warnings as evidence that the majority of prescribing of these medications in this context is dangerous and
contraindicated.

2
Greenblatt and Greenblatt
a “Dice” approach to behavorial symptoms of demen-
tia (“Describe, Investigate, Create, Evaluate”), which
stresses that a provider must investigate and rule out
an environmental cause of any problem behavior be-
fore considering any medication.33 Caregiver education
is also a critical component of nonpharmacological
management, given the possibility that controllable
factors (eg, temperature, pain, or speciic fears) underlie
the agitation seen in a certain percentage of patients
with behavioral disorders. One study reported that
prophylactic pain management in dementia patients
produced a therapeutic effect similar to that seen with
antipsychotics, though this approach included the use
of analgesics.34 Personalized social interaction, psy-
chosocial treatment, simulated presence therapy, and
reminiscence therapy also produce a modest clinical
beneit,30,35 as do sensory and music therapies.31,36
When behavioral symptoms take the form of “sun-
downing,” melatonin therapy has been associated with
at best modest symptom improvement; light therapy
has also been investigated in these patients.2,4 Most of
these interventions are dificult to study because in ran-
domized, controlled trials, researchers and observers
cannot easily be blinded.
It is likely that non-drug therapies alleviate agitation
on a short-term basis in some fraction of dementia
patients. However, these interventions require consider-
able human resources that are not necessarily available
in many nursing homes, and they are less likely to be
effective in acute or emergent situations in which a
patient poses a danger to him-/herself or others.
Drug therapies that are potentially safer and more
effective than antipsychotics have been evaluated.30,37,38
Citalopram, an SSRI antidepressant, produces a sta-
tistically signiicant reduction in patient agitation, and
also leads to reduced anxiety on the part of caregivers.39
However, the eficacy of citalopram was compared
only to placebo, as opposed to a comparator antipsy-
chotic; in addition, this study reported adverse cog-
nitive and cardiac effects associated with citalopram.
Finally, citalopram, due to its mechanism of action, is
unlikely to be effective as an a prn treatment for patients
with acute intermittent agitation, as opposed to per-
sistent agitation. Galantamine, an acetylcholinesterase
inhibitor, was shown slightly inferior to risperidone,
an antipsychotic, in a randomized, controlled trial.40
The combination of dextromethorphan and quinidine
had clinically signiicant eficacy in at least 1 study,41
although it has not been directly compared to an-
tipsychotics. A number of other new and existing
compounds, including carbamazepine, cannabinoids,
mibampator, and prazosin, are currently under inves-
tigation, though no conclusive evidence about their
beneits is yet available.38 Thus, antipsychotics remain
a widely used option for the treatment of behavioral
3
symptoms of dementia in part because no other class of
medications has a risk-beneit ratio established as being
more favorable.
Eficacy of Antipsychotics for Behavioral
Symptoms of Dementia
Antipsychotics are not FDA-approved for this purpose,
and published evidence has not conclusively validated
their eficacy. A large meta-analysis (n > 100,000)
evaluating the eficacy of 4 atypical antipsychotics in
North American nursing homes yielded inconsistent
conclusions.42 A smaller meta-analysis (n = 1683)
found, in general, no statistically or clinically signiicant
behavioral symptom improvement in patients receiving
antipsychotics compared to placebo.43 A 2-year longi-
tudinal study of nursing home residents with dementia
found that antipsychotics were not associated with
improvement in cognition or activities of daily living.44
In a multicenter placebo-controlled trial, risperidone,
olanzapine, and quetiapine could not be distinguished
from placebo in terms of eficacy in elderly dementia
patients with psychosis, aggression, or agitation.45 At
least 1 further study has raised the question of whether
antipsychotics are superior to SSRIs for the treatment
of behavioral symptoms of dementia.46
However, other evidence indicates that antipsy-
chotics have at least modest eficacy. Two meta-analyses
of randomized, placebo-controlled trials involving
atypical antipsychotics (aripiprazole, olanzapine, que-
tiapine, risperidone; n = 5050 and 2511) found
consistent, statistically signiicant symptom improve-
ment in patients receiving antipsychotic compared
to placebo.47,48 Two further literature reviews con-
cluded that aripiprazole and risperidone signiicantly
improve both psychiatric symptoms and cognition after
3 months of treatment,49 with olanzapine associated
with signiicant improvement in 1 of the reviews.50 In
all, antipsychotics appear to be at least comparable to
placebo and possibly meaningfully eficacious in the
treatment of behavioral symptoms of dementia.
Two important issues are not fully resolved. First,
are conventional or atypical antipsychotics more effec-
tive? One study has demonstrated signiicantly greater
eficacy for olanzapine and risperidone compared with
promazine,51 but similar studies of this type are scarce.
Second, within each class, which agent(s) are most effec-
tive? Recent literature52 has not resolved this question,
with the relative eficacy of 4 atypical antipsychotics
dependent on which rating scale was used to assess
symptoms. Without these guidelines, clinicians who
prescribe antipsychotics at present often base their
therapeutic approach on their own clinical experience
and/or institutional habit.
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4 The Journal of Clinical Pharmacology / Vol 00 No 0 2016
Adverse Events and Excess Mortality
Associated With Antipsychotics
In April 2005, the FDA irst issued a warning re-
garding an increased risk of sudden death in elderly
dementia patients prescribed atypical antipsychotics.52
Although the FDA bulletin stated that it was based
upon “seventeen placebo controlled trials performed
with olanzapine, aripiprazole, risperidone or quetiapine
in elderly dementia patients with behavioral disorders,”
the results of these trials were not made available to
the public. In 2008, the agency attached a Black Box
Warning applicable to all atypical antipsychotics, citing
an increased risk of death in elderly dementia patients.
It is not clear whether the Black Box Warnings brought
about a subsequent decrease in antipsychotic use for be-
havioral symptoms of dementia.53–56 In the same year,
regulators also issued a new advisory that postulated
a similar risk of excess mortality in dementia patients
for both conventional and atypical antipsychotics. In
neither document were data from randomized, placebo-
controlled trials released. The FDA alert regarding
conventional antipsychotics cited 2 retrospective cohort
studies57,58 as evidence that these drugs increase the
risk of death compared to no treatment. However,
the brieing itself commented, “The methodological
limitations in these two studies preclude any conclusion
that conventional antipsychotics have a greater risk of
death with use than atypical antipsychotics.”59
Does the published evidence (not including the elu-
sive “seventeen placebo-controlled trials”) support the
FDA’s ruling on atypical and/or conventional antipsy-
chotics? The FDA’s comment on “methodological lim-
itations” introduces an important caveat. Confounding
by the severity of the underlying illness may seriously
compromise the validity of conclusions from case-
control studies evaluating the relative risk of mortality
among dementia patients.60,61 For antipsychotic versus
no-treatment or other-treatment comparisons, the core
methodologic limitation is that patients prescribed an
antipsychotic tend to have worse dementia and so have
an increased mortality risk for this reason alone. For
trials comparing conventional versus atypical antipsy-
chotics, clinicians might favor prescribing one class over
another depending on the nature and severity of the
underlying disease. This methodologic limitation can
in principle be overcome through prospective, random-
ized, placebo-controlled trials to determine the relative
mortality risks.
In a review of randomized, placebo-controlled tri-
als of atypical antipsychotics in elderly dementia
patients,47 the relative risk of death in the treatment
group relative to controls was found to be 1.52. The
number of deaths was 46 out of 2071 patients in
the placebo group (2.2%), and 120 out of 3336 in
the antipsychotic group (3.6%). In an earlier study,
the relative risk was 1.54, with 41 deaths out of 1851
patients (2.2%) and 118 out of 3353 patients (3.5%)
in the placebo and antipsychotic groups, respectively.62
However, a third large review49 found the relative
risk to be 1.06, which was not statistically signiicant,
although the same study reported signiicantly more
frequent adverse events in the active treatment group.
An earlier, smaller meta-analysis (n = 1721) also found
no increased mortality risk in dementia patients treated
with risperidone versus placebo.63 In these analyses,
there was considerable overlap and redundancy in the
trials that were considered. In general, the weight of
published placebo-controlled trials on this question
is somewhat limited. The available evidence suggests
that atypical antipsychotics when used in dementia
patients carry a risk of mortality that is no less—and
possibly greater—than that of placebo. There is no
clear evidence that establishes which speciic atypical
antipsychotic is associated with the greatest risk. A
large review of studies comparing individual agents
found evidence insuficient to suggest whether any
particular agent is safest or most hazardous.64
Studies comparing the safety risk associated with
atypical antipsychotics versus typical antipsychotics
have not been fully conclusive.65 At least 1 review
of retrospective studies comparing conventional an-
tipsychotics to placebo concluded that conventional
and atypical antipsychotics carry a similar mortal-
ity risk.66 An analysis of 17 placebo-controlled trials
(n = 2387) concluded that conventional antipsychotics
do not increase the risk of death compared to placebo
in elderly patients.67 A review of major cardiac adverse
events associated with antipsychotic agents found no
clinically signiicant difference between conventional
and atypical agents.68 In 1 study, autopsy data also
suggested that haloperidol is not associated with sud-
den death in dementia patients.69 However, 1 retro-
spective study found a greater relative risk associated
with conventional antipsychotics,70 as did 3 reviews of
observational studies.64,66,71 One of these found that hip
fracture, stroke, myocardial infarction, and ventricular
arrhythmia are among the factors that explain the
mortality difference between conventional and atypical
agents.71 A further review, which adjusted its relative
risk calculations to account for confounding by termi-
nal illness, also found conventional agents to carry a
greater relative risk of mortality than atypical agents.72
It appears, therefore, that conventional agents have at
best a safety proile similar to atypical agents, but most
likely carry a signiicantly increased relative mortality
risk.73
If an excess mortality hazard exists with con-
ventional or atypical antipsychotics, one potential
mechanism of drug-related deaths is a cardiovascular
4
Greenblatt and Greenblatt
event.74 Many conventional antipsychotics have sig-
niicant afinity for the hERG potassium channel
(human-ether-a-go-go); this can lead to prolongation
of the QTc interval and potentially to torsades de
pointes, a precursor of ventricular tachycardia.75–80
Thioridazine, pimozide, and sertindole are considered
to have relatively high risk in this context. Atypical
antipsychotics tend to have lower but nonzero hERG
afinity; risperidone prolongs QTc without affecting
QTc dispersion,81 which would be necessary to induce
ventricular arrhythmia. A large review of QTc prolon-
gation and torsades de pointes associated with atypical
antipsychotics82 concluded that atypical antipsychotics
do cause varying degrees of QTc prolongation, al-
though not necessarily associated with torsades de
pointes. The rarity of serious arrhythmias precluded
a conclusion about the relative risks associated with
individual drugs. As with the risk of all-cause mortal-
ity associated with antipsychotics, the risk of sudden
cardiac death associated with antipsychotics cannot be
adequately assessed through retrospective case-control
studies. The available evidence based on placebo-
controlled trials suggests that, if antipsychotics increase
sudden cardiac deaths in dementia patients, the mech-
anism may well involve QTc prolongation.83,84 Acute
myocardial infarction is another proposed mecha-
nism of antipsychotic-associated sudden cardiac death.
Dopamine type 3 (D3) receptor blockade has been
suggested to initiate a thrombogenic cascade and there-
fore could mediate an increased risk of myocardial
infarction.85 Venous thromboembolism has also been
suggested as a mechanism of antipsychotic-associated
mortality, although the literature on this question is
almost exclusively limited to retrospective case-control
studies. A longitudinal study86 found that the risk of
thromboembolism may be mediated by the onset of
hyperprolactinemia, a known adverse effect of atypical
antipsychotics,87 although the incidence of this event
in elderly dementia patients is not known. Finally,
sedating antipsychotics may increase the risk of aspi-
ration pneumonia as a cause of death; 1 study showed
a higher relative risk of pneumonia associated with
atypical agents versus conventional agents, although
this inding has not been replicated.64 Overall, further
investigation is needed to establish the mechanism by
which antipsychotics may increase the risk of cardiac
death, and what the individual patient risk factors
might be.
Clinical Considerations
Nonpharmacological management should be the initial
approach to patients with behavioral and psychological
symptoms of dementia. The Centers for Medicare and
Medicaid Services have produced a set of dementia
5
care principles that should be followed in the nurs-
ing home care of any patient with serious agitation
(Table 2).26 These emphasize the need for personalized
care and adequate stafing in nursing homes, such that
any new or worsening symptoms may be thoroughly
investigated and individually managed. “Sundowning”
poses an especially great challenge, since patients who
become agitated at night often have a more minimal
night staff to care for them; widespread improvement
may be needed in the adequacy of nursing home night
stafing. In reality, as these guidelines acknowledge,
a number of dementia patients will decline to the
point at which nonpharmacologic options would be
ineffective or incompletely effective—regardless of the
adequacy and skill of the nursing home staff—and
caregivers will need to consider other approaches. At
least 2 additional care algorithms have been devised
that may advise clinicians as to when pharmacolog-
ical interventions should be considered.29,88 From a
government perspective, the Department of Health
and Human Services has issued recommendations to
ensure adequate surveillance of Medicare antipsy-
chotic claims, with the goal that all antipsychotic pre-
scriptions be necessary and appropriately indicated26
(Table 3).
When faced with situations that may require phar-
macologic treatment, clinicians can take steps to assure
that therapy is ethical, and proceeds with the minimum
possible risk. Involvement of family and/or caregivers
is essential. Patients with behavioral symptoms may
not be able to give informed consent for drug treat-
ment. Consultation from an independent psychiatrist
or neurologist may be required for a determination
of a patient’s capacity to give informed consent. If a
clinician judges that a patient without capacity would
beneit most from an antipsychotic, the institution’s ad-
ministrative representative and/or legal counsel should
be consulted to identify the appropriate surrogate to
provide consent. In many cases this may be a close
family member or other individual able to act as the
patient’s advocate or surrogate.
The clinician should then meet with the patient’s
family/caregivers and present a series of facts objec-
tively (Table 4). A summary of the meeting, and the
speciic topics that were discussed, are entered into
the patient’s medical record. After receiving this in-
formation, the patient’s family/caregivers must weigh a
variety of ethical considerations. Other pharmacolog-
ical options should then be discussed, along with the
available evidence regarding their eficacy. The clinician
should also offer a realistic prognosis for the patient,
including the possible need for more austere nondrug
interventions.
If antipsychotic treatment is initiated, the clinician
should begin therapy at the lowest effective dose and for
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6 The Journal of Clinical Pharmacology / Vol 00 No 0 2016

Table 2. Dementia Care Principles

Principle Details

Person-Centered Care CMS requires nursing homes to provide a supportive environment

that promotes comfort and recognizes individual needs and
preferences.
Quality and Quantity of Staff The nursing home must provide staff, both in terms of quantity
(direct care as well as supervisory staff) and quality to meet the
needs of the residents as determined by resident assessments and
individual plans of care.
Thorough Evaluation of New or Worsening Behaviors Residents who exhibit new or worsening behavioral symptoms
should have an evaluation by the interdisciplinary team, including
the physician, in order to identify and address treatable medical,
physical, emotional, psychiatric, psychological, functional, social, and
environmental factors that may be contributing to behaviors.
Individualized Approaches to Care Current guidelines from the United States, United Kingdom,
Canada and other countries recommend use of individualized
approaches as a irst line intervention (except in documented
emergency situations or if clinically contraindicated) for behavioral
symptoms. Utilizing a consistent process that focuses on a
resident’s individual needs and tries to understand behavior as a
form of communication may help to reduce behavioral expressions
of distress in some residents.
Critical Thinking Related to Antipsychotic Drug Use In certain cases, residents may beneit from the use of medications.
The resident should only be given medication if clinically indicated
and as necessary to treat a speciic condition and target symptoms
as diagnosed and documented in the record. Residents who use
antipsychotic drugs must receive gradual dose reductions and
behavioral interventions, unless clinically contraindicated, in an
effort discontinue these drugs.
Interviews With Prescribers Surveyors are instructed to evaluate the process of care. Surveyors
interview the attending physician or other primary care provider,
behavioral health specialist, pharmacist and other team members to
better understand the reasons for using a psychopharmacological
agent or any other interventions for a speciic resident.
Engagement of Resident and/or Representative in Decision-Making In order to ensure judicious use of psychopharmacological
medications, residents (to the extent possible) and/or family or
resident representatives must be involved in the discussion of
potential approaches to address behavioral symptoms. These
discussions with the resident and/or family or representative
should be documented in the medical record.

Reproduced from the Centers for Medicare and Medicaid Services (CMS) Guidelines.12

Table 3. Recommendations to Ensure Adequate Surveillance of Medicare Antipsychotic Medication Reimbursement Claims26

1. Facilitate access to information necessary to ensure accurate coverage and reimbursement determinations.
2. Assess whether survey and certiication processes offer adequate safeguards against unnecessary antipsychotic drug use in nursing homes.
3. Explore alternative methods beyond survey and certiication processes to promote compliance with federal standards regarding unnecessary drug use in
nursing homes.
4. Take appropriate action regarding the claims associated with erroneous payments.

the shortest duration possible. International prescribing
guidelines have been proposed whereby the maximum
appropriate duration for antipsychotic use in dementia
patients is 12 weeks.10 Table 5 shows stipulations by the
Centers for Medicare and Medicaid Services regarding
the maximum recommended daily dose of various
antipsychotic agents. Any patient receiving an antipsy-
chotic should be monitored as closely and assessed
as frequently as possible. Family/caregivers should, if
possible, be given frequent updates as to the patient’s
status as therapy is initiated. The goal of treatment
should be to ease the patient’s distress without pro-
ducing excessive sedation or incurring undue risk of
adverse events. Clinical judgment and experience are
needed to select and titrate the dosage of the most
appropriate antipsychotic medication.

6
Greenblatt and Greenblatt 7

Table 4. Topics Proposed for Discussions Between the Treating Physician and the Patient’s Family or Caregivers

1. The patient’s symptoms can no longer be nonpharmacologically managed in a way that preserves the patient’s dignity and/or ensures a reasonable
environment for other patients. (Note that if the patient poses an immediate physical danger to the self or others, this is a critical consideration. In this
scenario, a caregiver’s consent may not be necessary before starting antipsychotic therapy.)
2. Potentially reversible and treatable causes of the patient’s symptoms have been evaluated and ruled out.
3. There are no approved drug treatments for the patient’s observed symptoms, but based on available evidence and the clinician’s experience, antipsychotics
are more likely than not to ease symptoms to a greater degree than placebo. Therefore, the clinician recommends starting antipsychotic therapy at this time.
4. There is considerable, but not overwhelming, evidence that antipsychotics are associated with an increased risk of sudden death in dementia patients. It is not
clear which individual drugs carry a greater or lesser mortality risk. (It may be useful for clinicians to provide their own experience with this clinical situation.)
5. The FDA has issued a Black Box Warning regarding the above risk. However, this does not mean that the patient is likely to die once he or she begins
antipsychotic therapy, or that prescribing is not permitted. The absolute risk with any drug is small. A Black Box Warning is a cautionary statement regarding
the risks associated with a drug, not a statement as to whether the potential beneits may outweigh the potential risks.

Table 5. Daily Dose Limits for Antipsychotic Medications Used to Treat prescribed. However, drug therapy may be necessary in
Residents With Behavioral Symptoms of Dementia many such patients, especially if they pose a danger to
Antipsychotic Name Maximum Total Daily Dosage (mg) themselves or danger/signiicant disruption to others.
In the absence of other FDA-approved treatments,
Chlorpromazine (FG) 75
antipsychotics remain an option for clinicians, although
Fluphenazine (FG) 4
Haloperidol (FG) 2 the treatment of behavioral symptoms with these med-
Loxapine (FG) 10 ications entails considerable precautions. Consultation
Molindone (FG) 10 with caregivers/family and alignment at each step of the
Perphenazine (FG) 8 treatment process are essential.
Thioridazine (FG) 75
Thiothixene (FG) 7
Triluoperazine (FG) 8 Funding
Aripiprazole (SG) 10 No sources of funding were involved in this study.
Clozapine (SG) 50
Olanzapine (SG) 5
Quetiapine (SG) 150 Declaration of Conlicting Interests
Risperidone (SG) 2 The authors have no conlicts of interest to declare.
Ziprasidone (SG) (Not adequately studied)

Reproduced from the Centers for Medicare and Medicaid Services (CMS)
Guidelines.26
FG, irst-generation agent; SG, second-generation agent.
Conclusion
Conventional and atypical antipsychotics may have
modest eficacy in the management of patients with
behavioral and psychological symptoms of dementia.88
However, a risk of excess mortality has been con-
sistently observed in dementia patients treated with
antipsychotics. The mechanism of mortality may be
cardiovascular in nature, involving either arrhythmia
susceptibility from QTc prolongation or increased
thrombogenesis. Conventional antipsychotics are likely
to carry a greater risk of mortality than atypical an-
tipsychotics, in addition to the known risk of extrapyra-
midal side effects (involuntary movement disorders)
associated with these drugs. It is unclear whether par-
ticular conventional or atypical agents are either safer
or more hazardous than others.
Guidelines exist about how new or worsening be-
havioral symptoms should be managed in a nurs-
ing home setting; nonpharmacological interventions
should always be tried before a new medication is
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Inggrid Budhi Pangestu Adji (201610330311098)

Penggunaan Antipsikotik untuk Pengobatan Gejala Perilaku Demensia

H. Karl Greenblatt,BA and David J.Greenblatt,MD
Abstrak
Obat-obatan antipsikotik banyak digunakan dalam penatalaksanaan gejala psikologis dan
perilaku demensia. Sedangkan nonfarmakologis intervensi harus menjadi pengobatan lini
pertama untuk gejala perilaku demensia, ini sering tidak layak dan / atau tidak efektif.
Konvensional dan agen antipsikotik atipikal tampaknya memiliki kemanjuran klinis
sederhana hingga sedang dalam pengobatan gejala-gejala ini, meskipun tidak jelas agen mana
yang paling efektif. Tidak ada bukti konklusif bahwa obat alternatif yang tersedia lebih aman
dan lebih efektif daripada antipsikotik. Sejumlah penelitian telah menunjukkan peningkatan
risiko kematian terkait dengan antipsikotik pada pasien dengan gejala perilaku demensia,
meskipun peningkatan risiko yang diamati dapat dikacaukan oleh keparahan penyakit dan /
atau faktor penentu kesehatan yang sudah ada sebelumnya. Mekanismenya peningkatan
risiko kematian tidak sepenuhnya ditetapkan, tetapi cenderung melibatkan kejadian
kardiovaskular. Mungkin, meskipun tidak pasti, yang konvensional antipsikotik dikaitkan
dengan jumlah yang lebih besar dari hasil yang buruk daripada antipsikotik atipikal. Pada
pasien tertentu dengan perilaku refraktori gejala, antipsikotik adalah pilihan pengobatan yang
layak. Pertimbangan utama untuk resep antipsikotik untuk populasi ini diterbitkan dalam
peraturan pedoman, dan termasuk minimalisasi dosis dan durasi pengobatan, evaluasi ulang
gejala secara terus-menerus, dan keterlibatan pengasuh.
Kata kunci : antipsikotik, gejala perilaku, demensia, panti jompo

Demensia ditandai dengan hilangnya kognitif secara progresif dan fungsi sosial, dengan onset
paling umum setelah usia 65. Beberapa jenis demensia diketahui, termasuk Alzheimer,
vaskular, tubuh Lewy, dan frontotemporal; masing-masing memiliki neuropatologis yang
berbeda dasar tetapi presentasi gejala yang sama. Alzheimer adalah yang paling umum. Di
Amerika Serikat, Alzheimer terlibat sebagai penyebab 85.000 kematian pada tahun 2013,
dan diperkirakan akan mempengaruhi 5,2 juta orang Amerika.

Gejala utama dari setiap demensia adalah ingatan gangguan, tetapi gejala kognitif lainnya
dapat mencakup disorientasi serta kesulitan berbicara, perencanaan, atau mengorganisir
pemikiran. Sekelompok gejala lain, sering disebut sebagai "psikosis Alzheimer" atau gejala
perilaku dan psikologis demensia, umumnya melibatkan perubahan kepribadian, tidak pantas
perilaku, agitasi dan agresi, dan paranoia. Di beberapa pasien, perilaku ini memanifestasikan
dirinya terutama di malam hari, dalam hal ini disebut "sundowning" atau "Sindrom matahari
terbenam," dan biasanya dikelola dengan cara yang sama untuk bentuk lain dari gejala
perilaku demensia.

Penurunan yang terkait dengan demensia tidak dapat dipulihkan, dan perawatan farmakologis
yang disetujui oleh Makanan dan Administrasi Obat (FDA) menyediakan paling tidak
sementara perbaikan gejala. Inhibitor kolinesterase (seperti donepezil) dan penghambat
reseptor NMDA (seperti memantine) dapat meningkatkan kognisi pada pasien demensia

11
Inggrid Budhi Pangestu Adji (201610330311098)

tahap awal, tetapi biaya mereka dan profil efek samping menimbulkan tantangan signifikan
bagi dokter. Saat ini tidak ada yang disetujui FDA perawatan khusus untuk perilaku dan
psikologis gejala demensia, yang sering kali merupakan paling meresahkan dan menuntut
dari pengasuh perspektif. Sejumlah obat psikotropika adalah banyak digunakan "off-label"
untuk mengobati gejala-gejala ini.

Ini termasuk inhibitor reuptake serotonin selektif (SSRI) antidepresan (misalnya, sertraline,
citalopram), penstabil suasana hati (mis., karbamazepin, valproat), dan, paling umum, obat
antipsikotik. Kedua antipsikotik "konvensional" generasi pertama (misalnya, haloperidol,
chlorpromazine) dan generasi kedua Antipsikotik “atipikal” (mis., Risperidon, quetiapine)
digunakan untuk tujuan ini.

Banyak pasien dengan demensia dirawat di rumah sakit pengaturan panti jompo. Pada
2013, hampir 50% dari AS penghuni panti jompo memiliki diagnosis demensia. Gejala
perilaku menghadirkan dilema untuk menyusui staf rumah dan dokter karena perilaku yang
mengganggu atau berbahaya membutuhkan perhatian dan sumber daya yang tidak selalu
tersedia. Penggunaan antipsikotik obat-obatan di panti jompo sangat luas. Tahun 2004 Survei
National Nursing Home menemukan bahwa 26% dari penghuni panti jompo menerima
antipsikotik; 40% dari ini adalah off-label.

Peresepan obat antipsikotik untuk pasien panti jompo dengan demensia adalah
kontroversial dan masalah polarisasi. Laporan dalam pers awam sering menyatakan bahwa
penggunaan antipsikotik di panti jompo merupakan penganiayaan terhadap orang tua dan
penggunaan “bahan kimia” yang tidak etis pengekangan. ”7–9 Ini rumit, terbukti berdasarkan
fakta penilaian apakah antipsikotik adalah pilihan yang layak untuk pengobatan gejala
perilaku demensia. Tujuan ulasan ini adalah untuk mengevaluasi keadaan di mana
antipsikotik dapat bermanfaat dalam populasi ini, dan untuk menimbulkan klinis
pertimbangan untuk memastikan penggunaannya yang tepat. Berdasarkan pada pencarian
basis data PubMed, ulasan akan menarik dari perwakilan (meskipun tidak harus benar-benar
komprehensif) pengambilan sampel literatur yang membahas kemanjuran, keamanan, dan
peran terapeutik antipsikotik pada demensia.

Kontroversi seputar Antipsikotik untuk Perilaku dan Psikologis Gejala Demensia

Dugaan antipsikotik yang diresepkan untuk demensia pasien tidak diperlukan, berbahaya, dan
bahkan tidak etis kadang diungkapkan oleh orang awam pers, pengacara penggugat,
kelompok advokasi pasien, ahli medikolegal, dan profesional perawatan kesehatan. Klaim ini
mungkin sebagian didorong oleh valid laporan anekdotal pasien demensia yang mengalami
hasil yang buruk disebabkan oleh obat antipsikotik menggunakan. Pendukung pandangan ini
umumnya mengangkat masalah yang berkaitan untuk staf fasilitas perawatan, "pengekangan
kimia," penagihan Medicare yang tidak pantas, promosi farmasi untuk resep di luar label, dan
risiko kematian terkait dengan antipsikotik (Tabel 1).

Tabel 1. Poin yang Umum Dibahas oleh Penentang Penggunaan Obat Antipsikotik pada
Pasien dengan Gejala Perilaku dan Psikologis Demensia

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1. Rumah jompo tidak memiliki staf yang memadai dan tidak memiliki kapasitas untuk
mengelola perilaku sulit secara nonfarmakologis. Jadi, antipsikotik adalah sama dengan
"pembatasan kimia" yang digunakan terutama untuk kenyamanan staf panti jompo, bukan
untuk kesejahteraan pasien. Ketika seperti itu "Pengekangan" digunakan, persetujuan
berdasarkan informasi seringkali ditahan dari keluarga sebelum antipsikotik ditentukan.

2. Tindakan hukum telah dimulai terhadap panti jompo individual yang dituduh menagih
Medicare untuk obat yang tidak perlu atau resep untuk tidak disetujui indikasi. Satu laporan
pemerintah menemukan bahwa 51% dari klaim Medicare untuk antipsikotik atipikal pada
tahun 2007 adalah “salah.” Farmasi produsen juga telah didenda karena "secara agresif"
memasarkan antipsikotik ke panti jompo untuk indikasi yang tidak disetujui FDA. Jenis acara
ini digunakan untuk mendukung pandangan bahwa motif keuntungan sebagian mendasari
resep antipsikotik dalam demensia.

3. FDA telah mengeluarkan Black Box Warning mengenai peningkatan risiko kematian pada
pasien demensia lanjut usia yang diresepkan antipsikotik. Penentang resep antipsikotik
menafsirkan peringatan ini sebagai bukti bahwa sebagian besar resep obat ini dalam konteks
ini berbahaya dan kontraindikasi.

Menanggapi masalah ini, lembaga pemerintah, kelompok advokasi pasien, dan

masyarakat profesional di Indonesia Amerika Serikat dan tempat lain di dunia telah
berkembang pendekatan untuk memodifikasi dan mengurangi luasnya resep antipsikotik di
panti jompo. Masalah kekurangan staf di panti jompo adalah kenyataan yang tidak
menguntungkan, dan resep yang tidak pantas dan / atau promosi antipsikotik kemungkinan
terjadi. Tidak ada bukti yang jelas tentang kejadian masa lalu atau saat ini dari pelanggaran
ini. Mengenai FDA Black Box Warning, ini secara umum adalah pernyataan objektif risiko
yang diamati yang tidak mencerminkan potensi manfaat obat, juga tidak berarti bahwa
seorang pasien harus atau tidak harus menerima obat. Misalnya, Antidepresan SSRI
membawa Peringatan Kotak Hitam tentang ide bunuh diri pada anak-anak dan remaja, namun
obat ini termasuk yang paling banyak diresepkan— sering dengan manfaat terapeutik yang
cukup besar — untuk ini populasi. Beberapa pakar dan kelompok pemerintah memiliki,
dengan interpretasi yang benar tentang Peringatan Kotak Hitam dalam pikiran, mengambil
posisi pada kesesuaian antipsikotik untuk demensia. Laporan 2011 dari Perhimpunan
Apoteker Konsultan Amerika menyimpulkan bahwa antipsikotik mungkin sesuai beberapa
pasien demensia, asalkan obatnya ditunjukkan dengan tepat (di mana resep off-label tidak
setara dengan indikasi yang tidak tepat), spesifik dan tujuan pengobatan yang
didokumentasikan ada, pasien dipantau secara ketat, dan obatnya digunakan sebagai sehemat
mungkin. Selain itu, pedoman dirilis oleh Pusat Layanan Medicare dan Medicaid di Jakarta
2013 menyatakan bahwa antipsikotik mungkin tepat hanya ketika digunakan untuk
mengobati gejala spesifik yang terkait dengan kondisi medis yang terdokumentasi dan
terdiagnosis.

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Alternatif Antipsikotik untuk Gejala Perilaku Demensia

Baik alternatif farmakologis dan nonfarmakologis untuk penggunaan antipsikotik
telah dipelajari, dengan intervensi nonfarmakologis dipertimbangkan secara universal
pengobatan lini pertama. Panel 2014 dirumuskan pendekatan "Dice" untuk gejala perilaku
demensia ("Jelaskan, Selidiki, Buat, Evaluasi"), yang menekankan bahwa penyedia harus
menyelidiki dan mengesampingkan penyebab lingkungan dari setiap perilaku bermasalah
sebelumnya mempertimbangkan pengobatan apa pun. Pendidikan pengasuh juga merupakan
komponen penting nonfarmakologis manajemen, mengingat kemungkinan yang terkendali
faktor (misalnya, suhu, rasa sakit, atau ketakutan spesifik) yang mendasari agitasi terlihat
pada persentase pasien tertentu dengan gangguan perilaku. Satu studi melaporkan itu
manajemen nyeri profilaksis pada pasien demensia menghasilkan efek terapi yang mirip
dengan yang terlihat dengan antipsikotik, meskipun pendekatan ini termasuk penggunaannya
analgesik. Interaksi sosial yang dipersonalisasi, psikososial pengobatan, terapi kehadiran
disimulasikan, dan terapi reminiscence juga menghasilkan klinis yang sederhana manfaat,
seperti halnya terapi sensori dan musik. Ketika gejala perilaku berupa "sundowning," terapi
melatonin telah dikaitkan dengan paling baik perbaikan gejala sederhana; terapi cahaya juga
telah diselidiki pada pasien ini. Sebagian besar intervensi ini sulit dipelajari karena secara
acak,uji coba terkontrol, peneliti dan pengamat tidak mudah dibutakan.
Sangat mungkin bahwa terapi non-obat mengurangi agitasi dalam jangka pendek di
sebagian kecil dari demensia pasien. Namun, intervensi ini perlu dipertimbangkan sumber
daya manusia yang belum tentu tersedia di banyak panti jompo, dan mereka cenderung
kurang efektif dalam situasi akut atau darurat di mana pasien menimbulkan bahaya bagi
dirinya sendiri atau orang lain.
Terapi obat yang berpotensi lebih aman dan lebih banyak efektif daripada
antipsikotik telah dievaluasi. Citalopram, antidepresan SSRI, menghasilkan secara statistic
pengurangan agitasi pasien yang signifikan, dan juga menyebabkan berkurangnya kecemasan
pada pihak pengasuh.
Namun, kemanjuran citalopram dibandingkan hanya untuk plasebo, berlawanan dengan
antipsikotik komparator; selain itu, penelitian ini melaporkan kognitif yang merugikan dan
efek jantung yang terkait dengan citalopram.
Akhirnya, citalopram, karena mekanisme aksinya, adalah tidak mungkin efektif sebagai
pengobatan prn untuk pasien dengan agitasi intermiten akut, yang bertentangan dengan
persisten agitasi. Galantamine, sebuah asetilkolinesterase inhibitor, ditunjukkan sedikit lebih
rendah daripada risperidone, antipsikotik, dalam uji coba terkontrol secara acak.
Kombinasi dekstrometorfan dan quinidine memiliki kemanjuran yang signifikan secara klinis
dalam setidaknya 1 studi, walaupun belum secara langsung dibandingkan dengan
antipsikotik.
Sejumlah lainnya baru dan yang sudah ada senyawa, termasuk carbamazepine, cannabinoids,
mibampator, dan prazosin, saat ini sedang diselidiki, meskipun tidak ada bukti konklusif
tentang mereka manfaatnya belum tersedia. Jadi, antipsikotik tetap ada pilihan yang banyak
digunakan untuk pengobatan perilaku gejala demensia sebagian karena tidak ada kelas lain
obat memiliki rasio risiko-manfaat yang ditetapkan lebih menguntungkan.

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Khasiat Antipsikotik untuk Gejala Perilaku Demensia

Antipsikotik tidak disetujui FDA untuk tujuan ini, dan bukti yang dipublikasikan
belum divalidasi secara meyakinkan kemanjuran mereka. Meta-analisis besar (n> 100.000)
mengevaluasi kemanjuran 4 antipsikotik atipikal di Rumah jompo di Amerika Utara tidak
konsisten kesimpulan. Meta-analisis yang lebih kecil (n = 1683) ditemukan, secara umum,
tidak signifikan secara statistik atau klinis perbaikan gejala perilaku pada pasien yang
menerima antipsikotik dibandingkan dengan plasebo. Sebuah studi selama 2 tahun penghuni
panti jompo dengan demensia menemukan bahwa antipsikotik tidak berhubungan dengan
peningkatan kognisi atau aktivitas kehidupan sehari-hari. Dalam uji coba terkontrol plasebo
multisenter, risperidone, olanzapine, dan quetiapine tidak dapat dibedakan dari plasebo dalam
hal kemanjuran pada demensia lansia pasien dengan psikosis, agresi, atau agitasi. Di
Setidaknya 1 studi lebih lanjut telah menimbulkan pertanyaan apakah antipsikotik lebih
unggul daripada SSRI untuk perawatan gejala perilaku demensia.
Namun, bukti lain menunjukkan bahwa antipsikotik setidaknya memiliki khasiat
sederhana. Dua meta-analisis uji coba acak, terkontrol plasebo yang melibatkan antipsikotik
atipikal (aripiprazole, olanzapine, quetiapine, risperidone; n = 5050 dan 2511) ditemukan
konsisten, peningkatan gejala yang signifikan secara statistic pada pasien yang menerima
antipsikotik dibandingkan plasebo. Dua ulasan literatur lebih lanjut disimpulkan aripiprazole
dan risperidone secara signifikan meningkatkan gejala kejiwaan dan kognisi setelah 3 bulan
pengobatan, 49 terkait dengan olanzapine dengan peningkatan signifikan dalam 1
ulasan.Semua, antipsikotik tampaknya paling tidak sebanding plasebo dan mungkin
bermakna manjur di pengobatan gejala perilaku demensia.
Dua masalah penting belum sepenuhnya terselesaikan. Pertama, Apakah
antipsikotik konvensional atau atipikal lebih efektif? Satu studi telah menunjukkan secara
signifikan lebih besar kemanjuran untuk olanzapine dan risperidone dibandingkan dengan
promazine, 51 tetapi studi serupa dari jenis ini langka. Kedua, dalam setiap kelas, agen mana
yang paling efektif?
Literatur terbaru52 belum menjawab pertanyaan ini, dengan efikasi relatif dari 4 antipsikotik
atipikal tergantung pada skala peringkat mana yang digunakan untuk menilai gejala. Tanpa
pedoman ini, dokter yang meresepkan antipsikotik saat ini sering mendasarkan mereka
pendekatan terapeutik pada pengalaman klinis mereka sendiri dan / atau kebiasaan
institusional.

Kejadian Buruk dan Kematian Berlebih Terkait Dengan Antipsikotik

Pada April 2005, FDA pertama kali mengeluarkan peringatan tentang peningkatan
risiko kematian mendadak pada lansia pasien demensia diresepkan antipsikotik atipikal.
Meskipun buletin FDA menyatakan bahwa itu didasarkan setelah "tujuh belas uji coba
terkontrol plasebo dilakukan dengan olanzapine, aripiprazole, risperidone atau quetiapine
pada pasien demensia lansia dengan gangguan perilaku”. Hasil uji coba ini tidak tersedia
untuk masyarakat. Pada 2008, agensi melampirkan Black BoxWarnings berlaku untuk semua
antipsikotik atipikal, mengutip peningkatan risiko kematian pada pasien demensia lansia.
Tidak jelas apakah Black BoxWarnings dibawa tentang penurunan selanjutnya dalam
penggunaan antipsikotik untuk perilaku gejala demensia. Pada tahun yang sama, regulator
juga mengeluarkan penasihat baru yang didalilkan risiko serupa kematian berlebih pada

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pasien demensia untuk kedua antipsikotik konvensional dan atipikal. Dalam kedua dokumen
tersebut tidak ada data dari uji coba acak terkontrol plasebo yang dirilis. Lansiran FDA
tentang antipsikotik konvensional mengutip 2 kelompok retrospektif mempelajari sebagai
bukti bahwa obat ini meningkatkan risiko kematian dibandingkan tanpa perawatan. Namun,
briefing itu sendiri berkomentar, “Metodologisnya keterbatasan dalam dua studi ini
menghalangi setiap kesimpulan bahwa antipsikotik konvensional memiliki risiko lebih besar
kematian dengan penggunaan daripada antipsikotik atipikal".
Apakah bukti yang dipublikasikan (tidak termasuk yang sulit dipahami "Tujuh belas
uji coba terkontrol plasebo") mendukung Peraturan FDA tentang antipsikotik atipikal dan /
atau konvensional? Komentar FDA tentang "keterbatasan metodologis" memperkenalkan
peringatan penting. Perancu oleh keparahan penyakit yang mendasarinya mungkin serius
kompromi validitas kesimpulan dari casecontrol penelitian yang mengevaluasi risiko relatif
kematian di antara pasien demensia. Untuk antipsikotik versus tidak ada pengobatan atau
perbandingan pengobatan lainnya, intinya Keterbatasan metodologis adalah bahwa pasien
yang diresepkan antipsikotik cenderung memiliki demensia yang lebih buruk dan begitu juga
peningkatan risiko kematian karena alasan ini saja. Untuk uji coba membandingkan
antipsikotik konvensional versus atipikal, dokter mungkin lebih suka meresepkan satu kelas
lain tergantung pada sifat dan tingkat keparahan penyakit yang mendasarinya. Keterbatasan
metodologis ini dapat pada prinsipnya diatasi melalui prospektif, acak, uji coba terkontrol
plasebo untuk menentukan kerabat risiko kematian.
Dalam ulasan uji coba acak terkontrol placebo antipsikotik atipikal pada demensia
lansia pasien, 47 risiko relatif kematian dalam perawatan kelompok relatif terhadap kontrol
ditemukan 1,52. Itu jumlah kematian adalah 46 dari 2071 pasien di tahun kelompok plasebo
(2,2%), dan 120 dari 3336 pada kelompok antipsikotik (3,6%). Dalam studi sebelumnya,
risiko relatif adalah 1,54, dengan 41 kematian dari 1851 pasien (2,2%) dan 118 dari 3353
pasien (3,5%) dalam plasebo dan kelompok antipsikotik, masing-masing. Namun, ulasan
besar ketiga menemukan kerabat risiko menjadi 1,06, yang tidak signifikan secara statistik,
walaupun penelitian yang sama dilaporkan lebih signifikan efek samping yang sering pada
kelompok pengobatan aktif. Sebelumnya, meta-analisis yang lebih kecil (n = 1721) juga
ditemukan tidak ada peningkatan risiko kematian pada pasien demensia yang dirawat dengan
risperidone versus placebo. Dalam analisis ini, ada banyak tumpang tindih dan redundansi di
uji coba yang dipertimbangkan. Secara umum, berat menerbitkan uji coba terkontrol plasebo
untuk pertanyaan ini agak terbatas. Bukti yang tersedia menunjukkan antipsikotik atipikal
bila digunakan dalam demensia pasien membawa risiko kematian yang tidak kurang — dan
mungkin lebih besar dari plasebo. Tidak ada bukti jelas yang menetapkan atipikal spesifik
mana antipsikotik dikaitkan dengan risiko terbesar. Sebuah ulasan besar studi yang
membandingkan agen individu bukti yang ditemukan tidak cukup untuk menyarankan apakah
ada agen tertentu paling aman atau paling berbahaya.
Studi membandingkan risiko keamanan yang terkait dengan antipsikotik atipikal
versus antipsikotik khas belum sepenuhnya konklusif. Setidaknya 1 ulasan studi retrospektif
membandingkan antipsikotik konvensional untuk plasebo menyimpulkan bahwa
konvensional
dan antipsikotik atipikal membawa angka kematian yang serupa risiko. Analisis 17 uji coba
terkontrol placebo (n = 2387) menyimpulkan bahwa antipsikotik konvensional jangan

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meningkatkan risiko kematian dibandingkan dengan placebo pada pasien manula. Ulasan
tentang efek samping jantung utama peristiwa yang terkait dengan agen antipsikotik tidak
ditemukan perbedaan klinis yang signifikan antara konvensional dan agen atipikal. Dalam 1
penelitian, data otopsi juga menyarankan bahwa haloperidol tidak berhubungan dengan tiba-
tiba kematian pada pasien demensia. Namun, 1 retrospektif studi menemukan risiko relatif
yang lebih besar terkait dengan antipsikotik konvensional, seperti yang dilakukan 3 ulasan
studi observasional. Salah satunya menemukan pinggul itu fraktur, stroke, infark miokard,
dan ventrikel aritmia adalah beberapa faktor yang menjelaskan perbedaan kematian antara
konvensional dan atipikal agen. Tinjauan lebih lanjut, yang menyesuaikan kerabatnya
perhitungan risiko untuk memperhitungkan perancu oleh terminal penyakit, juga menemukan
agen konvensional untuk membawa risiko kematian relatif lebih besar daripada agen atipikal.
Tampaknya, oleh karena itu, bahwa agen konvensional memiliki terbaik profil keselamatan
mirip dengan agen atipikal, tetapi kebanyakan kemungkinan membawa angka kematian
relatif yang meningkat secara signifikan risiko.
Jika bahaya kematian berlebih ada dengan antipsikotik konvensional atau atipikal,
salah satu mekanisme potensial kematian terkait obat adalah kejadian kardiovaskular. Banyak
antipsikotik konvensional memiliki afinitas yang signifikan untuk saluran kalium hERG
(human-ether-a-go-go); ini dapat menyebabkan perpanjangan dari interval QTc dan
berpotensi untuk torsades de pointes, sebuah prekursor dari takikardia ventrikel.
Thioridazine, pimozide, dan sertindole dianggap memiliki risiko yang relatif tinggi dalam
konteks ini. Antipsikotik atipikal cenderung memiliki hERG yang lebih rendah tetapi tidak
nol afinitas; risperidone memperpanjang QTc tanpa mempengaruhi dispersi QTc, yang perlu
dilakukan aritmia ventrikel. Ulasan besar perpanjangan QTc dan torsades de pointes yang
terkait dengan atipikal antipsikotik menyimpulkan bahwa antipsikotik atipikal memang
menyebabkan berbagai derajat perpanjangan QTc, meskipun tidak selalu terkait dengan
torsades de pointes. Kelangkaan aritmia serius terhalang kesimpulan tentang risiko relatif
yang terkait dengan obat individu. Seperti halnya risiko semua penyebab kematian terkait
dengan antipsikotik, risiko kematian jantung mendadak terkait dengan antipsikotik tidak
dapat dinilai secara memadai melalui studi kasus kontrol retrospektif. Bukti yang tersedia
berdasarkan uji coba terkontrol plasebo menunjukkan bahwa, jika antipsikotik meningkatkan
kematian jantung mendadak pada pasien demensia, mekanismenya mungkin melibatkan
perpanjangan QTc. Infark miokard akut adalah mekanisme lain yang diusulkan dari kematian
jantung mendadak terkait antipsikotik. Blokade reseptor Dopamin tipe 3 (D3) telah
disarankan untuk memulai kaskade trombogenik dan karenanya dapat memediasi
peningkatan risiko infark miokard. Tromboemboli vena juga telah terjadi disarankan sebagai
mekanisme kematian terkait antipsikotik, meskipun literatur tentang pertanyaan ini hampir
secara eksklusif terbatas pada studi kasus-kontrol retrospektif. Sebuah studi longitudinal86
menemukan bahwa risiko tromboemboli dapat dimediasi oleh timbulnya hiperprolaktinemia,
efek samping atypical yang diketahui merugikan. Antipsikotik, meskipun kejadian peristiwa
ini pada pasien demensia lansia tidak diketahui. Akhirnya, penenang antipsikotik dapat
meningkatkan risiko pneumonia aspirasi sebagai penyebab kematian; 1 penelitian
menunjukkan risiko relatif lebih tinggi dari pneumonia terkait dengan agen atipikal
dibandingkan agen konvensional, meskipun temuan ini belum direplikasi.64 Secara
keseluruhan, penyelidikan lebih lanjut diperlukan untuk menetapkan mekanisme dimana

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antipsikotik dapat meningkatkan risiko kematian akibat jantung, dan apa faktor risiko pasien
individu mungkin.

Pertimbangan Klinis
Manajemen nonfarmakologis harus menjadi yang pertama pendekatan kepada
pasien dengan perilaku dan psikologis gejala demensia. Pusat untuk Medicare dan Layanan
Medicaid telah menghasilkan satu set demensia Pertimbangan Klinis Manajemen
nonfarmakologis harus menjadi yang pertama pendekatan kepada pasien dengan perilaku dan
psikologis gejala demensia. Pusat untuk Medicare dan Layanan Medicaid telah menghasilkan
serangkaian prinsip dementiacare yang harus diikuti dalam perawatan perawatan di rumah
setiap pasien dengan agitasi serius (Tabel 2) . Ini menekankan perlunya personalisasi
perawatan dan kepegawaian yang memadai di panti jompo, sedemikian rupa setiap gejala
baru atau yang memburuk mungkin menyeluruh diselidiki dan dikelola secara individual.
“Hari Minggu” menimbulkan tantangan yang sangat besar, karena pasien yang menjadi
gelisah di malam hari sering memiliki yang lebih minimal staf malam untuk merawat mereka;
peningkatan luas mungkin diperlukan dalam kecukupan malam perawatan di rumah
kepegawaian. Pada kenyataannya, seperti diakui panduan ini, sejumlah pasien demensia akan
menurun ke titik di mana pilihan nonfarmakologis akan menjadi tidak efektif atau tidak
sepenuhnya efektif — terlepas dari kecukupan dan keterampilan staf panti jompo — dan
pengasuh perlu mempertimbangkan pendekatan lain. Di setidaknya 2 algoritma perawatan
tambahan telah dirancang yang mungkin memberi tahu dokter tentang kapan farmakologis
intervensi harus dipertimbangkan. Dari perspektif pemerintah, Departemen Kesehatan dan
Layanan Kemanusiaan telah mengeluarkan rekomendasi untuk memastikan pengawasan yang
memadai terhadap antipsikotik Medicare mengklaim, dengan tujuan bahwa semua resep
antipsikotik
diperlukan dan ditunjukkan dengan tepat (Tabel 3).

Tabel 2. Prinsip Perawatan Demensia

Person-Centered Care (CMS) membutuhkan panti jompo untuk menyediakan lingkungan
yang mendukung yang mempromosikan kenyamanan dan mengenali kebutuhan individu dan
preferensi.

Kualitas dan Kuantitas Staf Rumah jompo harus menyediakan staf, baik dari segi
kuantitas (perawatan langsung serta staf pengawas) dan kualitas untuk memenuhi kebutuhan
penduduk sebagaimana ditentukan oleh penilaian penduduk dan rencana perawatan
individual.

Evaluasi Teliti Perilaku Baru atau Memburuk Warga yang menunjukkan gejala perilaku
baru atau memburuk harus dievaluasi oleh tim interdisipliner, termasuk dokter, untuk
mengidentifikasi dan mengatasi masalah medis yang dapat diobati, fisik, emosional,
kejiwaan, psikologis, fungsional, sosial, dan faktor lingkungan yang mungkin berkontribusi
terhadap perilaku.

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Pendekatan Individual untuk Peduli Pedoman Saat Ini dari Amerika Serikat, Inggris,
Kanada dan negara-negara lain merekomendasikan penggunaan individual pendekatan
sebagai intervensi lini pertama (kecuali dalam dokumentasi situasi darurat atau jika
kontraindikasi klinis) untuk perilaku gejala. Memanfaatkan proses yang konsisten yang
berfokus pada kebutuhan individu residen dan mencoba memahami perilaku sebagai bentuk
komunikasi dapat membantu mengurangi ekspresi perilaku kesusahan di beberapa warga.

Berpikir Kritis Terkait dengan Penggunaan Obat Antipsikotik Dalam kasus tertentu,
penghuni bisa mendapat manfaat dari penggunaan obat-obatan. Warga hanya boleh diberi
obat jika diindikasikan secara klinis dan jika perlu untuk mengobati kondisi tertentu dan
gejala target sebagaimana didiagnosis dan didokumentasikan dalam catatan. Warga yang
menggunakan obat antipsikotik harus menerima pengurangan dosis bertahap dan intervensi
perilaku, kecuali kontraindikasi klinis, dalam upaya menghentikan obat-obatan ini.

Wawancara dengan Para Prescriber Para surveyor diinstruksikan untuk mengevaluasi

proses perawatan. Surveyor mewawancarai dokter yang menghadiri atau penyedia perawatan
primer lainnya, spesialis kesehatan perilaku, apoteker dan anggota tim lainnya lebih
memahami alasan menggunakan psikofarmakologis agen atau intervensi lain untuk penduduk
tertentu.
Keterlibatan Penduduk dan / atau Perwakilan dalam Pengambilan Keputusan Untuk
memastikan penggunaan psikofarmakologis yang bijaksana obat-obatan, penghuni (sejauh
mungkin) dan / atau keluarga atau perwakilan residen harus dilibatkan dalam diskusi
pendekatan potensial untuk mengatasi gejala perilaku. Ini diskusi dengan residen dan / atau
keluarga atau perwakilan harus didokumentasikan dalam rekam medis.

Reproduced from the Centers for Medicare and Medicaid Services (CMS) Guidelines.12

Tabel 3. Rekomendasi untuk Memastikan Surveilans yang memadai dari Klaim Penggantian
Medali Obat Antipsikotik
1. Memfasilitasi akses ke informasi yang diperlukan untuk memastikan cakupan yang akurat
dan penentuan penggantian.
2. Menilai apakah survei dan proses sertifikasi menawarkan perlindungan memadai terhadap
penggunaan obat antipsikotik yang tidak perlu di panti jompo.
3. Jelajahi metode alternatif di luar proses survei dan sertifikasi untuk mempromosikan
kepatuhan dengan standar federal mengenai penggunaan narkoba yang tidak perlu di
Indonesia
rumah jompo.
4. Ambil tindakan yang tepat terkait klaim yang terkait dengan pembayaran yang salah.

Ketika dihadapkan pada situasi yang mungkin memerlukan farmakologis

pengobatan, dokter dapat mengambil langkah-langkah untuk memastikan terapi itu etis, dan
hasil dengan minimum kemungkinan risiko. Keterlibatan keluarga dan / atau pengasuh sangat

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Inggrid Budhi Pangestu Adji (201610330311098)

penting. Pasien dengan gejala perilaku mungkin tidak dapat memberikan persetujuan untuk
perawatan obat. Konsultasi dari psikiater independent atau ahli saraf mungkin diperlukan
untuk penentuan dari kapasitas pasien untuk memberikan persetujuan. Jika sebuah dokter
menilai bahwa seorang pasien tanpa kapasitas akan paling diuntungkan dari antipsikotik,
administrasi Lembaga perwakilan dan / atau penasihat hukum harus dikonsultasikan untuk
mengidentifikasi pengganti yang tepat untuk berikan persetujuan. Dalam banyak kasus ini
mungkin penutupan anggota keluarga atau individu lain yang dapat bertindak sebagai
advokasi atau surrogate pasien.
Dokter kemudian harus bertemu dengan pasien keluarga / pengasuh dan menyajikan
serangkaian fakta secara objektif (Tabel 4). Ringkasan pertemuan, dan topik khusus yang
dibahas, dimasukkan ke dalam rekam medis pasien. Setelah menerima informasi ini, keluarga
/ pengasuh pasien harus menimbang berbagai pertimbangan etis. Farmakologis lainnya opsi
kemudian harus didiskusikan, bersama dengan bukti yang tersedia mengenai kemanjurannya.
Dokter juga harus menawarkan prognosis yang realistis untuk pasien, termasuk kemungkinan
kebutuhan untuk nondrug yang lebih keras intervensi.
Jika pengobatan antipsikotik dimulai, dokter harus memulai terapi pada dosis
efektif terendah dan untuk durasi sesingkat mungkin. Pedoman peresepan internasional telah
diusulkan di mana durasi maksimum yang tepat untuk penggunaan antipsikotik pada pasien
demensia adalah 12 minggu. Tabel 5 menunjukkan ketentuan oleh Pusat Layanan Medicare
dan Medicaid mengenai dosis harian maksimum yang direkomendasikan dari berbagai agen
antipsikotik. Setiap pasien yang menerima antipsikotik harus dipantau sedekat mungkin dan
dinilai sesering mungkin. Keluarga / pengasuh harus, jika mungkin, sering diberi pembaruan
tentang status pasien ketika terapi dimulai. Tujuan dari perawatan haruslah untuk
meringankan tekanan pasien tanpa menghasilkan sedasi yang berlebihan atau menimbulkan
risiko yang tidak semestinya dari efek samping. Penilaian dan pengalaman klinis diperlukan
untuk memilih dan mentitrasi dosis obat antipsikotik yang paling tepat.

Tabel 4. Topik yang Diusulkan untuk Diskusi Antara Dokter yang Mengobati dan Keluarga
Pasien atau Pengasuh
1. Gejala-gejala pasien tidak lagi dapat dikelola secara nonfarmakologis dengan cara yang
menjaga martabat dan / atau memastikan pasien masuk akal. lingkungan untuk pasien lain.
(Perhatikan bahwa jika pasien menimbulkan bahaya fisik langsung pada diri atau orang lain,
ini merupakan pertimbangan kritis. Dalam hal ini skenario, persetujuan pengasuh mungkin
tidak diperlukan sebelum memulai terapi antipsikotik.)
2. Penyebab potensial gejala reversibel dan dapat diobati pasien telah dievaluasi dan
disingkirkan.
3. Tidak ada perawatan obat yang disetujui untuk gejala yang diamati pasien, tetapi
berdasarkan bukti yang tersedia dan pengalaman dokter, antipsikotik lebih mungkin untuk
tidak meredakan gejala sampai tingkat yang lebih besar daripada plasebo. Karena itu, dokter
menyarankan untuk memulai terapi antipsikotik pada saat ini.
4. Ada banyak bukti, tetapi tidak berlebihan, bahwa antipsikotik dikaitkan dengan
peningkatan risiko kematian mendadak pada pasien demensia. Bukan itu jelas obat mana

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Inggrid Budhi Pangestu Adji (201610330311098)

yang membawa risiko kematian yang lebih besar atau lebih kecil. (Mungkin bermanfaat bagi
dokter untuk memberikan pengalaman mereka sendiri dengan situasi klinis ini.)
5. FDA telah mengeluarkan Black Box Warning mengenai risiko di atas. Namun, ini tidak
berarti bahwa pasien kemungkinan besar akan meninggal begitu dia mulai
terapi antipsikotik, atau resep yang tidak diizinkan. Risiko absolut dengan obat apa pun kecil.
Peringatan Black Box adalah pernyataan peringatan tentang risiko yang terkait dengan obat,
bukan pernyataan tentang apakah manfaat potensial dapat melebihi risiko potensial.

Tabel 5. Batas Dosis Harian untuk Obat Antipsikotik Digunakan untuk Mengobati Pasien
dengan Gejala Perilaku
Demensia

Kesimpulan
Antipsikotik konvensional dan atipikal mungkin ada kemanjuran sederhana dalam
pengelolaan pasien dengan gejala perilaku dan psikologis demensia. Namun, risiko kematian
yang berlebihan secara konsisten diamati pada pasien demensia yang diobati antipsikotik.
Mekanisme kematian mungkin bersifat kardiovaskular, melibatkan aritmia kerentanan dari
perpanjangan QTc atau meningkat trombogenesis. Kemungkinan antipsikotik konvensional
untuk membawa risiko kematian yang lebih besar daripada antipsikotik atipikal, selain risiko
ekstrapiramidal yang diketahui efek samping (gangguan gerakan tak disengaja) terkait
dengan obat ini. Tidak jelas apakah khusus agen konvensional atau atipikal lebih aman
atau lebih berbahaya dari yang lain.
Ada pedoman tentang bagaimana perilaku baru atau memburuk gejala harus dikelola
dalam menyusui pengaturan rumah; intervensi nonfarmakologis harus selalu dicoba sebelum
obat baru diresepkan. Namun, terapi obat mungkin diperlukan di banyak pasien seperti itu,

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Inggrid Budhi Pangestu Adji (201610330311098)

terutama jika mereka membahayakan diri mereka sendiri atau bahaya / gangguan signifikan
terhadap orang lain. Dengan tidak adanya perawatan lain yang disetujui FDA, antipsikotik
tetap menjadi pilihan bagi dokter pengobatan gejala perilaku dengan obat-obatan ini
memerlukan tindakan pencegahan yang cukup. Konsultasi dengan pengasuh / keluarga dan
penyelarasan pada setiap langkah proses perawatan sangat penting.

Nama : Inggrid Budhi Pangestu Adji

NIM : 201610330311098

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Review Article
www.ijrap.net

REVIEW ON ATYPICAL ANTIPSYCHOTICS: AN APPROACH TOWARDS A BETTER TREATMENT OF

PSYCHOSIS
Aryendu Kumar Saini *, Hemendra Pati Tripathi
Student, Pharmacy Department, Pranveer Singh Institute of Technology, Kanpur, UP, India

Received on: 11/11/16 Revised on: 22/11/16 Accepted on: 28/12/16

*Corresponding author
E-mail: aryendu77@gmail.com

DOI: 10.7897/2277-4343.076244

ABSTRACT

Psychosis is a mental disorder which is associated with impaired relationship with reality. It can be an indication of serious mental disorders like
Alzheimer’s disease, some types of epilepsy, infection in the brain, tumor in the brain and many more. Delusion and hallucinations are experienced
with the people having the psychosis. One of the major psychoses is Schizophrenia from which a lot of people with psychosis suffer today. The
antipsychotic agents or drugs are the first line drugs for the treatment of schizophrenia. They are also used for other complications such as acute
mania and bipolar disorder. This article is about the atypical drugs, their comparison with the typical antipsychotics on the premise of safety and
adverse effects. This article also encompasses the aspects like haloperidol induced apoptosis, which are sufficient to certify that why atypical
antipsychotics are used more and are better than typical antipsychotics despite having different side effects.

Keywords: Psychosis, Schizophrenia, Dopamine, Antipsychotics, Extrapyramidal, Neuroleptics

INTRODUCTION
Psychosis is a psychiatric disorder in which patient is not aware
of his illness (insight is absent) and refuses to take the treatment.
Major psychoses are schizophrenia and mood disorders like
mania, depression and bipolar disorder1. Psychotic persons have
an impaired relationship with the reality. The most common and
the most important psychosis is schizophrenia2. The most
recommended drugs which are used to treat psychosis are called
as antipsychotic medications that include typical and atypical
antipsychotics. However worthy typical antipsychotics may be;
they are not better and safer than atypical antipsychotics. With
the approval and introduction of atypical antipsychotics in the
market, typical use is getting diminished and going into
pharmaceutical dustbin. This has led to the increased price of
atypical antipsychotics and has become a ground reality as well
as the reason why typical antipsychotics are more prescribed to
the poor people by the physicians in spite of knowing that the
typical antipsychotics risks outweigh its benefits. Atypical
antipsychotics have tremendous benefits over typical
antipsychotics like they are capable of treating both positive and
negative symptoms of schizophrenia that lacks with typical
antipsychotics. They don’t interfere with the endocrine process.
Patients suffer from neurolepsis which is described by the
features like psychomotor slowing and emotional quitting, when
they are given typical antipsychotics. What will schizophrenic
people will do if he suffers a lot from side effects rather from the
disease he or she is suffering? The most recognized benefit
associated with atypical antipsychotics is their less or no
potential to cause Extrapyramidal side effects or symptoms that
is most troublesome and people suffers more from these
symptoms than the symptoms of disease itself. Moreover,
atypical antipsychotics are neuron protective while typical
antipsychotics cause apoptosis. Atypical drugs prevent
progressive tissue loss which is associated with schizophrenia
and at the same time stimulate the extension of axon and
dendrite, promote neurogenesis and cell survival3. It may be a
lot easier to treat the patients of psychosis when the scientists
will find the exact cause of psychosis.
This article is not only about atypical antipsychotics, but also
about the symptoms associated with psychosis, different
available antipsychotics, their mechanism of action, assessment
of benefits and limitations related to typical and atypical
antipsychotics and the reasons why atypical antipsychotics are
still safer and used more than typical antipsychotics despite
having metabolic and other side effects. The integration of all
these is important to justify that atypical antipsychotic use is a
better and safer approach for the treatment of psychosis than
typical drugs.
Symptoms Associated With Schizophrenia
Schizophrenia (one of the psychosis) is characterized by marked
thinking disturbance in which thinking, ability to perceive,
communication, social functioning and attention get altered.
Symptoms of Schizophrenia are positive, negative and cognition
dysfunctions. Positive symptoms are those that are normally
many times experienced by the individual, but they are
persistent in the people with schizophrenia. In the positive
symptoms, there are delusions, disorganized speech, racing
thoughts, hallucinations (tactile, olfactory, auditory, visual and
gustatory) while in the negative symptoms; there is alteration of
normal human behavior, thought pattern, disorganized thoughts,
lack of emotion or flat expressions, lack of motivation, lack
desire to form relationships, inability to experience pleasure.
Cognitive dysfunction is the core characteristic of schizophrenia
and the schizophrenic person has less ability to comprehend and
acquire the knowledge. Different cognitive capabilities like
learning, perception, memory, ability to solve problems,
attentiveness get affected in the schizophrenia. Some of the
affected cognitive areas become apparent even before the
appearance of positive symptoms related to schizophrenia.
According to severity, dysfunctions in the cognition processes

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get to appear and they get more prominent with the first episode
of schizophrenia and attainment of middle age.4
Causative Factors
Psychosis and schizophrenia are not one and the same thing.
There are different types of psychosis like bipolar illness,
organic psychosis, delusional disorder, schizoaffective disorder,
etc. and schizophrenia is one among them. Psychosis is a
collective term which is used to describe psychotic symptoms.
Different conditions like cerebrovascular accident (CVA), brain
tumors, brain infections or the use of drugs like cocaine,
amphetamine etc., can also lead to psychotic symptoms.
The etiology is still unknown, but there are proposals on the
genetic, environmental and neuronal developmental factors5.
Psychoses can be organic and caused due to risk factors like
central anti-cholinergic drugs, N-methyl D-aspartate receptor
antagonists like phencyclidine, a definite disease process like
dementia or it can be idiopathic6. Its exact cause is not known,
but the basic flaw seems to involve the hyperactivity of the
dopaminergic neurons in the mesolimbic pathway7. Other
neurotransmitters like 5-HT (5-hydroxytryptamine) and NA
(Nor-adrenaline) also probably play a role in this disorder.
Although there are many hypotheses behind schizophrenia, but
DA (Dopamine) hypothesis is the most recognized. This can be
understood from the fact that the drugs which enhance the
dopaminergic neuronal transmission such as levodopa,
amphetamines (DA releaser) and apomorphine (DA agonist),
increase or exacerbate the schizophrenia8. However, there too
are the defects in the DA hypothesis like decrease in the
symptoms of psychosis by blocking the activity of 5-HT2 and
alpha receptor that may not involve blocking of dopamine
activity in the mesolimbic system. Dopamine hypothesis does
not explain the cognitive deficits (meso-cortical dysfunction)
and psycho mimetic effects of activation of other pathways
(example: D-lysergic acid) 9. D-lysergic acid is a 5-HT2A agonist
that can produce psychotic symptoms.
Treatment of Psychosis
At present, there is no drug in any system of medicine that can
prove to completely cure the psychosis. They can only help to
manage the disease and the symptoms associated with it. In
modern medical science, there are therapies like psychotherapy,
mood stabilizing drugs, counseling and support from the health
care professionals and family, etc. Before the treatment, proper
medical diagnosis is necessary to find whether it is
schizophrenia or any other psychosis. The drugs in the
traditional system of medicines like Ayurveda may be able to
treat the disease, but their pharmaceutical studies in the terms of
‘pharmacokinetics’, ‘pharmacodynamics’ and ‘efficacy’ need to
be found out. However, this article has nothing to do with the
other systems of medicines except Allopathy. The drugs that are
used for the treatment of psychosis are called as Antipsychotic
drugs. These drugs are of great importance for relieving the
symptoms of psychosis and helping to prevent further episodes
of psychotic illness10, 11.
Antipsychotics are classified as ‘Typical’ and ‘Atypical’
Antipsychotics. They are shown in the table 1.
Mechanism of Action of Typical and Atypical Antipsychotics
Dopamine was discovered and categorized as a neurotransmitter
in the late 1950s by the Swedish Neuropharmacologist- Arvid
Carlsson12. There exist four pathways or systems of
dopaminergic receptor in the central nervous system. These
systems or pathways include Mesolimbic pathway, Mesocortical
pathway, Nigrostriatal pathway and Tuberoinfundibular
pathway.
These four pathways are relevant to the mechanism of action
and adverse effects of antipsychotic drugs13. All of these
pathways influence the cognitive behavior, coordination of
voluntary movement, thinking and learning. Over firing of
dopamine in these pathways produces different symptoms of
schizophrenia. Typical antipsychotics are the drugs which
mainly act by blocking the D2 receptor effectively. They bind
tightly to D2 receptor, which means the affinity for binding is
high. They can block H1 (histamine), M1 (muscarinic) and α1
(alpha) receptors. They increase the dopaminergic transmission
in dopamine pathways. Atypical antipsychotics are those which
yet bind with D2 receptor, but loosely as the affinity of atypical
antipsychotic for D2 receptor is less. They get dissociated from
the dopamine receptor easily due to this. They have a very good
affinity for 5HT2A receptor14. Some of the atypical
antipsychotics are 5HT1A agonist like Clozapine and
Ziprasidone. In addition to this, atypical antipsychotic or second
generation antipsychotics have α1, H1, 5-HT2C and M1 antagonist
activity.
Adverse Effects and Limitations of Typical Antipsychotics
By the 1970, it was clearly recognized that the key
pharmacological property of all Neuroleptics was their ability to
block the D2 receptors in the mesolimbic pathway. This action
has been proved to be responsible not only for the antipsychotic
activity, but also for the side effect that is neurolepsis15. Typical
antipsychotics or traditional antipsychotics are classically called
as neuroleptic drugs. Neurolepsis is characterized by
psychomotor slowing or decreased motor activity, emotional
quitting and indifference to the surroundings. This is the reason
why they are also named as neuroleptic drugs. Sleep may occur,
but the person can be aroused and can respond to commands. As
we know that Schizophrenia is manifested as positive
symptoms, negative symptoms and cognitive dysfunction. The
conventional or typical antipsychotics treat only positive
symptoms, negative and cognition dysfunctions of schizophrenia
are not treated by the typical antipsychotic which is a limitation
of them.
When significant numbers of D2 receptors are blocked by the
typical antipsychotics in the nigrostriatal pathway, then EPS
(Extra pyramidal symptoms) get to appear16. The extra
pyramidal symptoms are the major limitations due to which
typical antipsychotics are not preferred over atypical
antipsychotics. The extra pyramidal system regulates posture
and skeletal muscle tone. Extrapyramidal symptoms (also called
extrapyramidal side effects) have got their name because they
are the symptoms of disorders in this system. They are the drug
induced movement disorders17. Extrapyramidal side effects are
the neurological disorder. Neurological disorders can be
classified into “Acute” and “Tardive” syndromes. Acute
movement disorders are Akathisia (motor restlessness),
Dystonia (continuous spasm and muscle contractions) and
Pseudo Parkinsonism (characteristic symptoms due to rigidity)
and they appear within weeks or hours of initiation of treatment
or by increasing the dose of typical antipsychotic18. Tardive
dystonia is a kind of Tardive dyskinesia. It is a movement
disorder that is marked by involuntary muscular contractions
that is caused due to potent dopamine receptor blocker like
typical antipsychotics19. Extrapyramidal symptoms and their
clinical features are shown in the Table 2.
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They possess anti-cholinergic effects like blurred vision,
constipation, etc., in the body due to their potency to block
cholinergic (muscarinic) receptors. These side effects are more
seen with thioridazine, which is a typical antipsychotic. Due to
their alpha 1 blocking activity, they interfere with the adrenergic
functions and show the effects like postural hypotension and
difficulty in ejaculation (in males) which can be problematic in
adults. As they block the H1 receptors, so they also produce
sedation. Low potency drugs like chlorpromazine are highly
sedative whereas high potency drugs cause less sedation. Both
the typical and atypical antipsychotics can decrease the seizure
threshold and can precipitate convulsions in an epileptic patient.
However, seizures are more common with the low potency
typical antipsychotic drugs20. Thioridazine can cause arrhythmia
(prolongation of the QT interval). Retinal damage limits the
long term administration. In case of typical antipsychotics; the
more is the potency, more is the extra pyramidal symptoms and
low is the anticholinergic activity. Low potency drugs like
chlorpromazine has significant α blocking activity.
Moreover, their prolonged use can lead to weight gain (with all
except haloperidol). Interference with the dopaminergic
transmission in the pituitary and hypothalamus leads to
‘Amenorrhea’, ‘Galactorrhoea’ and ‘Gynecomastia’ as the level
of prolactin hormone gets increased which is not a problem in
the case of atypical antipsychotics. Clinical consequences which
are associated with hyperprolactinemia are well documented in
women on antipsychotics, in whom the prevalence of
symptomatic hyperprolactinemia reaches fifty percent or more,
the most common symptoms being the galactorrhoea and
irregularities in the menstruation21.
The combination of all these side effects that have been
mentioned above are very likely to affect the patient’s qualities
of life adversely and their desire to continue with and adhere to
typical antipsychotic therapy.
Adverse Effects of Atypical Antipsychotics and Limitations
The word 'atypical' has been most often used to describe the
action of Clozapine, and in fact this compound has been
regarded as the prototype for a new class of antipsychotic
drug22. All atypical antipsychotics (except ziprasidone) cause
metabolic side effects like weight gain, hyperlipidemia and Type
II diabetes. Atypical antipsychotics on the basis of their
potential to cause metabolic side effects are shown in Table 3.
They cause metabolic disorders rather neurological disorders as
compared to typical antipsychotics. Despite their benefits
outweigh their risks, but there too are some serious adverse
effects with the use of atypical antipsychotic like weight gain,
Type II diabetes mellitus, hyperlipidemia, QT interval
prolongation, sexual side effects. Overall, weight gain and
obesity are more troublesome with atypical antipsychotics than
with typical antipsychotics. Of the atypical antipsychotics,
Clozapine and Olanzapine have the most significant effect on
weight. The incidence of weight gain with Clozapine is regarded
to be the most significant and ranges from 4% to 31%.
Olanzapine follows Clozapine in significant weight gain with an
incidence of 5% to 40%. A meta-analysis by Allison and
colleagues suggested that olanzapine was associated with a
mean weight gain of 4.15 kg, while the Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) trial indicated 30%
of patients taking olanzapine experienced a weight gain of more
than 7% from baseline (mean increase of 9.4 kg)23. Ziprasidone
and Aripiprazole have a very less incidence on weight gain.
There are many evidences from the case reports of patients that
clearly suggest that new onset type 2 diabetes mellitus have
been noted with clozapine and Olanzapine. Quetiapine and
Risperidone showed no effect like this. Clozapine does not seem
to cause hyperprolactinaemia, but it shows the same spectrum of
anticholinergic and antiadrenergic side effects as with the
typical antipsychotic24, but it causes agranulocytosis that limits
its use.
Partial agonist action on 5-HT1A receptors can give deprivation
of weight gain for an antipsychotic; this is very much relevant
for Ziprasidone but it enhances the risk of prolonged QT interval
and must be less used in the patients having cardiac diseases.
Ziprasidone causes QT interval prolongation. Opposite to this,
the blockade of the 5-HT3 receptor removes the risk for
prolonged QT interval but then it has a higher risk of weight
gain. Relation to the 5-HT3 receptor increases glucose uptake
and this is more seen with atypical antipsychotic drugs like
Clozapine and Olanzapine.
However, patients who have to be treated with atypical
antipsychotic drugs like Sertindole and Ziprasidone should
receive a baseline ECG (Electrocardiogram) before the
treatment is started, if any of the following mentioned cardiac
risk factors are present: personal history of syncope, known
cardiac disease, a family history of sudden death at under age of
40 years (especially if both the parent had sudden death) or
congenital long QT syndrome. A subsequent ECG is indicated if
the patient presents with symptoms that are associated with
prolonged QT interval (e.g. syncope) 25. Besides, Clozapine is
associated with myocarditis; it is contra-indicated in patients
with severe heart diseases. Quetiapine can cause cataract.
Hyperprolactinemia has most commonly seen with the use of
Risperidone than with the other atypical antipsychotics. Its
active metabolite which is Paliperidone has less risk of
metabolic side effects.
Benefits of Atypical Antipsychotics Due To Which They Are
Better and More Preferred Than Typical Antipsychotics
despite Having Side Effects
The most important reason for using atypical antipsychotics
despite having metabolic and other adverse effects is their low
potential to cause extra pyramidal side effects or the
neurological side effects burden on the patient. Unlike typical
antipsychotic, they have very less risk of tardive dyskinesia and
other extra pyramidal related side effects. Typical antipsychotics
like chlorpromazine exhibit the property to cause neurolepsis
which is not found in the case of atypical antipsychotics.
Neurolepsis is characterized by slowness or the absence of
motor movements and behavioral indifference that is not
tolerated by the schizophrenic patient. Atypical antipsychotics
have also been found to treat the negative symptoms of
schizophrenia as compared to typical antipsychotics.
We all are quite aware about the treatment resistant
schizophrenia in which the patient does not respond to the
treatment or in which at least two adequate trials of classical or
typical antipsychotics have been done and the patient has
residual persistent moderate to severe positive symptoms,
negative symptoms and poor work function. So in that case
clozapine is a good drug as it can treat this condition. It also
suppresses the positive as well as the negative symptoms of
schizophrenia26. Not only this, clozapine which is an atypical
antipsychotic is the first drug which is FDA approved for use as
an anti-suicide.
The typical antipsychotics of phenothiazine category are very
well associated and established causes of liver injury arising
within one to four weeks of treatment. During the 1960s and
early 1970s, chlorpromazine was one of the most common and
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recognized cause of liver diseases. Although some of the
atypical antipsychotics are also associated with liver disease, but
clinically apparent liver injury with jaundice from these atypical
agents is very rare27. Decrease of the dose leads to normalization
of enzymes of liver, particularly in the cases of Risperidone and
Clozapine.
Most of the adverse effects of the atypical antipsychotics can be
prevented if the proper therapeutic dose monitoring is done as
many of them are dose dependent e.g. Clozapine induced
convulsions are purely dose dependent28. Another great
justification of this statement can be seen in a survey that was
done on diabetes associated with clozapine, it was found that
glycemic control got improved when clozapine was stopped in
the 78% of individuals who developed diabetes. 62% of these
patients did not require hypoglycemic drug29. For olanzapine
associated diabetes, Koller and Doraiswamy presented that 78%
of patients had improved glucose level once the olanzapine dose
was decreased30.
Typical antipsychotics cause apoptosis of neurons in the brain.
When haloperidol, which is a typical antipsychotic, was found to
cause apoptosis, the implications were serious. There is loss of
gray matter in schizophrenia in the frontal cortex and due to this
there is expansion of lateral ventricle and third ventricle.
Dendrite length is reduced by 50%. The loss of gray matter is
much more progressive during the course of disease that
exacerbates the condition towards worst. So the drug that causes
the loss of grey matter cannot be a good treatment. Different
experiments have been done to validate this fact of ‘haloperidol
induced apoptosis’. On the basis of those, it was found that there
was increase of the oxygen reactive species or free radicals,
which arise from mitochondria and free radicals cause DNA
damage which is a very well known fact. Opposite to this, the
second generation or the atypical antipsychotics cause less
injury to neuronal cells. They enhance the cell survival and
neurogenesis31. So from these entire one can very well
understand that still atypical antipsychotics are of greater
importance than typical antipsychotics.

The treatment and management become a lot easier when the Table 1: Classification of antipsychotics32
‘Diabetologist’ and ‘Psychiatrist’ work together to monitor
impaired glucose tolerance and to lessen the risk of Typical Antipsychotics Atypical Antipsychotics
cardiovascular diseases in the schizophrenic people. · Phenothiazine · Clozapine
1. Chlorpromazine · Olanzapine
Neurogenesis, which we all know is the process of formation of 2. Thioridazine · Quetiapine
neurons. They are continuously formed in some specific regions 3. Trifluoperazine · Iloperidone
of the adult brain (in the human, neurogenesis continuously 4. Fluphenazine · Risperidone
occurs in two regions throughout the adulthood which is the · Thioxanthenes · Paliperidone
sub-angular zone and the striatum) which is contrary to the 1. Flupenthixol · Ziprasidone
popular belief that neurogenesis does not take place in the adult
2. Thiothixene · Lurasidone
· Butyrophenones · Aripiprazole
brain.
· Brexipiprazole
1. Haloperidol
· Asenapine
2. Droperidol
Atypical antipsychotic enhance the neurogenesis and counteract 3. Penfluridol
· Sertindole
the effect of haloperidol and reverse the effects of haloperidol · Miscellaneous
· Zotepine
induced toxicity by inverse agonist action on 5HT receptors, 1. Pimozide
2. Loxapine · Cariprazine
especially those which are the subset of 2A.
3. Molindone

Table 2: Extrapyramidal symptoms and their associated clinical features

Extrapyramidal symptoms Clinical features

Acute muscular dystonia Torticollis, Locked jaw, Oculogyric crisis or Spasm of other muscles.
Pseudo-parkinsonism Parkinsonian gait, Tremor, Instability.
Tardive dyskinesia Purposeless involuntary movements like chewing of cheeks or puffing of cheeks.
Akathisia Repetitive motions, Agitations or irresistible desire to move in the absence of anxiety

Table 3: Atypical antipsychotics as per their potential to cause metabolic side effects

Potential Atypical Antipsychotic Drugs

High potential Olanzapine and Clozapine
Intermediate potential Quetiapine
Low potential Risperidone and Paliperidone
Least potential Ziprasidone, Aripiprazole, Iloperidone and Asenapine

CONCLUSION compared to typical antipsychotics, which is a major significant

A number of different atypical antipsychotics have superior
efficacy when it comes to treatment of positive, negative,
cognitive symptoms of schizophrenia with typical
antipsychotics. The typical antipsychotic drugs were the reliable
treatment for the treatment of psychosis until the introduction of
clozapine but now they are replacing the typical antipsychotics
very fast and this can be justified from their high cost price.
Although the treatment of schizophrenia got revolutionized by
typical antipsychotics, but the imperfection or the drawbacks
caused due to these drugs is decreasing their use. All atypical
antipsychotics have less risk of extra pyramidal side effects as
factor for the patients. They also have less risk to cause
hyperprolactinemia, which is more associated with typical
antipsychotic. It cannot be overstated that atypical
antipsychotics are free of adverse effects, but most of the time it
has been found that side effects are dose dependent and can be
managed by the health care professional if the treatment is done
properly.
Moreover, the benefits of atypical antipsychotics outweigh the
risks associated when compared to typical antipsychotics. By
considering all of the factors above, it can be said that atypical

77

26
 Aryendu Kumar Saini & Hemendra Pati Trpathi / Int. J. Res. Ayurveda Pharm. 7(6), Nov - Dec 2016
antipsychotic drugs use is a better approach for the treatment of
psychosis.
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Cite this article as:
Aryendu Kumar Saini, Hemendra Pati Tripathi. Review on
atypical antipsychotics: an approach towards a better treatment
of psychosis. Int. J. Res. Ayurveda Pharm. Nov - Dec
2016;7(6):74-78 http://dx.doi.org/10.7897/2277-4343.076244
78
27
Dinda Saskia Chairunnisa (201610330311047)

ULASAN TENTANG ATYPICAL ANTIPSIKOSIS : PENDEKATAN MENUJU

TERAPI PSIKOSIS YANG LEBIH BAIK
Psikosis adalah penyakit psikiatrik dimana pasien tidak sadar dengan penyakitnya
(insight buruk) dan menolak dilakukan terapi. Psikosis mayor diantaranya skizofrenia dan
mood disorder seperti mania, depresi dan bipolar.Pasien psikotik tidak memiliki hubungan
yang baik dengan kenyataan. Kasus yang sering terjadi yaitu skizofrenia. Obat yang
direkomendasikan adalah golongan antipsikotik yang termasuk typical dan atypical
antipsikotik. Obat atypical antipsikotik memiliki manfaat yang tidak dimiliki typical
antipsikotik seperti bisa mengobati gejala positif dan negatif dari skizofrenia, tidak
mengganggu proses endokrin. Selain itu, antipsikotik atypical merupakan neuron protektif
sedangkan antipsikotik typical menyebabkan apoptosis.
Gejala yang terkait dengan skizofrenia
Skizofrenia ditandai dengan ganguan dalam berpikir,berkomunikasi, fungsi social dan
perhatian yang berubah. Gejala dari skizofrenia adalah gejala positif, negative, dan disfungsi
kognitif. Gejala positif yang ditemukan yaitu delusi, bicara yang disorganisasi, halusinasi
(visual, auditorik). Gejala negatif yang ditemukan yaitu ekspresi yang datar, tidak bisa
merasakan senang, berkurangnya motivasi. Disfungsi kognitif adalah gejala inti dari
skizofrenia, seperti berukurangnya daya belajar, persepsi, memori, kemampuan dalam
memecahkan masalah.
Faktor penyebab
Etiologi masih belum diketahui, tetapi terdapat hubungan genetic, lingkungan dan
faktor perkembangan neuronal. Psikotik bisa organic dan disebabkan karena beberapa faktor
resiko seperti obat central antikolinergik, N-methyl D-aspartate reseptor antagonis seperti
phencyclidine. Penyebab umumnya ialah hiperaktivasi dari neuron dopaminergic di jalur
mesolimbik. Neurotransmiter lain seperti 5-HT dan NA juga berperan dalam kasus ini. Salah
satu hipotesis dibalik skizofrenia adalah hipotesis dopamine. Obat seperti levodopa,
amphetamine (DA releaser) dan apomorphine (DA agonis) dapat meningkatkan kejadian
skizofrenia.
Terapi psikosis
Tidak ada obat yang benar-benar menyembuhkan psikosis. Obat yang adahanya dapat
menangani gejala yang timbul. Terapi yang dimaksud adalah psikoterapi seperti obat untuk
menstabilkan mood, konseling, dan dukungan dari keluarga. Obat-obatan yang digunakan
untuk menerapi psikosis disebut obat antipsikotik. Obat ini penting untuk menurunkan gejala
psikosis dan membantu mencegah episode yang lebih jauh dari penyakit psikotik.

28
Dinda Saskia Chairunnisa (201610330311047)

Gambar 1. Obat typical dan atypical antipsikotik

Mekanisme typical dan atypical antipsikotik
Jalur utama yang berperan ialah terdapat empat jalur reseptor dopamine di system
saraf pusat. Empat jalur itu merupakan jalur mesolimbic, mesokortikal, nigostriatal, dan
tuberoinfundibular. Empat jalur terebut akan mempengaruhi sikap kognitif, koordinasi,
pergerakan yang disadari dan berpikir. Hiperaktivasi dari dopamine akan menyebabkan
munculnya gejsala skizofrenia.
Typical antipsikotik adalah obat yang memblok reseptor D2, tetapi tidak hanya D2,
mereka juga bisa memblok H1, M1, dan alpha1 reseptor. Atypical antipsikotik juga memblok
reseptor D2 tetapi afinitas terhadap D2 longgar. Afinitas terhadap reseptor 5HT2A baik dan
beberapa antipsikotik atypical adalah 5HT1A agonis seperti clozapine dan ziprasidone.
Efek samping dan batasan dari antipsikotik typical
Antipsikotik typical juga disebut obat neuroleptic. Neurolepsis ditandai dengan
kelambatan psikomotor, berkurangnya aktivitas motoric. Obat typical antipsikotik hanya
mnegobati gejala positif saja. Ketika reseptor D2 diblok oleh obat typical antipsikotik di jalur
nigostriatal maka EPS (Extra pyramidal symptoms) akan muncul yaitu berupa acute
movement disorder, dystonia dan pseudo parkinsonism yang muncul dalam beberapa jam
hingga minggu setelah terapi.

Antipsikotik typical seperti obat thioridazine memberikan efek antikolinergik seperti

pandangan yang kabur, konstipasi, dan sebagainya. Hal ini terjadi karena aktivitas blok dari
alfa 1. Jika obat tersebut memblok H1 reseptor maka akan terjadi efek sedasi seperti pada
obat chlorpromazine.

29
Dinda Saskia Chairunnisa (201610330311047)

Efek samping dan batasan dari antipsikotik atypical

Semua obat antipsikotik atypical menyebabkan efek smaping metabolic seperti
peningkatan berat badan, hiperlipidemi dan diabetes tipe II.

Aksi parsial agonis dari reseptor 5HT1A bisa memberikan efek peningkatan berat
badan. Pasien yang diberikan terapi obat antipsikotik atypical seperti Sertrindole dan
Ziprasidone dapat dilakukan pemeriksaan EKG sebelum dilakukan terapi obat karena untuk
mengetahui resiko jantung.
Keuntungan antipsikotik atypical disbanding antipsikotik typical
Salah satu keuntungan utamanya yaitu antipsikotik atypical tidak memberikan efek
EPS. Antipsikotik atypical juga dapat mengobati gejala negative dari skizofrenia. Salah satu
contoh obat antispikotik atypical yaitu clozapine yang dapat mengatasi gejala positif dan juga
negative dari skizofrenia serta telah dibuktikan oleh FDA sebagai obat anti bunuh diri. Efek
samping dari obat antipikotik atypical dapat dicegah dengan memonitor dosis.
Kesimpulan
Antipsikotik atypical memiliki efikasi yang lebih besar dari antipsikotik typical dalam
mengatasi gejala positif, negative, dan gangguan kognitif pada pasien skizofrenia. Semua
obat antipsikotik atypical memiliki sedikit resiko dalam efek ekstrapiramidal dibandingkan
antipsikotik typical. Dapat dikatakan bahwa antipsikotik atypical merupakan obat yang lebih
baik dalam hal terapi psikosis.

30
 British Medical Bulletin Advance Access published May 8, 2015

British Medical Bulletin, 2015, 1–11

doi: 10.1093/bmb/ldv017

Antipsychotic medication in schizophrenia:

a review
John Lally†,* and James H. MacCabe‡
†
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s

Downloaded from http://bmb.oxfordjournals.org/ at Freie Universitaet Berlin on May 12, 2015

College London, London, United Kingdom, and ‡National Psychosis Service, South London and Maudsley
NHS Foundation Trust, London, United Kingdom
*Correspondence address. Department of Psychosis Studies, PO63, Institute of Psychiatry, Psychology & Neuroscience
(IoPPN), King’s College London, De Crespigny Park, London SE5 8AF. Tel: +(0044) (0)20 7848 0216; Fax: +(0044) 020 7848 0287;
E-mail john.lally@kcl.ac.uk
Accepted 1 April 2015

Abstract
Introduction: Antipsychotic medications are mainstays in the treatment of
schizophrenia and a range of other psychotic disorders.
Sources of data: Recent meta-analyses of antipsychotic efficacy and toler-
ability have been included in this review, along with key papers on anti-
psychotic use in schizophrenia and other psychotic illnesses.
Areas of agreement: The heterogeneity in terms of individuals’ response to
antipsychotic treatment and the current inability to predict response leads to
a trial-and-error strategy with treatment choice. Clozapine is the only effect-
ive medication for treatment-resistant schizophrenia.
Areas of controversy: There are a significant number of side effects asso-
ciated with antipsychotic use. With a reduction in the frequency of extrapyr-
amidal side effects with the use of second-generation antipsychotics, there
has been a significant shift in the side effect burden, with an increase in the
risk of cardiometabolic dysfunction.
Growing points: There exist small and robust efficacy differences between
medications (other than clozapine), and response and tolerability to each
antipsychotic drug vary, with there being no first-line antipsychotic drug that
is suitable for all patients.
Areas timely for developing research: A focus on the different symptom
domains of schizophrenia may lead to endophenotypic markers being identi-
fied, e.g. for negative symptoms and cognitive deficits (as well as for positive
symptoms) that can promote the development of novel therapeutics, which

© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
31
2 J. Lally et al., 2015, Vol. 0, No. 0

will rationally target cellular and molecular targets, rather than just the dopa-
mine 2 receptor. Future developments will target additional processes,
including glutamatergic, cholinergic and cannabinoid receptor targets and
will utilize personalized medicine techniques, such as pharmacogenetic var-
iants and biomarkers allowing for a tailored and safer use of antipsychotics.
Key words: schizophrenia, antipsychotic medication, psychotic disorders

Introduction with excess dopaminergic activity in the mesolimbic

Antipsychotic medications are primarily indicated for pathway (leading to positive symptoms of psychosis)

Downloaded from http://bmb.oxfordjournals.org/ at Freie Universitaet Berlin on May 12, 2015

the treatment of schizophrenia and other psychotic
disorders [including schizoaffective disorder, delu-
sional disorder and bipolar affective disorder (BPAD)].
They have traditionally been categorized as first-gener-
ation (formerly known as ‘typical’ or ‘conventional’)
antipsychotics (FGAs) or second-generation antipsy-
chotics (SGAs) (formerly ‘atypical’ antipsychotics).
The burden of side effects associated with FGAs,
in particular debilitating extrapyramidal side effects
(EPSEs), led to the introduction of the SGA medica-
tions in the 1990s. The SGAs have a lower propensity
to cause EPSEs (i.e. acute dystonias, akathisia, parkin-
sonism and tardive dyskinesia) compared with the
FGAs, and these properties, aligned with their differen-
tiating receptor profiles, led them to be labelled as
‘atypical’.1 The 8 SGAs that are currently licensed for
use in the UK (12 in total are licensed in Europe) were
modelled on the pharmacological profile of clozapine,
due to its low propensity to cause EPSEs and superior
effectiveness in refractory schizophrenia.2 The SGAs
are associated with a lesser burden of EPSEs at moder-
ate doses (though they are not free from inducing
EPSEs, with some such as aripiprazole carrying a
risk of akathisia of ∼10%), but many are associated
with increased risk of cardiometabolic abnormalities,
including weight gain, dyslipidaemia and glucose
dysregulation.
Mechanism of antipsychotic action
D2 receptor antagonism in the brain is a general
pharmacodynamic property of all antipsychotics;
this has given rise to the hypothesis that schizophre-
nia involves a dysregulation of dopaminergic circuits
and reduced dopaminergic signalling in the mesocor-
tical pathway (leading to negative symptoms). Evi-
dence for the dopamine hypothesis comes from not
only the efficacy of D2 receptor antagonists, but also
through the effects of D2 agonists such as amphet-
amine in precipitating psychosis and the effects of
dopamine-depleting drugs such as reserpine in redu-
cing psychotic symptoms.3
Antipsychotic action has consistently been shown
to occur when the occupation of striatal D2 recep-
tors is more than 65%, but further increases in the
level of D2 blockade are not associated with improved
antipsychotic efficacy; rather, it leads to the onset of
side effects such as EPSEs and hyperprolactinaemia.
A threshold dose for EPSEs occurs when ∼80% of the
D2 receptors are occupied and for hyperprolactinae-
mia when D2 blockade exceeds 72%.4 Despite the
association of striatal dopamine blockade with the
risk of EPSEs, it is important to note that this is not
the critical site of action for therapeutic effect, which
occurs most prominently in the mesolimbic brain
system.
Clozapine: a special case
Clozapine is unique among antipsychotic medica-
tions and can be viewed as a standalone ‘third class’
of antipsychotic. It is the only antipsychotic medica-
tion that has proven effectiveness in treatment-resist-
ant schizophrenia (TRS). The precise mechanism of
clozapine’s superior effectiveness in TRS has not
been established, but some 50–60% of patients with
schizophrenia refractory to other antipsychotics will
respond to clozapine.5 Clozapine produces robust
antipsychotic effect at <65% threshold of striatal D2

32
Antipsychotic medication in schizophrenia, 2015, Vol. 0, No. 0
receptor blockade,4 suggesting that beyond D2
receptor blockade in the striatum, other receptors or
mechanisms also contribute to its therapeutic effect.
Clozapine and TRS are considered in greater
detail in the following text.
Clinical efficacy of FGA versus SGA
The introduction of SGAs was thought to be a revolu-
tion in the treatment of schizophrenia. Initially, claims
were made that the SGAs had better efficacy for
positive and negative symptomatology and cognitive
deficits as well as improved tolerability. However, over
time, this initial enthusiasm and optimism for thera-
peutic advantages for the SGAs as a class have
diminished.
The Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE)6 and the Cost Utility of the
Latest Antipsychotic Drugs in Schizophrenia Study
(CUtLASS),7 which compared FGAs and SGAs,
failed to show a difference between FGAs and SGAs
in rates of treatment discontinuation, improvement
in psychotic symptoms or quality of life.6,7 CATIE
further failed to demonstrate that SGAs were more
effective in the reduction of negative or cognitive
symptoms than FGAs. The results of CATIE and
CUtLASS demonstrated similarities in treatment
response, though with SGAs carrying a lower risk of
tardive dyskinesia. Further evidence for clozapine’s
unique position among antipsychotics was provided,
with it found to be superior to other SGAs in both
CATIE and CUtLASS.
In 2012, a multi-treatment meta-analysis asses-
sing the efficacy of antipsychotic medication in ran-
domized controlled trials (RCTs) in patients with
schizophrenia demonstrated that all antipsychotic
medications were significantly more effective than
placebo. This showed that antipsychotics had a relapse
rate of 28% compared with a relapse rate of 64% for
placebo over a 7–12-month follow-up period.8 The
effect size is comparable with that seen for many treat-
ments for non-psychiatric disorders, such as hyperten-
sion, hypercholesterolaemia and type 2 diabetes.9 This
indicates that antipsychotic medications are not less
effective when prescribed for their target conditions,
than those used by other medical specialties.
3
In a more recent meta-analysis, the separation of
antipsychotic medications into FGA and SGA group-
ings has been further called into question, with
similar efficacy between the groups seen.10 The most
efficacious antipsychotics in this meta-analysis were
the SGAs that were first developed, with small but
robust differences seen in efficacy for amisulpride,
olanzapine and risperidone (and for clozapine, but
the effect for clozapine was diminished by the exclu-
sion of studies with TRS patients).
Downloaded from http://bmb.oxfordjournals.org/ at Freie Universitaet Berlin on May 12, 2015
Antipsychotic medication and adverse
effects
In Leuchts’ meta-analysis,10 amisulpride proved to
be the best in terms of tolerability, with less discon-
tinuation due to side effects compared with placebo.
Haloperidol was the worst drug for discontinuation
rates compared with placebo. Haloperidol was iden-
tified as the medication most likely to cause EPSEs,
while weight gain and metabolic dysfunction were
most notably identified with the use of olanzapine
and clozapine (and to a lesser extent with risperidone
and quetiapine),10 findings that have been consist-
ently replicated in other studies.11
Cardiometabolic adverse effects
Higher rates of modifiable cardiovascular risk factors
are seen in schizophrenia, with 33% of patients with
schizophrenia meeting the criteria for metabolic
syndrome throughout the course of the illness.12 The
increased risk for cardiometabolic risk factors is
multifactorial with genetic factors and the cumulative
long-term effect of poor health behaviours and long-
term exposure to antipsychotic drug postulated as
causes.
SGAs are associated with higher rates of meta-
bolic dysfunction compared with FGAs (though
FGAs such as chlorpromazine are associated with
increased cardiometabolic risk and it remains the
case that the cardiometabolic risk associated with FGAs
has not been as extensively studied as with SGAs).
Clozapine and olanzapine both have the greatest
affinity for 5-HT2C and Histamine (H) 1 receptors
and the greatest weight gain potential, which can
33
4 J. Lally et al., 2015, Vol. 0, No. 0
occur early in the course of treatment,13 before plat-
eauing as the treatment continues.11 The most dra-
matic weight gain is seen in antipsychotic naïve
patients over the first 6 weeks of treatment and for
the majority, those with initial weight gain did not
lose that weight thereafter, even after switching to
more weight-neutral antipsychotics.14 SGAs such as
aripiprazole, lurasidone and asenapine have a more
neutral metabolic side effect profile.
Physical health monitoring
It is recommended that all patients while treated with
antipsychotics are monitored regularly for cardiome-
tabolic risk factors. Despite this, and the cumulative
cardiometabolic risk factors, monitoring of physical
health parameters in those treated with schizophre-
nia continues to be poor.15 For an individual starting
an antipsychotic for the first time (and for any future
antipsychotic changes), the following are recom-
mended to be monitored: weight, at baseline, then
weekly for the first 6 weeks, then at 12 weeks, at
1 year, and then annually ( plotted on a chart) (more
frequently at the start of treatment as rapid early
weight gain may predict severe weight gain in the
longer term14); waist circumference at baseline and
then annually ( plotted on a chart) (waist size or BMI
have been suggested as a simple screening test for
metabolic syndrome in schizophrenia12); and blood
pressure, fasting blood glucose, HbA1c, and blood
lipid and serum prolactin levels at baseline, at 12
weeks, at 1 year, and then at least annually.16
Further, pharmacological and non-pharmacological
interventions for weight loss and cardiometabolic dys-
function should be initiated when required.
Choice of antipsychotic
At present, there are no specific biomarkers or phar-
macogenetic tests to guide the choice of treatment.
According to the National institute for health and
care excellence guidelines, a person presenting with a
first episode of schizophrenia or a first episode of
psychosis (FEP) should be offered treatment with an
antipsychotic. The onset of the response to treatment
is highly variable, but meta-analysis has indicated that
the largest part of antipsychotic medication effect
takes place within the first week (excluding the use of
clozapine), and thereafter the improvements are more
marginal.17
If a patient does not have a response to anti-
psychotic treatment at 4–6 weeks, then the recom-
mendation is to switch to an antipsychotic medication
with a different receptor-binding profile.18 It is impor-
tant to ensure that the patient is adherent to treatment
and that it is not a case of medication intolerability
that has led to a poor response. Antipsychotic medica-
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tions should be titrated to a therapeutic dose (e.g.
olanzapine 5–10 mg daily or risperidone 2–4 mg
daily in the first episode of schizophrenia) in order to
assess treatment response. It is only a small propor-
tion of patients with an FEP (∼15–20%) that will not
have a further episode of psychosis, but at this stage
of the illness, it is not possible to predict who will not
relapse once maintenance treatment is discontinued.
How long to continue?
Maintenance treatment is recommended for all, with
first-episode patients treated for at least 1 year, while
those with multi-episodes should have treatment for
at least 5 years. Further, the severity of the acute
episode, namely the degree of symptomatology that
somebody presents with and the risk of violence and
suicidality, which may be associated with the acute
episode, will increase the likelihood that longer-term
maintenance treatment be recommended. The dis-
continuation of antipsychotic medication has been
shown to be associated with a fivefold increased risk
of relapse over a 5-year follow-up period compared
with maintenance therapy.19 It is standard practice
to continue the medication that was effective in the
acute phase as long as it is well tolerated.
Switching antipsychotics
There are different methods for switching anti-
psychotic medications, if required for clinical inef-
fectiveness or intolerability. This may involve a
crossover where one medication is gradually tapered
while the second medication is concurrently titrated
to its full dose. Another approach is to abruptly stop
34
Antipsychotic medication in schizophrenia, 2015, Vol. 0, No. 0
the first drug with the introduction of the new drug
at a therapeutic dose (most appropriately used in
cases of acute psychosis in an inpatient setting), or
the original medication is slowly discontinued and
only when it is stopped will the next medication
be started (best used for those with a low risk of
relapse). With any switch of antipsychotic medication,
the individual is at heightened risk of a deterioration
and psychotic relapse or exacerbation, necessitating
a close monitoring of the individuals mental state
during this switching process.
Treatment-resistant schizophrenia
(TRS) and clozapine
Approximately 30% of patients with schizophrenia
will not respond to the use of FGAs or SGAs. The
failure to respond to two different antipsychotics, at
therapeutic doses and for a sufficient duration (gener-
ally taken to be 6-8 weeks of antipsychotic therapy)
means that a person meets the criteria for treatment
resistance. The only medication with proven effective-
ness in this subgroup of patients with TRS is clozapine.
In the UK, some 50–60% of patients will respond to
clozapine, with a 30% response rate achieved at 6
weeks of clozapine treatment and a higher response
rate achieved over longer treatment periods with up to
60–70% responding at 1 year.5 This prolonged period
of ongoing clinical response over the first year of treat-
ment is unique to clozapine among antipsychotic medi-
cations. It has been shown that clozapine does not
have superior efficacy in comparison with other anti-
psychotics in the treatment of first-episode psychosis,20
reinforcing the hypothesis that TRS constitutes a sub-
group schizophrenia patient population, with differ-
ences in pathological processes.
However, clozapine use varies widely depending
on geography, with the prevalence of clozapine use
being lower in most countries than the ∼30% of
patients who are likely to benefit from clozapine,
and substantial evidence exists that it is only used
after a delay of several years.21 This is partly due to
the nature and degree of side effects that it can cause,
including agranulocytosis, which affects some 0.8%
of patients prescribed clozapine and is associated
with a mortality of 1 in 10 000 of clozapine-treated
5
patients in the UK. In the UK, clozapine is only pre-
scribed in conjunction with the weekly measurement
of the white cell count for the first 18 weeks of
treatment, followed by a fortnightly white cell count
measurement for the next 34 weeks and then fol-
lowed by monthly white cell counts for as long as the
patient is maintained on clozapine. It is likely that
the fear of adverse medication reactions (by clini-
cians and patients alike) and the inconvenience of
therapeutic monitoring of full blood counts (FBCs)
so early in the course of clozapine use are factors
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contributing to this delay.
Clozapine is relatively free of EPSEs, though it
carries a heavy burden of other adverse reactions.
In addition to haematological adverse reactions, it
can also cause sedation, weight gain, constipation,
hypersalivation and rarely myocarditis and cardio-
myopathy. However, despite the high rate of adverse
effects associated with clozapine, there is evidence
that it is associated with reduced mortality compared
with other antipsychotics, with this reduction in
mortality not entirely explained by a reduction in
suicide risk.22
Medication non-adherence
Non-adherence to medication is more common in any
chronic illness, though rates of non-adherence are
higher in schizophrenia than other chronic illnesses.23
Non-adherence with antipsychotic treatment is high,
with up to 75% of patients at 2 years post hospital dis-
charge being non-adherent with antipsychotic medica-
tion.24 It can occur due to intolerable side effects, lack
of insight, the persistence of residual psychotic symp-
toms and poor therapeutic alliance. The discontinu-
ation of antipsychotics is associated with a worse
prognosis, with increased rates of relapse, rehospitali-
zation and suicide.25 Partial adherence with antipsy-
chotics is similarly associated with an increased risk of
relapse and rehospitalization, when compared with
complete medication adherence. Strategies to support
individual adherence with medication are important
to ensure that medication gaps are limited in order to
improve long-term prognosis. These interventions can
be particularly important in the early stages of the
illness, where medication partial or non-adherence
35
6 J. Lally et al., 2015, Vol. 0, No. 0
can have devastating effects on the longer-term illness
course. Interventions include psychoeducation, motiv-
ational interviewing techniques, integration of the
importance of antipsychotic use into a relapse pre-
vention and recovery model, and a pharmacy-based
intervention consisting of easy-use packaging, refill
reminders and medication education.26
Long-acting injection (depot)
medications and combination/
high-dose therapy
The use of antipsychotic long-acting injections (LAIs)
(also known as depots) is recommended when a pat-
ient expresses a preference for this treatment or when
there is evidence of non-adherence with oral medica-
tions. The use of LAIs ensures that clinicians know
when a patient has taken medication or when they
stop it. It remains to be clearly established that LAIs
are more effective than oral antipsychotic medication,
though a recent meta-analysis indicated that LAIs had
reduced rates of relapse compared with oral antipsy-
chotics,8 with specific study designs tending to more
consistently support the effectiveness of LAIs. A
Finnish naturalistic study showed that the use of LAIs
led to a threefold reduction in the rates of rehospitali-
zation compared with the oral formulation of the
same antipsychotic.27 However, a recent large RCT
did not show superiority of risperidone LAI versus
oral medications.28
Pipotiazine palmitate (Piportil®) may be asso-
ciated with less-frequent EPSEs18 but is scheduled to
be withdrawn from the UK market and discontinued
in March 2015 (due to a global shortage of an active
ingredient of the compound).
There are four LAI formulations of SGAs, namely
risperidone, paliperidone, olanzapine embonate and ari-
piprazole; and four FGAs depot medications, namely
haloperidol decanoate, flupentixol decanoate, zuclo-
penthixol decanoate and fluphenazine decanoate.
Antipsychotic polypharmacy
Combination antipsychotic treatment (i.e. two or
more different antipsychotics), which is also known
as antipsychotic polypharmacy, is a frequently used
practice. The reported prevalence of antipsychotic
polypharmacy ranges from 7 to 50%.29 There is often
a lack of clear pharmacological rationale for combin-
ing antipsychotics that provide the same putative anti-
psychotic dopamine D2 receptor blockade and little
information to know what the mechanism of action
of multiple antipsychotics in the brain is. Further,
combining antipsychotics can lead to high overall dose
and an increased burden of adverse effects, along with
an increased risk for drug–drug interactions, as well as
variability in serum levels and increased difficulty for
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patients in remaining adherent to the treatment
regimen. There is no clear evidence to support combin-
ation antipsychotics,29 and it is best to reserve the use
of combination treatments for those who have a docu-
mented lack of response to antipsychotic monotherapy
and who may be intolerant of clozapine, thus restrict-
ing their access to this medication. If clinicians decide
to use combination antipsychotics, they should be
guided by the pharmacodynamic profiles of the com-
bined antipsychotics, with the aim of using antipsy-
chotics with differing receptor-binding profiles.
High-dose antipsychotic use
The majority of side effects associated with anti-
psychotic treatments are dose related, and the use of
high-dose antipsychotics [i.e. above British National
Formulary (BNF)-licensed maximum doses] is asso-
ciated with a higher rate of adverse effects (such as
sedation, constipation, postural hypotension, EPSEs,
QTc prolongation and sudden cardiac death). The
use of high-dose antipsychotic treatment should only
be used in exceptional circumstances, and care
should be taken if combination antipsychotics are
used, to ensure that the combined dose equivalence
is not >100% of the BNF-licenced maximum dose.
High-dose antipsychotic therapy is defined by the
Royal College of Psychiatrists (RCPsych) as a total
daily dose of a single antipsychotic that exceeds the
upper limit stated in the BNF, or a total daily dose of
two or more antipsychotics that exceeds the BNF
maximum as calculated by percentages using the
antipsychotic dose ready reckoner [example calcula-
tion: fluphenazine depot 100 mg monthly (50%)
and olanzapine 15 mg daily (75%) = 50% + 75% =
36
Antipsychotic medication in schizophrenia, 2015, Vol. 0, No. 0
125% (>100% therefore ‘high dose’)].30 For all
those treated with high-dose antipsychotics, it is
important to regularly monitor for metabolic abnor-
malities and for evidence of ECG changes, especially
QTc prolongation.
Clinical indications for antipsychotics
Antipsychotic medications are effective in a range of
disorders other than schizophrenia. In addition to
their antipsychotic effects, antipsychotics may also
have mood-stabilising, antimanic, antidepressant and
anxiolytic effects.
Bipolar affective disorder (BPAD)
Multiple international guidelines recommend the use
of antipsychotic medication in the treatment of all
stages of BPAD.18,31,32 For acute mania, antipsycho-
tics (particularly olanzapine, risperidone and quetia-
pine) along with mood stabilisers are consistently
identified as primary treatment options. A recent
meta-analysis identified that antipsychotics are more
effective than mood stabilisers in the treatment of
acute mania.33 Olanzapine and quetiapine are recom-
mended first-line treatments for bipolar depression.
Both quetiapine and olanzapine are associated with a
rapid onset of action in bipolar depression, with effi-
cacy demonstrated from the first week of treatment
onwards. In clinical practice, quetiapine is now con-
sidered more for its mood-stabilising properties than
for its antipsychotic effects. Similarly, the antipsycho-
tics that are indicated for acute mania are generally
recommended for maintenance therapy in BPAD.
Clozapine has evidence of effectiveness in refractory
mania and should be considered for this.
Unipolar depression
The use of antipsychotics as augmentation treatment
options in unipolar depression and anxiety disorders is
an off-label use, meaning that this use is not formally
licensed (but with a growing evidence base to indicate
the efficacy of certain antipsychotics). For treatment-
resistant unipolar depression (TRD), antipsychotics
are used as off-label augmentation strategies. There is
7
evidence to support the use of quetiapine, aripiprazole,
olanzapine and risperidone as antidepressant augmen-
tation strategies in TRD, with the best evidence existing
for the use of quetiapine and aripiprazole.34 Quetia-
pine (150–300 mg daily) is licensed in the UK as an
antidepressant augmentation strategy.35 Antipsycho-
tics for augmentation in TRD are prescribed at lower
doses than what would be used in schizophrenia or
BPAD (e.g. olanzapine 5–12.5 mg/day, quetiapine
150–300 mg/day). In psychotic depression, the com-
bination of an antipsychotic and antidepressant is
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more effective than the use of an antidepressant alone,
with olanzapine combined with fluoxetine probably
the best evidenced combination.36
Anxiety disorders
Antipsychotic medications have long been used as
augmentation strategies for anxiety disorders, with
the best evidence for their use as selective serotonin
reuptake inhibitor augmentation strategies in obses-
sive compulsive disorder (OCD) and for the use of
quetiapine in generalized anxiety disorder (GAD).37
Update on new antipsychotics
In the UK, several SGAs are now off patent, including
risperidone, olanzapine, amisulpride and quetiapine
(instant-release formulation). However, given the het-
erogeneous patient response to and tolerability of
antipsychotics, there remains a need to improve the
therapeutic efficacy of available agents and to aid
choice in improving treatment tolerability for patients.
The newer branded SGAs, asenapine and lurasidone,
have less impact on weight and metabolic parameters
than older agents such as olanzapine.
Paliperidone
Paliperidone is the active metabolite of risperidone
and is available in oral and LAI formulations, both
demonstrating efficacy and tolerability and a delay in
time to relapse in schizophrenia. It is not hepatically
metabolised, making it safe to use in hepatic impair-
ment and with limited risk of pharmacokinetic drug
interactions.18 Paliperidone is further licensed for the
37
8 J. Lally et al., 2015, Vol. 0, No. 0
treatment of psychotic and manic symptoms of
schizoaffective disorder. Its adverse effect profile is
similar to that of the parent compound risperidone,
with increased weight gain, hyperprolactinaemia
and EPSEs at higher doses, along with case reports
of tardive dyskinesia.38 At doses of 9–12 mg of oral
paliperidone (equivalent to risperidone 4–6 mg
daily), the risk of EPSEs is increased. The therapeutic
dose range is 6–9 mg once daily (equivalent to risper-
idone 3–4 mg daily).18
Paliperidone palmitate is the LAI formulation,
which achieves active serum levels within days of ini-
tiation and allows deltoid, rather than gluteal muscle
administration.
Asenapine
Asenapine has demonstrated efficacy in the acute
and maintenance phases of schizophrenia treatment
and in the treatment of acute mania in BPAD, but it
is only currently licensed for the treatment of mania
in the UK.35 Asenapine has high affinity for multiple
serotonin receptors, with antagonism at 5-HT2A,
5-HT2C and 5-HT7 and 5-HT1A agonism, along
with potent D2 and D3 antagonism and some hista-
mine (H) 1 antagonism.18
Asenapine is subject to first-pass metabolism and
thus inactive if swallowed. It is, therefore, available
only as an orally disintegrating tablet, meaning that it
is absorbed via oral mucosa. This is in contrast to the
other antipsychotic orodispersible tablets of olanza-
pine, risperidone and aripiprazole, all of which must
be swallowed to be effective. This means that patients
must be informed that asenapine cannot be swallowed
and that food or drink must be avoided for at least 10
min after administration.
Asenapine does not require dose titration and can
be dosed at 5 mg bd for acute schizophrenia with doses
of up to 10 mg twice daily shown efficacy in preventing
relapses in schizophrenia. Asenapine has a half-life of
24 h and as such could theoretically be prescribed as a
once-daily medication, but the efficacy of a once-daily
prescription remains to be studied in trials. It appears
to be a metabolically neutral antipsychotic with low
propensity to cause weight gain (though some evidence
for a higher propensity for weight gain in acute mania
exists) and has little effect on prolactin levels.39 It can
cause akathisia (increased occurrence at 10 mg twice-
daily dosing compared with 5 mg twice daily), sedation
and taste disturbance.40
Lurasidone
Lurasidone is licensed for the treatment of schizo-
phrenia35 and has shown efficacy as an adjunctive
treatment for bipolar depression, and it is a licensed
therapy for bipolar depression in the USA.
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Lurasidone has full D2 antagonism and is an
antagonist at 5HT2A and 5HT7 receptors, with par-
tial agonism at 5-HT1A receptors, and with low af-
finity for 5HT2C, H1 and muscarinic receptors.40
Lurasidone is a once-daily prescription, simplifying its
administration. It is dosed in adults at 37 mg once
daily initially and increased if necessary to a maximum
of 148 mg once daily. For schizophrenia, a dose range
of 37–148 mg daily is recommended, with a lower dose
range of 18.5–120 mg daily, recommended for bipolar
depression (lurasidone at lower doses of 20–60 mg
daily has been shown to be as clinically efficacious in
bipolar depression, as at the higher dose range of 80–
100 mg/day). Lurasidone is metabolized by CYP3A4
enzymes, meaning that its dose should be reduced
when used with concomitant CYP3A4 inhibitors (e.g.
diltiazem, erythromycin).
Lurasidone is generally well tolerated, with low inci-
dences of weight gain and metabolic dysfunction. It is
associated with akathisia (increased incidence at doses
of 120 mg or greater), sedation and nausea, but simi-
larly to asenapine, despite been a full D2 antagonist, it
is not associated with higher incidences of EPSEs
(excluding akathisia) and hyperprolactinaemia.40
Conclusions
Maintaining the status Quo in antipsychotic
treatment
It remains the case that there has been no fundamen-
tal innovation in psychopharmacology for schizo-
phrenia since the discovery of clozapine in the late
1950s. This is further exacerbated by the recent
retreat of the pharmaceutical industry away from
38
Antipsychotic medication in schizophrenia, 2015, Vol. 0, No. 0
research and development in psychiatric disorders.
For all the benefits bought by antipsychotics and the
initially perceived advantages of SGAs, we are still
working with medications that are not fully effective
and often carry significant adverse effect burdens.
SGAs or FGAs?
Despite the lack of clear-cut differences in clinical
efficacy between SGAs and FGAs (with the exception
of clozapine), the introduction of the SGAs from
the early 1990s onwards represented meaningful
steps in attempting to improve pharmacotherapy for
patients with schizophrenia. While we are improving
our knowledge of what different treatments can and
cannot do,10 we still remain a long way from being
able to recommend with precision, specific treat-
ments for individual patients, in terms of the clinical
response and lack of adverse events. There is also no
longitudinal evidence to support attempts to identify
those patients who will and who will not require
long-term antipsychotic medication with FGAs or
SGAs.
Change in approach to medication
development
There is a growing consensus in academic psychiatry,
acknowledging that schizophrenia is not a single
disease entity and that the positive symptoms of psych-
osis (delusions, hallucinations) which antipsychotics
work best to treat, are only one aspect of the disorder’s
pathology. We need to focus future pharmaceutical
development on symptoms domains of schizophrenia,
with a particular need for treatments to target negative
symptoms and cognitive impairments in schizophrenia.
A more concentrated focus on the different symptom
domains may lead to endophenotypic markers being
identified for negative symptoms and cognitive deficits
(as well as for positive symptoms) that can promote
novel medication discovery. If medications are discov-
ered for separate symptom domains of schizophrenia,
then we could expect to be able to develop concurrent
medication strategies, with antipsychotics used in
combination with medications for negative symptoms
or along with those that have cognitive enhancing
effects.
9
Novel therapeutic strategies
Our current level of knowledge regarding the patho-
genesis of schizophrenia continues to improve,
leading to the hope that in future novel therapeutics
that will rationally target cellular and molecular
targets, rather than just the D2 receptor, can be devel-
oped. All antipsychotic medications that have been
developed over the past six decades have been based
on the targeting of D2 receptors, and later the charac-
teristic 5-HT2A antagonism of SGAs. Future develop-
ments will target additional processes, including
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glutamatergic, cholinergic and cannabinoid receptor
targets, and the emerging field of pharmacogenetics
will aim for treatments to be tailored to individual
patients in terms of efficacy and tolerability.
Conclusion
The heterogeneity in terms of individuals’ response
to antipsychotic treatment and the current inability
to predict response leads to a trial-and-error strategy
with treatment. It remains the case that we are no
closer to mirroring the effects of clozapine in TRS,
with its mechanism of action proving elusive to iden-
tify and replicate in other antipsychotic therapies
for schizophrenia.
Funding
Dr Lally and Dr MacCabe are both supported by
CRESTAR (CRESTAR project, http://www.crestar-
project.eu/) EU-FP7 grant number 279227; Dr
MacCabe is supported by STRATA (MRC grant no.
MR/L011794/) and by the National Institute for
Health Research (NIHR), Biomedical Research
Centre for Mental Health at the South London and
Maudsley NHS Foundation Trust and Institute of
Psychiatry, Psychology and Neuroscience, Kings
College London.
The views expressed are those of the authors and
not necessarily those of the NHS, the NIHR or the
Department of Health.
Conflict of Interest statement
None declared.
39
10
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Antipsychotic medication in schizophrenia: a review

JohnLally, and JamesH.MacCabe
BritishMedicalBulletin,2015,1–11 doi:10.1093/bmb/ldv017

Pendahuluan
Obat-obatan antipsikotik terutama diindikasikan untuk pengobatan skizofrenia dan
gangguan psikotik lainnya termasuk gangguan schizoafektif, gangguan delusi dan gangguan
bipolar affektif (BPAD). Mereka secara tradisional telah dikategorikan sebagai antipsikotik
(FGA) generasi pertama (sebelumnya dikenal sebagai 'antipsikotik' khas 'atau' konvensional ')
atau antipsikotik generasi kedua (SGA) (sebelumnya' antipsikotik 'atipikal'). Beban efek
samping yang terkait dengan FGA, khususnya efek samping ekstrapiramidal yang
melemahkan (EPSEs), menyebabkan pengenalan obat-obatan SGA pada 1990-an. SGA
memiliki kecenderungan yang lebih rendah untuk menyebabkan EPSEs (yaitu distonia akut,
akatisia, parkinsonisme dan tardive dyskinesia) dibandingkan dengan FGA, dan properti ini,
disejajarkan dengan profil reseptor yang berbeda, menyebabkan mereka diberi label sebagai
'tidak khas'. SGA yang saat ini dilisensikan sebagai berlisensi untuk digunakan di Inggris
total dilisensikan di Eropa) dimodelkan pada profil farmakologis clozapine, karena
kecenderungannya yang rendah untuk menyebabkan EPSE dan efektivitas yang unggul dalam
skizofrenia refraktori. SGA dikaitkan dengan beban EPSE yang lebih rendah di dosis sedang
(walaupun mereka tidak bebas dari penginduksi EPSEs, dengan beberapa seperti aripiprazole
membawa risiko akathisia ∼10%), tetapi banyak yang dikaitkan dengan peningkatan risiko
kelainan kardiometabolik, termasuk kenaikan berat badan, dislipidaemia dan disregulasi
glukosa.
Mekanisme kerja antipsikotik
Antagonisme reseptor D2 di otak adalah properti farmakodinamik umum dari semua
antipsikotik; ini memunculkan hipotesis bahwa skizofrenia melibatkan disregulasi sirkuit
dopaminergi dengan aktivitas dopaminergik berlebih di jalur mesolimbik (mengarah ke gejala
positif psikosis) dan berkurangnya sinyal dopaminergik di jalur mesokortikal (mengarah ke
gejala negatif). Bukti untuk hipotesis dopamin tidak hanya berasal dari kemanjuran antagonis
reseptor D2, tetapi juga melalui efek agonis D2 seperti amfetamin dalam psikosis pemicu dan
efek obat penipis dopamin seperti reserpin dalam mengurangi gejala psikotik. Tindakan
antipsikotik secara konsisten telah terbukti terjadi ketika pekerjaan reseptor D2 striatal lebih
dari 65%, tetapi peningkatan lebih lanjut dalam tingkat D2blockadearendid kaitkan dengan
efikasi antipsikotik ditingkatkan; melainkan mengarah pada timbulnya efek samping seperti
EPSEs dan hiperprolaktinemia. Dosis ambang untuk EPSEdapat terjadi ketika 80% reseptor
D2 ditempati dan untuk hiperprolaktinemia ketika blokade D2 melebihi 72%. Meskipun
terdapat hubungan blokir striatal dopamin dengan risiko EPSE, penting untuk dicatat bahwa
ini bukan tempat tindakan kritis untuk efek terapi, yang terjadi paling menonjol di sistem otak
mesolimbik
Clozapine: sebuah kasus khusus Clozapine unik di antara obat-obatan antipsikotik dan dapat
dipandang sebagai 'antipsikotik kelas tiga' yang berdiri sendiri. Ini adalah satu-satunya obat
antipsikotik yang telah terbukti efektif dalam skizofrenia yang resistan terhadap pengobatan
(TRS). Mekanisme yang tepat dari efektivitas superior clozapine dalam TRS belum
ditetapkan, tetapi sekitar 50-60% pasien dengan skizofrenia yang refrakter terhadap

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antipsikotik lain akan menanggapi clozapine. Clozapine menghasilkan efek antipsikotik yang
kuat pada <65% ambang batas blok reseptor D2 striatal, menyatakan bahwa di luar blokade
reseptor D2 di striatum, reseptor atau mekanisme lain juga berkontribusi terhadap efek
terapeutiknya. Clozapine dan TRS dipertimbangkan secara lebih rinci dalam teks berikut.
Khasiat klinis FGA versus SGA.
Pengenalan SGA dianggap sebagai revolusi dalam pengobatan skizofrenia. Awalnya,
klaim dibuat bahwa SGA memiliki efikasi yang lebih baik untuk gejala dan kognitif positif
dan negatif serta peningkatan tolerabilitas. Namun, seiring waktu, antusiasme dan optimisme
awal ini untuk keuntungan terapeutik untuk SGA sebagai kelas telah berkurang. Uji Klinis
Antipsikotik Efektivitas Intervensi (CATIE) dan Utilitas Biaya Obat Antipsikotik Terbaru
dalam Studi Schizophrenia (CUtLASS), yang membandingkan FGA dan SGA, gagal
menunjukkan perbedaan antara FGA dan SGA dalam tingkat penghentian pengobatan,
peningkatan. dalam gejala psikotik atau kualitas hidup. CATIE lebih lanjut gagal
menunjukkan bahwa SGA lebih efektif dalam pengurangan gejala negatif atau kognitif
daripada FGA. Hasil CATIE dan CUtLASS menunjukkan kesamaan dalam respon
pengobatan, meskipun dengan SGA membawa risiko tardive dyskinesia yang lebih rendah.
Bukti lebih lanjut untuk posisi unik clozapine di antara antipsikotik disediakan, dengan itu
ditemukan lebih unggul dibandingkan SGA lain di kedua CATIE dan CUtLASS. Pada 2012,
sebuah meta-analisis multi-perawatan yang menilai kemanjuran obat antipsikotik dalam uji
coba terkontrol acak (RCT) pada pasien dengan skizofrenia menunjukkan bahwa semua obat
antipsikotik secara signifikan lebih efektif daripada plasebo. Ini menunjukkan bahwa
antipsikotik memiliki tingkat kekambuhan 28% dibandingkan dengan tingkat kekambuhan
64% untuk plasebo selama periode tindak lanjut 7-12 bulan. Ukuran efeknya sebanding
dengan yang terlihat pada banyak perawatan untuk gangguan non-kejiwaan , seperti
hipertensi, hiperkolesterolemia dan diabetes tipe 2. Ini menunjukkan bahwa obat antipsikotik
tidak kurang efektif ketika diresepkan untuk kondisi target mereka, yang digunakan oleh
spesialisasi medis lainnya.Dalam meta-analisis yang lebih baru, pemisahan obat antipsikotik
menjadi pengelompokan FGA dan SGA telah dipertanyakan lebih lanjut, dengan kemanjuran
serupa di antara kelompok-kelompok yang terlihat. Antipsikotik yang paling manjur dalam
meta-analisis ini adalah SGA yang pertama kali dikembangkan , dengan perbedaan kecil tapi
kuat terlihat dalam efikasi untuk amisulpride, olanzapine dan risperidone (dan untuk
clozapine, tetapi efek untuk clozapine berkurang oleh pengecualian studi dengan pasien rawat
jalan).
Obat antipsikotik dan efek samping
Dalam meta-analisis Leuchts, amisulpride terbukti menjadi yang terbaik dalam hal
tolerabilitas, dengan penghentian lebih sedikit karena efek samping dibandingkan dengan
plasebo. Haloperidol adalah obat terburuk untuk tingkat penghentian dibandingkan dengan
plasebo. Haloperidol diidentifikasi sebagai obat yang paling mungkin menyebabkan EPSE,
sementara pertambahan berat badan dan disfungsi metabolik yang paling menonjol
diidentifikasi dengan penggunaan olanzapine dan clozapine (dan juga untuk ditukar dengan
obat dengan steroid dan quetiapine), temuan yang telah secara konsisten direplikasi dalam
berbagai studi.

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Efek samping kardiometabolik

Tingkat yang lebih tinggi dari faktor risiko kardiovaskular yang dapat dimodifikasi
terlihat pada skizofrenia, dengan 33% pasien skizofrenia memenuhi kriteria untuk sindrom
metabolik selama perjalanan penyakit. Peningkatan risiko untuk faktor risiko kardiometabolik
bersifat multifaktorial dengan faktor genetik dan efek jangka panjang kumulatif dari perilaku
kesehatan yang buruk dan paparan jangka panjang terhadap obat antipsikotik yang
dipostulasikan sebagai penyebabnya. SGA dikaitkan dengan tingkat disfungsi metabolik yang
lebih tinggi dibandingkan dengan FGA (meskipun FGA seperti chlorpromazine dikaitkan
dengan peningkatan risiko kardiometabolik dan tetap bahwa risiko kardiometabolik yang
terkait dengan FGA belum diteliti secara ekstensif seperti SGA). Clozapine dan olanzapine
keduanya memiliki afinitas terbesar untuk reseptor 5-HT2C dan Histamine (H) 1 dan potensi
pertambahan berat badan terbesar, yang dapat terjadi pada awal perjalanan pengobatan,
sebelum meningkat seiring perawatan berlanjut. Kenaikan berat badan yang paling dramatis
terlihat pada pasien yang naif antipsikotik selama 6 minggu pertama pengobatan dan
mayoritas, mereka yang mengalami kenaikan berat badan awal tidak kehilangan berat badan
setelahnya, bahkan setelah beralih ke antipsikotik yang lebih berat-netral. SGA seperti
aripiprazole, lurasidone dan asenapine memiliki profil efek samping metabolik yang lebih
netral.
Pemantauan kesehatan fisik
Dianjurkan agar semua pasien yang diobati dengan antipsikotik dipantau secara
teratur untuk faktor risiko kardiometabolik. Meskipun demikian, dan faktor risiko
kardiometabolik kumulatif, pemantauan parameter kesehatan fisik pada mereka yang diobati
dengan schizophreniacontinu menjadi buruk. Untuk seseorang yang memulai antipsikotik
untuk pertama kalinya (dan untuk setiap perubahan antipsikotik di masa depan), yang berikut
ini direkomendasikan untuk dipantau: berat badan, pada awal, kemudian setiap minggu
selama 6 minggu pertama, kemudian pada 12 minggu, pada 1 tahun, dan kemudian setiap
tahun (diplot pada grafik) (lebih sering pada awal pengobatan karena pertambahan berat
badan yang cepat dapat memprediksi kenaikan berat badan yang parah dalam jangka
panjang); lingkar pinggang pada awal dan kemudian setiap tahun (diplot pada achart) (ukuran
pinggang atau BMI telah disarankan sebagai tes skrining sederhana untuk sindrom metabolik
pada skizofrenia); dan tekanan darah, glukosa darah puasa, HbA1c, dan kadar lipid dan
prolaktin serum darah pada awal, pada 12 minggu, pada 1 tahun, dan kemudian minimal
setiap tahun. Selanjutnya, intervensi farmakologis dan non-farmakologis untuk penurunan
berat badan dan disfungsi kardiometabolik harus dimulai jika diperlukan.
Pilihan antipsikotik
Saat ini, tidak ada biomarker spesifik atau tes farmakogenetik untuk memandu pilihan
pengobatan. Menurut lembaga nasional untuk pedoman kesehatan dan perawatan prima,
seseorang yang mengalami skizofrenia episode pertama atau episode psikosis (FEP) pertama
harus ditawarkan pengobatan dengan antipsikotik. Permulaan respon terhadap pengobatan
sangat bervariasi, tetapi meta-analisis telah menunjukkan itubagian terbesar dari efek obat
antipsikotik terjadi dalam minggu pertama (tidak termasuk penggunaan clozapine), dan
setelah itu perbaikannya lebih marjinal. Jika seorang pasien tidak memiliki respons terhadap

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pengobatan antipsikotik pada 4-6 minggu, maka rekomendasinya adalah beralih ke

pengobatan anantipsikotik dengan profil pengikatan reseptor yang berbeda. Penting untuk
memastikan bahwa pasien patuh terhadap pengobatan dan bahwa itu bukan kasus
ketidaktoleranan pengobatan yang mengarah pada tanggapan yang buruk. Obat antipsikotik
harus dititrasi ke dosis terapeutik (mis. Olanzapine 5-10 mg setiap hari atau risperidon 2-4
mg setiap hari dalam episode skizofrenia pertama) untuk menilai respons pengobatan. Hanya
sebagian kecil dari pasien dengan FEP (∼15-20%) yang tidak akan memiliki episode psikosis
lebih lanjut, tetapi pada tahap penyakit ini, tidak mungkin untuk memprediksi siapa yang
tidak akan kambuh setelah perawatan perawatan dihentikan.

Berapa lama untuk melanjutkan?

Perawatan pemeliharaan direkomendasikan untuk semua, dengan pasien episode
pertama dirawat setidaknya selama 1 tahun, sedangkan mereka dengan multi-episode harus
menjalani perawatan setidaknya selama 5 tahun. Lebih lanjut, keparahan episode akut, yaitu
tingkat simptomatologi yang dialami seseorang dan risiko kekerasan dan bunuh diri, yang
mungkin terkait dengan episode akut, akan meningkatkan kemungkinan pengobatan
perawatan jangka panjang direkomendasikan. Penghentian pengobatan antipsikotik telah
terbukti berhubungan dengan peningkatan risiko kekambuhan lima kali lipat selama 5 tahun
masa tindak lanjut dibandingkan dengan terapi pemeliharaan. Ini adalah praktik standar untuk
melanjutkan pengobatan yang efektif pada fase akut asalkan ditoleransi dengan baik.
Berganti antipsikotik
Ada berbagai metode untuk mengganti obat antipsikotik, jika diperlukan untuk
ketidakefektifan klinis atau intolerabilitas. Ini mungkin melibatkan crossover di mana satu
obat secara bertahap dikurangi sementara obat kedua secara bersamaan dititrasi ke dosis
penuh. Pendekatan lain adalah menghentikan secara tiba-tiba obat pertama dengan pemberian
obat baru pada dosis terapeutik (paling tepat digunakan dalam kasus-kasus psikosis akut
dalam pengaturan rawat inap), atau obat asli secara perlahan dihentikan dan hanya ketika itu
dihentikan akan obat berikutnya dimulai (paling baik digunakan bagi mereka dengan risiko
kambuh yang rendah) .Dengan beralihnya pengobatan antipsikotik, individu berisiko tinggi
mengalami penurunan dan kambuhan atau eksaserbasi psikotik, mengharuskan pemantauan
ketat kondisi mental individu selama ini. proses switching.
Skizofrenia yang resistan terhadap pengobatan (TRS) dan clozapine.
Sekitar 30% pasien dengan skizofrenia tidak akan menanggapi penggunaan FGA atau
SGA. Kegagalan untuk menanggapi dua antipsikotik yang berbeda, pada dosis terapeutik dan
untuk durasi yang cukup (umumnya dianggap 6-8 minggu terapi antipsikotik) berarti
seseorang memenuhi kriteria untuk resistensi pengobatan. Satu-satunya obat dengan
efektivitas terbukti dalam sub kelompok pasien ini dengan TRS adalah clozapine. Di Inggris,
sekitar 50-60% pasien akan merespons clozapine, dengan tingkat respons 30% dicapai pada 6
minggu pengobatan clozapine dan tingkat respons yang lebih tinggi dicapai selama periode
perawatan yang lebih lama dengan hingga 60-70% merespons pada 1 tahun . Respon klinis
berkelanjutan yang berkepanjangan ini selama tahun pertama pengobatan adalah unik untuk
clozapine di antara obat-obatan antipsikotik. Telah ditunjukkan bahwa clozapine tidak
memiliki kemanjuran yang lebih baik dibandingkan dengan antipsikotik lain dalam

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pengobatan psikosis episode pertama, memperkuat hipotesis bahwa TRS merupakan populasi
pasien skizofrenia subkelompok, dengan proses-proses yang berbeda secara psikologis.
Namun, penggunaan clozapine sangat bervariasi tergantung pada geografi, dengan
prevalensi penggunaan clozapine lebih rendah di sebagian besar negara dibandingkan ∼30%
pasien yang cenderung mendapat manfaat dari clozapine, dan ada bukti substansial bahwa itu
hanya digunakan setelah penundaan beberapa kali. tahun. Ini sebagian disebabkan oleh sifat
dan tingkat efek samping yang dapat ditimbulkannya, termasuk agranulositosis, yang
mempengaruhi sekitar 0,8% pasien yang diresepkan clozapine dan dikaitkan dengan
mortalitas 1 banding 10.000 dari yang diobati dengan clozapine.pasien di Inggris. Di Inggris,
clozapine hanya diresepkan bersamaan dengan pengukuran mingguan jumlah sel putih untuk
18 minggu pertama pengobatan, diikuti oleh pengukuran jumlah sel putih setiap dua minggu
selama 34 minggu ke depan dan kemudian diikuti oleh jumlah sel putih bulanan selama lama.
sementara pasien dirawat dengan clozapine. Sangat mungkin bahwa ketakutan akan reaksi
obat yang merugikan (oleh dokter dan pasien sama) dan ketidaknyamanan pemantauan terapi
jumlah darah lengkap (FBC) begitu awal dalam penggunaan clozapine adalah faktor yang
berkontribusi terhadap keterlambatan ini. Clozapine relatif bebas dari EPSEs, meskipun itu
membawa beban berat dari reaksi merugikan lainnya. Selain efek samping hematologis, juga
dapat menyebabkan sedasi, penambahan berat badan, konstipasi, hipersalivasi, dan jarang
miokarditis dan kardiomiopati. Namun, meskipun tingkat efek samping yang tinggi terkait
dengan clozapine, ada bukti bahwa itu terkait dengan penurunan angka kematian
dibandingkan dengan antipsikotik lainnya, dengan penurunan angka kematian ini tidak
sepenuhnya dijelaskan oleh pengurangan risiko bunuh diri.
Ketidakpatuhan obat
Ketidakpatuhan terhadap pengobatan lebih umum pada setiap penyakit kronis,
meskipun tingkat ketidakpatuhan lebih tinggi pada skizofrenia daripada penyakit kronis
lainnya. Ketidakpatuhan pada pengobatan antipsikotik tinggi, dengan hingga 75% pasien
pada 2 tahun pasca keluar rumah sakit. tidak patuh dengan obat antipsikotik. Hal ini dapat
terjadi karena efek samping yang tidak dapat ditoleransi, kurangnya wawasan, bertahannya
gejala psikotik residual dan aliansi terapeutik yang buruk. Penghentian antipsikotik dikaitkan
dengan prognosis yang lebih buruk, dengan meningkatnya angka kekambuhan, rawat inap
dan bunuh diri. Kepatuhan parsial dengan antipsikotik juga dikaitkan dengan peningkatan
risiko kekambuhan dan rawat inap, jika dibandingkan dengan kepatuhan minum obat
lengkap. Strategi untuk mendukung kepatuhan individu dengan obat-obatan penting untuk
memastikan bahwa kesenjangan obat terbatas untuk meningkatkan prognosis jangka panjang.
Intervensi ini dapat menjadi sangat penting pada tahap awal penyakit, di mana pengobatan
parsial atau tidak patuhdapat memiliki efek yang menghancurkan pada perjalanan penyakit
jangka panjang. Intervensi mencakup pendidikan psikoedukasi, teknik wawancara motivasi,
integrasi pentingnya penggunaan antipsikotik ke dalam model pencegahan dan pemulihan
kambuh, dan intervensi berbasis farmasi yang terdiri dari pengemasan yang mudah
digunakan, pengingat isi ulang dan pendidikan edukasi.
Obat injeksi jangka panjang dan terapi kombinasi / dosis tinggi
Penggunaan suntikan long-acting antipsikotik (LAI) (juga dikenal sebagai depot)
direkomendasikan ketika pasien menyatakan preferensi untuk perawatan ini atau ketika ada
bukti ketidakpatuhan dengan obat oral. Penggunaan LAI memastikan bahwa dokter tahu

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kapan pasien telah minum obat atau kapan mereka menghentikannya. Masih harus dipastikan
bahwa LAI lebih efektif daripada obat antipsikotik oral, meskipun meta-analisis baru-baru ini
menunjukkan bahwa LAI telah mengurangi tingkat kekambuhan dibandingkan dengan
antipsikotik oral, dengan desain studi khusus cenderung lebih konsisten mendukung
efektivitas LAI. Sebuah studi naturalistik Finlandia menunjukkan bahwa penggunaan LAI
menyebabkan penurunan tiga kali lipat dalam tingkat rawat inap dibandingkan dengan
formulasi oral antipsikotik yang sama. Namun, RCT besar baru-baru ini tidak menunjukkan
keunggulan risperidone LAI dibandingkan obat oral. Pipotiazine palmitate (Piportil®) dapat
dikaitkan dengan EPSE yang lebih jarang tetapi dijadwalkan untuk ditarik dari pasar Inggris
dan dihentikan pada bulan Maret 2015 (karena kekurangan global dari bahan aktif senyawa).
Ada empat formulasi LAI dari SGA, yaitu risperidone, paliperidone, olanzapine embonate
dan aripiprazole; dan empat obat depot FGA, yaitu haloperidol decanoate, flententixol
decanoate, zuclopenthixoldecanoate dan flhenazinedecanoate.
Polifarmasi antipsikotik Kombinasi pengobatan antipsikotik (mis. Dua atau lebih
antipsikotik yang berbeda), yang juga dikenal sebagai polifarmasi antipsikotik, adalah obat
yang sering digunakanpraktek. Prevalensi polifarmasi antipsikotik yang dilaporkan berkisar
antara 7 hingga 50% .29 Sering kali tidak ada alasan farmakologis yang jelas untuk
menggabungkan antipsikotik yang memberikan blokade reseptor antipsikotik dopamin D2
yang sama dan sedikit informasi untuk mengetahui mekanisme aksi beberapa antipsikotik di
otak. Lebih lanjut, menggabungkan pemindaian antipsikotik mengarah pada dosis
keseluruhan yang tinggi dan peningkatan beban efek samping, bersama dengan peningkatan
risiko interaksi obat-obat, serta variabilitas dalam kadar serum dan peningkatan kesulitan
untuk pasien yang tetap patuh pada rejimen pengobatan. tidak ada bukti yang jelas untuk
mendukung kombinasi antipsikotik, dan yang terbaik adalah mencadangkan penggunaan
pengobatan kombinasi untuk mereka yang memiliki kurangnya tanggapan terhadap
monoterapi antipsikotik dan yang mungkin tidak toleran terhadap clozapine, sehingga
membatasi akses mereka ke obat ini. Jika dokter memutuskan untuk menggunakan kombinasi
antipsikotik, mereka harus dipandu oleh profil farmakodinamik dari antipsikotik kombinasi,
dengan tujuan menggunakan antipsikotik dengan profil pengikatan reseptor yang berbeda.
Poli antipsikotik
Pengobatan kombinasi antipsikotik (mis. Dua atau lebih antipsikotik yang berbeda),
yang juga dikenal sebagai polifarmasi antipsikotik, adalah praktik yang sering digunakan.
Prevalensi polifarmasi antipsikotik yang dilaporkan berkisar antara 7 hingga 50%. Seringkali
tidak ada alasan farmakologis yang jelas untuk menggabungkan antipsikotik yang
memberikan blokade reseptor dopamin D2 antipsikotik yang diduga sama dan sedikit
informasi untuk mengetahui apa mekanisme kerja beberapa antipsikotik di otak. Lebih lanjut,
menggabungkan pemindaian antipsikotik mengarah pada dosis keseluruhan yang tinggi dan
peningkatan beban efek samping, bersama dengan peningkatan risiko interaksi obat-obat,
serta variabilitas dalam kadar serum dan peningkatan kesulitan untuk pasien yang tetap patuh
pada rejimen pengobatan. tidak ada bukti yang jelas untuk mendukung kombinasi
antipsikotik, dan yang terbaik adalah mencadangkan penggunaan pengobatan kombinasi
untuk mereka yang memiliki kurangnya tanggapan terhadap monoterapi antipsikotik dan
yang mungkin tidak toleran terhadap clozapine, sehingga membatasi akses mereka ke obat
ini. Jika dokter memutuskan untuk menggunakan antipsikotik kombinasi, mereka harus

47
Evi Rizki Saraswati (201610330311015)

dipandu oleh profil farmakodinamik dari antipsikotik kombinasi, dengan tujuan

menggunakan antipsikotik dengan profil pengikatan reseptor yang berbeda.
Penggunaan antipsikotik dosis tinggi
Sebagian besar efek samping yang terkait dengan perawatan antipsikotik terkait
dengan dosis, dan penggunaan antipsikotik dosis tinggi [mis. di atas British National
Formulary (BNF) dosis maksimum maksimum] dikaitkan dengan tingkat efek samping yang
lebih tinggi (seperti sedasi, konstipasi, hipotensi postural, EPSEs, perpanjangan QTc, dan
kematian jantung mendadak). Penggunaan pengobatan antipsikotik dosis tinggi hanya boleh
digunakan dalam keadaan luar biasa, dan perawatan harus diambil jika kombinasi
antipsikotik digunakan, untuk memastikan bahwa kesetaraan dosis kombinasi tidak> 100%
dari dosis maksimum yang dilisensikan oleh BNF. Terapi antipsikotik dosis tinggi
didefinisikan oleh Royal College of Psychiatrists (RCPsych) sebagai total dosis harian dari
antipsikotik tunggal yang melebihi batas atas yang dinyatakan dalam BNF, atau dosis harian
rata-rata dua atau lebih antipsikotik yang melebihi BNF maksimal dihitung berdasarkan
persentase menggunakan penghitung dosis siap antipsikotik [contoh perhitungan: flavenazin
depot 100 mg per bulan (50%) dan olanzapine 15 mg setiap hari (75%) = 50% + 75% =125%
(> 100% karena itu 'dosis tinggi')] .30 Untuk semua yang diobati dengan antipsikotik dosis
tinggi, penting untuk secara teratur memantau kelainan metabolik dan untuk bukti perubahan
EKG, terutama perpanjangan QTc.
Indikasi klinis untuk antipsikotik
Obat-obatan antipsikotik efektif untuk berbagai gangguan selain skizofrenia. Selain
efek antipsikotiknya, antipsikotik juga dapat menstabilkan suasana hati, antimanik,
antidepresan, dan efek ansiolitik.
Bipolaraffectivedisorder (BPAD)
Beberapa pedoman internasional merekomendasikan penggunaan obat antipsikotik
dalam pengobatan semua tahap BPAD. Untuk mania akut, antipsikotik (terutama olanzapine,
risperidone, dan quetiapine) bersama dengan penstabil suasana hati secara konsisten
diidentifikasi sebagai pengobatan primer. pilihan. Sebuah meta-analisis baru-baru ini
mengidentifikasi bahwa antipsikotik lebih efektif daripada penstabil suasana hati dalam
pengobatan mania akut. Olanzapine dan quetiapine direkomendasikan sebagai pengobatan
lini pertama untuk depresi bipolar. Quetiapine dan olanzapine dikaitkan dengan onset aksi
yang cepat pada depresi bipolar, dengan kemanjuran yang ditunjukkan sejak minggu pertama
perawatan dan seterusnya. Dalam praktik klinis, quetiapine sekarang dianggap lebih untuk
sifat penstabil mood daripada efek antipsikotiknya. Demikian pula, antipsikotik yang
diindikasikan untuk mania akut umumnya direkomendasikan untuk terapi pemeliharaan di
BPAD. Clozapine memiliki bukti efektifitas dalam mania refrakter dan harus
dipertimbangkan.
Unipolar depression
Penggunaan antipsikotik sebagai pilihan perawatan augmentasi dalam unipolardepresi
dan kecemasan adalah gangguan penggunaan di luar label, yang berarti bahwa penggunaan
ini tidak dilisensikan secara resmi (tetapi dengan basis bukti yang berkembang untuk
menunjukkan kemanjuran antipsikotik tertentu). Untuk depresi unipolar yang resisten

48
Evi Rizki Saraswati (201610330311015)

terhadap pengobatan, antipsikotik digunakan sebagai strategi augmentasi tanpa label.

Adadibuktikan dengan mendukung penggunaanproketiapine, aripiprazole, olanzapine dan
risperidone sebagai antidepresan augmentationstrategiesdiTRD, dengan bukti yang ada untuk
penggunaan quetiapine dan aripiprazole. Quetiapine (150-300mg setiap hari) dilisensikan di
Inggris. dari apa yang akan digunakan dalam skizofrenia atau BPAD (misalnya olanzapine 5-
12,5mg / hari, quetiapine 150-300mg / hari). Pada depresi psikotik, kombinasi antipsikotik
dan antidepresan lebih efektif daripada penggunaan antidepresan saja, dengan olanzapine
yang dikombinasikan dengan fluoxetine mungkin dikombinasi dengan kombinasi yang kuat.
Anxiety disorders Obat antipsikotik telah lama digunakan sebagai strategi augmentasi untuk
gangguan kecemasan, dengan bukti terbaik untuk penggunaannya sebagai strategi augmentasi
inhibitor serotonin reuptake selektif dalam gangguan kompulsif obsesif (OCD) dan untuk
penggunaan quetiapine in generalized anxiety disorder (GAD). Pembaruan antipsikotik Di
Inggris, beberapa SGA sekarang tidak memiliki hak paten, termasuk risperidon, olanzapine,
amisulpride dan quetiapine (formulasi pelepasan instan). Namun, mengingat respons pasien
yang heterogen terhadap dan tolerabilitas antipsikotik, masih ada kebutuhan untuk
meningkatkan efikasi terapeutik dari agen yang tersedia dan untuk membantu pilihan dalam
meningkatkan pengobatan yang tidak dapat ditoleransi untuk pasien. SGA bermerek yang
lebih baru, asenapine dan lurasidone, memiliki dampak yang lebih kecil pada berat badan dan
parameter metabolik daripada agen yang lebih besar seperti sasolanzapine.
Paliperidone
Paliperidone adalah metabolit aktif risperidone dan tersedia dalam formulasi oral dan
LAI, keduanya menunjukkan kemanjuran dan tolerabilitas dan keterlambatan waktu untuk
kambuh dalam skizofrenia. Ini tidak dimetabolisme hati, membuatnya aman untuk digunakan
dalam gangguan hati dan dengan risiko terbatas interaksi obat farmakokinetik. pengobatan
gejala psikotik dan manik dari gangguan schizoafektif. Profil efek sampingnya mirip dengan
risperidon senyawa induk, dengan peningkatan berat badan, hiperprolaktinemia, dan EPSE
pada dosis yang lebih tinggi, bersama dengan laporan kasus tardive dyskinesia.38 Pada dosis
palatidon oral 9-12 mg (setara dengan risperidon 4) –6 mg setiap hari), risiko EPSEs
meningkat. Doserangeis terapeutik 6-9 mg setiap hari (setara dengan peridone 3- 3 mg setiap
hari). Paliperidone palmitate adalah formulasi LAI, yang mencapai kadar serum aktif dalam
beberapa hari inisiasi dan memungkinkan deltoid, daripada pemberian otot gluteal.
Asenapine
Asenapine telah menunjukkan kemanjuran dalam fase akut dan fase perawatan
perawatan skizofrenia dan dalam pengobatan mania akut di BPAD, tetapi saat ini hanya
diizinkan untuk perawatan mania di Inggris. Asenapine memiliki afinitas tinggi untuk
beberapa reseptor serotonin, dengan antagonisme pada 5-HT2A, 5-HT2C dan 5-HT7 dan 5-
HT1A agonisme, bersama dengan antagonisme D2 dan D3 yang kuat dan beberapa
antagonisme histamin (H). Asenapine tunduk pada metabolisme lintas pertama dan dengan
demikian tidak aktif jika tertelan. Oleh karena itu, ini hanya tersedia sebagai tablet
disintegrasi oral, yang berarti diserap melalui mukosa mulut. Ini kontras dengan tablet
olanzapine, risperidone, dan aripiprazole antipsikotik orodispersible lainnya, yang semuanya
harus ditelan agar efektif. Ini berarti bahwa pasien harus diberitahu bahwa enapine tidak
dapat ditelan dan makanan atau minuman harus dihindari setidaknya 10 menit setelah
pemberian. Asenapine tidak memerlukan titrasi dosis dan dapat diberikan dosis 5 mg untuk

49
Evi Rizki Saraswati (201610330311015)

skizofrenia akut dengan dosis hingga 10mg dua kali sehari menunjukkan kemanjuran dalam
mencegah kekambuhan skizofrenia. Asenapine memiliki paruh 24 jam dan dengan demikian
secara teoritis dapat diresepkan sebagai obat sekali sehari, tetapi kemanjuran resep sekali
sehari tetap harus dipelajari dalam uji coba. Tampaknya menjadi antipsikotik metabolik netral
dengan kecenderungan rendah untuk menyebabkan penambahan berat badan (meskipun
beberapa bukti untuk kecenderungan yang lebih tinggi untuk kenaikan berat badan pada
mania akut).ada) dan memiliki sedikit efek pada kadar prolaktin. Ini dapat menyebabkan
akathisia (peningkatan kejadian pada dosis 10mg dua kali sehari dibandingkan dengan 5mg
dua kali sehari), sedasi dan gangguan rasa.
Lurasidone
Lurasidone dilisensikan untuk pengobatan skizofrenia35 dan telah menunjukkan
kemanjuran sebagai pengobatan tambahan untuk depresi bipolar, dan itu adalah terapi
berlisensi untuk depresi bipolar di AS. Lurasidone memiliki antagonisme D2 penuh dan
merupakan antagonis pada reseptor 5HT2A dan 5HT7, dengan agonisme parsial pada
reseptor 5-HT1A, dan dengan afinitas rendah untuk reseptor 5HT2C, H1 dan muscarinic.40
Lurasidoneisa pada saat dailyprescription, menyederhanakan administrasi. Dosis ini diberikan
pada orang dewasa dengan 37mg sekali sehari pada awalnya dan meningkat jika perlu hingga
maksimum148 mg setiap hari. Forschizophrenia, dengan perbandingan 37–148mg, setiap hari
direkomendasikan, dengan rentang dosis yang lebih rendah18.5-120mg setiap hari,
disarankan untuk depresi bipolar (lurasidone pada dosis rendah telah ditunjukkan hingga 20-
60 mg setiap hari). berkhasiat secara klinis pada depresi bipolar, seperti pada kisaran dosis
yang lebih tinggi yaitu 80-100 mg / hari). Lurasidone dimetabolisme oleh enzim CYP3A4,
yang berarti bahwa dosisnya harus dikurangi ketika digunakan bersamaan dengan
penghambat CYP3A4 (mis. Diltiazem, erythromycin). Lurasidone umumnya ditoleransi
secara umum, dengan risiko penambahan berat badan dan disfungsi metabolisme. Hal ini
terkait dengan akathisia (peningkatan insidensi pada dosis 120mg atau lebih besar), sedasi
dan mual, tetapi serupa dengan asenapine, meskipun telah menjadi antagonis D2 penuh, itu
tidak terkait dengan insiden EPSE yang lebih tinggi (tidak termasuk ataksia) dan
hiperprolaktinemia.
Kesimpulan: Mempertahankan status quoin antipsikotik pasien tetap menjadi kasus bahwa
tidak ada inovasi mendasar dalam psikofarmakologi untuk skizofrenia sejak ditemukannya
clozapine pada akhir 1950-an. Ini semakin diperburuk oleh mundurnya industri farmasi baru-
baru penelitian dan pengembangan dalam gangguan kejiwaan. Untuk semua manfaat yang
dibeli oleh antipsikotik dan keuntungan yang dirasakan semula dari SGA, kami masih
bekerja dengan obat-obatan yang tidak sepenuhnya efektif.
SGAs or FGA?
Meskipun kurangnya perbedaan yang jelas dalam efikasi klinis antara SGA dan FGA
(dengan konsepsi clozapine), pengenalan SGA dari awal 1990-an dan seterusnya merupakan
langkah yang berarti dalam upaya meningkatkan farmakoterapi untuk pasien dengan
skizofrenia. Sementara kami meningkatkan pengetahuan kami tentang apa yang bisa dan
tidak bisa dilakukan oleh perawatan yang berbeda, 10 kami masih jauh dari kemampuan
untuk merekomendasikan dengan presisi, perawatan khusus untuk masing-masing pasien,
dalam hal respon klinis dan kurangnya efek samping. Juga tidak ada bukti longitudinal untuk
mendukung upaya mengidentifikasi pasien yang akan dan yang tidak akan memerlukan obat

50
Evi Rizki Saraswati (201610330311015)

antipsikotik jangka panjang dengan FGA atau SGA.Perubahan perkembangan aplikasi

psikomedikasi Ada konsensus yang berkembang dalam psikiatri akademis, mengakui bahwa
skizofrenia bukanlah entitas penyakit tunggal dan bahwa gejala positif psikosis (delusi,
halusinasi) yang antipikotik bekerja dengan cara terbaik, adalah satu-satunya pengetahuan
dari patologi yang tertindas. Kita perlu memfokuskan pengembangan obat di masa depan
pada domain gejala skizofrenia, dengan kebutuhan khusus untuk perawatan untuk
menargetkan gejala negatif dan gangguan kognitif dalam skizofrenia.
Fokus yang lebih terkonsentrasi pada domain gejala yang berbeda dapat menyebabkan
penanda endophenotypic diidentifikasi untuk gejala negatif dan defisit kognitif (serta untuk
gejala positif) yang dapat mempromosikan penemuan obat baru. Jika obat ditemukan untuk
domain simtom gejala skizofrenia yang terpisah, maka kita dapat berharap untuk dapat
mengembangkan strategi pengobatan saat ini, dengan antipsikotik yang digunakan dalam
kombinasi dengan obat untuk gejala negatif atau bersama dengan yang memiliki efek
peningkatan kognitif. Strategi Terapi Baru Tingkat pengetahuan kita saat ini mengenai
patogenesis skizofrenia terus meningkat, yang mengarah pada harapan bahwa dalam terapi
baru di masa depan yang secara rasional akan menargetkan target seluler dan molekuler, dan
lebih baik daripada reseptor D2, dapat dikembangkan. Semua obat antipsikotik yang telah
dikembangkan selama enam dekade terakhir telah didasarkan pada penargetan reseptor D2,
dan kemudian karakteristik5-HT2Aantagonism dari SGA. Pengembangan yang
dikembangkan akan menargetkan proses tambahan, termasuk target reseptor glutamatergic,
kolinergik dan kanabinoid, dan bidang farmakogenik yang muncul akan bertujuan untuk
perawatan yang akan disesuaikan dengan masing-masing pasienintefisiensi dan
tolerabilitas.Kesimpulan Heterogenitas dalam hal tanggapan individu terhadap pengobatan
antipsikotik dan ketidakmampuan saat ini untuk memprediksi tanggapan mengarah ke strategi
coba-coba dengan pengobatan. Tetap menjadi kasus bahwa kita tidak lebih dekat untuk
mencerminkan efek clozapine pada TRS, dengan mekanisme kerjanya terbukti sulit untuk
diidentifikasi dan ditiru dalam terapi antipsikotik lainnya untuk schizophrenia.

51
See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/321079742

Antidepressants: Mechanism of Action, Toxicity and Possible Amelioration

Article · September 2017

DOI: 10.15406/jabb.2017.03.00082

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 Journal of Applied Biotechnology & Bioengineering
Research Article
Antidepressants: mechanism of action, toxicity and
possible amelioration
Abstract
Depression being a state of sadness may be defined as a psychoneurotic disorder
characterised by mental and functional activity, sadness, reduction in activity,
difficulty in thinking, loss of concentration, perturbations in appetite, sleeping,
and feelings of dejection, hopelessness and generation of suicidal tendencies. It
is a common and recurrent disorder causing significant morbidity and mortality
worldwide. The antidepressant compounds used against depression are reported to
be used also for treating pain, anxiety syndromes etc. They have been grouped in five
different categories such as
i. Tricyclic antidepressants (TCAs)
ii. Selective serotonin-reuptake inhibitors (SSRIs)
iii. Monoamine oxidase inhibitors (MAOIs)
iv. Serotonin-norepinephrine reuptake inhibitor (SNRI) and
v. Non-TCA antidepressants based on their mode of action.
Most of the antidepressants have been reported to possess adverse effects on the health
of users. The present review article focuses on an updated current of antidepressants,
their mechanism of actions, pathophysiology of these compounds, their side effects
and the strategies to combat the drug induced toxicity. An account of phytochemicals
found to be acting as antidepressant is also included.
Keywords: depression, antidepressants, toxicity, neurotransmitters, biomarkers
Abbreviations: TCAs, tricyclic antidepressants; SSRIs, selec-
tive serotonin-reuptake inhibitors; MAOIs, monoamine oxidase inhi-
bitors; SNRI, serotonin-norepinephrine reuptake inhibitor; PMDD,
premenstrual dysphoric disorder; SAD, seasonal affective disorder;
PMS, premenstrual syndrome; NE, norepinephrine; 5-HT, 5-hydroxy-
tryptamine; DA, dopamine; CNS, central nervous system; NRI, nora-
drenalin speciic reuptake inhibitor
Introduction
Depression may be deined in terms of a state of feeling sad. It
may also be deined as a psychoneurotic disorder characterised
by mental and functional activity, sadness, reduction in activity,
dificulty in thinking, loss of concentration, perturbations in appetite,
sleeping, and feelings of dejection, hopelessness and generation of
suicidal tendencies.1 It is a common and recurrent disorder causing
signiicant morbidity and mortality worldwide.2,3 Depression, a
kind of mental illness, includes arousal of grief which may affect
the overall thinking process, behaviour and feelings.1 Such persons
suffer froman imbalanced sleep and sleeping disorders.4–6 Several
workers7,8 have described the causes of depression which include
genetic, heterogeneous parental behaviour to the siblings, neglect
and sexual abuse. In addition, certain conditions like dificulties in
job, relationships, natural disasters, inances, child birth, catastrophic
injury, loss of life of loved ones and menopause.9,10 It is known that
different brain regions may mediate the onset of variety of symptoms of
depression as they regulate emotions, neural circuitry and mood. There
is meagre information available about the underlying mechanisms of
Submit Manuscript | http://medcraveonline.com J Appl Biotechnol Bioeng. 2017;3(5):437‒448.
© 2017 Khushboo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and build upon your work non-commercially.
Open Access
Volume 3 Issue 5 - 2017
Khushboo, Sharma B
Department of Biochemistry, University of Allahabad, India
Correspondence: B Sharma, Department of Biochemistry,
University of Allahabad, Allahabad 211002, UP, India,
Email sharmabi@yahoo.com
Received: June 29, 2017 | Published: September 01, 2017
their regulations. The malfunctioning of the hypothalamus region of
the brain has been found to be associated with very less or too much
sleep, disinterest in sex and other activities of enjoyment. Depression
in general has three main forms such as
i. Psychotic depression characterised by severe depression,
ii. Postpartum depression characterised by perturbations in the levels
of hormones and physical features after child birth and
iii. Seasonal Affective Disorder (SAD) concerning specially the win-
ter months with less sunlight.11
In the women, the depression arises also due to extra work load,
domestic responsibilities, child care, strained relationship, care of aged
parents and poverty. In addition to all these indices, the psychological,
biological and hormonal factors also signiicantly contribute in
depression. The premenstrual dysphoric disorder (PMDD) or
premenstrual syndrome (PMS) and osteoporosis in women can play
important role in development of depression. Depression in men may
be associated with sufferings from serious diseases such as cancer
and cardiac diseases, extreme tiredness, irritation, disinterest in once-
pleasurable activities, loss of balance, less sleep and getting aggressive.
In older men, arteriosclerotic depression (vascular depression) has
been observed. The depression which may lead to suicide in the
children may be associated to the emerging sexuality and onset of
puberty. The present article is an endeavour to illustrate an updated
account and varied aspects of depression such as its pathophysiology,
symptoms, diagnosis, treatment with drugs and their mode of actions,
toxicity and use of plant products as potential antidepressants.
437
53
 Copyright:
Antidepressants: mechanism of action, toxicity and possible amelioration ©2017 Khushboo et al. 438

Pathophysiology of depression
There are no useful biomarkers or imaging abnormalities to
determine pathophysiology of depression during life time. The post-
mortem study of brain does not reveal any consistent structural or
neurochemical abnormality. Majority of the currently available
medications were discovered empirically. Most current theories are
based on “amine hypothesis.12” The most important hypothesis of
mood disorder is related to the alterations in the levels of biogenic
amines.13–15 It states that depression is caused by a functional deiciency
of catecholamines, particularly norepinephrine (NE), whereas mania
is caused by a functional excess of catecholamines at the critical
synapses in the brain. The occurrence of depression has been found
to be associated with the alterations in the levels of biogenic amines
in the brain such as NE, dopamine (DA) and epinephrine, indolamine,
serotonin, 5-hydroxytryptamine (5-HT) and two catecholamines.
Antidepressants
reuptake inhibitor (SSRI), which affects the brain serotonin level.
Antidepressants may recover the signs of depression, but also exert
some side-effects. They are used in the medication of a number of
symptoms, including not only depression, some anxiety disorder,
nervousness, OCD, manic-depressive disorders, bedwetting in
childhood, major depressive disorder, diabetic peripheral neuropathic
pain, social fretfulness, post-traumatic stress disorder etc. and some
conclude, but not perfect in ibromyalgia, chronic hives (allergic
reaction), lashes, drug induced hyperhidrosis (sweating in excess),
premenstrual symptoms, pruritus (itching), nervosa, tourette, binge
eating disorder etc. The medicines achieve their desired function
by adversely inluencing the concentrations of neurotransmitters
in the brain such as NE, serotonin and dopamine and the central
nervous system (CNS). Based on the mode of actions, a group of
antidepressants contain 17 substances which can be further divided
into subgroups. The commonly used medicines against depression are
summarised in Table 1.

Antidepressants are those drugs which help in the reduction in Antidepressants and their classiication
symptoms of depressive disorders by altering chemical imbalances Imipramine was discovered in 1958 as an antidepressant regimen.17
of neurotransmitters in the brain. The change in mood and The antidepressants have been divided into ive groups:
behaviour is due to chemical imbalance. Neurotransmitters are the
communication link between neurons in the brain. Neurotransmitters i. Tricyclic antidepressants (TCAs),
are located in vesicles found in nerve cells. The neurotransmitters
ii. Selective serotonin-reuptake inhibitors (SSRIs),
such as serotonin, dopamine and noradrenaline or norepinephrine are
released by the exonic end of one nerve and received by the other; iii. Monoamine oxidase inhibitors (MAOIs),
the phenomenon called as reuptake. The antidepressants inhibit
reuptake of neurotransmitters through selective receptors thereby iv. Serotonin-norepinephrine reuptake inhibitor (SNRI) and
increasing the concentration of speciic neurotransmitter around the v. Non-TCA antidepressants.
nerves in the brain. One of such antidepressant is selective serotonin
Table1 Commonly used antidepressants and their mechanisms of actions16

Sr.
ATC-Code
No.
1 N06AA04
2 N06AA06
3 N06AA09
4 N06AA10
5 N06AA21
6 N06AB03
7 N06AB04
8 N06AB05
9 N06AB06
10 N06AB08
11 N06AB10
Name of
Pharmaceutical name Mechanism of action
substance
Clomipramine Anafranil- Novartis + generics Serotonin-norepinephrine reuptake inhibitors
Trimipramine Surmontil- sanoiaventis Serotonin-norepinephrine reuptake inhibitors
Amitriptyline Saroten- lundbecktryptizol- msd Serotonin-norepinephrine reuptake inhibitors
Nortriptyline Sensaval- lundbeck Serotonin-norepinephrine reuptake inhibitors
Maprotiline Ludiomil- Novartis + generics Serotonin-norepinephrine reuptake inhibitors
Fluoxetine Fontex- lilly + generics Serotonin Reuptake inhibitors
Citalopram Cipramil- lundbeck + generics Serotonin Reuptake inhibitors
Paroxetine Seroxat- glaxosk + generics Serotonin Reuptake inhibitors
Sertraline Zoloft-Pizer + generics Serotonin Reuptake inhibitors
Fluvoxamine Fevarin- solvaypharma Serotonin Reuptake inhibitors
Escitalopram Cipralex- lundbeck Serotonin Reuptake inhibitors

12 N06AG02 Moclobemide Aurorix- roche + generics MAO inhibitor

The TCAs block the reuptake of both norepinephrine (NE) and
serotonin (5HT). This phenomenon being the primary mechanism
of actions of antidepressants brings changes in the physiological
behaviour of neuro-receptors. TCAs have also been reported to block
muscarinic, alpha1 adrenergic and histaminic receptors. However,
these molecules may lead to occurrence of different side effects in
patients as summarised in Table 2.
Mourilhe20 have reported that the Selective serotonin-reuptake
inhibitors (SSRIs) may block the reuptake of 5HT and increase
synaptic 5HT transmission. The SSRIs have very little or insigniicant
effect on the reuptake of other neurotransmitters. It has been
observed that SSRIs does not display any activity at the muscarinic
and histaminergic receptors which probably results into minute anti-
cholinergic (ACH) and sedative effects (Table 3).
The mechanisms of actions of different antidepressants such
as monoamine oxidase inhibitors (MAOIs), phenelzine (Nardil)
and tranylcypromine (Parnate) associate with the inhibition of
the enzymatic conversion of 5HT and NE into their corresponding

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448.
DOI: 10.15406/jabb.2017.03.00082

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metabolites. MAOIs are generally prescribed in cases of atypical or
drug resistant depression. These compounds contain a certain level of
toxicity. On the contrary to it, the moclobemide (manerix) has been
reported to be the irst reversible inhibitor of monoamine oxidase A
(RIMA). This molecule is found relatively more effective and safe.23
Another antidepressant, nefazodone (serzone) has properties of both:
it acts like SSRIs which blocks the reuptake of 5HT and also act as an
Table 2 Antidepressants and their side effects
antagonist of 5HT2 receptor23 thereby reducing the stimulating effects
similar to SSRIs. Nefazodone has structural and pharmacological
similarities to another antidepressant, trazodone (desyrel). The only
difference is that nefazodone binds with α1 receptors with low
afinity. All of these antidepressants do not signiicantly inluence
ACH mediated functions (Table 4).

Antidepressant
Sr. Therapeutic Toxicity in
substrate (Common Doses Side-effects References
No. index (TI) overdose
Name)

Confusion, Numbness and

Tingling In Your Arms and Legs,
Headache, Constipation Or
start with a dosage of 18
1 Amitriptyline Narrow Diarrhoea, Blurred Vision, Skin High
up to 100 mg/day
Rash, Swelling Of Your Face and
Tongue, Nausea, Unexpected
Weight Gain Or Loss

Dizziness or light headedness,

50 mg-100 mg
confusion, constipation,
2 Amoxapine maximum dose: 600 Narrow -
dificulty in urinating, dry
mg/day
mouth
Dizziness or light headedness,
25 mg, 100 mg, 250 confusion, constipation,
3 Clomipramine Narrow Moderate
mg/day dificulty in urinating, dry
mouth

Dizziness or light headedness,

confusion, constipation,
4 Desipramine 100-300 mg/day Narrow -
dificulty in urinating, dry
mouth

Dizziness or light headedness,

confusion, constipation,
4 Doxepin 25-300 mg/day Narrow -
dificulty in urinating, dry
mouth

Dizziness or light headedness,

Imipramine confusion, constipation,
5 10-50 mg/day Narrow High
Hydrochloride dificulty in urinating, dry
mouth

Dizziness or light headedness,

confusion, constipation,
6 Imipramine Pamoate 10-50 mg/day Narrow High
dificulty in urinating, dry
mouth

Dizziness or light headedness,

7 Maprotiline
8 Nortriptyline
9 Protriptyline
10 Trimipramine
confusion, constipation,
- Narrow -
dificulty in urinating, dry
mouth
Dizziness or light headedness,
confusion, constipation,
10-25 mg/day Narrow High
dificulty in urinating, dry
mouth
Dizziness or light headedness,
confusion, constipation,
- Narrow -
dificulty in urinating, dry
mouth
Dizziness or light headedness,
confusion, constipation, 19
- Narrow High
dificulty in urinating, dry
mouth

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448.
DOI: 10.15406/jabb.2017.03.00082

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Table 3 Side effects of use of SSRIs

Antidepressant
Sr. Therapeutic Toxicity due
substrate (Common Doses Side-Effects References
No. index to overdose
Name)

Nausea, Anxiety, Insomnia Dry Mouth,

Headache, Somnolence, Dizziness,
20-40 mg/ 21
1 Citalopram Wide Agitation, Anorexia, Diarrhoea, Moderate
day
Constipation, Tremor, Sweating, Sexual
Dysfunction

Nausea, Anxiety, Insomnia Dry Mouth,

10-20 mg Headache, Somnolence, Dizziness,
22
2 Fluoxetine and 4mg/ Wide Agitation, Anorexia, Diarrhoea, Low
day Constipation, Tremor, Sweating, Sexual
Dysfunction

Nausea , Anxiety, Insomnia Dry Mouth,

Headache, Somnolence, Dizziness,
50-100 mg/ 22
3 Fluvoxamine Wide Agitation, Anorexia, Diarrhoea, Low
day
Constipation, Tremor, Sweating, Sexual
Dysfunction

Nausea, Anxiety, Insomnia, Dry Mouth,

Headache, Somnolence, Dizziness,
20-30 mg/ 22
4 Paroxetine Wide Agitation, Anorexia, Diarrhoea, Low
day
Constipation, Tremor, Sweating, Sexual
Dysfunction

Nausea , Anxiety, Insomnia Dry Mouth,

Headache, Somnolence, Dizziness,
25-100 mg/ 22
5 Sertraline Wide Agitation, Anorexia, Diarrhoea, Low
day
Constipation, Tremor, Sweating, Sexual
Dysfunction

Nausea , Anxiety, Insomnia Dry Mouth,

Headache, Somnolence Dizziness
100-200mg/ 22
6 Nefazodone Wide Agitation Anorexia, Diarrhoea, -
day
Constipation, Tremor, Sweating, Sexual
Dysfunction

Nausea , Anxiety, Insomnia Dry Mouth,

Headache, Somnolence Dizziness
50-100 mg/ 22
7 Trazodone Wide Agitation Anorexia, Diarrhoea, -
day
Constipation, Tremor, Sweating, Sexual
Dysfunction

The activity of serotonin nor-epinephrine reuptake inhibitors
(SNRIs) does not exert any side effects such as sedation or hypotension
but display TCAs like activity.23 Higher doses of SNRIs have been
reported to mildly increase blood pressure. The above mentioned
antidepressants in adequate dosages exhibit same level of effects for
treatment of depression. Some of the SNRIs are duloxetine (Cymbalta),
venlafaxine (Effexor XR), desvenlafaxine (Pristiq, Khedezla) and
levomilnacipran (Fetzima). The irst line of antidepressants is the
Non-TCAs (NTCA) which includes SSRIs. These agents are relative
safer with better tolerability. Those patients which do not show any
response to other drugs or suffering from chronic pain or migraine are
given TCAs. However, the existing reports suggest that the secondary
amine TCAs (desipramine and nortriptyline) possess more side
effects than tertiary amine TCAs (Table 5). A comparative estimate
of antidepressants and their therapeutic properties are summarised in
Table 6.
Interaction of antidepressants with the cellular recep-
tors
As explained above, the MAOIs block the metabolism of
neurotransmitters such as NE, DA and 5-HT and cause increase in
the concentration of monoamine transmitters. The traditional MAOIs
(tranylcypromine) act in irreversible and non-selective manner
whereas the recently investigated MAOIs are reversible in binding
and very selective for MAO-A or MAO-B. TCAs is a combo drug30
containing at least ive chemical agents with different activities such
as a serotonin reuptake inhibitor activity, a norepinephrine reuptake
inhibitor activity, an anti-cholinergic anti-muscarinic activity, an alfa1-
adrenergic antagonist activity, and an antihistamine (H1) activity.31
When taken in overdose, they cause toxicity in terms of lethal cardiac
arrhythmias and seizures. The mechanism of action of TCAs relies
on the inhibition of reuptake of serotonin and NE.31 The different

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448.
DOI: 10.15406/jabb.2017.03.00082

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Antidepressants: mechanism of action, toxicity and possible amelioration ©2017 Khushboo et al. 441

members of TCAs display differential inhibition activity on 5HT were more potent at NE reuptake pump. The drug toxicity of TCAs
and NE transporters. Clomipramine has been reported to be the most has been explained in terms of their effects on certain receptors such
potent at 5-HT reuptake pump whereas desipramine and maprotiline as H1, M1, and alfa1.
Table 4 Doses and side effects of some other antidepressants

Antidepressant
Sr. Therapeutic Toxicity in
substrate (Common Doses Side-effects References
No. index overdose
Name)

Dizziness, Headache, Tremors Or

40-60 mg/ 24
1 Isocarboxazid Wide Shaking; Constipation, Nausea; Or Dry High
day
Mouth.

Dizziness, Headache, Drowsiness, Sleep

Disturbances (Including Insomnia,
25
2 Phenelzine 60 mg/day Wide Hypersomnia), Fatigue, Weakness, High
Tremors, Twitching, Myoclonic
Movements, Hyperrelexia

Scleroderma, Flare-Up Of Cystic Acne,

Ataxia, Confusion, Disorientation,
26
3 Tranylcypromine 60 mg/day Wide Memory Loss, Urinary Frequency, Low
Urinary Incontinence, Urticaria, Fissuring
In Corner Of Mouth, Akinesia

Nausea, Dry Mouth, Constipation,

27
4 Moclobemide 300 mg/day Wide Diarrhoea, Anxiety, Restlessness, High
Insomnia, Dizziness

Table 5 Doses and adverse effects of application of Non-TCA (NTCA) antidepressants

Antidepressant
Sr. substrate Therapeutic Toxicity in
Doses Side-effects References
No. (Common index overdose
Name)

Dizziness Abnormal Changes In Liver 22

1 Agomelatine 25-50 mg/day Narrow Unclear
Function Tests Abdominal Pain

Insomnia, Nausea, Pharyngitis, Weight

2 Bupropion 150 mg/day Narrow Loss, Constipation, Dizziness, Headache, Moderate
And Xerostomia

Asthenia, Constipation, Diarrhea,

Dizziness, Drowsiness, Fatigue,
3 Duloxetine 60 mg/day Wide Moderate
Hypersomnia, Insomnia, Nausea, Sedation,
Headache, and Xerostomia.

Drowsiness, Liver Dysfunction, Jaundice,

4 Mianserin
Gynaecomastia, Convulsions, Hypomania,
Hypotension, Hypertension; Coma,
30-200 mg/day Narrow Low
Arthralgia, Oedema, Tachycardia,
Bradycardia,Vomiting, Dizziness and
Ataxia, Anti-cholinergic Effects

Urinating problem, Dry Mouth, Sweating,

5 Reboxetine
Tingling or Numbness of The Hands
or Feet, Constipation, Increase in
8mg/Day Narrow Low
Blood Pressure, Increase in Heart
Rate, Impotence, Insomnia, Headache,
Dizziness, Nausea, Decreased Appetite

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448.
DOI: 10.15406/jabb.2017.03.00082

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Table Continued..

Antidepressant
Sr. substrate Therapeutic Toxicity in
Doses Side-effects References
No. (Common index overdose
Name)

Blurred vision, Dizziness, Drowsiness,

Headache, Nausea,Vomiting, and
6 Trazodone 150-400 mg/day Wide Xerostomia Syncope, Edema, Ataxia, Low
Confusion, Diarrhea, Hypotension,
Insomnia, Sedation, and Tachycardia

Bipolar Disorder (Manic Depression);

Cirrhosis Or Other Liver Disease, Kidney
75 mg/day with Disease, Heart Disease, High Blood
Food (37.5 mg/ Pressure, High Cholesterol, Diabetes;
7 Venlafaxine Narrow Moderate
day if Anxious or Narrow-Angle Glaucoma, A Thyroid
Debilitated) Disorder, A History of Seizures, A
Bleeding or Blood Clotting Disorder, Low
Levels of Sodium in Your Blood

Table 6 A comparative estimate of antidepressants and their therapeutic properties.28,29

Sr. Type of Anti- Name of Anti- Dietary

Half-life Availability Reference
No. depressants depressant consideration

Citalopram About 36 hours Tablet Contains Lactose

Escitalopram About 30 hours Tablets -

Dispersible
1 SSRIs 96-144 hours (4-6 28
Fluoxetine Tablets*/ Contains Gelatin
Days)
Capsules

Fluvoxamine 17-22 Hours Tablet -

Paroxetine About 24 Hours Tablet -

Sertraline 22-36 Hours Tablet -

Duloxetine 8-17 Hours Capsules Contains Gelatin
2 SNRIs
Venlafaxine 4-7 Hours Capsules Contains Gelatin
Amitriptyline 9-25 Hours Tablets -
About 50 Hours
Dosulepin 36 Hours -
(Just Over 2 Days)

Clomipramine 36 Hours Tablets -

33-80 Hours (1.5-
Doxepin Capsules Contains Lactose
3.3 Days)

3 Tricyclics Imipramine About 19 Hours Liquid Contains Lactose

Lofepramine 12-24 Hours Tablets Contains Lactose

Nortriptyline About 36 Hours Tablets Contains Lactose

Trimipramine About 23 Hours Capsules Contains Lactose

Mianserin 6-39 Hours Tablets Contains Lactose

Tricyclic-Related
4
Drugs
Trazodone 5-13 Hours Tablets Contains Lactose

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448.
DOI: 10.15406/jabb.2017.03.00082

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Table Continued...

Sr. Type of Anti- Name of Anti- Dietary

Half-life Availability Reference
No. depressants depressant consideration

Isocarboxazid About 36 Hours Tablets Contains Lactose

Requires Food
Phenelzine 11-12 Hours Tablets
Restrictions
5 MAOIs
Requires Food
Moclobemide 2-4 Hours Tablets
Restrictions
Requires Food
Tranylcypromine About 2 Hours Tablets
Restrictions

Agomelatine 1-2 Hours Tablets Contains Lactose

Mirtazapine 20-40 Hours Liquid -

6 Others Reboxetine About 13 Hours Tablets -

Triptafen N/A Tablets -

Vortioxetine About 66 Hours Tablets -

*Dispersible tablets will disintegrate quickly in the mouth or can be mixed with water, orange juice or apple juice.
*All other antidepressants currently available do not contain lactose or gelatin, and do not require any speciic dietary restrictions, although caution when
drinking alcohol is a recommended for all antidepressants.

Selective serotonin reuptake inhibitors (SSRIs)
SSRIs are known to selectively inhibit serotonin transport. Some
of the SSRIs are luoxetine (Prozac, Selfemra), paroxetine (Paxil,
Pexeva), sertraline (Zoloft), citalopram (Celexa) and escitalopram
(Lexapro). This action of SSRIs results into abrupt increase in
serotonin in the somatodendritic area of serotonergic neurons
which causes desensitization of the somatodendritic serotonin-1A
autoreceptors.31–33 As a result, the neuronal impulse low is increased.33
It causes increased release of serotonin from axon terminals, which
culminates into desensitization of postsynaptic serotonin receptors.
Desensitization of these receptors may contribute to the therapeutic
actions of SSRIs or it could account for the development of tolerance
to acute side effects of SSRIs. The pharmacological analysis of SSRIs
suggests that these agents may cause strong but slow disinhibition of
5-HT neurotransmission in the central nervous system (CNS). In this
case, the actions of antidepressants are mediated by a pathway from
midbrain raphe to prefrontal cortex.34,35 The side effects generated
by SSRIs include anxiety, sleep disturbances, sexual dysfunction
(decreased libido, reduced pleasurability and reduction in arousal),
and gastrointestinal disturbances.30 It is thought that the toxicity the
5-HT2 and 5-HT3 receptors of certain serotonergic pathways are
responsible. A reciprocal relationship exists between serotonin and
dopamine viz. serotonin tending to inhibit sexual functioning and
dopamine tending to enhance sexual functioning. It is believed that
serotonin pathway descending from brain stem down the spinal cord
to spinal neurons that mediate various spinal relexes is responsible for
the sexual dysfunction in the form of ejaculation and orgasm problems.
It has been reported that the enhanced serotonergic low through this
pathway inhibits sexual functioning. The serotonin’s negative effects
on sexual functioning are mediated via 5-HT2 receptors. Therefore
5-HT2 antagonists can reverse SSRIs induced sexual dysfunction.36,37
The antidepressant acting as serotonin/norepinephri-
ne/dopamine reuptake inhibitor (SNRI)
Stahl30 have demonstrated the pharmacologic effect of venlafaxine
and found it to be dose dependent. At low doses, it essentially acts as
an SSRI and at medium to high doses, it causes additional NE reuptake
inhibition and at very high doses, DA reuptake inhibition occurs.30,39
Other antidepressants such as nefazodone and trazodone act via
serotonin-2 receptor antagonism with serotonin reuptake blockade. It
is interesting to mention here that SSRIs stimulate 5-HT2 receptors
where as nefazodone and trazodone blocks the receptor.30 This action
of nefazodone and trazodone makes it safer antidepressants than the
SSRIs.
Depressants as norepinephrine and dopamine reup-
take inhibitor (Bupropion)
Bupropion is the only antidepressant that selectively acts on the
noradrenergic and dopaminergic systems and not on the serotonin
system.40 Bupropion exhibits dopaminergic and noradrenergic activity,
therefore it may exert positive effect in overcoming the attention
deicit disorder41 and in the treatment of smoking cessation.38 In
contrary to the beneits from this drug, bupropion has been shown to
induce some side effects such as overstimulation, agitation, insomnia
and nausea.30,39
Antidepressants showing α-2 antagonism plus seroto-
nin-2 and serotonin-3 antagonism
Mirtazapin, a noradrenergic and speciic serotonergic
antidepressant,43 has both pro-adrenergic and proserotonergic actions.
The pro-adrenergic and proserotonergic actions of mirtazapin are due
to its alpha2-antagonist properties i.e. disinhibition of both serotonin
and norepinephrine neurotransmission. Similar to nefazodone,
mirtazapine also does not exert any toxicity of SSRIs due to 5-HT2
stimulation. Since strong antihistamine properties are associated
to mirtazapin, it has some side effects such as weight gain and
sedation.30,39
The antidepressants acting as a noradrenalin speciic
reuptake inhibitor (NRI) (Reboxetine)
Reboxetine, a noradrenaline (norepinephrine) reuptake inhibitor,
is exclusively unrelated to TCA or SSRIs. The speciic properties of

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448.
DOI: 10.15406/jabb.2017.03.00082

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reboxetine includes its high afinity for the noradrenaline transporter,
and little afinity for other neuro receptors including serotonin,
dopamine, histamine, muscarinergic and alpha adrenergic sites.43
Antidepressants as a serotonin reuptake enhancer
(Tianeptine)
Tianeptine being, a tricyclic compound of dibenzothiazepine type
increases the presynaptic uptake of serotonin after single as well as
repeated administration, but this action is not linked to any effects
on the 5-HT post-synaptic systems.50,89 Tianeptine has no afinity for
alfa1 adrenergic and H1 antihistaminic receptors. Tianeptine can be
considered as the mid-position antidepressants. Defrance et al.45 have
Table 7 Phytochemicals acting as natural antidepressants
shown that tianeptine does not show any afinity for the muscarinic
receptors. Tianeptine has been reported to exert little toxicity
such as gastralgia, abdominal pain, dry mouth, anorexia, nausea,
vomiting, latulence, insomnia, drowsiness, nightmares, asthenia, and
tachycardia in certain patients44–46
Phytochemicals as antidepressants
Some phytochemicals are reported to act as antidepressants. These
chemicals present in the plant extracts are expected to be safer and
more cost effective than the existing antidepressants. Different ethno-
pharmaceutical properties of various plant extracts and their effects
are summarised in Table 7.

Common Part used Type of extract,

Plant Extract Effects References
name from the plant compound, doses
47
Allium macrostemon Chinese Garlic Bulb Water Extracts

Ethanolic Extract, dose- Behavioural Despair

48
Allium sativum Garlic Rhizome
25,50 and 100mg/kg
49
Aloysia polystachya Lemon Verbena Aerial Part Hydroethanolic Extract
Effect on Depression
50
Apocynum venetum Dogbane Aerial Part Dose-30-125mg/kg
Ethanolic Extract, dose- 51
Areca catechu Betel Nut Fruit Effect on Motor Activity
4-80mg/kg

Effect on Serotonergic And

Methanolic Extract, dose- Noradrenergic System And 52
Asparagus racemosus Satavari Root
100,200 and 400mg/kg Augmentation Of Antioxidant
Defences

Signiicant Antioxidant Effect,

Methanolic Extract, dose- 53
Bacoba monnieri Brahmi Aerial Part Anxiolytic Activity And Improve
20 and 40mg/kg
Memory Retention

Berberine, (An Alkaloid), Effect on CNS, Inhibit Monoamine 54

Berberis aristata Indian Barberry Root
dose-5,10 and 20mg/kg. Oxidase-A

Chai Hu, Hare’s 55

Bupleurum falcatum Root Methanolic Extract Psycho stimulant Effect
Ear Root

Ethanolic And
Roots And Effect on heraprutical Responses In 56
Cimicifuga racemosa Black Bugbane Isopropanolic Aqueous
Rhizomes Climacteric Women
Extracts
Ethanolic Extract, 50 or Effect on Cognitive Behaviour,
Clitoria ternatea Butterly Pea Root ,Bark 57
100mg/kg Anxiety, Depression, Stress
58
Crocus sativus Saffron Stigma Ethanolic Extract Effect on Depression

Aqueous Extract, dose- 59

Curcuma longa Turmeric Rhizome Mao Inhibition In Brain
140-560mg/kg for 14 days.

Emblica oficinalis Amla Fruit - Effect on Psychiatric Disorder 60

Ginkgo, Lipophilic Extract, dose- 50 Act As Anti-Stress and 61

Ginkgo biloba Leaves
Maidenhair Tree and 100mg/kg Antidepressant

Antidepressant Like and Antioxidant

Activity By Measuring Erythrocyte
62
Glycyrrhiza uralensis Mulethi Root Liquiritin (Flavones) Superoxide Dismutase (Sod) Activity
And Plasma Malondialdehyde (MDA)
Level

Aqueous Extract, Liquorice 63

Glycyrrhiza glabra Mulethi Root Effect on Inhibition Of Mao
Extract

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448.
DOI: 10.15406/jabb.2017.03.00082

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Table Continued..

Common Part used Type of extract,

Plant Extract Effects References
name from the plant compound, doses

Effect on Neurological Disorders 64

Hippeastrum vittatum Amaryllis Flower Alkaloids
And Neuro degenerative Disease
Hypericum
Neuro pharmacological Effect,
canariensel. Canary Island St 65
Aerial Part Methanolic Extract Helps In Muscle Relaxation, Anti-
And Hypericum .John Wort
cholinergic And Sedative Properties
glandulosum

Hypericum relexum Hypericum Aerial Part Methanolic Extract Effect on CNS 66

Kava Root/
Kaempferia parvilora Kava Kava Rhizome Extract Effect on Psychiatric Illness 67
Rhizome
68
Lafoensia pacari Didal Leaves - Effects on CNS

Magnolia bark and Honokiol and Magnolol, 69

Magnolia, Ginger Bark, Rhizome Effect on Synergistic Interaction
ginger rhizome Polysaccharides

Dwarf Water Marsiline, Sedative And Effect on Insomnia And Other 70

Marsilea minuta Root
Clover Anticonvulsant Property Mental Disorders
71
Mimosa pudica Sensitive Plant Leave Aqueous Extract Act As Tricyclic Antidepressants
Mitragynine An Active Effect on Diarrhea, Diabetes And 72
Mitragyna speciosa Kratom Leaves
Alkaloid Improve Blood Circulation
Bitter Gourd/ Methanol Extract, dose- 73
Momordica charantia Fruit
Bitter Melon 300mg/kg
Morinda oficinalis Indian Mulberry Root Dose- 25-50mg/kg Effective In Response Rate 74

75
Oscimum sanctum Tulsi Aerial Part

Ethanolic extract, dose- Effect on Central Monoaminergic

Paeonia lactilora pall Garden Peony Root 76
250 and 500mg/kg Neurotransmitter System

Amide (Alkaloid), dose- Antinociceptive Properties, Effect on 77

Piper laetispicum Piper Stem And Root
2mg/kg Pain And Depression

Effect on Anxiolytic And

Piplartine (An Amide) , 78
Piper tuberculatum Black Pepper Fruit Antidepressant Activities, Anxiety
dose- 50 and 100mg/kg
And Depression.

Effect on Serotonergic,
79
Polygala sabulosa Polygala Aerial Part Scopoletin, A Coumarin Dopaminergic And Noradrenergic
Systems

Effect on Monoamine Oxidase 80

Rhazyastricta White Henna Leaves Aqueous Extract
Inhibition

Interaction With The

Rosmarinusoficinalis Rosemary Fresh Juice Hydro-alcoholic Extract 81
Monoaminergic System
82
Salvia elegans Pineapple Sage Leave Hydroalcoholic Extract Putative Anxiolytic

Peruvian Pepper Pharmacological Effects, atleast At A 83

Schinusmolle L Leaves Hexenic Extract
Tree Preclinical Level

Interaction With Adrenergic,

Siphocampylus Hydroalcoholic Extract , 84
Siphocampylus Aerial Parts Dopaminergic, Glutamatergic And
verticillatus dose range-100-1000mg/kg
Serotonergic System

East Indian Globe Effect On Anxiety, Depression And 85

Sphaeranthu sindicus Whole Part Hydroalcoholic Extract
Thistle Convulsions

Lapacho, Taheboo Effect Of The Association Of The [86]

Tabebuia avellaneda Bark Ethanolic Extract
Tree Extract With The Antidepressants

Citation: Khushboo, Sharma B. Antidepressants: mechanism of action, toxicity and possible amelioration. J Appl Biotechnol Bioeng. 2017;3(5):437‒448.
DOI: 10.15406/jabb.2017.03.00082

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Antidepressants: mechanism of action, toxicity and possible amelioration ©2017 Khushboo et al. 446

Table Continued...
Common Part used Type of extract,
Plant Extract Effects References
name from the plant compound, doses
87
Tagetes lucida Marigolds Aerial Part - Effect On CNS
Petroleum Ether Extract,
48
Tinospora cardifolia Guduchi Whole Part dose- 50, 100 and 200mg/ Effect on Mao-A and Mao-B
kg.

Effect on Mild Sleep Disorders and

Valeriana oficinalis Valerian Root Ethanolic Extract 48
Nervous Tension

Methanolic and Aqueous 89

Valeriana wallichi Indian Valeriana Root Bark
Extract
Bioactive Glyco Effect on Anxiolytic And 90
Withania somnifera Ashwagandha Aerial Part
withanolides Antidepressant Action

Conclusion 4. Partonen T, Lönnqvist J. Seasonal affective disorder. Lancet.

Depression is a serious psychological condition but it can
be effectively treated with available therapies. The stock of
antidepressants available may be selectively used for treating
depression safely without any side effects. The right medication to
an individual depends on the clinico-physiological conditions of
the patient such as symptoms, possible side effects, and interaction
with other medications, state of pregnancy or breast feeding and the
mental conditions. Different classes of antidepressants are in practice
depending on the type and requirement of depression. Antidepressants
include selective serotonin reuptake inhibitors (SSRIs), Serotonin
and norepinephrine reuptake inhibitors (SNRIs), Norepinephrine
and dopamine reuptake inhibitors (NDRIs: Bupropion (Wellbutrin,
Aplenzin, Forivo XL), Atypical antidepressants (trazodone
(Oleptro), mirtazapine (Remeron) and vortioxetine (Brintellix)),
Tricyclic antidepressants (imipramine (Tofranil), nortriptyline
(Pamelor), amitriptyline, doxepin, trimipramine (Surmontil),
desipramine (Norpramin) and protriptyline (Vivactil)), Monoamine
oxidase inhibitors (MAOIs: tranylcypromine (Parnate), phenelzine
(Nardil) and isocarboxazid (Marplan)) and other medications such as
such as mood stabilizers or antipsychotics all as well as anti-anxiety
and stimulant medications. Many of these medications have their side
effects. It could be however worthwhile to investigate the plant based
principles to be used as more effective and safe chemotherapeutic
compared to the currently used synthetic regimen.
Acknowledgements
Khushboo is grateful to UGC-New Delhi for inancial support in
the form of a fellowship.
Conlict of interest
The author declares no conlict of interest.
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Journal of Applied Biotechnology & Bioengineering

Volume 3 Issue 5 - 2017
Khushboo, Sharma B
Department of Biochemistry, University of Allahabad, India
Antidepresan: mekanisme kerja, toksisitas dan kemungkinan perbaikan

Abstrak
Depresi sebagai keadaan kesedihan dapat didefinisikan sebagai gangguan psikoneurotik yang
ditandai oleh aktivitas mental dan fungsional, kesedihan, pengurangan aktivitas, kesulitan
berpikir, kehilangan konsentrasi, gangguan nafsu makan, tidur, dan perasaan kesal,
keputusasaan, dan kecenderungan ingin bunuh diri.. Ini adalah gangguan umum dan berulang
yang menyebabkan morbiditas dan mortalitas yang signifikan di seluruh dunia. Senyawa
antidepresan yang digunakan melawan depresi dilaporkan juga digunakan untuk mengobati rasa
sakit, sindrom kegelisahan, dll. Mereka telah dikelompokkan dalam lima kategori berbeda
seperti:

1. Antidepresan trisiklik (TCA)

2. Inhibitor serotonin-reuptake selektif (SSRI)
3. Inhibitor monoamine oksidase (MAOIs)
4. Serotonin-norepinefrin reuptake inhibitor (SNRI) dan
5. Antidepresan non-TCA berdasarkan mode aksi mereka.

Sebagian besar antidepresan telah dilaporkan memiliki efek buruk pada kesehatan pengguna.
Artikel ulasan ini berfokus pada arus terbaru antidepresan, mekanisme kerjanya, patofisiologi
senyawa-senyawa ini, efek sampingnya dan strategi untuk memerangi toksisitas yang diinduksi
oleh obat. Akun phytochemical yang ditemukan juga termasuk bertindak sebagai antidepresan

Kata kunci: depresi, antidepresan, toksisitas, neurotransmiter, biomarker

Singkatan: TCA, antidepresan trisiklik; SSRI, inhibitor serotonin-reuptake selektif; MAOI,

inhibitor monoamine oksidase; SNRI, inhibitor reuptake serotonin-norepinefrin; PMDD,
gangguan dysphoric pramenstruasi; SAD, gangguan afektif musiman; PMS, sindrom
pramenstruasi; NE, norepinefrin; 5-HT, 5-hydroxytryptamine; DA, dopamin; SSP, sistem saraf
pusat; NRI, inhibitor reuptake spesifik noradrenalin

Pendahuluan
Depresi dapat didefinisikan sebagai keadaan perasaan sedih. Ini juga dapat didefinisikan sebagai
gangguan psikoneurotik yang ditandai oleh aktivitas mental dan fungsional, kesedihan,
pengurangan aktivitas, kesulitan dalam berpikir, kehilangan konsentrasi, gangguan nafsu makan,

65
Fredy Satriadi (201610330311127)

tidur, dan perasaan kesal, keputusasaan dan timbulnya kecenderungan untuk bunuh diri. Ini
adalah suatu kelainan umum dan berulang yang menyebabkan morbiditas dan mortalitas yang
signifikan di seluruh dunia. Depresi, sejenis penyakit mental, termasuk rangsangan kesedihan
yang dapat memengaruhi proses berpikir, perilaku, dan perasaan secara keseluruhan. . Beberapa
pekerja telah menggambarkan penyebab depresi yang meliputi genetik, perilaku orangtua yang
heterogen kepada saudara kandung, pengabaian dan pelecehan seksual. Selain itu, kondisi
tertentu seperti kesulitan dalam pekerjaan, hubungan, bencana alam, keuangan, kelahiran anak,
cedera katastropik, kehilangan nyawa orang yang dicintai dan menopause. Diketahui bahwa
daerah otak yang berbeda dapat memediasi timbulnya berbagai gejala depresi karena mereka
mengatur emosi, sirkuit saraf dan suasana hati. Ada sedikit informasi yang tersedia tentang
mekanisme yang mendasari pengaturan mereka. Kerusakan pada daerah hipotalamus otak telah
ditemukan, berhubungan dengan kurang atau terlalu banyaknya frekuensi tidur, tidak tertarik
pada seks dan kegiatan kesenangan lainnya. Depresi secara umum memiliki tiga bentuk utama
seperti
1) Depresi psikotik ditandai dengan depresi berat,
2) Depresi pascapersalinan ditandai dengan gangguan pada kadar hormon dan fitur fisik
setelah kelahiran anak dan
3) Seasonal Affective Disorder (SAD) tentang bulan-bulan musim dingin dengan sinar
matahari lebih sedikit.
Pada wanita, depresi muncul juga karena beban kerja ekstra, tanggung jawab rumah
tangga, perawatan anak, hubungan tegang, perawatan orang tua lanjut usia dan kemiskinan.
Selain semua indeks ini, faktor psikologis, biologis dan hormonal juga berkontribusi secara
signifikan dalam depresi. Gangguan dysphoric pramenstruasi (PMDD) atau sindrom
pramenstruasi (PMS) dan osteoporosis pada wanita dapat memainkan peran penting dalam
perkembangan depresi. Depresi pada pria dapat dikaitkan dengan penderitaan dari penyakit
serius seperti kanker dan penyakit jantung, kelelahan ekstrim, iritasi, tidak tertarik pada aktivitas
yang menyenangkan, kehilangan keseimbangan, kurang tidur, dan menjadi agresif. Pada pria
yang lebih tua, depresi arteriosklerotik (depresi vaskular) telah diamati. Depresi yang dapat
menyebabkan bunuh diri pada anak-anak dapat dikaitkan dengan munculnya seksualitas dan
masa pubertas. Artikel ini adalah upaya untuk menggambarkan akun yang diperbarui dan
berbagai aspek depresi seperti patofisiologi, gejala, diagnosis, pengobatan dengan obat-obatan
dan cara kerjanya, toksisitas dan penggunaan produk tanaman sebagai antidepresan potensial

Patofisiologi depresi
Tidak ada biomarker atau kelainan pencitraan yang berguna untuk menentukan patofisiologi
depresi selama masa hidup. Studi postmortem otak tidak mengungkapkan adanya kelainan
struktural atau neurokimia yang konsisten. Mayoritas obat yang tersedia saat ini ditemukan
secara empiris. Kebanyakan teori saat ini didasarkan pada "hipotesis amina.12" Hipotesis paling
penting dari gangguan suasana hati terkait dengan perubahan kadar amina biogenik. 13-15
menyatakan bahwa depresi disebabkan oleh defisiensi fungsional katekolamin, khususnya

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Fredy Satriadi (201610330311127)

Norepinefrin (NE), sedangkan mania disebabkan oleh kelebihan fungsional katekolamin pada
sinapsis kritis di otak. Terjadinya depresi telah dikaitkan dengan perubahan kadar amina
biogenik di otak seperti NE, dopamin (DA) dan epinefrin, indolamin, serotonin, 5-
hydroxytryptamine (5-HT) dan dua katekolamin

Antidepresan
Antidepresan adalah obat yang membantu mengurangi gejala gangguan depresi dengan
mengubah ketidakseimbangan kimiawi neurotransmiter di otak. Perubahan suasana hati dan
perilaku disebabkan oleh ketidakseimbangan kimia. Neurotransmitter adalah penghubung
komunikasi antara neuron di otak. Neurotransmitter terletak di vesikel yang ditemukan di sel-sel
saraf. Neurotransmitter seperti serotonin, dopamin dan noradrenalin atau norepinefrin dilepaskan
oleh ujung eksonik satu saraf dan diterima oleh yang lain; fenomena yang disebut sebagai
reuptake. Antidepresan menghambat pengambilan kembali neurotransmitter melalui reseptor
selektif sehingga meningkatkan konsentrasi neurotransmitter spesifik di sekitar saraf di otak.
Salah satu antidepresan tersebut adalah serotonin selektif reuptake inhibitor (SSRI), yang
mempengaruhi tingkat serotonin otak. Antidepresan dapat memulihkan tanda-tanda depresi,
tetapi juga menimbulkan beberapa efek samping. Mereka digunakan dalam pengobatan sejumlah
gejala, termasuk tidak hanya depresi, beberapa gangguan kecemasan, gugup, OCD, gangguan
manik-depresi, mengompol di masa kanak-kanak, gangguan depresi utama, nyeri neuropatik
perifer diabetik, keresahan sosial, stres pascatrauma gangguan dll dan beberapa menyimpulkan,
tetapi tidak sempurna pada fibromyalgia, gatal-gatal kronis (reaksi alergi), berkedip,
hiperhidrosis yang diinduksi obat (berkeringat berlebihan), gejala pramenstruasi, pruritus (gatal),
nervosa, turet, gangguan pesta makan dll. Obat-obatan mencapai fungsi yang diinginkan dengan
mempengaruhi konsentrasi neurotransmitter di otak seperti NE, serotonin dan dopamin dan
sistem saraf pusat (CNS).
Berdasarkan mode tindakan, sekelompok antidepresan mengandung 17 zat yang dapat dibagi lagi
menjadi subkelompok. Obat-obatan yang biasa digunakan untuk melawan depresi dirangkum
dalam Tabel 1.
Antidepressan dan klasifikasinya :
Antidepresan dibagi menjadi 5 kelompok :
I. Antidepresan trisiklik (TCA),
II. Inhibitor serotonin-reuptake selektif (SSRI),
III. Inhibitor monoamine oksidase (MAOIs),
IV. Serotonin-norepinefrin reuptake inhibitor (SNRI) dan
V. Antidepresan Non-TCA.
Tabel 1 Antidepresan yang umum digunakan dan mekanisme kerjanya
Sr. ATC- Name of Pharmaceutical name Mechanism of action
No. Code substance
1 N06AA04 Clomipramine Anafranil- Novartis + Serotonin-norepinephrine
generics reuptake inhibitors

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Fredy Satriadi (201610330311127)

2 N06AA06 Trimipramine Surmontil- sanofiaventis Serotonin-norepinephrine

reuptake inhibitors
3 N06AA09 Amitriptyline Saroten- Serotonin-norepinephrine
lundbecktryptizol- msd reuptake inhibitors
4 N06AA10 Nortriptyline Sensaval- lundbeck Serotonin-norepinephrine
reuptake inhibitors
5 N06AA21 Maprotiline Ludiomil- Novartis + Serotonin-norepinephrine
generics reuptake inhibitors
6 N06AB03 Fluoxetine Fontex- lilly + generics Serotonin Reuptake inhibitors
7 N06AB04 Citalopram Cipramil- lundbeck + Serotonin Reuptake inhibitors
generics
8 N06AB05 Paroxetine Seroxat- glaxosk + Serotonin Reuptake inhibitors
generics
9 N06AB06 Sertraline Zoloft-Pfizer + generics Serotonin Reuptake inhibitors
10 N06AB08 Fluvoxamine Fevarin- solvaypharma Serotonin Reuptake inhibitors
11 N06AB10 Escitalopram Cipralex- lundbeck Serotonin Reuptake inhibitors
12 N06AG02 Moclobemide Aurorix- roche + MAO inhibitor
generics

TCA memblokir reuptake norepinefrin (NE) dan serotonin (5HT). Fenomena ini
menjadi mekanisme utama aksi antidepresan membawa perubahan dalam perilaku fisiologis
neuro-reseptor. TCA juga telah dilaporkan memblokir reseptor muskarinik, alrenergik, dan
histaminik. Namun, molekul-molekul ini dapat menyebabkan terjadinya efek samping yang
berbeda pada pasien seperti yang dirangkum dalam Tabel 2.
Mourilhe20 telah melaporkan bahwa inhibitor serotonin-reuptake selektif (SSRI) dapat
menghalangi reuptake 5HT dan meningkatkan transmisi 5HT sinaptik. SSRI memiliki efek yang
sangat kecil atau tidak signifikan pada pengambilan kembali neurotransmiter lainnya. Telah
diamati bahwa SSRI tidak menampilkan aktivitas apa pun pada reseptor muskarinik dan
histaminergik yang mungkin menghasilkan antikolinergik menit (ACH) dan efek sedatif (Tabel
3).

Mekanisme aksi antidepresan yang berbeda seperti inhibitor monoamine oksidase

(MAOIs), phenelzine (Nardil) dan tranylcypromine (Parnate) dikaitkan dengan penghambatan
konversi enzimatik dari 5HT dan NE menjadi terkait metabolisme. MAOI umumnya diresepkan
dalam kasus atipikal atau depresi yang resistan terhadap obat. Senyawa ini mengandung tingkat
toksisitas tertentu. Sebaliknya, moclobemide (manerix) telah dilaporkan sebagai inhibitor
reversibel pertama dari monoamine oxidase A (RIMA). Molekul ini ditemukan relatif lebih
efektif dan aman.23 Antidepresan lain, nefazodone (serzone) memiliki sifat keduanya: ia
bertindak seperti SSRI yang menghambat reuptake 5HT dan juga bertindak sebagai antagonis
reseptor 5HT223 sehingga mengurangi efek stimulasi yang mirip dengan SSRI . Nefazodone

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Fredy Satriadi (201610330311127)

memiliki kesamaan struktural dan farmakologis dengan antidepresan lain, trazodone (desyrel).
Satu-satunya perbedaan adalah bahwa nefazodone berikatan dengan reseptor α1 dengan afinitas
rendah. Semua antidepresan ini tidak mempengaruhi fungsi yang dimediasi ACH secara
signifikan (Tabel 4).

Tabel 2 Antidepresan dan efek sampingnya

Sr. Antidepressant Doses Therapeutic Side-effects Toxicity in
No. substrate index (TI) overdose
(Common Name)
1 Amitriptyline start with a Narrow Confusion, Numbness High
dosage of up to and Tingling In Your
100 mg/day Arms and Legs,
Headache, Constipation
Or Diarrhoea, Blurred
Vision, Skin Rash,
Swelling Of Your Face
and Tongue, Nausea,
Unexpected Weight
Gain Or Loss
2 Amoxapine 50 mg-100 mg Narrow Dizziness or light -
maximum headedness, confusion,
dose: 600 constipation, difficulty
mg/day in urinating, dry mouth
3 Clomipramine 25 mg, 100 Narrow Dizziness or light Moderate
mg, 250 headedness, confusion,
mg/day constipation, difficulty
in urinating, dry mouth
4 Desipramine 100-300 Narrow Dizziness or light -
mg/day headedness, confusion,
constipation, difficulty
in urinating, dry mouth
4 Doxepin 25-300 mg/day Narrow Dizziness or light -
headedness, confusion,
constipation, difficulty
in urinating, dry mouth
5 Imipramine 10-50 mg/day Narrow Dizziness or light High

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Fredy Satriadi (201610330311127)

Hydrochloride headedness, confusion,

constipation, difficulty
in urinating, dry mouth
6 Imipramine 10-50 mg/day Narrow Dizziness or light High
Pamoate headedness, confusion,
constipation, difficulty
in urinating, dry mouth
7 Maprotiline - Narrow Dizziness or light -
headedness, confusion,
constipation, difficulty
in urinating, dry mouth
8 Nortriptyline 10-25 mg/day Narrow Dizziness or light High
headedness, confusion,
constipation, difficulty
in urinating, dry mouth
9 Protriptyline - Narrow Dizziness or light -
headedness, confusion,
constipation, difficulty
in urinating, dry mouth
10 Trimipramine - Narrow Dizziness or light High
headedness, confusion,
constipation, difficulty
in urinating, dry mouth

Table 3 Antidepresan: mekanisme kerja, toksisitas dan kemungkinan perbaikan

Sr. Antidepressant Doses Therapeutic Side-Effects Toxicity due References

No. substrate index to overdose
(Common
Name)
1 Citalopram 20-40 Wide Nausea, Anxiety, Moderate 21
mg/ Insomnia Dry
day Mouth, Headache,
Somnolence,
Dizziness,
Agitation, Anorexia,
Diarrhoea,
Constipation,
Tremor, Sweating,

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Fredy Satriadi (201610330311127)

Sexual Dysfunction

2 Fluoxetine 10-20 Wide Nausea, Anxiety, Low 22

mg Insomnia Dry
and Mouth, Headache,
4mg/ Somnolence,
day Dizziness,
Agitation, Anorexia,
Diarrhoea,
Constipation,
Tremor, Sweating,
Sexual Dysfunction
3 Fluvoxamine 50- Wide Nausea , Anxiety, Low 22
100 Insomnia Dry
mg/ Mouth, Headache,
day Somnolence,
Dizziness,
Agitation, Anorexia,
Diarrhoea,
Constipation,
Tremor, Sweating,
Sexual Dysfunction
4 Paroxetine 20-30 Wide Nausea, Anxiety, Low 22
mg/ Insomnia, Dry
day Mouth, Headache,
Somnolence,
Dizziness,
Agitation, Anorexia,
Diarrhoea,
Constipation,
Tremor, Sweating,
Sexual Dysfunction
5 Sertraline 25- Wide Nausea , Anxiety, Low 22
100 Insomnia Dry
mg/ Mouth, Headache,
day Somnolence,
Dizziness,
Agitation, Anorexia,
Diarrhoea,
Constipation,
Tremor, Sweating,

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Fredy Satriadi (201610330311127)

Sexual Dysfunction

6 Nefazodone 100- Wide Nausea , Anxiety, - 22

200m Insomnia Dry
g/ day Mouth, Headache,
Somnolence
Dizziness Agitation
Anorexia,
Diarrhoea,
Constipation,
Tremor, Sweating,
Sexual Dysfunction
7 Trazodone 50- Wide Nausea , Anxiety, - 22
100 Insomnia Dry
mg/ Mouth, Headache,
day Somnolence
Dizziness Agitation
Anorexia,
Diarrhoea,
Constipation,
Tremor, Sweating,
Sexual Dysfunction

Aktivitas inhibitor reuptake serotonin nor-epinefrin (SNRI) tidak memberikan efek

samping seperti sedasi atau hipotensi tetapi menunjukkan aktivitas seperti TCA. 23 Dosis SNRI
yang lebih tinggi dilaporkan sedikit meningkatkan tekanan darah. Antidepresan yang disebutkan
di atas dalam dosis yang memadai menunjukkan tingkat efek yang sama untuk pengobatan
depresi. Beberapa SNRI adalah duloxetine (Cymbalta), venlafaxine (Effexor XR),
desvenlafaxine (Pristiq, Khedezla) dan levomilnacipran (Fetzima). Baris pertama antidepresan
adalah Non-TCA (NTCA) yang mencakup SSRI. Agen-agen ini relatif lebih aman dengan
tolerabilitas yang lebih baik. Pasien-pasien yang tidak menunjukkan respons terhadap obat lain
atau menderita sakit kronis atau migrain diberikan TCA. Namun, laporan yang ada menunjukkan
bahwa TCA amina sekunder (desipramine dan nortriptyline) memiliki lebih banyak efek
samping daripada TCA amina tersier (Tabel 5). Perkiraan perbandingan antidepresan dan sifat
terapeutiknya dirangkum dalam Tabel 6.

Interaksi antidepresan dengan reseptor seluler Seperti dijelaskan di atas, MAOI memblokir
metabolisme
Neurotransmiter seperti NE, DA dan 5-HT dan menyebabkan peningkatan konsentrasi
pemancar monoamina. MAOI tradisional (tranylcypromine) bertindak secara ireversibel dan
non-selektif sedangkan MAOI yang baru-baru ini diselidiki bersifat reversibel dalam pengikatan

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dan sangat selektif untuk MAO-A atau MAO-B. TCA adalah obat kombo30 yang mengandung
setidaknya lima agen kimia dengan aktivitas berbeda seperti aktivitas inhibitor reuptake
serotonin, aktivitas inhibitor reuptake norepinefrin, aktivitas anti-muskarinik anti-kolinergik,
aktivitas antagonis alfa1-adrenergik, dan antihistamin (H1) aktivitas.31 Ketika dikonsumsi dalam
dosis tinggi, mereka menyebabkan toksisitas dalam hal aritmia jantung dan kejang yang
mematikan. Mekanisme kerja TCA bergantung pada penghambatan reuptake serotonin dan
NE.31 Perbedaannya anggota TCA menampilkan aktivitas penghambatan diferensial pada
transporter 5HT dan NE. Clomipramine telah dilaporkan sebagai yang paling kuat pada pompa
reuptake 5-HT sedangkan desipramine dan maprotilin lebih kuat pada pompa reuptake NE.
Toksisitas obat TCA telah dijelaskan dalam hal efeknya pada reseptor tertentu seperti H1, M1,
dan alfa1.

Tabel 4 Dosis dan efek samping dari beberapa antidepresan lainnya

Sr. Antidepressant Doses Therapeutic Side-effects Toxicity Referenc
No. substrate index in es
(Common Name) overdose
1 Isocarboxazid 40-60 mg/ Wide Dizziness, High 24
day Headache,
Tremors Or
Shaking;
Constipation,
Nausea; Or Dry
Mouth.
2 Phenelzine 60 mg/day Wide Dizziness, High 25
Headache,
Drowsiness, Sleep
Disturbances
(Including
Insomnia,
Hypersomnia),
Fatigue,
Weakness,
Tremors,
Twitching,
Myoclonic
Movements,
Hyperreflexia
3 Tranylcypromine 60 mg/day Wide Scleroderma, Low 26
Flare-Up Of Cystic
Acne, Ataxia,

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Confusion,
Disorientation,
Memory Loss,
Urinary
Frequency,
Urinary
Incontinence,
Urticaria,
Fissuring In
Corner Of Mouth,
Akinesia
4 Moclobemide 300 mg/day Wide Nausea, Dry High 27
Mouth,
Constipation,
Diarrhoea,
Anxiety,
Restlessness,
Insomnia,
Dizziness

Table 5 Doses and adverse effects of application of Non-TCA (NTCA) antidepressants

Sr. No. Antidepressant Doses Therapeutic Side-effects Toxicity in
substrate index overdose
(Common
Name)
1 Agomelatine 25-50 Narrow Dizziness Unclear
mg/day Abnormal
Changes In
Liver
Function
Tests
Abdominal
Pain
2 Bupropion 150 mg/day Narrow Insomnia, Moderate
Nausea,
Pharyngitis,
Weight Loss,
Constipation,
Dizziness,
Headache,

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Fredy Satriadi (201610330311127)

And
Xerostomia
3 Duloxetine 60 mg/day Wide Asthenia, Moderate
Constipation,
Diarrhea,
Dizziness,
Drowsiness,
Fatigue,
Hypersomnia
, Insomnia,
Nausea,
Sedation,
Headache,
and
Xerostomia.
4 Mianserin 30-200 Narrow Drowsiness, Low
mg/day Liver
Dysfunction,
Jaundice,
Gynaecomast
ia,
Convulsions,
Hypomania,
Hypotension,
Hypertension
; Coma,
Arthralgia,
Oedema,
Tachycardia,
Bradycardia,
Vomiting,
Dizziness
and Ataxia,
Anti-
cholinergic
Effects
5 Reboxetine 8mg/Day Narrow Urinating Low
problem, Dry
Mouth,
Sweating,

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Fredy Satriadi (201610330311127)

Tingling or
Numbness of
The Hands or
Feet,
Constipation,
Increase in
Blood
Pressure,
Increase in
Heart Rate,
Impotence,
Insomnia,
Headache,
Dizziness,
Nausea,
Decreased
Appetite
6 Trazodone 150-400 Wide Blurred Low
mg/day vision,
Dizziness,
Drowsiness,
Headache,
Nausea,
Vomiting,
and
Xerostomia
Syncope,
Edema,
Ataxia,
Confusion,
Diarrhea,
Hypotension,
Insomnia,
Sedation, and
Tachycardia
7 Venlafaxine 75 mg/day Narrow Bipolar Moderate
with Food Disorder
(37.5 mg/ (Manic
day if Depression);
Anxious or Cirrhosis Or

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Fredy Satriadi (201610330311127)

Debilitated) Other Liver

Disease,
Kidney
Disease,
Heart
Disease,
High Blood
Pressure,
High
Cholesterol,
Diabetes;
Narrow-
Angle
Glaucoma, A
Thyroid
Disorder, A
History of
Seizures, A
Bleeding or
Blood
Clotting
Disorder,
Low Levels
of Sodium in
Your Blood

Tabel 6 Perkiraan perbandingan antidepresan dan sifat terapeutiknya

Sr. No. Type of Anti- Name of Anti- Half-life Availability Dietary
depressants depressant consideration
Citalopram About 36 Tablet Contains
hours Lactose
Escitalopram About 30 Tablets -
hours
Fluoxetine 96-144 hours Dispersible Contains
1. SSRIs (4-6 Days) Tablets*/ Gelatin
Capsules
Fluvoxamine 17-22 Hours Tablet -
Paroxetine About 24 Tablet -
Hours
Sertraline 22-36 Hours Tablet -

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Fredy Satriadi (201610330311127)

Duloxetine 8-17 Hours Capsules Contains

Gelatin
Venlafaxine 4-7 Hours Capsules Contains
Gelatin
Amitriptyline 9-25 Hours Tablets -
Dosulepin About 50 36 Hours -
SNRIs Hours (Just
2.
Over 2 Days)
Clomipramine 36 Hours Tablets -
Doxepin 33-80 Hours Capsules Contains
(1.5- 3.3 Lactose
Days)
Imipramine About 19 Liquid Contains
Hours Lactose
Lofepramine 12-24 Hours Tablets Contains
Tricyclics Lactose
3.
Nortriptyline About 36 Tablets Contains
Hours Lactose
Trimipramine About 23 Capsules Contains
Hours Lactose
Mianserin 6-39 Hours Tablets Contains
Lactose
Trazodone 5-13 Hours Tablets Contains
Tricyclic-
Lactose
Related
4. Isocarboxazid About 36 Tablets Contains
Drugs
Hours Lactose
Phenelzine 11-12 Hours Tablets Requires
Food
Restrictions
Moclobemide 2-4 Hours Tablets Requires
Food
Restrictions
Tranylcypromine About 2 Tablets Requires
5. MAOIs Hours Food
Restrictions
Agomelatine 1-2 Hours Tablets Contains
Lactose
Mirtazapine 20-40 Hours Liquid -
Reboxetine About 13 Tablets -
6. Other
Hours

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Fredy Satriadi (201610330311127)

Triptafen N/A Tablets -

Vortioxetine About 66 Tablets -
Hours

* Tablet dispersi akan hancur dengan cepat di mulut atau dapat dicampur dengan air, jus jeruk
atau jus apel. * Semua antidepresan lain yang saat ini tersedia tidak mengandung laktosa atau
gelatin, dan tidak memerlukan batasan diet tertentu, meskipun hati-hati saat minum alkohol
direkomendasikan untuk semua antidepresan

Inhibitor reuptake serotonin selektif (SSRI)

SSRI diketahui secara selektif menghambat transpor serotonin. Beberapa SSRI adalah fluoxetine
(Prozac, Selfemra), paroxetine (Paxil, Pexeva), sertraline (Zoloft), citalopram (Celexa) dan
escitalopram (Lexapro). Tindakan SSRI ini menghasilkan peningkatan serotonin secara tiba-tiba
di area somatodendritik neuron serotonergik yang menyebabkan desensitisasi serotonin
somatodendritic serotonin-1A autoreceptor. Sebagai hasilnya, aliran impuls neuron meningkat.33
Hal ini menyebabkan peningkatan pelepasan serotonin dari terminal akson, yang berujung pada
desensitisasi reseptor serotonin postinaptik Desensitisasi reseptor ini dapat berkontribusi pada
tindakan terapi SSRI atau dapat menjelaskan perkembangan toleransi terhadap efek samping
akut SSRI. Analisis farmakologis SSRI menunjukkan bahwa agen ini dapat menyebabkan
disinhibisi 5-HT neurotransmisi yang kuat tetapi lambat dalam sistem saraf pusat (SSP). Dalam
hal ini, aksi antidepresan dimediasi oleh jalur dari otak tengah ke korteks prefrontal. Efek
samping yang ditimbulkan oleh SSRI termasuk kecemasan, gangguan tidur, disfungsi seksual
(penurunan libido, berkurangnya kesenangan dan pengurangan gairah), dan gangguan
gastrointestinal.30 Diperkirakan bahwa toksisitas reseptor 5-HT2 dan 5-HT3 dari jalur
serotonergik tertentu bertanggung jawab. Hubungan timbal balik ada antara serotonin dan
dopamin yaitu. serotonin cenderung menghambat fungsi seksual dan cenderung dopamin untuk
meningkatkan fungsi seksual. Dipercayai bahwa jalur serotonin turun dari batang otak ke
sumsum tulang belakang ke neuron tulang belakang yang memediasi berbagai refleks tulang
belakang bertanggung jawab atas disfungsi seksual dalam bentuk masalah ejakulasi dan orgasme.
Telah dilaporkan bahwa peningkatan aliran serotonergik melalui jalur ini menghambat fungsi
seksual. Efek negatif serotonin pada fungsi seksual dimediasi melalui reseptor 5-HT2. Oleh
karena itu antagonis 5-HT2 dapat membalikkan SSRI yang disebabkan oleh disfungsi seksual.
Antidepresan yang bertindak sebagai serotonin / norepinefrin / dopamin reuptake inhibitor
(SNRI)
Stahl30 telah menunjukkan efek farmakologis venlafaxine dan menemukan bahwa itu
tergantung pada dosis. Pada dosis rendah, ini pada dasarnya bertindak sebagai SSRI dan pada
dosis sedang hingga tinggi, menyebabkan penghambatan reuptake NE tambahan dan pada dosis
sangat tinggi, terjadi penghambatan reuptake DA.30,39 Antidepresan lain seperti nefazodone dan
tindakan trazodon melalui reseptor serotonin-2 antagonisme dengan serotonin reuptake blokade.

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Fredy Satriadi (201610330311127)

Sangat menarik untuk disebutkan di sini bahwa SSRI menstimulasi reseptor 5-HT2 ketika
nefazodon dan trazodon menghambat reseptor.30 Tindakan nefazodon dan trazodon ini
menjadikannya antidepresan yang lebih aman daripada SSRI.
Anti Depresan sebagai norepinefrin dan inhibitor reuptake dopamin (Bupropion)
Bupropion adalah satu-satunya antidepresan yang secara selektif bekerja pada sistem
noradrenergik dan dopaminergik dan tidak pada serotonin sistem.40 Bupropion menunjukkan
aktivitas dopaminergik dan noradrenergik, oleh karena itu dapat memberikan efek positif dalam
mengatasi gangguan defisit perhatian41 dan dalam pengobatan penghentian merokok.38
Bertolak belakang dengan manfaat dari obat ini, bupropion telah terbukti menimbulkan beberapa
efek samping seperti seperti stimulasi berlebihan, agitasi, insomnia dan mual

Antidepressan menunjukkan antagonisme α-2 plus antagonisme serotonin-2 dan serotonin-3

Mirtazapin, sebuah antidepresan serotonergik noradrenergik dan spesifik, 43 memiliki
aksi pro-adrenergik dan proserotonergik. Tindakan pro-adrenergik dan proserotonergik dari
mirtazapin disebabkan oleh sifat-sifat antagonis alfa2nya, yaitu penghancuran neurotransmisi
serotonin dan norepinefrin. Mirip dengan nefazodone, mirtazapine juga tidak menggunakan
toksisitas SSRI karena stimulasi 5-HT2. Karena sifat antihistamin yang kuat dikaitkan dengan
mirtazapin, ia memiliki beberapa efek samping seperti penambahan berat badan dan sedation.
Antidepresan bertindak sebagai noradrenalin spesifik reuptake inhibitor (NRI) (Reboxetine)
Reboxetine, inhibitor reuptake noradrenalin (norepinefrin), secara eksklusif tidak
terkait dengan TCA atau SSRI. Sifat spesifik dari reboxetine termasuk afinitas tinggi untuk
transporter noradrenalin, dan sedikit afinitas untuk reseptor neuro lainnya termasuk serotonin,
dopamin, histamin, situs muskarinergik dan alfa adrenergik.
Antidepresan bertindak sebagai Serotonin reuptake (Tianeptine)
Tianeptine sedang, senyawa trisiklik jenis dibenzothiazepine meningkatkan serapan presinaptik
serotonin setelah pemberian tunggal maupun berulang, tetapi tindakan ini tidak terkait dengan
efek pada sistem post-sinaptik 5-HT.50,89 Tianeptine memiliki tidak ada afinitas untuk reseptor
antihistamin alfa1 adrenergik dan H1. Tianeptine dapat dianggap sebagai antidepresan posisi
menengah. Defrance et al.45 miliki menunjukkan bahwa tianeptin tidak menunjukkan afinitas
terhadap reseptor muskarinik. Tianeptine telah dilaporkan mengeluarkan sedikit toksisitas seperti
gastralgia, sakit perut, mulut kering, anoreksia, mual, muntah, perut kembung, insomnia, kantuk,
mimpi buruk, asthenia, dan takikardia pada pasien tertentu.
Fitokimia sebagai antidepresan.
Beberapa fitokimia dilaporkan bertindak sebagai antidepresan. Bahan kimia ini hadir
dalam ekstrak tanaman diharapkan lebih aman dan lebih hemat biaya daripada antidepresan yang
ada. Sifat etnofarmasi yang berbeda dari berbagai ekstrak tumbuhan dan efeknya dirangkum
dalam Tabel 7
Table 7 Phytochemicals acting as natural antidepressants
Plant Extract Common Part used from the Type of extract, Effects
name plant compound, doses

80
Fredy Satriadi (201610330311127)

Allium Chinese Bulb Water Extracts Behavioural Despair

macrostemon Garlic
Allium Garlic Rhizome Ethanolic
sativum Extract, dose-
25,50 and
100mg/kg
Aloysia Lemon Aerial Part Hydroethanolic Effect on Depression
polystachya Verbena Extract
Apocynum Dogbane Aerial Part Dose-30-
venetum 125mg/kg
Areca catechu Betel Nut Fruit Ethanolic Effect on Motor
Extract, dose- 4- Activity
80mg/kg
Asparagus Satavari Root Methanolic Effect on Serotonergic
racemosus Extract, dose- And Noradrenergic
100,200 and System And
400mg/kg Augmentation Of
Antioxidant Defences
Bacoba Brahmi Aerial Part Methanolic Significant Antioxidant
monnieri Extract, dose- 20 Effect, Anxiolytic
and 40mg/kg Activity And Improve
Memory Retention
Berberis Indian Root Berberine, (An Effect on CNS, Inhibit
aristata Barberry Alkaloid), dose- Monoamine Oxidase-A
5,10 and
20mg/kg.
Bupleurum Chai Hu, Root Methanolic Psycho stimulant Effect
falcatum Hare’s Extract
Ear Root
Cimicifuga Black Roots And Ethanolic And Effect on heraprutical
racemosa Bugbane Rhizomes Isopropanolic Responses In
Aqueous Extracts Climacteric Women
Clitoria Butterfly Root ,Bark Ethanolic Effect on Cognitive
ternatea Pea Extract, 50 or Behaviour, Anxiety,
100mg/kg Depression, Stress
Crocus Saffron Stigma Ethanolic Extract Effect on Depression
sativus
Curcuma Turmeric Rhizome Aqueous Extract, Mao Inhibition In Brain
longa dose- 140-
560mg/kg for 14

81
Fredy Satriadi (201610330311127)

days.
Emblica Amla Fruit - Effect on Psychiatric
officinalis Disorder
Ginkgo biloba Ginkgo, Leaves Lipophilic Act As Anti-Stress and
Maidenha Extract, dose- 50 Antidepressant
ir Tree and 100mg/kg
Glycyrrhiza Mulethi Root Liquiritin Antidepressant Like
uralensis (Flavones) and Antioxidant
Activity By Measuring
Erythrocyte Superoxide
Dismutase (Sod)
Activity And Plasma
Malondialdehyde
(MDA) Level
Glycyrrhiza Mulethi Root Aqueous Extract, Effect on Inhibition Of
glabra Liquorice Extract Mao

Plant Extract Common Part used Type of Effects References

name from the plant extract,
compound,
doses
Hippeastrum Amaryllis Flower Alkaloids Effect on 64
vittatum Neurological
Disorders
And Neuro
degenerative
Disease
Hypericum Canary Island Aerial Part Methanolic Neuro 65
canariensel. St .John Wort Extract pharmacologi
And cal Effect,
Hypericum Helps In
glandulosum Muscle
Relaxation,
Anti-
cholinergic
And Sedative
Properties
Hypericum Hypericum Aerial Part Methanolic Effect on 66
reflexum Extract CNS

82
Fredy Satriadi (201610330311127)

Kaempferia Kava Kava Kava Root/ Rhizome Effect on 67

parviflora Rhizome Extract Psychiatric
Illness
Lafoensia Didal Leaves - Effects on 68
pacari CNS
Magnolia Magnolia, Bark, Honokiol and Effect on 69
bark and Ginger Rhizome Magnolol, Synergistic
ginger Polysaccharid Interaction
rhizome es
Marsilea Dwarf Water Root Marsiline, Effect on 70
minuta Clover Sedative And Insomnia And
Anticonvulsan Other Mental
t Property Disorders
Mimosa Sensitive Leave Aqueous Act As 71
pudica Plant Extract Tricyclic
Antidepressan
ts
Mitragyna Kratom Leaves Mitragynine Effect on 72
speciosa An Active Diarrhea,
Alkaloid Diabetes And
Improve
Blood
Circulation
Momordica Bitter Gourd/ Fruit Methanol 73
charantia Bitter Melon Extract, dose-
300mg/kg
Morinda Indian Root Dose- 25- Effective In 74
officinalis Mulberry 50mg/kg Response
Rate
Oscimum Tulsi Aerial Part 75
sanctum
Paeonia Garden Peony Root Ethanolic Effect on 76
lactiflora pall extract, dose- Central
250 and Monoaminerg
500mg/kg ic
Neurotransmit
ter System
Piper Piper Stem And Amide Antinocicepti 77
laetispicum Root (Alkaloid), ve Properties,
dose- 2mg/kg Effect on Pain

83
Fredy Satriadi (201610330311127)

And
Depression
Piper Black Pepper Fruit Piplartine (An Effect on 78
tuberculatum Amide) , Anxiolytic
dose- 50 and And
100mg/kg Antidepressan
t Activities,
Anxiety And
Depression.
Polygala Polygala Aerial Part Scopoletin, A Effect on 79
sabulosa Coumarin Serotonergic,
Dopaminergic
And
Noradrenergic
Systems
Rhazyastricta White Henna Leaves Aqueous Effect on 80
Extract Monoamine
Oxidase
Inhibition
Rosmarinusof Rosemary Fresh Juice Hydro- Interaction 81
ficinalis alcoholic With The
Extract Monoaminerg
ic System
Salvia elegans Pineapple Leave Hydroalcoholi Putative 82
Sage c Extract Anxiolytic
Schinusmolle Peruvian Leaves Hexenic Pharmacologi 83
L Pepper Tree Extract cal Effects,
atleast At A
Preclinical
Level
Siphocampylu Siphocampylu Aerial Parts Hydroalcoholi Interaction 84
s verticillatus s c Extract , With
dose range- Adrenergic,
100- Dopaminergic
1000mg/kg ,
Glutamatergic
And
Serotonergic
System
Sphaeranthu East Indian Whole Part Hydroalcoholi Effect On 85

84
Fredy Satriadi (201610330311127)

sindicus Globe Thistle c Extract Anxiety,

Depression
And
Convulsions
Tabebuia Lapacho, Bark Ethanolic Effect Of The [86]
avellaneda Taheboo Tree Extract Association
Of The
Extract With
The
Antidepressan
ts

Kesimpulan
Depresi adalah kondisi psikologis yang serius tetapi dapat diobati secara efektif dengan terapi
yang tersedia. Stok antidepresan yang tersedia dapat digunakan secara selektif untuk mengobati
depresi dengan aman tanpa efek samping. Obat yang tepat untuk seseorang tergantung pada
kondisi klinis-fisiologis pasien seperti gejala, kemungkinan efek samping, dan interaksi dengan
obat lain, keadaan kehamilan atau menyusui dan kondisi mental. Kelas antidepresan yang
berbeda dalam praktik tergantung pada jenis dan kebutuhan depresi. Antidepresan termasuk
inhibitor reuptake serotonin selektif (SSRI), Serotonin dan norepinefrin reuptake inhibitor
(SNRI), Norepinefrin dan inhibitor reuptake dopamin (NDRI: Bupropion (Wellbutrin, Aplenzin,
Forfivo XL), antidepresan atipikal (trazo) (Oleptro), mirtazapine (Remeron) dan vortioxetine
(Brintellix)), antidepresan Trisiklik (imipramine (Tofranil), nortriptyline (Pamelor),
amitriptyline, doxepin, doberepin, trimipramine (Surmontil)) desipramine (Norpramin) dan
rotriptyline (Vivactil)), inhibitor Monoamine oxidase (MAOIs: tranylcypromine (Parnate),
phenelzine (Nardil) dan isocarboxazid (Marplan)) dan obat-obatan lain seperti penstabil suasana
hati atau antipsikotik, semua obat anti-kecemasan dan stimulan. Banyak dari obat ini memiliki
efek sampingnya. Akan tetapi bermanfaat untuk menyelidiki prinsip berbasis tanaman untuk
digunakan sebagai kemoterapi yang lebih efektif dan aman dibandingkan dengan rejimen sintetis
yang saat ini digunakan. Ucapan Terima Kasih Khushboo berterima kasih kepada UGC-New
Delhi untuk dukungan keuangan dalam bentuk persekutuan. Konflik kepentingan Penulis
menyatakan tidak ada konflik kepentingan.

85
 Neuropsychiatric Disease and Treatment
Open Access Full Text Article
Novel treatment options in depression
and psychosis
Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 91.200.82.23 on 27-Jul-2018
eva Ceskova
Petr Silhan
Department of Psychiatry, University
Hospital Ostrava, Ostrava, Czech
Republic
For personal use only.
Correspondence: eva Ceskova
Department of Psychiatry, Faculty
Hospital Brno, Jihlavska 20, 625 00
Brno – Bohunice, Czech Republic
Tel +420 532 232 569
Fax +420 532 233 706
email eva.ceskova@gmail.com
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http://dx.doi.org/10.2147/NDT.S157475
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open access to scientific and medical research
Review
Abstract: In spite of tremendous development in central nervous system research, current
treatment is suboptimal, especially in severe mental disorders. In medicine, there are two
main methods of improving the health care provided: seeking new treatment procedures
and perfecting (optimizing) the existing ones. Optimization of treatment includes not only
practical tools such as therapeutic drug monitoring but also implementation of general trends
in the clinical practice. New pharmacological options include new more sophisticated forms
of monoaminergic drugs, old drugs rediscovered on the base of a better understanding of
pathophysiology of mental illnesses, and drugs aimed at new treatment targets. In depression,
treatment resistance to antidepressive pharmacotherapy represents one of the most important
clinical challenges. Switching to monotherapy with new multimodal/multifunctional anti-
depressants and augmentation with new atypical antipsychotics (aripiprazole and brexpip-
razole) may be promising options. Further, current evidence supports utility and safety of
adjunctive treatment of nutraceuticals. Novel approaches being studied include ketamine and
opioids. Recent advances in technology and emerging knowledge about dysfunctional brain
circuits and neuroplasticity have led to the development of different new neuromodulation
techniques usually used as add-on therapy. Antipsychotics are still the cornerstone of the
current treatment of schizophrenia. Two new partial dopamine agonists, brexpiprazole and
cariprazine, are now available in addition to aripiprazole. Although the mechanisms of action
are similar, the two agents differ in terms of their pharmacodynamic profiles. Further, two
new formulations of long-acting injections of second-generation antipsychotics (aripiprazole
lauroxil and 3-month paliperidone palmitate) were introduced into clinical practice. New
treatment options not yet available include cannabidiol, glutamate modulators, and nicotine
receptors agonists.
Keywords: optimization of treatment, multimodal/multifunctional antidepressants, partial
dopamine agonists, glutamate modulators, nicotine receptors agonists
Introduction (burden of mental disease)
Mental disorders are a major public health concern. The global lifetime prevalence
of mental disorders in adults is estimated to be between 12.2% and 48.6%.1 Mental
disorders are also a leading contributor to the global disease burden: in 2013, 5.4%
of global disability-adjusted life years and 17.4% of global years lived with disability
were due to mental disorders.2
However, current treatment is suboptimal, especially in severe mental disorders
such as depressive disorder and schizophrenia. There are two main methods of
improving the health care provided: seeking new treatment procedures and perfecting
(optimizing) the existing ones.
Neuropsychiatric Disease and Treatment 2018:14 741–747 741
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and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you
hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission
for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
86
 Ceskova and Silhan
Optimizing the treatment
in psychiatry
In all of medicine there is a general consensus, encoded in
treatment guidelines, that treatment should be evidence-
based, measurement-based, complex, and individualized
(personalized).
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However, the introduction of these principles in clinical
practice is not at all satisfactory. This fact calls for better
education of medical students, physicians in primary care,
specialists, and all prescribers, and for improvement of the
current treatment.
Measurement-based care, increasingly recognized as a
treatment enhancement, has become more common with
availability of paper or computerized questionnaires and
structured interviews. It provides opportunities to increase
precision, consistency, and appropriateness of care. However,
clinicians are still reluctant to incorporate measurement of
outcomes into their practices. The reasons for this resistance
For personal use only.
are manifold.
Despite the clear and positive evidence for the use of
antipsychotics and antidepressants (ADs) that have informed
corresponding treatment guidelines, there are substantial
reasons to search for ways to improve treatment effective-
ness. Emerging evidence indicates that treatment context
profoundly affects psychopharmacological interventions.
This supports the idea of complex treatment, which includes
not only pharmacotherapy but also psychosocial approaches.
Pharmacological approaches should always be combined
with nonpharmacological approaches, optimizing environ-
mental influences. The influence of psychotropic drugs on
brain functions is in continuous interaction with brain plas-
ticity stimulated by environmental influences. The positive
contextual factors such as support of positive social interac-
tions and regular physical activities should be introduced
into clinical practice.3
Clinicians tailor (personalize) treatment depending on
particular clinical features, the individual psychopathology,
individual risk profile, and patient’s experience and prefer-
ence, even in the absence of strong evidence that such features
are truly predictive. Further, patients differ in their ability
to absorb, distribute, metabolize, and excrete drugs due to
concurrent disease, age, concomitant medication, or genetic
peculiarities. The importance of sex-related pharmacologic
differences in drug pharmacokinetics and pharmacodynamics
is now indisputable.4 To overcome problems of nonresponse
or adverse reactions due to pharmacokinetic abnormalities,
it is helpful to monitor the pharmacokinetic characteristics
of individual patients and optimize the drug concentration.
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The analysis and interpretation of plasma levels (therapeutic
drug monitoring, TDM) is available; however, this method
has not yet been used routinely and it seems unlikely that
TDM will become a standard of care for all agents and all
patients. Published guidelines for TDM indicate for which
patients and what circumstances TDM is cost-effective.
Further, TDM presents an adherence-improving strategy
that has a tremendous potential for reducing health care
costs, personal suffering, and the burden on families.5 Low
adherence is a major problem of long-term psychotropic
treatment. Insufficient adherence in psychiatry, especially
in psychotic patients (~50%), has severe consequences. Its
prevalence has not changed significantly with the introduc-
tion of new medications.6
Aiming for more precise treatment, individualization may
help to ensure optimal outcomes.7 To achieve true precision
in pharmacotherapy, it may be necessary to identify and
deploy treatment-specific predictors of response. Combinato-
rial pharmacogenomic testing encompassing more complete
genomic information by combining moderate-risk alleles has
become commercially available.8
Patient-centered medicine seeks to focus attention first on
the need and concerns of the patient and to consider social
and economic factors.9 Knowledge of the pharmacology of
psychiatric medications is necessary but not sufficient for the
delivery of appropriate, safe, and effective care. The clinician
needs to devote adequate time for communicating treatment
needs to patients and develop a strong treatment alliance that
persists even during symptomatic exacerbations.10
Depression
Major depressive disorder (MDD) is a widespread disease,
with a lifetime prevalence of 15% and an annual incidence
of ~7%. It is associated with significant costs in qual-
ity of life, loss of work productivity, and a high risk of
mortality.11
About two-thirds of patients do not achieve full remis-
sion, which is key to restoring full functioning and preventing
relapse. After excluding pseudoresistance, several treatment
strategies are available for these patients, such as changing,
augmenting, and combining ADs.
New treatment options currently
available
Multimodal ADs
Multimodal ADs have more than one mode of action, ie,
reuptake inhibition and activity on membrane-bound recep-
tors, pooling two distinct modes of neural signaling. Through
Neuropsychiatric Disease and Treatment 2018:14
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 Dovepress
these multimodal mechanisms, they produce a downstream
effect on interconnected neurotransmitter systems. The dif-
ferences among available multimodal/multifunctional ADs
are based on their action at receptor subtypes. Against this
background, we feature the new (the last registered) ADs
vortioxetine (Trintellix) and vilazodone (Viibryd) with
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regard to their serotonin receptor targets 5-HT1A, 5-HT3,
and 5-HT7, which may account for their specific effects on
certain symptoms of depression (eg, cognition and anxiety)
as well as a characteristic side effect profile. The efficacy of
new multimodal ADs has not yet been tested in treatment-
resistant depression.12,13
Drugs targeting the glutamatergic system might open up
a promising new territory for the development of drugs to
meet the needs of patients with major depression.
Ketamine
Ketamine is an anesthetic drug with N-methyl-D-aspartate
For personal use only.
(NMDA) glutamate receptor antagonist activity, which
may provide a novel AD mechanism. Ketamine has several
brand names for the drugs in which it is the sole medica-
tion. According to a recently published systematic search
for relevant randomized trials, ketamine does indeed have a
rapid but transient AD effect. However, there is substantial
heterogeneity in clinical response, and ketamine’s underlying
mechanisms of action are not entirely understood.14,15
The observation that a single intravenous dose of gluta-
matergic modulator ketamine produces a robust and rapid
AD effect was a turning point that opened the way for other,
more selective glutamatergic modulators (intranasal esket-
amine, rapastinel).16
New drugs
Opioids
The AD potential of opioids has been known for centuries,
but their dependence-producing properties led to the rapid
adoption of monoamine-based ADs once they become
available in the 1950s. Nowadays, a growing body of pre-
clinical and clinical evidence supporting the hypothesis that
mood disorders involve deregulation of the endogenous
opioid system is emerging. The contemporary clinical
use of opioid agonists as ADs in clinical practice remains
highly limited because of unresolved issues of abuse and
dependence.17 To overcome the limitations of opioid agonists,
a combination of a µ and κ opioid partial agonist, buprenor-
phine, and a mu opioid antagonist samidorphan were devel-
oped. The results of a multicenter, randomized, double-blind,
placebo-controlled study have shown that the modulation
Neuropsychiatric Disease and Treatment 2018:14
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Novel treatment options in depression and psychosis
of the opiate system may be a novel treatment approach for
treatment-resistant depression.18
Psychedelics
The psychedelic drugs, including lysergic acid diethylamide
and psilocybin, were used extensively in the treatment of
mood disorders and other psychiatric conditions, before their
prohibition in the late 1960s.19 A recently published system-
atic review of clinical treatment studies using psychedelics
in patients with broadly defined depression included 423
individuals in 19 studies, and 335 (79.2%) showed clinician-
judged improvement after treatment with psychedelics.20
A recently completed pilot study in the UK favors the use of
psilocybin with psychological support in treatment-resistant
depressive disorder. Psychedelics may exert therapeutic
effects for psychiatric disorders by acutely destabilizing
local brain network hubs and global network connectivity,
providing the occasion for brain network “resetting” after
the acute effects have resolved.21
New augmentation strategy
The most evidence-based augmentation of specific serotonin
reuptake inhibitors is an augmentation with atypical antip-
sychotics. Recently, the spectrum of atypical antipsychotics
used in this indication has been enlarged by brexpiprazole
(Rexulti, approved by the US Food and Drug Administration
in 2015), a new partial dopamine agonist.22
Recently, several reviews showed evidence of efficacy
of a safe augmentation strategy – nutraceuticals. The coad-
ministration of standardized pharmaceutical-grade nutrients,
referred to as nutraceuticals, may provide an effective and
safe approach to enhancing AD effects, by either synergisti-
cally augmenting a particular activity of an AD or providing a
range of additional biological effects.23 All nutraceuticals are
generally well tolerated, with gastrointestinal adverse events
most commonly reported across all nutraceutical groups.
Current evidence supports adjunctive use of S-adenosylme-
thionine, methylfolate, omega-3, and vitamin D with ADs
to reduce depressive symptoms.23
However, depression is not simply the result of neu-
rotransmitter abnormalities. A large body of evidence points
to a deregulated endocrine and inflammatory response system
and reduced neurogenesis, in the pathogenesis of depression.
MDD is associated with a deregulation of immune response
and with chronic inflammatory activity as reflected by
abnormal profiles of circulating pro- and anti-inflammatory
cytokines. Several studies indicate that the adjunctive use of
anti-inflammatory agents in patients with MDD improves
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743
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88
 Ceskova and Silhan
depressive symptoms, in particular in treatment-resistant
depression with an inflammatory profile as defined by a
C-reactive protein.24 Several anti-Il-1 β-targeted compounds
have been recently developed, including antibodies and Il-1β
receptor antagonist. Targeting interleukin-1β may be useful
for subgroups of patients with inflammatory depression that
Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 91.200.82.23 on 27-Jul-2018
is defined by clinical features of trauma, resistance to AD,
and raised interleukin-1 levels.25
Further, advances in technology and emerging knowledge
about the dysfunctional brain circuits underlying depression
and neuroplasticity have led to the development of different
new neuromodulation techniques (transcranial magnetic
stimulation, vagus nerve stimulation, and deep brain stimula-
tion) usually used as add-on therapy.26
Schizophrenia
Schizophrenia, a chronic brain disorder that affects ~1%
of the adult population and ~26 million people worldwide,
For personal use only.
is considered among the most disabling and economically
catastrophic medical disorders as ranked by the World
Health Organization.27 Only ~10%–15% of people who
suffer from schizophrenia maintain full-time employment
of any type.28
Because the etiology of schizophrenia is unknown, the
goals of treatment are to eliminate disease-related symptoms
and to enhance functioning. The cornerstone of the current
treatment is antipsychotic medication. Antipsychotics vary
in terms of tolerability and safety concerns, and patients
themselves differ in terms of preexisting risk factors and
comorbidities that make drug selection often challenging.
New treatment options currently
available
Antipsychotics
In addition to aripiprazole, two new dopamine receptor partial
agonists, brexpiprazole and cariprazine (Vraylar), are now
available. Although the mechanisms of action are similar,
the three agents differ in terms of their pharmacodynamic
profiles.29 Compared with aripiprazole, brexpiprazole has
low intrinsic activity at the dopamine D2 receptor and has an
approximately tenfold higher affinity for serotonin 5-HT1A
and 5-HT2A receptors, potentially enhancing tolerability.
When cariprazine was compared with aripiprazole, similar
D2 and three- to tenfold greater D3 versus D2 selectivity
was observed for cariprazine. It remains unknown whether
targeting the dopamine D3 receptor over the dopamine D2
receptor is clinically advantageous, but theoretically dop-
amine D3 preferring agents may exert procognitive effects.
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Although all three medications are approved for the treat-
ment of schizophrenia, both aripiprazole and brexpiprazole
are also approved for adjunctive treatment of MDD, and
both aripiprazole and cariprazine are also approved for
acute treatment of manic or mixed episodes associated with
bipolar I disorder.
In Phase III of clinical development is a novel antip-
sychotic lumateperone with a unique pharmacological
profile. Lumateperone, combining potent 5-HT2A receptor
antagonism with cell-type-specific dopamine and glutamate
receptor modulation plus serotonin reuptake inhibition, is
a novel modulator of serotonin, dopamine, and glutamate
neurotransmission.30
New formulations of antipsychotics
Long-acting injections (LAIs) of the second-generation
antipsychotics provide continuous therapy facilitating patient
participation in treatment and enhancing their recovery.
Although LAIs may improve treatment adherence, only a
minority of medication-nonadherent patients receive them.
Significant reductions in health care utilization or costs asso-
ciated with schizophrenia have been demonstrated in some
studies of LAI antipsychotics, although other studies have
not demonstrated these effects and showed cost-neutrality or
even greater cost usually in context with the type of study (eg,
observations of naturalistic studies contrary to randomized
controlled studies).31,32
Recently, two new LAI formulations of second-gener-
ation antipsychotics have become available, aripiprazole
lauroxil (Aristada) and 3-month paliperidone palmitate
(Invega Sustenna and Invega Trinza). In October, 2015, the
US Food and Drug Administration approved aripiprazole
lauroxil, a prodrug of aripiprazole, for the treatment of adults
with schizophrenia. Enzyme-mediated hydrolysis likely con-
verts the injected aripiprazole lauroxil to N-hydroxymethyl
aripiprazole, which is then hydrolyzed to aripiprazole.
Aripiprazole lauroxil works primarily as a result of the
activity and affinities for the D2 receptors of the parent drug,
aripiprazole, and, to a lesser extent, of its major metabolite,
dehydroaripiprazole, which also represents 30%–40% of
the aripiprazole exposure in plasma. Aripiprazole lauroxil
is metabolized extensively in the liver via cytochrome P450
CYP isoenzymes 3A4 and 2D6. Its pharmacokinetic profile
led to approval of dosing intervals of every 6 weeks for the
882 mg dose. The overall tolerability is consistent with what
is known about oral aripiprazole.33
A new formulation of paliperidone palmitate, paliperidone
palmitate 3-month formulation that was recently approved in
Neuropsychiatric Disease and Treatment 2018:14
89
 Dovepress
the US for the maintenance treatment of schizophrenia, offers
a substantially longer dosing interval of once every 3 months
than is available for typical or new-generation atypical LAI
formulations (1 monthly). No clinically relevant differ-
ences were observed in pharmacokinetic exposures between
3-month and 1-month formulations. Both have similar toler-
Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 91.200.82.23 on 27-Jul-2018
ability profiles and no new safety issues were detected. The
new paliperidone LAI with its 3-month dosing interval is a
unique option for relapse prevention in schizophrenia.34
LAI antipsychotics eliminate the need for daily dosing,
typically ensure sustained plasma levels for several weeks,
and help to reliably monitor adherence. The new LAI options
provide additional flexibility in terms of increasing the time
between injections.
New treatment options not yet
available in clinical practice
Cannabidiol (CBD)
For personal use only.
The endocannabinoid system is a highly promising new
pharmacological target in the context of schizophrenia.
Modulation of this system by the main psychoactive com-
ponent in cannabis, Δ9-tetrahydrocannabinol, induces acute
psychotic effects and cognitive impairment. However, the
nonpsychotropic, plant-derived cannabinoid agent CBD may
have antipsychotic properties and thus may be a promising
new agent in the treatment of schizophrenia. The first small-
scale clinical studies with CBD for the treatment of patients
with psychotic symptoms further confirmed the potential of
CBD as an effective, safe, and well-tolerated antipsychotic
compound, although large randomized clinical trials will
be needed before this novel therapy can be introduced into
clinical practice.35
Treatment options for negative
symptoms and cognitive dysfunction
Glutamate modulators
The glutamatergic system has been implicated in the
pathophysiology of schizophrenia and affective disorders.
A key component is the dysfunction of the glutamatergic
receptor, N-methyl-D-aspartate receptor (NMDAR). Sub-
stances regulating activation/inhibition of the NMDAR are
promising in therapeutic approaches to negative symptoms,
cognition, and mood.36 Schizophrenia is related to cognitive
and negative symptoms, which often are resistant to current
treatment approaches.
The NMDAR hypofunction theory of schizophrenia pro-
poses that enhancement of the receptor function may lead to
efficacy against schizophrenia. Consistent with this theory,
Neuropsychiatric Disease and Treatment 2018:14
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Novel treatment options in depression and psychosis
recent clinical trials have demonstrated that the enhancement
of NMDAR function by potentiating the glycine site of the
receptor is efficacious in the treatment of negative and pos-
sibly cognitive symptoms of schizophrenia.37 Metabotropic
glutamate receptors (mGluRs) have attracted significant
attention as potential drug targets. This is due to the belief
that metabotropic receptor targeting provides a way for
modulating glutamate tone and phasic release in a subtler
manner than that which can be achieved through glutamate
ionotropic receptors. Specifically, emerging preclinical and
clinical data suggest that activation of Group II mGluRs is a
promising approach for the treatment of schizophrenia. Fur-
ther, metabotropic glutamate receptor subtype 5 (mGluR5),
encoded by the GRM5 gene, represents a compelling novel
drug target for the treatment of schizophrenia. Accordingly,
mGluR5 positive allosteric modulators show encouraging
therapeutic potential in preclinical schizophrenia models,
particularly for the treatment of cognitive dysfunctions.36,38
Nicotine receptors agonists
The excessive cigarette smoking exhibited by schizophrenic
patients suggests that they might be self-medicating to ame-
liorate certain aspects of the characteristic positive, negative,
and cognitive symptoms associated with the disease. Morpho-
logical examinations found alterations in nicotinic receptors
in postmortem tissue from schizophrenic individuals com-
pared to controls, especially in the α7 nicotinic acetylcholine
receptors (α7 nAChRs) subtypes. These data were consistent
with molecular biology studies which demonstrated asso-
ciations between polymorphisms in gene coding for these
receptors and schizophrenia. The available data show that
α7 nAChR activation did not improve positive symptoms,
whereas a beneficial effect against negative symptoms was
observed repeatedly. The clinical evidence that α7 nAChR
activation leads to improvement of cognitive dysfunction in
schizophrenia still remains somewhat equivocal, although the
data for encenicline are encouraging. Currently, some other
α7 nAChR agonists remain in clinical development.39,40
Conclusion
Before developing new psychoactive drugs, it is our duty to
optimize the usage of those currently available. Many psy-
chotropic medications are available, but achieving optimal
therapeutic response can be challenging. Schizophrenia and
MDD are heterogeneous disorders and medication responses
(and tolerability) vary across patients. As always, having
additional choices can offer greater opportunities for suc-
cess. With better understanding of pathophysiology, there
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 Ceskova and Silhan
is a revival of new old drugs. In depression, we can see the
arrival of the first robust and rapid-acting AD drug in the near
future. In schizophrenia, given the challenges with patient
adherence to oral regimens and since relapse leads to serious
medical and psychosocial consequences, the future of phar-
macotherapy is likely to include improved long-term delivery
Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 91.200.82.23 on 27-Jul-2018
systems. In both depressive and schizophrenic disorders,
glutamatergic modulators likely represent a very promising
alternative to monoaminergic AD monotherapy.
Advances in genomics and cell biology have increased
the opportunity for rational design of targeted drugs. Targeted
therapies may offer enhanced efficacy and improved selec-
tivity and therefore less toxicity. As immediate challenge
facing the field is to make progress in the development and
identification of personalized treatments, perhaps through
the application of biomarkers.
Acknowledgment
For personal use only.
The paper was presented at the 13th Congress of the European
Association for Clinical Pharmacology and Therapeutics
(EACPT) in Prague, Czech Republic, June 24–27, 2017,
and the abstract has been published in the EACPT Clinical
Therapeutics journal.
Disclosure
EC has received speaker’s honoraria from Angelini Pharma
and Jahnssen Cilag, Czech Republic, and PS has received
speaker’s honoraria from Lundbeck, Czech Republic, and
Servier, Czech Republic. The authors report no other conflicts
of interest in this work.
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PILIHAN PENGOBATAN BARU DALAM DEPRESI DAN PSIKOSIS

Artikel ini diterbitkan dalam Dove Press Journal berikut: Neuropsychiatric Disease Treatment
Eva Ceskova, Per Sihan
Departemen Psikiatri, Rumah Sakit Universitas Ostrava, Ostrava, Republik Ceko

Abstrak: Terlepas dari perkembangan yang luar biasa dalam penelitian sistem saraf pusat,
pengobatan saat ini adalah suboptimal, terutama pada gangguan mental yang parah. Dalam
kedokteran, ada dua metode utama untuk meningkatkan perawatan kesehatan yang
disediakan: mencari prosedur perawatan baru dan menyempurnakan (mengoptimalkan) yang
sudah ada. Optimalisasi pengobatan tidak hanya mencakup alat praktis seperti pemantauan
obat terapeutik tetapi juga penerapan tren umum dalam praktik klinis. Pilihan farmakologis
baru termasuk bentuk baru obat monoaminergik yang lebih canggih, obat lama ditemukan
kembali atas dasar pemahaman yang lebih baik tentang patofisiologi penyakit mental, dan
obat yang ditujukan untuk target pengobatan baru. Pada depresi, resistensi pengobatan
terhadap farmakoterapi antidepresif merupakan salah satu tantangan klinis yang paling
penting. Beralih ke monoterapi dengan antidepresan multimodal / multifungsi baru dan
augmentasi dengan antipsikotik atipikal baru (aripiprazole dan brexpiprazole) dapat menjadi
pilihan yang menjanjikan. Selanjutnya, bukti saat ini mendukung utilitas dan keamanan
pengobatan tambahan nutraceuticals. Pendekatan baru yang sedang dipelajari meliputi
ketamin dan opioid. Kemajuan terbaru dalam teknologi dan pengetahuan yang muncul
tentang sirkuit otak yang disfungsional dan neuroplastisitas telah mengarah pada
pengembangan berbagai teknik neuromodulasi baru yang biasanya digunakan sebagai terapi
tambahan. Antipsikotik masih menjadi landasan pengobatan skizofrenia saat ini. Dua agonis
dopamin parsial baru, brexpiprazole dan cariprazine, sekarang tersedia di samping
aripiprazole. Meskipun mekanisme kerjanya serupa, kedua agen berbeda dalam hal profil
farmakodinamiknya. Lebih lanjut, dua formulasi baru injeksi jangka panjang antipsikotik
generasi kedua (aripiprazole lauroxil dan paliperidone palmitate 3 bulan) diperkenalkan ke
dalam praktik klinis. Pilihan pengobatan baru belum tersedia termasuk kanabidiol, modulator
glutamat, dan agonis reseptor nikotin.
Kata kunci: optimalisasi pengobatan, antidepresan multimodal / multifungsi, agonis
dopamin parsial, modulator glutamat, agonis reseptor nikotin

Pendahuluan (Beban Penyakit Mental)

Gangguan mental adalah masalah kesehatan masyarakat yang utama. Prevalensi global
seumur hidup dari gangguan mental pada orang dewasa diperkirakan antara 12,2% dan
48,6%.1 Gangguan mental juga merupakan kontributor utama beban penyakit global: pada
2013, 5,4% dari tahun-tahun kehidupan yang disesuaikan dengan disabilitas global dan
17,4% dari tahun global hidup dengan kecacatan disebabkan oleh gangguan mental.2
Namun, pengobatan saat ini adalah suboptimal, terutama pada gangguan mental berat
seperti gangguan depresi dan skizofrenia. Ada dua metode utama untuk meningkatkan

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Farah Shania (201610330311184)
layanan kesehatan yang disediakan: mencari prosedur perawatan baru dan menyempurnakan
(mengoptimalkan) yang sudah ada.

Mengoptimalkan Perawatan Dalam Psikiatri

Dalam semua obat ada konsensus umum, yang dikodekan dalam pedoman pengobatan,
bahwa pengobatan harus berdasarkan bukti, berdasarkan pengukuran, kompleks, dan
individual (dipersonalisasi).
Namun, pengenalan prinsip-prinsip ini dalam praktik klinis sama sekali tidak
memuaskan. Fakta ini membutuhkan pendidikan siswa kedokteran yang lebih baik, dokter di
layanan primer, spesialis, dan semua resep, dan untuk perbaikan perawatan saat ini.
Perawatan berbasis pengukuran, semakin diakui sebagai peningkatan pengobatan, telah
menjadi lebih umum dengan ketersediaan kertas atau kuesioner terkomputerisasi dan
wawancara terstruktur. Ini memberikan peluang untuk meningkatkan presisi, konsistensi, dan
kesesuaian perawatan. Namun, dokter masih enggan untuk memasukkan pengukuran hasil ke
dalam praktik mereka. Alasan penolakan ini bermacam-macam.
Meskipun bukti yang jelas dan positif untuk penggunaan antipsikotik dan antidepresan
(AD) yang telah menginformasikan pedoman pengobatan yang sesuai, ada alasan substansial
untuk mencari cara untuk meningkatkan efektivitas pengobatan. Bukti yang muncul
menunjukkan bahwa konteks pengobatan sangat mempengaruhi intervensi
psikofarmakologis. Ini mendukung gagasan perawatan kompleks, yang tidak hanya
mencakup farmakoterapi tetapi juga pendekatan psikososial. Pendekatan farmakologis harus
selalu dikombinasikan dengan pendekatan nonfarmakologis, mengoptimalkan pengaruh
lingkungan. Pengaruh obat-obatan psikotropika pada fungsi otak adalah interaksi terus
menerus dengan plastisitas otak yang dirangsang oleh pengaruh lingkungan. Faktor
kontekstual positif seperti dukungan interaksi sosial positif dan aktivitas fisik rutin harus
dimasukkan ke dalam praktik klinis.3
Dokter menyesuaikan pengobatan (personalisasi) tergantung pada fitur klinis tertentu,
psikopatologi individu, profil risiko individu, dan pengalaman dan preferensi pasien, bahkan
tanpa adanya bukti kuat bahwa fitur tersebut benar-benar dapat diprediksi. Lebih lanjut,
pasien berbeda dalam kemampuan mereka untuk menyerap, mendistribusikan,
memetabolisme, dan mengeluarkan obat karena penyakit bersamaan, usia, pengobatan yang
bersamaan, atau kekhasan genetik. Pentingnya perbedaan farmakologis terkait seks dalam
farmakokinetik obat dan farmakodinamik sekarang tidak dapat dibantah lagi.4 Untuk

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Farah Shania (201610330311184)
mengatasi masalah reaksi yang tidak responsif atau efek samping karena kelainan
farmakokinetik, akan membantu untuk memantau karakteristik farmakokinetik setiap pasien
dan mengoptimalkan konsentrasi obat. Analisis dan interpretasi kadar plasma (pemantauan
obat terapeutik, TDM) tersedia; Namun, metode ini belum digunakan secara rutin dan
tampaknya tidak mungkin bahwa TDM akan menjadi standar perawatan untuk semua agen
dan semua pasien. Pedoman yang dipublikasikan untuk TDM menunjukkan pasien mana dan
keadaan apa TDM hemat biaya. Lebih jauh, TDM menyajikan strategi peningkatan
kepatuhan yang memiliki potensi luar biasa untuk mengurangi biaya perawatan kesehatan,
penderitaan pribadi, dan beban keluarga.5 Kepatuhan yang rendah adalah masalah utama
perawatan psikotropika jangka panjang. Kurangnya kepatuhan dalam psikiatri, terutama pada
pasien psikotik (~ 50%), memiliki konsekuensi parah. Prevalensinya tidak berubah secara
signifikan dengan diperkenalkannya obat baru.6
Bertujuan untuk perawatan yang lebih tepat, individualisasi dapat membantu untuk
memastikan hasil yang optimal.7 Untuk mencapai ketepatan yang benar dalam farmakoterapi,
mungkin perlu untuk mengidentifikasi dan menggunakan prediktor respon pengobatan yang
spesifik. Pengujian farmakogenomik kombinatorial yang mencakup informasi genom yang
lebih lengkap dengan menggabungkan alel risiko sedang telah tersedia secara komersial.8
Obat yang berpusat pada pasien berusaha untuk memusatkan perhatian pertama pada
kebutuhan dan perhatian pasien dan untuk mempertimbangkan faktor sosial dan ekonomi.9
Pengetahuan tentang farmakologi obat psikiatri diperlukan tetapi tidak cukup untuk
pengiriman perawatan yang tepat, aman, dan efektif. Dokter perlu mencurahkan waktu yang
cukup untuk mengkomunikasikan kebutuhan perawatan kepada pasien dan mengembangkan
aliansi perawatan yang kuat yang bertahan bahkan selama eksaserbasi simptomatik.10

Depresi
Gangguan depresi mayor (MDD) adalah penyakit yang tersebar luas, dengan prevalensi
seumur hidup 15% dan kejadian tahunan ~ 7%. Ini terkait dengan biaya yang signifikan
dalam kualitas hidup, hilangnya produktivitas kerja, dan risiko kematian yang tinggi.11
Sekitar dua pertiga pasien tidak mencapai remisi penuh, yang merupakan kunci untuk
memulihkan fungsi penuh dan mencegah kekambuhan. Setelah mengecualikan
pseudoresisten, beberapa strategi pengobatan tersedia untuk pasien ini, seperti mengubah,
menambah, dan menggabungkan ADs.

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Farah Shania (201610330311184)

Opsi Perawatan Baru Saat Ini Tersedia

Multimodal ADs
Multimodal ADs memiliki lebih dari satu mode aksi, yaitu, reuptake inhibisi dan
aktivitas pada reseptor yang terikat membran, menyatukan dua mode pensinyalan saraf yang
berbeda. Melalui mekanisme multimodal ini, mereka menghasilkan efek hilir pada sistem
neurotransmitter yang saling berhubungan. Perbedaan antara AD multimodal / multifungsi
yang tersedia didasarkan pada aksinya pada subtipe reseptor. Terhadap latar belakang ini,
kami menampilkan vortioxetine (Trintellix) dan vilazodone (Viibryd) AD yang baru
(terdaftar terakhir) berkaitan dengan target reseptor serotonin mereka 5-HT1A, 5-HT3, dan 5-
HT7, yang dapat menjelaskan efek spesifik mereka pada gejala-gejala depresi tertentu
(misalnya, kognisi dan kecemasan) serta profil efek samping yang khas. Kemanjuran
multimodal ADs baru belum diuji pada depresi yang resisten terhadap pengobatan.12,13
Obat yang menargetkan sistem glutamatergik mungkin membuka wilayah baru yang
menjanjikan untuk pengembangan obat untuk memenuhi kebutuhan pasien dengan depresi
berat.

Ketamin
Ketamin adalah obat bius dengan aktivitas antagonis reseptor glutamat N-metil-d-
aspartat (NMDA), yang dapat memberikan mekanisme AD baru. Ketamine memiliki
beberapa nama merek untuk obat-obatan yang merupakan satu-satunya obat. Menurut
pencarian sistematis yang baru-baru ini dipublikasikan untuk uji coba acak yang relevan,
ketamin memang memiliki efek AD yang cepat namun sementara. Namun, ada heterogenitas
substansial dalam respon klinis, dan mekanisme aksi ketamin yang mendasarinya tidak
sepenuhnya dipahami.
Pengamatan bahwa dosis tunggal modulator ketamin glutamatergik intravena
menghasilkan efek AD yang kuat dan cepat adalah titik balik yang membuka jalan bagi
modulator glutamatergik lain yang lebih selektif (esranamin intranasal, rapastinel).16

Obat Baru
Opioid
Potensi opioid AD telah dikenal selama berabad-abad, tetapi sifat memproduksi
ketergantungannya menyebabkan adopsi cepat dari AD berbasis monoamine begitu mereka
tersedia pada tahun 1950-an. Saat ini, semakin banyak bukti praklinis dan klinis yang
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Farah Shania (201610330311184)
mendukung hipotesis bahwa gangguan mood melibatkan deregulasi sistem opioid endogen.
Penggunaan klinis agonis opioid kontemporer sebagai AD dalam praktik klinis masih sangat
terbatas karena masalah pelecehan dan ketergantungan yang belum terselesaikan.17 Untuk
mengatasi keterbatasan agonis opioid, kombinasi agonis parsial opioid μ dan κ, buprenorfin,
dan opioid mu samidorphan antagonis dikembangkan. Hasil penelitian multisenter, acak,
double-blind, terkontrol plasebo telah menunjukkan bahwa modulasi sistem opiat mungkin
merupakan pendekatan pengobatan baru untuk depresi yang resistan terhadap pengobatan.18

Psychedelics
Obat-obatan psikedelik, termasuk diethylamide acid lysergic acid dan psilocybin,
digunakan secara luas dalam pengobatan gangguan suasana hati dan kondisi kejiwaan
lainnya, sebelum larangan mereka pada akhir 1960-an.19 Sebuah tinjauan sistematis baru-baru
ini yang diterbitkan dari studi perawatan klinis menggunakan psychedelics pada pasien
dengan definisi yang luas depresi termasuk 423 orang dalam 19 studi, dan 335 (79,2%)
menunjukkan peningkatan penilaian klinis setelah perawatan dengan psychedelics.20 Sebuah
studi percontohan yang baru-baru ini selesai di Inggris mendukung penggunaan psilocybin
dengan dukungan psikologis dalam gangguan depresi yang resisten terhadap pengobatan.
Psychedelics dapat memberikan efek terapi untuk gangguan kejiwaan dengan
mendestabilisasi secara akut hub jaringan otak lokal dan konektivitas jaringan global,
memberikan kesempatan untuk jaringan otak "mengatur ulang" setelah efek akut telah
diselesaikan.21

Strategi Augmentasi Baru

Augmentasi yang paling berdasarkan bukti dari inhibitor reuptake serotonin spesifik
adalah augmentasi dengan antipsikotik atipikal. Baru-baru ini, spektrum antipsikotik atipikal
yang digunakan dalam indikasi ini telah diperbesar oleh brexpiprazole (Rexulti, disetujui oleh
US Food and Drug Administration pada 2015), agonis dopamin parsial baru.22
Baru-baru ini, beberapa ulasan menunjukkan bukti kemanjuran strategi augmentasi
yang aman - nutraceuticals. Pemberian bersama nutrisi tingkat farmasi standar, yang disebut
sebagai nutraceuticals, dapat memberikan pendekatan yang efektif dan aman untuk
meningkatkan efek AD, baik dengan secara sinergis menambah aktivitas tertentu dari AD
atau menyediakan serangkaian efek biologis tambahan.23 Semua nutraceuticals umumnya
ditoleransi dengan baik, dengan efek samping gastrointestinal paling sering dilaporkan di

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semua kelompok nutraceutical. Bukti saat ini mendukung penggunaan tambahan S-
adenosylmethionine, methylfolate, omega-3, dan vitamin D dengan AD untuk mengurangi
gejala depresi.23
Namun, depresi bukan hanya akibat kelainan neurotransmitter. Sejumlah besar bukti
menunjuk pada endokrin dan sistem respons inflamasi yang dideregulasi dan mengurangi
neurogenesis, dalam patogenesis depresi. MDD dikaitkan dengan deregulasi respon imun dan
dengan aktivitas inflamasi kronis yang dicerminkan oleh profil abnormal sitokin pro dan
antiinflamasi yang beredar. Beberapa penelitian menunjukkan bahwa penggunaan tambahan
agen antiinflamasi pada pasien dengan MDD meningkatkan gejala depresi, khususnya pada
depresi yang resisten terhadap pengobatan dengan profil inflamasi sebagaimana didefinisikan
oleh protein C-reaktif.24 Beberapa obat anti-Il-1 yang ditargetkan senyawa telah
dikembangkan baru-baru ini, termasuk antibodi dan antagonis reseptor Il-1β. Penargetan
interleukin-1β mungkin berguna untuk subkelompok pasien dengan depresi inflamasi yang
ditentukan oleh fitur klinis trauma, resistensi terhadap AD, dan peningkatan level interleukin-
1.25
Selanjutnya, kemajuan dalam teknologi dan pengetahuan yang muncul tentang sirkuit
otak disfungsional yang mendasari depresi dan neuroplastisitas telah menyebabkan
pengembangan berbagai teknik neuromodulasi baru (stimulasi magnetik transkranial,
stimulasi saraf vagus, dan stimulasi otak dalam) yang biasanya digunakan sebagai terapi
tambahan.26

Skizofrenia
Skizofrenia, kelainan otak kronis yang memengaruhi ~ 1% dari populasi orang dewasa
dan ~ 26 juta orang di seluruh dunia, dianggap sebagai kelainan medis yang paling
melumpuhkan dan berbahaya secara ekonomi sebagaimana diperingkat oleh Organisasi
Kesehatan Dunia.27 Hanya ~ 10% –15% dari orang yang menderita skizofrenia
mempertahankan pekerjaan penuh waktu apa pun jenisnya.28
Karena etiologi skizofrenia tidak diketahui, tujuan pengobatan adalah menghilangkan
gejala terkait penyakit dan meningkatkan fungsi. Landasan dari pengobatan saat ini adalah
obat antipsikotik. Antipsikotik bervariasi dalam hal toleransi dan masalah keamanan, dan
pasien itu sendiri berbeda dalam hal faktor risiko dan komorbiditas yang sudah ada
sebelumnya yang membuat pemilihan obat sering menantang.

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Opsi Perawatan Baru Saat Ini Tersedia

Antipsikotik
Selain aripiprazole, dua agonis parsial reseptor dopamin baru, brexpiprazole dan
kariprazin (Vraylar), sekarang tersedia. Walaupun mekanisme kerjanya serupa, ketiga agen
berbeda dalam hal profil farmakodinamiknya.29 Dibandingkan dengan aripiprazole,
brexpiprazole memiliki aktivitas intrinsik yang rendah pada reseptor dopamin D2 dan
memiliki afinitas sepuluh kali lipat lebih tinggi untuk serotonin 5-HT1A dan 5-HT2A reseptor,
berpotensi meningkatkan tolerabilitas. Ketika kariprazin dibandingkan dengan aripiprazole,
D2 yang sama dan tiga hingga sepuluh kali lipat D3 lebih besar dibandingkan dengan
selektivitas D2 diamati untuk kariprazin. Masih belum diketahui apakah menargetkan reseptor
Dopamin D3 di atas reseptor Dopamin D2 secara klinis menguntungkan, tetapi secara teoritis
agen-agen yang lebih disukai dopamin D3 dapat memberikan efek procognitive. Meskipun
ketiga obat disetujui untuk pengobatan skizofrenia, baik aripiprazole dan brexpiprazole juga
disetujui untuk pengobatan tambahan MDD, dan aripiprazole dan kariprazine juga disetujui
untuk pengobatan akut manik atau episode campuran yang terkait dengan gangguan bipolar I.
Pada Fase III perkembangan klinis adalah lumateperon antipsikotik baru dengan profil
farmakologis yang unik. Lumateperone, menggabungkan antagonisme reseptor 5-HT2A yang
kuat dengan modulasi reseptor glutamat tipe sel dan modulasi reseptor glutamat ditambah
penghambatan reuptake serotonin, adalah modulator baru serotin, dopamin, dan
neurotransmisi glutamat.30

Formulasi Baru Antipsikotik

Suntikan long-acting (LAI) dari antipsikotik generasi kedua menyediakan terapi
berkelanjutan yang memfasilitasi partisipasi pasien dalam pengobatan dan meningkatkan
pemulihannya. Meskipun LAI dapat meningkatkan kepatuhan pengobatan, hanya sebagian
kecil pasien yang tidak meminum obat yang menerimanya. Pengurangan signifikan dalam
pemanfaatan layanan kesehatan atau biaya yang terkait dengan skizofrenia telah dibuktikan
dalam beberapa studi antipsikotik LAI, meskipun penelitian lain belum menunjukkan efek ini
dan menunjukkan netralitas biaya atau bahkan biaya yang lebih besar biasanya dalam konteks
dengan jenis penelitian (misalnya, pengamatan studi naturalistik bertentangan dengan studi
terkontrol acak), 31,32
Baru-baru ini, dua formulasi LAI baru antipsikotik generasi kedua telah tersedia,
aripiprazole lauroxil (Aristada) dan paliperidone palmitate 3 bulan (Invega Sustenna dan

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Farah Shania (201610330311184)
Invega Trinza). Pada Oktober 2015, Badan Pengawas Obat dan Makanan AS menyetujui
aripiprazole lauroxil, obat penawar aripiprazole, untuk perawatan orang dewasa dengan
skizofrenia. Hidrolisis yang dimediasi enzim cenderung mengubah aripiprazole lauroxil yang
disuntikkan menjadi N-hydroxymethyl aripiprazole, yang kemudian dihidrolisis menjadi
aripiprazole. Aripiprazole lauroxil bekerja terutama sebagai hasil dari aktivitas dan afinitas
untuk reseptor D2 dari obat induk, aripiprazole, dan, pada tingkat lebih rendah, dari metabolit
utamanya, dehydroaripiprazole, yang juga mewakili 30% -40% dari paparan aripiprazole di
plasma. Aripiprazole lauroxil dimetabolisme secara luas di hati melalui isoenzim sitokrom
P450 CYP 3A4 dan 2D6. Profil farmakokinetiknya menyebabkan persetujuan interval
pemberian dosis setiap 6 minggu untuk dosis 882 mg. Toleransi keseluruhan konsisten
dengan apa yang diketahui tentang aripiprazole oral.33
Formulasi baru paliperidone palmitate, paliperidone palmitate formulasi 3 bulan yang
baru-baru ini disetujui di AS untuk perawatan skizofrenia, menawarkan interval dosis yang
lebih lama sekali setiap 3 bulan daripada yang tersedia untuk formulasi LAI atipikal generasi
baru atau khas (1 bulanan). Tidak ada perbedaan yang relevan secara klinis yang diamati
dalam paparan farmakokinetik antara formulasi 3 bulan dan 1 bulan. Keduanya memiliki
profil tolerabilitas yang sama dan tidak ada masalah keamanan baru yang terdeteksi. LAI
paliperidone baru dengan interval dosis 3 bulan adalah pilihan unik untuk pencegahan
kambuh pada skizofrenia.34
Antipsikotik LAI menghilangkan kebutuhan dosis harian, biasanya memastikan kadar
plasma berkelanjutan selama beberapa minggu, dan membantu memantau kepatuhan secara
andal. Opsi LAI baru memberikan fleksibilitas tambahan dalam hal meningkatkan waktu
antara injeksi.

Pilihan Pengobatan Baru Belum Tersedia Dalam Praktik Klinis

Cannabidiol (CBD)
Sistem endocannabinoid adalah target farmakologis baru yang sangat menjanjikan
dalam konteks skizofrenia. Modulasi sistem ini oleh komponen psikoaktif utama dalam
ganja, Δ9-tetrahydrocannabinol, menginduksi efek psikotik akut dan gangguan kognitif.
Namun, agen cannabinoid CBD nonpsikotropik yang diturunkan dari tanaman mungkin
memiliki sifat antipsikotik dan karenanya dapat menjadi agen baru yang menjanjikan dalam
pengobatan skizofrenia. Studi klinis skala kecil pertama dengan CBD untuk pengobatan
pasien dengan gejala psikotik lebih lanjut mengkonfirmasi potensi CBD sebagai senyawa

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Farah Shania (201610330311184)
antipsikotik yang efektif, aman, dan ditoleransi dengan baik, meskipun uji klinis acak besar
akan diperlukan sebelum terapi baru ini dapat dimasukkan ke dalam praktik klinis.35

Pilihan Pengobatan Untuk Gejala Negatif Dan Disfungsi Kognitif

Modulator Glutamat
Sistem glutamatergik telah terlibat dalam patofisiologi skizofrenia dan gangguan
afektif. Komponen utama adalah disfungsi reseptor glutamatergik, reseptor N-metil-d-
aspartat (NMDAR). Zat yang mengatur aktivasi / penghambatan NMDAR menjanjikan
dalam pendekatan terapi untuk gejala negatif, kognisi, dan suasana hati.36 Skizofrenia terkait
dengan gejala kognitif dan negatif, yang sering resisten terhadap pendekatan pengobatan saat
ini.
Teori hipofungsi NMDAR dari skizofrenia mengusulkan bahwa peningkatan fungsi
reseptor dapat menyebabkan kemanjuran terhadap skizofrenia. Konsisten dengan teori ini, uji
klinis baru-baru ini telah menunjukkan bahwa peningkatan fungsi NMDAR dengan
mempotensiasi situs glisin dari reseptor berkhasiat dalam pengobatan gejala skizofrenia
negatif dan mungkin kognitif dari skizofrenia.37 Reseptor glutamat metabotropik (mGluR)
telah menarik perhatian yang signifikan sebagai target obat potensial. Hal ini disebabkan oleh
keyakinan bahwa penargetan reseptor metabotropik memberikan cara untuk memodulasi
nada glutamat dan pelepasan fasa secara lebih subtil daripada yang dapat dicapai melalui
reseptor ionotropik glutamat. Secara khusus, data praklinis dan klinis yang muncul
menunjukkan bahwa aktivasi mGluRs Kelompok II adalah pendekatan yang menjanjikan
untuk pengobatan skizofrenia. Lebih lanjut, metabotropik glutamat reseptor subtipe 5
(mGluR5), yang dikodekan oleh gen GRM5, mewakili target obat baru yang menarik untuk
pengobatan skizofrenia. Dengan demikian, modulator alosterik positif mGluR5 menunjukkan
potensi terapi yang mendorong dalam model skizofrenia praklinis, terutama untuk
pengobatan disfungsi kognitif.36,38

Agonis Reseptor Nikotin

Merokok berlebihan yang diperlihatkan oleh pasien skizofrenia menunjukkan bahwa
mereka mungkin mengobati sendiri untuk memperbaiki aspek-aspek tertentu dari gejala
positif, negatif, dan gejala kognitif yang terkait dengan penyakit ini. Pemeriksaan morfologis
menemukan perubahan reseptor nikotinat dalam jaringan postmortem dari individu
skizofrenik dibandingkan dengan kontrol, terutama dalam α7 reseptor asetilkolin nikotinat

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Farah Shania (201610330311184)
(α7 nAChRs). Data ini konsisten dengan studi biologi molekuler yang menunjukkan
hubungan antara polimorfisme dalam pengkodean gen untuk reseptor dan skizofrenia ini.
Data yang tersedia menunjukkan bahwa aktivasi α7 nAChR tidak meningkatkan gejala
positif, sedangkan efek menguntungkan terhadap gejala negatif diamati berulang kali. Bukti
klinis bahwa aktivasi α7 nAChR mengarah pada peningkatan disfungsi kognitif pada
skizofrenia masih tetap agak samar-samar, meskipun data untuk encenicline
menggembirakan. Saat ini, beberapa agonis α7 nAChR lainnya masih dalam pengembangan
klinis.39,40

Kesimpulan
Sebelum mengembangkan obat psikoaktif baru, adalah tugas kita untuk
mengoptimalkan penggunaan obat-obatan yang tersedia saat ini. Banyak obat psikotropika
tersedia, tetapi mencapai respons terapeutik yang optimal dapat menjadi tantangan.
Skizofrenia dan MDD adalah kelainan heterogen dan respons obat (dan tolerabilitas)
bervariasi antar pasien. Seperti biasa, memiliki pilihan tambahan dapat menawarkan peluang
keberhasilan yang lebih besar. Dengan pemahaman patofisiologi yang lebih baik, ada
kebangkitan obat lama baru. Dalam depresi, kita dapat melihat kedatangan obat AD pertama
yang kuat dan beraksi cepat dalam waktu dekat. Dalam skizofrenia, mengingat tantangan
dengan kepatuhan pasien terhadap rejimen oral dan karena kekambuhan menyebabkan
konsekuensi medis dan psikososial yang serius, masa depan farmakoterapi kemungkinan
akan mencakup peningkatan sistem pengiriman jangka panjang. Pada kedua gangguan
depresi dan skizofrenik, modulator glutamatergik kemungkinan merupakan alternatif yang
sangat menjanjikan untuk monoterapi AD monoaminergik.
Kemajuan dalam genomik dan biologi sel telah meningkatkan kesempatan untuk desain
rasional obat yang ditargetkan. Terapi yang ditargetkan dapat menawarkan peningkatan
efikasi dan peningkatan selektivitas dan karenanya toksisitas yang lebih rendah. Sebagai
tantangan langsung yang dihadapi bidang ini adalah untuk membuat kemajuan dalam
pengembangan dan identifikasi perawatan pribadi, mungkin melalui penerapan biomarker.

Pengakuan
Makalah ini dipresentasikan pada Kongres ke-13 Asosiasi Eropa untuk Farmakologi
Klinik dan Terapi (EACPT) di Praha, Republik Ceko, 24-27 Juni 2017, dan abstraknya telah
diterbitkan dalam jurnal EACPT Clinical Therapeutics journal.
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Farah Shania (201610330311184)

Penyingkapan
EC telah menerima honorarium pembicara dari Angelini Pharma dan Jahnssen Cilag,
Republik Ceko, dan PS telah menerima honorarium pembicara dari Lundbeck, Republik
Ceko, dan Servier, Republik Ceko. Penulis melaporkan tidak ada konflik kepentingan dalam
karya ini.

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 ®
SAFER USE OF HIGH RISK MEDICINES
ANTIDEPRESSANTS IN PREGNANCY & BREASTFEEDING - DELIVER SAFE CHOICES
4 PROVIDE PRECONCEPTION COUNSELLING FOR YOUNG WOMEN PRESCRIBED
4DISCUSS NON-PHARMACOLOGICAL INTERVENTIONS
ANTIDEPRESSANT MEDICINES
4CONSIDER ANTIDEPRESSANTS FOR MODERATE TO SEVERE DEPRESSION
4BE AWARE THAT ALL ANTIDEPRESSANTS CARRY SOME RISK DURING PREGNANCY
4PROVIDE INFORMATION ABOUT COMPATABILITY WITH BREASTFEEDING
Mental health problems during the perinatal period are
common; antenatal anxiety or depression is experienced by
up to 10% of women, increasing up to 16% postnatally. Early
intervention produces the best outcomes for mothers and their
families.1 When women irst become pregnant, or if they are
planning a pregnancy, enquire about any family or personal
history of mental illness.2 All pregnant women should be
screened for psychosocial risk factors; mental wellbeing
should be considered as important as physical health.1
PROVIDE PRECONCEPTION COUNSELLING FOR
YOUNG WOMEN PRESCRIBED ANTIDEPRESSANT
MEDICINES
Women who are currently prescribed antidepressants
and considering a family should be given preconceptual
counselling. It is wise to anticipate potential risks should she
become pregnant and proactively discuss these risks with her.3
Discuss treatment preference, eficacy, tolerability and the
risks of continuing or stopping medicines.2
The risks of stopping an antidepressant, changing to an
alternative, and starting medicines during pregnancy need to
be carefully evaluated.4 Stopping an antidepressant may put
the newborn baby at risk if the mother suffers from a relapse
and is unable to provide a suficient level of care to her baby. If
women taking antidepressants become pregnant, advise them
not to suddenly stop taking their medicine because there is a
high risk of relapse (68%).5 If deemed appropriate withdraw
slowly over 1-2 months to reduce the risk of withdrawal
symptoms and increase the likelihood of detecting a relapse.
If a medicine is working well, it is usually preferable to
continue with it rather than risk switching to a medicine that
may not be effective. Consider a discussion with, or referral to
a maternal mental health (MMH) team.
Note: Lithium therapy should always be managed by a
specialist service during pregnancy; seek immediate advice
from a MMH team for these cases.
Best Care for Everyone
1
DISCUSS NON-PHARMACOLOGICAL INTERVENTIONS
All women presenting with depression during pregnancy or
breastfeeding should be managed on a case-by-case basis.4
Any treatment offered should involve collaborative decision
making with the woman and her partner, including a full
discussion of the potential risks and beneits.1 Take into
consideration that the symptoms of depression might hamper
decision-making.3 Enhanced social support and psychological
therapy should be considered before prescribing medicines,
especially if the symptoms are mild or occur during the irst
trimester.2
Up to 80% of mothers experience the ‘baby blues’ 3-5 days
after giving birth. This is transient and self-limiting, usually
dissipating within 10 days.1 Arrange a plan for follow-up to
ensure persistent or worsening symptoms are effectively
identiied and managed.
Note: Worsening depression can lead to increased use of
alcohol, illicit substances and smoking.
CONSIDER ANTIDEPRESSANTS FOR MODERATE
TO SEVERE DEPRESSION
If pregnant or breastfeeding women have moderate to severe
depression, discuss the risks and beneits of antidepressants,
and the risks of no antidepressant therapy.2 Maternal anxiety
and depression can have detrimental effects on foetal and
infant development, and on mother-infant attachment.1
Untreated antenatal depression is associated with low birth
weight and poor self-care of the mother and neonate, which
may escalate to self-harm and infant neglect.5 Women already
receiving antidepressants who are at high risk of relapse
are best maintained on antidepressants during and after
pregnancy.5
For moderate to severe depression, it is preferable to select
antidepressants with the lowest risk proile.2 (see Table 1)
Deinitions of pregnancy categories are listed in Table 2.
➥ continued
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SAFER USE OF HIGH RISK MEDICINES Best Care for Everyone

ANTIDEPRESSANTS IN PREGNANCY & BREASTFEEDING 2

Table 1. Antidepressant Categories for Pregnancy and increase in the overall risk of any malformation with
Breastfeeding6 antidepressants. The studies that do show an increased risk
of cardiac malformation suggest an absolute risk of 0.86-2%,
Medicine Pregnancy6 Breastfeeding7
compared to the background rate of 0.8%.8
TCAs *
C Compatible
Some studies suggest that SSRIs, particularly high dose
Citalopram C Compatible
paroxetine in the irst trimester may be associated with
Escitalopram** C Compatible congenital heart defects. Note that these include anomalies
Fluoxetine #
C Compatible such as small ventrical septal defects which often close
Mirtazapine C Compatible during childhood.9
Paroxetine ##
D Compatible
Neonatal withdrawal
Sertraline B Compatible If antidepressants are used late in pregnancy, there may be a
Venlafaxine C Compatible risk of neonatal withdrawal.2 Symptoms include behavioural
Compatible - An acceptably low relative infant dose or no signiicant changes and irritability which are generally self-limiting
plasma concentrations or no adverse effects in breastfed infants7 and can also be linked to nicotine exposure and maternal
*
Imipramine - some consider pregnancy D6 depression itself.2,10 Venlafaxine and paroxetine have a
*
Doxepin - avoid during breastfeeding7 relatively higher risk of neonatal withdrawal, so should
**
Escitalopram - preferred to citalopram during breastfeeding6
only be considered if the patient has not tolerated or not
#
Fluoxetine - other SSRIs are usually preferred during breastfeeding7
responded to safer options.6
##
Paroxetine - some consider pregnancy C and the safest SSRI
for breastfeeding6 Neonatal withdrawal symptoms should be discussed with
the mother in advance; the postnatal midwife (and Plunket
ALL ANTIDEPRESSANTS CARRY SOME RISK nurse) should also be informed.
DURING PREGNANCY
Pregnancy-induced hypertension (PIH)
Depressive symptoms during pregnancy are associated
Antidepressants, in particular paroxetine, have been
with foetal growth changes and pre-term birth. The risks
associated with pregnancy induced hypertension (PIH).11
associated with antidepressants may include congenital
Other risk factors for hypertension should also considered,
abnormalities, pre-term birth, neonatal withdrawal
including smoking, obesity, alcohol, lack of exercise, and
symptoms, persistent pulmonary hypertension of the
untreated depression.
newborn (PPHN) and neurobehavioural effects.7

Involve the family as appropriate and consider consulting Persistent pulmonary hypertension
with, or referring to a MMH team or other available All SSRIs have been associated with persistent pulmonary
psychiatric service for advice.2 hypertension of the newborn (PPHN) if taken late in
pregnancy (after 20 weeks gestation). This potentially life-
For newly diagnosed depression in pregnant women,
threatening neonatal syndrome is very rare. In the general
consider treatment options that are most compatible with
population PPHN occurs in around 2 per 1000 live births.
breastfeeding. Sertraline or escitalopram are currently
When expectant mothers are exposed to SSRIs during
the most preferred SSRIs to use during pregnancy and
pregnancy this risk increases to 3 per 1000.12
breastfeeding. Venlafaxine and paroxetine have a relatively
Note: There is some evidence to suggest that all women with
higher risk of neonatal withdrawal,6 so should only be
depression, regardless of SSRI use, are more likely to give
considered if the patient has not tolerated or not responded
birth to infants with PPHN.13
to safer options.
Post-partum haemorrhage
Birth defects
There is some evidence to suggest that SSRIs decrease
There is conlicting information about the risk of birth
platelet function and potentially increase the risk of bruising
defects following antidepressant use during pregnancy,
and bleeding.5 Observational studies suggest that SSRIs may
and most malformations have no known cause.3 Individual
studies mostly demonstrate no statistically signiicant ➥ continued

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SAFER USE OF HIGH RISK MEDICINES
ANTIDEPRESSANTS IN PREGNANCY & BREASTFEEDING
be associated with post-partum haemorrhage, although the
absolute increased risk is likely to be low,14 and the evidence
is mixed.5
Overdose risks
Although TCAs have been widely used by pregnant women
over many years and are generally considered safe for the
foetus, they are often considered second-line because of poor
tolerability (eg sedation and constipation) and poor outcome
in case of maternal overdose.2
PROVIDE INFORMATION ABOUT COMPATABILITY
WITH BREASTFEEDING
If an antidepressant has been used successfully during
pregnancy, for many women it is most appropriate to remain
on the same medicine post-partum, rather than changing
medicines at a time when they are at their most vulnerable.
The amount that an infant is exposed to via breastmilk is less
than in-utero, and continuing with the same medicine while
breastfeeding may also minimise withdrawal symptoms in
the infant.5 It is advisable to closely observe new mothers
for symptoms of depressive relapse post-partum, even if no
alterations are made to their medicines.
The extent of exposure to the infant depends on many
factors, including protein binding (to maternal plasma) and
lipophilicity. Sertraline, escitalopram, paroxetine, nortriptyline
and imipramine have low to undetectable infant serum levels
when the mother is breastfeeding, with no reports of short
term adverse events.15,6 These options may be preferable if
the mother is initiating an antidepressant post-partum.
Note: Escitalopram is generally preferred to citalopram
because there are lower serum levels detected in breastfed
infants.
Fluoxetine is considered the least preferred SSRI for
breastfeeding, especially for newborn infants because it has
the highest infant serum levels.6 Paroxetine is considered
the safest SSRI for breastfeeding, but may be less favourable
during pregancy.6 The long term consequences of exposure to
SSRIs via breastmilk to infant neurobehavioural development
are unknown.16 With all medicines, it is advised to prescribe
the lowest effective dose possible to breastfeeding women.5,17
The most amount of experience with breastfeeding is with
TCAs, and with the exception of doxepin, they are generally
considered to be compatible.18 TCAs have a very low transfer
Best Care for Everyone
3
into breastmilk compared with other antidepressants.8 SSRIs
are often preferred for depression, but TCAs are a useful
option if women have not responded well. Discuss with a
MMH team if there are any concerns. It is necessary to weigh
potential risk against the known beneits of breastfeeding
and the detrimental effects of psychiatric illness on the
development of the infant and other children in the home.6
Note: Medicines are more likely to accumulate in premature
infants because clearance is impaired. Breastfeeding
immediately prior to a dose may help to minimise infant
exposure, but considering newborn babies feed every 2-4
hours it is almost impossible to time the dose so the baby
receives the lowest exposure.18
Table 2. Medicines in pregnancy classiications6
Medicines that have been taken by a large
Category
number of pregnant women without harmful
A
effects on the foetus.
Medicines that have been taken by only a limited
number of pregnant women without harmful
effects on the foetus.
Category
B Studies in animals may have shown an increase
of foetal damage, the signiicance of which is
uncertain in humans.
These medicines have caused, or may
be suspected of causing harmful effects
on the foetus or neonate without causing
malformations. These should be given only if the
potential beneit justiies the potential risk to the
Category
C foetus.
Either studies in animals have revealed adverse
effects on the foetus and there are no controlled
studies in women or studies in women and
animals are not available.
There is positive evidence of human foetal
risk, but the beneits from use in pregnant
Category women may be acceptable despite the risk (eg
D if the medicine is needed in a life-threatening
situation, or for a serious disease for which safer
options cannot be used or are ineffective).
The risk of the medicine in pregnant women
Category clearly outweighs any possible beneit. It is
X contraindicated in women who are or may
become pregnant.
➥ continued
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SAFER USE OF HIGH RISK MEDICINES Best Care for Everyone

ANTIDEPRESSANTS IN PREGNANCY & BREASTFEEDING 4

ACKNOWLEDGEMENTS
We would like to thank Dr Aram Kim, Consultant Psychiatrist, Maternal
Mental Health, and Emma McPhee, Mental Health Pharmacist, Waitemata
District Health Board, for their valuable contribution to this bulletin.

REFERENCES
1. The Australian and New Zealand College of Obstetricians and Gynaecologists. Perinatal Anxiety
and Depression College Statement C-Obs48. Review 2015
www.ranzcog.edu.au/college-statements-guidelines.html#obstetrics (Accessed 08-12-15)
2. Tilyard M. Depression in the antenatal and postnatal periods. Best Practice Journal Special
Edition 2010:15-17 ISSN 1177-5645 www.mentalhealth.org.nz/assets/Uploads/Best-Practice-
Journal-Depression-in-the-antenatal-and-postantal-periods-2010-NZ.pdf (Accessed 07-12-15)
3. Friedman SH. The ethics of treating depression in pregnancy. Journal of Primary Healthcare.
2015;7(1):81-3 www.rnzcgp.org.nz/assets/documents/Publications/JPHC/March-2015/
JPHCEthicsMarch2015.pdf (Accessed 22-03-16)
4. Medsafe Prescriber Update. The use of antidepressants in pregnancy. 2010;31(3):23 www.
medsafe.govt.nz/profs/PUArticles/TheUseofAntidepressantsSept10.htm (Accessed 08-12-15)
5. Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines in Psychiatry, 12th edition.
Wiley 2015 p541-75
6. Postnatal depression and family – whanau New Zealand trust. Mothers Matter.
www.mothersmatter.co.nz/Medications/Lactation.asp (Accessed 29-02-16)
7. The New Zealand Formulary www.nzf.org.nz (Accessed 07-12-15)
8. United Kingdom teratology information service (UKTIS). Use of paroxetine in pregnancy 2014
(version 2). www.medicinesinpregnancy.org/bumps/monographs/USE-OF-PAROXETINE-IN-
PREGNANCY (Accessed 22-01-2016)
9. Stewart D, Vigod S. Risks of antidepressants during pregnancy: Selective serotonin reupatake
inhibitors (SSRIs). Uptodate database 2016. www.uptodate.com
10. Yonkers KA, Wisner KL, Stewart DE et al. The management of depression during pregnancy: a
report from the American Psychiatric Association and the American College of Obstetricians
and Gynecologists. 2009 31(5):403-13 www.sciencedirect.com/science/article/pii/
S0163834309000619 (Accessed 09-12-15)
11. De Vera MA, Berard A. Antidepressant use during pregnancy and the risk of pregnancy-induced
hypertension. British Journal of Clinical Pharmacology. 2012:74(2):362-9 http://onlinelibrary.
wiley.com/doi/10.1111/j.1365-2125.2012.04196.x/pdf ( Accessed 21-01-16)
12. Huybrechts KF, Bateman BT, Palmsten K et al. Antidepressant use late in pregnancy and risk
of persistent pulmonary hypertension of the newborn. JAMA 2015:313(21) 2142-51 http://jama.
jamanetwork.com/article.aspx?articleid=2300602 (Accessed 21-01-16)
13. Koren G, Nordeng H. SSRIs and persistent pulmonary hypertension of the newborn. British
Medical Journal 2011;343:d7642
14. Bruning AHL, Heller HM, Kieviet N et al. Antidepressants during pregnancy and postpartum
haemorrhage: a systematic review. European Journal of Obstetrics and Gynecology and
Reproductive Biology. 2015;189:38-47.
15. Scottish Intercollegiate Guidelines Network (SIGN). Management of perinatal mood
disorders. SIGN 127 2012 www.sign.ac.uk/pdf/sign127.pdf (Accessed 08-12-15)
16. Briggs GC, Freeman RK. Drugs in pregnancy and lactation: a reference guide to fetal and
neonatal risk. Lippincott Williams & Wilkins Philadelphia. 2015. ISBN: 978-1-4511-9082-3
17. Bazire S. Psychotropic Drug Directory. The professionals’ pocket handbook and aide memoire.
Lloyd-Reinhold Communications LLP 2012. p 225, 268-9
18. Gardiner S, Begg E. Drug safety in lactation. Medsafe Prescriber Update 2001;21:10-23. www.
medsafe.govt.nz/Profs/PUarticles/lactation.htm (Accessed 07-12-15)

For further information on other high-risk medicines visit our website at: www.saferx.co.nz

No: 0182-01-084, Issued May 2016, Review May 2019

DISCLAIMER: This information is provided to assist primary care health professionals with the use of prescribed medicines. Users of this information must always consider current
best practice and use their clinical judgement with each patient. This information is not a substitute for individual clinical decision making. Issued by the Quality Use of Medicines Team
at Waitemata District Health Board, email: feedback@saferx.co.nz

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ANTIDEPRESSAN PADA KEHAMILAN DAN IBU MENYUSUI

MENYEDIAKAN PEMBIMBINGAN PRECONCEPTION UNTUK WANITA MUDA

YANG DITETAPKAN OBAT ANTIDEPRESSAN

Wanita yang saat ini diresepkan antidepresan dan mempertimbangkan sebuah keluarga harus
diberikan konseling prakonseptual. Bertujuan untuk mengantisipasi potensi risiko jika dia
hamil. Membahas preferensi pengobatan, kemanjuran, tolerabilitas, dan risiko melanjutkan
atau menghentikan obat-obatan., Risiko menghentikan antidepresan, berganti ke suatu
alternatif, dan memulai obat-obatan selama kehamilan perlu dievaluasi dengan hati-hati.
Menghentikan antidepresan dapat membahayakan bayi yang baru lahir jika ibu menderita
kambuh dan tidak mampu memberikan tingkat yang memadai. merawat bayinya. Jika wanita
yang menggunakan antidepresan sedang hamil, anjurkan mereka untuk tidak berhenti minum
obat secara tiba-tiba karena ada risiko kambuh yang tinggi (68%) .Jika dianggap tepat, tarik
perlahan selama 1-2 bulan untuk mengurangi risiko gejala penarikan dan meningkatkan
kemungkinan mendeteksi kekambuhan.
Jika obat bekerja dengan baik, biasanya lebih baik meneruskannya daripada risiko beralih ke
obat yang mungkin tidak efektif. Pertimbangkan diskusi dengan, atau rujukan ke tim
kesehatan mental ibu (MMH).
Catatan: Terapi lithium harus selalu dikelola oleh layanan spesialis selama kehamilan;
mencari saran segera dari tim MMH untuk kasus-kasus ini.

DISKUSI INTERVENSI NON-FARMAKOLOGI

Semua wanita yang mengalami depresi selama kehamilan atau menyusui harus dikelola
berdasarkan kasus per kasus.4 Setiap perawatan yang ditawarkan harus melibatkan
pengambilan keputusan kolaboratif dengan wanita dan pasangannya, termasuk diskusi
lengkap tentang risiko potensial dan manfaatnya.1 Mempertimbangkan bahwa gejala depresi
dapat menghambat pengambilan keputusan. Peningkatan dukungan sosial dan terapi
psikologis harus dipertimbangkan sebelum meresepkan obat-obatan, terutama jika gejalanya
ringan atau terjadi selama trimester pertama.2
Hingga 80% ibu mengalami 'baby blues' 3-5 hari setelah melahirkan. Ini bersifat sementara
dan sembuh sendiri, biasanya menghilang dalam 10 hari.1 Menyusun rencana tindak lanjut
untuk memastikan gejala persisten atau memburuk secara efektif diidentifikasi dan dikelola.

PERTIMBANGKAN ANTIDEPRESSAN dari MODERATE ke severe

UNTUK MENGATASI DEPRESI

Jika wanita hamil atau menyusui mengalami depresi sedang hingga berat, diskusikan risiko
dan manfaat antidepresan, dan risiko tidak ada terapi antidepresan.2 Kecemasan dan depresi
ibu dapat memiliki efek merusak pada perkembangan janin dan bayi, dan pada keterikatan
ibu-bayi. 1 Depresi antenatal yang tidak diobati dikaitkan dengan berat lahir rendah dan
perawatan ibu dan neonatus yang buruk, yang dapat meningkat menjadi melukai diri sendiri
dan pengabaian bayi.5 Wanita yang sudah menerima antidepresan yang berisiko tinggi
kambuh paling baik dipertahankan pada antidepresan selama dan setelah kehamilan.5
Untuk depresi sedang hingga berat, lebih disukai untuk memilih antidepresan dengan profil
risiko terendah.2 (lihat Tabel 1) Definisi kategori-kategori kehamilan tercantum dalam Tabel
2

110
Diandra Erieka Putri (201610330311036)

translate : compatible = sesuai

medicine = obat obatan
pregnancy = kehamilan

SEMUA ANTIDEPRESSAN MEMILIKI BEBERAPA RESIKO SELAMA KEHAMILAN

Gejala depresi selama kehamilan berhubungan dengan perubahan pertumbuhan janin dan
kelahiran prematur. Risiko yang terkait dengan antidepresan dapat mencakup kelainan
bawaan, kelahiran prematur, gejala penarikan neonatal, hipertensi paru persisten pada bayi
baru lahir (PPHN) dan efek neurobehavioural.
Libatkan keluarga sebagaimana layaknya dan pertimbangkan untuk berkonsultasi dengan,
atau merujuk ke tim MMH atau layanan psikiatrik lain yang tersedia untuk nasihat.
Untuk depresi yang baru didiagnosis pada wanita hamil, pertimbangkan pilihan perawatan
yang paling sesuai dengan menyusui. Sertraline atau escitalopram saat ini
SSRI yang paling disukai untuk digunakan selama kehamilan dan menyusui. Venlafaxine dan
paroxetine memiliki risiko relatif lebih tinggi untuk penarikan neonatal, 6 jadi harus
dipertimbangkan jika pasien tidak mentolerir atau tidak menanggapi pilihan yang lebih aman.

Cacat lahir
Ada informasi yang bertentangan tentang risiko cacat lahir setelah penggunaan antidepresan
selama kehamilan, dan sebagian besar malformasi tidak diketahui penyebabnya. Studi
individu kebanyakan menunjukkan tidak ada yang signifikan secara statistik.
meningkatkan risiko keseluruhan malformasi apa pun dengan antidepresan. Studi yang
menunjukkan peningkatan risiko malformasi jantung menunjukkan risiko absolut 0,86-2%,
dibandingkan dengan tingkat latar belakang 0,8% .8

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Beberapa penelitian menunjukkan bahwa SSRI, khususnya paroxetine dosis tinggi pada
trimester pertama mungkin berhubungan dengan kelainan jantung bawaan. Perhatikan bahwa
ini termasuk anomali seperti defek septum ventrikel kecil yang sering menutup selama masa
kanak-kanak.

Hipertensi yang diinduksi kehamilan (PIH)

Antidepresan, khususnya paroxetine, telah dikaitkan dengan kehamilan yang diinduksi
hipertensi (PIH) .11 Faktor risiko lain untuk hipertensi juga harus dipertimbangkan, termasuk
merokok, obesitas, alkohol, kurang olahraga, dan depresi yang tidak diobati.

Hipertensi paru persisten

Semua SSRI telah dikaitkan dengan hipertensi paru persisten pada bayi baru lahir (PPHN)
jika dikonsumsi di akhir kehamilan (setelah usia kehamilan 20 minggu). Sindrom neonatal
yang berpotensi mengancam jiwa ini sangat jarang. Dalam populasi umum, PPHN terjadi
pada sekitar 2 per 1000 kelahiran hidup. Ketika ibu hamil terpapar SSRI selama kehamilan,
risiko ini meningkat menjadi 3 per 1.000,12
Catatan: Ada beberapa bukti yang menunjukkan bahwa semua wanita dengan depresi,
terlepas dari penggunaan SSRI, lebih cenderung melahirkan bayi dengan PPHN.13
Perdarahan postpartum
Ada beberapa bukti yang menunjukkan bahwa SSRI menurunkan fungsi trombosit dan
berpotensi meningkatkan risiko memar dan pendarahan.5 Studi observasi menunjukkan
bahwa SSRI dapat dikaitkan dengan perdarahan postpartum, meskipun peningkatan risiko
absolut cenderung rendah, 14 dan bukti beragam.

MEMBERIKAN INFORMASI TENTANG KOMPATABILITAS DENGAN

BREASTFEEDING
Jika antidepresan berhasil digunakan selama kehamilan, bagi banyak wanita itu paling tepat
untuk tetap pada obat yang sama post-partum, daripada berubah obat-obatan pada saat
mereka paling rentan. Jumlah bayi yang terpajan melalui ASI lebih sedikit.

PENGGUNAAN OBAT RESIKO TINGGI

daripada in-utero, dan melanjutkan dengan obat yang sama saat menyusui juga dapat
meminimalkan gejala penarikan pada bayi.5 Dianjurkan untuk mengamati dengan cermat ibu
baru untuk gejala kambuh depresi setelah melahirkan, bahkan jika tidak ada perubahan yang
dilakukan pada obat-obatan mereka. Tingkat paparan bayi tergantung pada banyak faktor,
termasuk ikatan protein (plasma ibu) dan lipofilisitas. Sertraline, escitalopram, paroxetine,
nortriptyline dan imipramine memiliki kadar serum bayi rendah hingga tidak terdeteksi ketika
ibu menyusui, tanpa ada laporan efek samping jangka pendek. 15,6 Pilihan ini mungkin lebih
disukai jika ibu memulai antidepresan pasca melahirkan.

Catatan: Escitalopram umumnya lebih disukai daripada citalopram karena ada kadar serum
yang lebih rendah terdeteksi pada bayi yang disusui.

Fluoxetine dianggap sebagai SSRI yang paling tidak disukai untuk menyusui, terutama untuk
bayi baru lahir karena ia memiliki kadar serum bayi tertinggi. 6 Paroxetine dianggap sebagai
SSRI teraman untuk menyusui, tetapi mungkin kurang menguntungkan selama masa
kehamilan. 6 Konsekuensi jangka panjang dari paparan SSRI. melalui ASI hingga
perkembangan neurobehavioural bayi tidak diketahui.16 Dengan semua obat, disarankan
untuk meresepkan dosis efektif serendah mungkin untuk menyusui wanita.5,17

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Jumlah paling banyak pengalaman dengan menyusui adalah dengan TCA, dan dengan
pengecualian doxepin, mereka umumnya dianggap kompatibel. 18 TCA memiliki transfer
yang sangat rendah ke ASI dibandingkan dengan antidepresan lain.8 SSRI sering lebih
disukai untuk depresi, tetapi TCA adalah opsi yang bermanfaat jika wanita belum merespons
dengan baik. Diskusikan dengan tim MMH jika ada masalah. Penting untuk
mempertimbangkan potensi risiko terhadap manfaat menyusui yang diketahui dan dampak
buruk penyakit kejiwaan pada perkembangan bayi dan anak-anak lain di rumah.6
Catatan: Obat-obatan lebih mungkin menumpuk pada bayi prematur karena pembersihan
terganggu. Menyusui segera sebelum dosis dapat membantu meminimalkan paparan bayi,
tetapi mengingat bayi yang baru lahir menyusu setiap 2-4 jam hampir tidak mungkin untuk
menentukan waktu dosis sehingga bayi menerima paparan terendah.

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Hypnotic Discontinuation
i n C h ro n i c I n s o m n i a
Jonathan P. Hintze, MDa,*, Jack D. Edinger, PhDb

KEYWORDS
 Deprescribing  Discontinuation  Hypnotic  Benzodiazepines  Insomnia  Sleep disorder

KEY POINTS
 Patients with chronic insomnia are commonly prescribed hypnotic medications but discontinuation
of these medications is difficult to achieve.
 A gradual taper is preferred over abrupt cessation to avoid rebound insomnia and withdrawal
symptoms.
 Written information provided to the patient about medication discontinuation may be helpful.
 Cognitive behavioral therapy or behavioral therapies alone can improve hypnotic discontinuation
outcomes.
 There is limited evidence for adjunct medications to assist in hypnotic cessation for insomnia.

INTRODUCTION unsuccessful.11 This article discusses strategies

Insomnia disorder is common in adults and chil-
dren. The estimated prevalence ranges from 9%
to 15% in the general population, with higher prev-
alence in certain subpopulations.1–6 Hypnotic
medications are those that tend to produce
sleep and are frequently used to treat insomnia.7
Commonly used hypnotics in adults include benzo-
diazepines (BZDs), BZD receptor agonists (BzRAs),
antihistamines, antidepressants, melatonin recep-
tor agonists, orexin receptor antagonists, and
antipsychotics. Although there are currently no
medications for pediatric insomnia approved by
the US Food and Drug Administration, commonly
used medications include antihistamines, alpha
agonists, antidepressants, BZDs, BzRAs, and anti-
psychotics.8,9 The long-term health consequences
of using hypnotics are not well described, and cur-
rent guidelines recommend medication tapering
and discontinuation when possible.10 However,
hypnotic discontinuation is difficult and often
to discontinue hypnotics and evidence supporting
their use.
HYPNOTIC TAPER STRATEGIES
Abrupt Hypnotic Cessation
Rapid drug cessation is an option for many medica-
tions. However, rebound insomnia and withdrawal
symptoms may accompany abrupt hypnotic
discontinuation. Rebound insomnia is generally
defined as insomnia that is worse relative to base-
line. This was first described with the discontinua-
tion of triazolam12 and has since been reported
with several other BZDs13,14; sedating antidepres-
sants, including amitriptyline15 and trazodone16;
and BzRAs, though with conflicting reports.14,17–19
Additionally, withdrawal symptoms, largely defined
as the emergence of previously absent symptoms,
are frequently reported with abrupt discontinuation
of BZDs.20 Consequently, tapering hypnotics
is generally preferred to abrupt cessation.

Disclosure Statement: J.P. Hintze has no potential conflicts of interest or funding sources. J.D. Edinger conflicts
sleep.theclinics.com

of interest or funding: grant support from Merck, Philips, Respironics, Inc.

a
Division of Pediatric Sleep Medicine, University of South Carolina School of Medicine-Greenville, Greenville
Health System, 200 Patewood Drive, Suite A330, Greenville, SC 29615, USA; b Department of Medicine, Na-
tional Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA
* Corresponding author.
E-mail address: jhintze@ghs.org

Sleep Med Clin 13 (2018) 263–270

https://doi.org/10.1016/j.jsmc.2018.02.008
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264 Hintze & Edinger
Tapering Hypnotics
Reported tapering strategies vary widely, with no
consensus on the optimal tapering protocol. A
frequently described approach is a dose reduction
of 25% every 1 to 2 weeks until discontinued
completely.21–25 Complete discontinuation rates
ranged from 24% to 61% in these studies but
there is variability in the frequency of office visits
and the follow-up period in these reports. With-
drawal symptoms were commonly reported. A
slightly slower wean was used by Lopez-Peig
and colleagues.26 Subjects all took BZDs, and
were instructed to reduce their dose by 25% every
2 to 4 weeks. At the end of the taper period, 80.4%
had successfully discontinued their BZD, and 64%
remained BZD-free at 12 months. Another study
weaned subjects from various BZDs by 10% to
25% every 2 to 3 weeks, with an approximately
40% hypnotic abstinence rate maintained at
36 months, without significant sleep dissatisfac-
tion compared with a control group.27 Drake28
weaned subjects from temazepam by cutting
doses roughly in half every 2 weeks, from 10 mg
to 5 mg to 2 mg. Of the subjects, 59% successfully
completed the taper, with 52% remaining
hypnotic-free at follow-up 12 to 35 weeks later.
Lemoine and colleagues29 reported a similar taper
with 2 BzRAs, zopiclone and zolpidem. In that
study, subjects were weaned from zolpidem
10 mg to 5 mg for a week, followed by a placebo.
Similarly, subjects were weaned from zopiclone
7.5 mg to 3.75 mg for a week, followed by a pla-
cebo. This regimen was associated with signifi-
cantly higher withdrawal symptoms than the
control group that was not weaned. In contrast,
Raju and Meagher30 used a more flexible taper
protocol, in which subjects were able to control
the rate of withdrawal. Given control over the
weaning pace, some subjects rapidly discontinued
hypnotic use (19 of 68), whereas others preferred a
prolonged, yet complete, taper (13 of 68). The
remainder did not completely discontinue medica-
tion use. To the authors’ knowledge, there are
no studies specifically comparing the success
of different taper strategies. However, a clinical
trial is currently underway that will compare
different taper strategies among hypnotic-
dependent subjects.31
Many practitioners find it helpful to switch from a
short-acting to a long-acting BZD before initiating
a taper.27,32 This is done by switching to an equiv-
alent dose of a long-acting BZD, commonly diaz-
epam (Table 1). It is notable that a Cochrane
Review published in 2006 noted higher dropout
rates when tapering short half-life compounds
compared with long-acting BZDs.33 However,
Table 1
Approximate equivalent doses of
benzodiazepines to 5 mg diazepam
BZD Equivalent Dose (mg)
Alprazolam 0.25–0.5
Bromazepam 3–6
Lorazepam 0.5–1
Nitrazepam 5
Oxazepam 15
Temazepam 10
Triazolam 0.25
there was no difference in withdrawal symptoms
between the groups, so switching from a short-
acting to a long-acting BZD before a gradual taper
was not supported. The authors are unaware of
any studies specifically comparing the practice of
switching to a long-acting BZD before gradual
withdrawal versus a gradual withdrawal directly
from a short-acting BZD.
ADJUNCT THERAPIES
Regardless of the taper strategy, several adjunct
therapies have been studied to assist in hypnotic
discontinuation. These include various degrees
of patient education, psychological therapies,
and medications.
Written Patient Education
There is some evidence that simply providing writ-
ten information to patients can lead to hypnotic
discontinuation. In 1 study, chronic BZD users
were randomized to receive either routine care or
advice during a single consultation supplemented
by a self-help booklet.34 The intervention resulted
in a significant reduction in BDZ prescriptions
compared with routine care alone (18% vs 5%).
Several other studies used a letter sent to BZD
users encouraging BZD reduction, with complete
BZD cessation rates ranging from 14% to
27%.23,24,35–37
Psychological Therapies
Many studies have used psychological therapies
to aid in medication discontinuation. A brief
description of the different types of therapy is pro-
vided in Table 2.
Sleep hygiene education
Sleep hygiene education is routinely provided to
patients with insomnia. However, there is insuffi-
cient evidence to recommend sleep hygiene as a
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 Hypnotic Discontinuation in Chronic Insomnia
Table 2
Psychological therapies for insomnia
Therapy Description
Sleep hygiene Guidelines about practices
education and habits that support or
interfere with sleep (eg,
obtaining regular exercise,
avoid electronics before
bed)
Relaxation Techniques used to reduce
therapy muscular tension and
intrusive thought
processes interfering with
sleep
Stimulus Reinforcing the association
control of the bed with sleep by
therapy getting out of bed when
unable to fall asleep, only
going to bed when sleepy,
keeping a strict rise time,
and avoiding napping
Sleep Reducing the amount of
restriction time spent in bed to match
therapy actual sleep time, with
periodic adjustments as
necessary
Cognitive A method of challenging
therapy false beliefs about sleep
that contribute to
insomnia
Cognitive Combining cognitive
behavioral therapy with another
therapy behavioral treatment (eg,
sleep restriction or
stimulus control)
Self-efficacy Improving perceived coping
enhancement capabilities by providing
positive vicarious
experiences, discussing
obstacles from prior failed
attempts, and social
persuasion
stand-alone therapy regardless of the presence or
absence of hypnotic use.38 Additionally, the au-
thors are unaware of any studies that used sleep
hygiene alone as an intervention to assist in hyp-
notic discontinuation.
Relaxation therapy
Relaxation therapy is a technique used to reduce
muscular tension and intrusive thought processes
interfering with sleep, and involves tensing and
relaxing major muscle groups. Giblin and Clift39
studied the effects of relaxation therapy on hypno-
tic discontinuation in 20 subjects. Notably, their
265
intervention also included a discussion about
sleep and insomnia, hypnotics and their effects
on sleep, and general advice about problem-
solving and optimism. There was a significant
decrease in the number of subjects who resumed
nightly hypnotic use at 12 weeks in the treatment
group (2 of 10) compared with the control group
(8 of 10), without any significant difference be-
tween the groups in reported sleep onset latency
and overall sleep quality.
Lichstein and Johnson40 used relaxation ther-
apy for hypnotic cessation, resulting in a substan-
tial reduction (47%) in sleep medication use.
Lichstein and colleagues41 assessed the useful-
ness of progressive relaxation techniques in addi-
tion to a standard drug withdrawal program in a
randomized trial. All subjects had a 79% reduction
in hypnotic consumption, without any significant
difference between the groups. However, those
assigned to the relaxation group had fewer with-
drawal symptoms, greater sleep efficiency, and
higher reported quality of sleep.
Stimulus control therapy
Stimulus control therapy is a method pioneered by
Bootzin42 and is used to reestablish the associa-
tion between the bed and sleep. Patients are
encouraged to remove themselves from the bed
when unable to fall asleep, and only go to bed
when sleepy rather than at a designated bedtime.
They are also encouraged to keep a strict rise time
and to avoid napping. A study of 7 long-term hyp-
notic users found that most (6 of 7) were able to
reduce or stop their medication when stimulus
control therapy was used.43 Riedel and col-
leagues44 randomized 21 subjects to either a
medication withdrawal program, or the withdrawal
program and stimulus control therapy. Both
groups had significant reductions in the amount
of sleep medication use but the stimulus control
group also had significant improvements in total
sleep time, sleep efficiency, sleep quality, and
daytime sleepiness. Several other studies included
stimulus control therapy as part of their interven-
tion (see later discussion).
Sleep restriction therapy
Sleep restriction therapy is used to curtail the
amount of time spent awake in bed. This is done
by determining the amount of sleep a patient is
regularly getting and limiting the total allowable
time in bed to the same amount. For example, if
a patient is currently spending 10 hours in bed
per night but only sleeps 6 hours, then the amount
of time in bed per night would be limited to 6 to
6.5 hours, depending on the specific sleep restric-
tion protocol used.
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266 Hintze & Edinger
Although sleep restriction is a well-established
therapy for insomnia in general,45 Taylor and col-
leagues46 performed the only known study exam-
ining the effectiveness of sleep restriction in the
setting of hypnotic discontinuation. Forty-six
subjects were assigned to either sleep hygiene ed-
ucation or sleep restriction with medication with-
drawal. In the sleep restriction group, 52.6%
completely discontinued hypnotic medication
use, compared with 15.4% in the sleep hygiene
group. Additionally, there was improvement in
sleep-onset latency and sleep efficiency, which
was maintained through a 12-month follow-up
period.
Cognitive behavioral therapy
Cognitive therapy is the method of challenging
a patient’s current beliefs about sleep that
contribute to insomnia. Cognitive behavioral ther-
apy (CBT) combines behavioral therapy (eg, relax-
ation, stimulus control, sleep restriction) with
cognitive therapy to form a multicomponent and
omnibus intervention. Therefore, CBT is a combi-
nation therapy with variation depending on the
specific methods used. CBT has long been used
for insomnia and an early study demonstrated its
usefulness in hypnotic discontinuation.47 Several
subsequent studies have been performed.
Many studies specifically evaluated BZD cessa-
tion. Baillargeon and colleagues48 studied 65 sub-
jects with chronic insomnia taking BZDs nightly,
randomizing subjects to a gradual supervised ta-
per alone or combined with 8 weeks of CBT. At
treatment completion, more subjects had com-
plete drug cessation in the combined group (77%)
compared with the taper-alone group (38%), with
similar results at a 12-month follow-up (70% vs
24%). Although several other studies reported no
improvement in BZD discontinuation rates with
CBT,23,49,50 other measures of sleep quality were
generally improved. Morin and colleagues25
considered the differential effects of supervised
BZD withdrawal and CBT in their randomized trial.
Seventy-six subjects underwent supervised with-
drawal, CBT, or both. Although all groups had a
significant reduction in quantity (90%) and fre-
quency (80%) of BZD use, the combined treat-
ment group was the most successful at
achieving complete drug cessation (85%), with su-
pervised withdrawal and CBT alone producing
less-successful results (48% and 54% respec-
tively). Interestingly, the subjects in both groups
that received CBT reported greater improvement
in subjective sleep quality when compared with
the group who only had supervised drug with-
drawal. When a 24-month follow-up was conduct-
ed, 42.6% of subjects had resumed BZDs, with
greater relapse in the CBT-alone group (69.2%)
when compared with the combined (33.3%) and
supervised withdrawal (30.8%) groups.
BzRAs have also been studied. Zavesicka and
colleagues51 reported 15 zolpidem-dependent
subjects who were successfully weaned while
receiving CBT, with associated improved sleep ef-
ficiency and decreased wakefulness after sleep
onset. An 8-week hypnotic taper program,
including 53 subjects taking either BZDs or BzRAs,
found that those randomized to receive CBT had
improved sleep efficiency and decreased total
wake time when compared with the control
group.52 However, both groups successfully
reduced hypnotic use, with no significant additional
reduction in the CBT group. In contrast, Morgan
and colleagues53 found that CBT greatly reduced
hypnotic drug use while improving sleep efficiency
and reducing sleep onset latency in a cohort of 209
chronic hypnotic users. Lichstein and colleagues54
further validated the usefulness of CBT in hypnotic-
dependent insomnia patients using BZDs, BzRAs,
or sedating antidepressants by randomizing sub-
jects to CBT with drug withdrawal, placebo
biofeedback with drug withdrawal, or drug with-
drawal alone. There were no significant differences
between groups in medication reduction, which
decreased by 84% posttreatment, and 66% at a
12-month follow-up. However, only the CBT group
had significant improvement in sleep onset latency
and subjective sleep measures.
Self-efficacy enhancement
In some analyses of factors leading to success in
hypnotic cessation, an individual’s perceived
self-efficacy has been positively correlated with
medication cessation.50,55 To further pursue
the effect of self-efficacy on patient outcomes,
Yang and colleagues56 randomized 48 long-
term hypnotic users (BZDs or BzRAs) to a
standard drug taper alone or a self-efficacy
educational program followed by the same drug
taper. Those in the treatment group had a higher
percentage of dose reduction than those in the
taper-alone group, suggesting that self-efficacy
can be learned and can improve hypnotic cessa-
tion outcomes.
Pharmacologic Therapies
Several studies have evaluated the usefulness of
medications to assist in BZD discontinuation,
though generally in the setting of anxiety or other
psychological disorders. These have included
ondansetron,57 imipramine,58,59 buspirone,58–60
paroxetine,61 carbamazepine,62 pregabalin,63 pro-
gesterone,64 antihistamines,65 and propranolol.66
Only a few have examined the usefulness of
117
 Hypnotic Discontinuation in Chronic Insomnia
medications to assist in BZDs cessation specif-
ically for insomnia. There have also been some re-
ports of other supplements to aid in hypnotic
discontinuation.
Zopiclone
Withdrawal symptoms and rebound insomnia
have been shown to be less severe with BzRAs
compared with some BZDs.18 Therefore, some in-
vestigators have proposed using a BzRA as a
bridge to BZD discontinuation. Pat-Horenczyk
and colleagues67 studied 24 subjects taking fluni-
trazepam for insomnia. All underwent a 5-week
withdrawal protocol and were followed with nightly
actigraphy and serial polysomnograms during the
withdrawal period. One group was transitioned to
zopiclone and then weaned off, whereas the other
was weaned off flunitrazepam directly. Both
objective (polysomnogram and actigraphy) and
subjective (sleep diaries) measures were improved
in the zopiclone group compared with the flunitra-
zepam group. Similar positive findings were found
in other reports.68–70 Two studies indicated that
abrupt medication substitution yielded better re-
sults than gradual substitution.68,70
Melatonin
Some have postulated that melatonin therapy
could aid in the discontinuation of hypnotics. In a
large retrospective study of prolonged-release
melatonin, 31% discontinued hypnotic use (BZDs
or BzRAs) after the melatonin was started.71
Several randomized trials have also considered
the usefulness of melatonin in hypnotic discontin-
uation, specifically BZDs. Although 2 of these trials
showed some effectiveness,72,73 most found that
melatonin did not enhance BZD discontinua-
tion.74–78 A meta-analysis also concluded that
melatonin supplementation did not affect rates of
BZD discontinuation.79
Valerian
The evidence for the use of the herbal supplement
valerian in insomnia to date has been inconclu-
sive.80 However, Poyares and colleagues81 re-
ported some positive outcomes with the use of
valerian in BZD discontinuation. Subjects treated
with valerian had better subjective sleep quality
than the placebo group, with decreased wakeful-
ness after sleep onset at a 2-week polysomno-
gram, though with a longer sleep onset latency.
SUMMARY
Discontinuation of hypnotic medications is often
challenging. The current evidence suggests that
a gradual taper is preferred over abrupt discontin-
uation owing to both rebound insomnia and
267
withdrawal symptoms. However, an ideal taper
schedule has not been well-established. A clinical
trial is currently underway in an effort to improve
understanding of the ideal wean schedule.31 In
addition to tapering hypnotics, providing patients
with educational handouts may provide some
benefit. Psychological therapies are also benefi-
cial, with the most evidence supporting CBT in
conjunction with a hypnotic taper. Some patients
taking BZD hypnotics may benefit from bridging
drug cessation with a BzRA. In those cases, an im-
mediate switch to a BzRA was more beneficial
than a gradual switch. Other medical therapies
have not uniformly demonstrated benefit. More-
over, because most of the evidence for hypnotic
discontinuation was done with BZDs, it is not clear
that a similar approach can be made with sedating
antidepressants, antihistamines, or other hyp-
notics. Furthermore, the discontinuation of hyp-
notics in the pediatric population is based only
on the adult literature. Further research is needed
to better establish optimal hypnotic discontinua-
tion guidelines for both adults and children.
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Penghentian obat Hipnotik pada

Insomnia Kronik

Jonathan P. Hintze, MDa,*, Jack D. Edinger, PhDb

KATA KUNCI
Meresepkan Penghentian Hipnotik Benzodiazepines Insomnia
Gangguan Tidur

 Pasien dengan insomnia kronis biasanya diresepkan obat hipnotis tetapi

POIN PENTING

 Penurunan bertahap lebih disarankan dibandingkan penghentian secara

penghentian obat-obatan ini sulit dicapai.

 Informasi tertulis yang diberikan kepada pasien tentang penghentian

mendadak untuk mencegah adanya withdrawal symptoms.

 Terapi kognitif behavioral atau terapi behavioral saja dapat meningkatkan

pengobatan mungkin bermanfaat.

 Saat ini bukti obat tambahan dalam penghentian obat hipnotik untuk
hasil dari penghentian obat hipnotik

insomnia masih terbatas.

ini guidelines pengobatan

PENGANTAR merekomendasikan pengurangan obat
Gangguan insomnia sering terjadi pada dan penghentian jika
orang dewasa dan anak-anak. Estimasi memungkinkan.10 Namun,
prevalensi berkisar dari 9% hingga 15% penghentian hipnotik sulit dan sering
pada populasi umum, dengan prevalensi gagal.11 artikel ini membahas strategi
lebih tinggi pada subpopulasi tertentu.1–6 untuk menghentikan hipnotik dan
obat obatan hipnotik berfungsi untuk bukti yang mendukung
membuat tidur dan sering digunakan penggunaannya.
untuk mengobati insomnia.7 Hipnotik
yang umum digunakan pada orang dewasa STRATEGI PENURUNAN
antara lain benzodiazepine (BZDs), agonis BERTAHAP HIPNOTIK
reseptor BZD (BzRA), antihistamin, Penghentian hipnotik mendadak
antidepresan, resep melatonin untuk
agonis, antagonis reseptor orexin, dan Penghentian obat secara mendadak adalah
antipsikotik . Meskipun saat ini tidak ada pilihan bagi banyak pengobatan. Namun,
obat untuk insomnia pada anak yang rebound insomnia dan withdrawal
disetujui oleh Administrasi Makanan dan symptoms dapat menyertai dari
Obat-obatan AS, umumnya obat yang penghentian mendadak ini. Rebound
digunakan termasuk antihistamin, alfa insomnia umumnya didefinisikan sebagai
agonis, antidepresan, BZD, BzRA, dan insomnia yang lebih buruk dibandingkan
antipsikotik..8,9 penggunaan jangka dengan insomnia pada umumnya. Hal ini
panjang hipnotik terhadap kesehatan pertama kali dijelaskan dengan
tidak dijelaskan dengan baik dan saat diskontinuitas dari triazolam 12 dan sejak

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saat itu telah dilaporkan dengan beberapa
penggunaan BZD lainnya 13,14; obat
penenang, antidepresan, termasuk
amitriptilin15 dan trazodone16; dan
BzRAs, meskipun dengan laporan yang
saling bertentangan.14,17–19 Selain itu,
withdrawal symptoms, didefinisikan
sebagai munculnya gejala yang
sebelumnya tidak ada, sering dilaporkan
dengan penghentian mendadak dari
BZD,.20 Akibatnya penurunan
bertahap umumnya lebih disukai
daripada penghentian mendadak.
Penurunan Bertahap obat hipnotik
Studi tentang strategi tapering sangat
bervariasi, dan tidak adanya
consensus dari protokol tapering yang
optimal. Pendekatan yang sering
digambarkan adalah pengurangan
dosis 25% setiap 1 hingga 2 minggu
sampai benar-benar berhenti . 21 -
25 Tingkat penghentian total berkisar
antara 24% hingga 61% dalam studi
ini tetapi ada variabilitas dalam
frekuensi kunjungan kantor dan
periode tindak lanjut dalam laporan
ini. Dengan gejala drawal sering
dilaporkan. Sedikit memperpanjang
dari dari durasi tapering, digunakan
oleh Lopez-Peig dan koleganya. 26
Subjek semua mengambil BZD, dan
diinstruksikan untuk mengurangi
dosis mereka sebesar 25% setiap 2
hingga 4 minggu. Pada akhir periode
tapering, 80,4% telah berhasil
menghentikan BZD mereka, dan 64%
tetap bebas BZD pada 12 bulan. Studi
lain memberi subyek dari berbagai
variasi BZDs sebesar 10% sampai
25% setiap 2 hingga 3 minggu,
dengan perkiraan 40% tingkat pantang
hipnotis dipertahankan pada 36 bulan,
tanpa ketidakpuasan tidur yang
signifikan dibandingkan dengan
kelompok kontrol. 27 Drake, 28
memberi subjek dari temazepam
dengan memotong dosisnya kira-kira
setengah setiap 2 minggu, dari 10 mg
hingga 5 mg hingga 2 mg. Dari
subjek, 59% berhasil menyelesaikan
tapering, dengan 52% tersisa bebas
hipnotis pada tindak lanjut 12 hingga
35 minggu kemudian. Lemoine dan
rekannya 29 melaporkan penurunan
serupa dengan 2BzRA, zopiclone dan
zolpidem. Karena studi, subyek diberi
dari zolpidem 10 mg hingga 5 mg
selama seminggu, diikuti dengan
plasebo. Demikian pula, subjek diberi
zopiklon dari 7,5 mg hingga 3,75 mg
selama seminggu, diikuti oleh terapi
placebo. Rejimen ini dikaitkan dengan
signifikansi. withdrawal yang lebih
tinggi dari kelompok kontrol yang
tidak diberi. Sebaliknya, Raju dan
Meagher 30 menggunakan tapering
yang protokol lebih fleksibel, di mana
subyek dapat mengontrol tingkat
withdrawal. Diberikan kontrol atas
kecepatan memberi, beberapa subjek
dengan cepat dihentikan penggunaan
hypnotic (19 dari 68), sedangkan yang
lain lebih suka tapering
berkepanjangan, namun lengkap, (13
dari 68). Sisanya tidak sepenuhnya
menghentikan penggunaan
pengobatan.
Menurut sepengetahuan penulis, tidak
ada studi yang secara khusus
membandingkan keberhasilan dari
strategi tapering dengan metode yang
berbeda . Namun penelitian secara
klinis percobaan saat ini masih
berlangsung yang akan
membandingkan strategi tapering
berbeda di antara hipnotik.31
Banyak praktisi merasa terbantu untuk
beralih dari short-acting ke BZD long-
acting sebelum memulai
tapering. 27,32
Ini dilakukan dengan beralih ke dosis
equivalent BZD long acting, biasanya
diazepam ( Tabel 1 ). Perlu dicatat
bahwa Ulasan Cochrane yang
diterbitkan pada tahun 2006 mencatat
dropout rate yang lebih tinggi ketika
tapering senyawa paruh pendek
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dibandingkan dengan BZD atau saran selama konsultasi

yang bekerja lama . 33 ditambahkan dengam buklet self-
help. 34 Intervensi menyatakan ada
pengurangan yang signifikan dalam
pereesepan BDZ dibandingkan
dengan perawatan rutin saja (18% vs
5%). Beberapa penelitian lain
menggunakan surat yang dikirim ke
pengguna BZD mendorong
pengurangan BZD, dengan Tingkat
penghentian BZD komplit mulai dari
14% hingga 27%. 23,24,35 - 37

Terapi Psikologis
Namun, tidak ada perbedaan dalam
withdrawal antar grup, jadi beralih Banyak penelitian telah menggunakan
dari short acting ke long acting terapi psikologis untuk
sebelum tapering bertahap tidak
didukung . Para penulis tidak
memperhatikan setiap studi yang
secara khusus membandingkan
praktikum beralih ke BZD long-acting
sebelum bertahap withdrawal versus
withdrawal bertahap secara langsung
dari BZD kerja pendek.

TERAPI TAMBAHAN
Terlepas dari strategi tapering,
beberapa tambahan terapi telah
dipelajari untuk membantu
penghentian obat hipnotik. Ini
termasuk berbagai tingkatan
pendidikan pasien, terapi psikologis,
dan obat-obatan.

Pendidikan Tertulis pada Pasien

Ada beberapa bukti bahwa
memberikan informasi kepada pasien
dapat menyebabkan penghentian
hipnotik.
Dalam 1 studi , pengguna BZD kronis
secara acak menerima perawatan rutin

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membantu penghentian pengobatan . Lichstein dan rekannya 41 menilai

singkatnya berbagai jenis terapi ada manfaat teknik relaksasi
di Tabel 2 . progresif sebagai tambahan dengan
program withdrawal obat standar di
Pendidikan hygiene uji coba acak. Semua subjek
mengalami pengurangan 79% dalam
Pendidikan higiene tidur disediakan
konsumsi hipnosis, tanpa perbedaan
secara rutin untuk penderita
signifikan antara kelompok. Namun
insomnia. Namun, ada Bukti untuk
demikian. ditugaskan untuk kelompok
merekomendasikan sleep hygine
relaksasi memiliki beberapa tanpa
sebagai terapi yang berdiri sendiri
gejala menggambar, efisiensi tidur
terlepas dari ada atau tidak adanya
yang lebih besar, dan kualitas tidur
penggunaan hipnosis.38 Selain itu,
yang dilaporkan lebih tinggi.
penulis tidak mengetahui adanya
penelitian yang menggunakan sleep
hygine sendiri sebagai intervensi
untuk membantu dalam penghentian Terapi kontrol rangsangan
hipnotic.
Terapi kontrol rangsangan adalah
metode yang dipelopori oleh
Bootzin 42 dan digunakan untuk
Terapi relaksasi membangun kembali asosiasi antara
tempat tidur dan tidur. Pasien
Terapi relaksasi adalah teknik yang
didorong untuk melepaskan diri dari
digunakan untuk mengurangi
tempat tidur ketika tidak dapat
ketegangan otot dan proses berpikir
tertidur, dan hanya pergi tidur saat
yang mengganggu tidur, dan
mengantuk bukan pada waktu tidur
melibatkan ketegangan dan
yang diinginkan. Mereka juga
mengendurkan kelompok otot
didorong untuk menjaga waktu tidur
utama. Giblin dan Clift 39 mempelajari
yang ketat dan untuk menghindari
efek terapi relaksasi pada penghentian
hipnotik ke 20 subjek. Interverensi tidur sebentar.
mereka juga temasuk dalam diskusi Sebuah studi tentang 7 pengguna
tentang tidur dan insomnia, obat hipnotik jangka panjang, menemukan
hipnotik dan efeknya pada tidur, serta bahwa sebagian besar (6 dari 7) dapat
saran secara general tentang problem mengurangi atau menghentikan
solving dan sifat optimis. pengobatannya saat stimulus terapi
kontrol digunakan. 43 Riedel dan
Ada penurunan yang signifikan pada
kolega 44 secara acak pada 21 subjek
subjek yang dilanjutkan penggunaan
untuk program withdrawal obat, atau
hipnotis malam hari pada 12 minggu
withdrawal program
dalam pengobatan kelompok (2 dari
dan terapi kontrol stimulus . Kedua
10) dibandingkan dengan kelompok
kelompok mengalami pengurangan
kontrol (8 dari 10), tanpa perbedaan
signifikan dalam jumlah penggunaan
signifikan antara kelompok dalam
obat tidur tetapi kontrol stimulus
latensi onset tidur dilaporkan dan
kelompok juga mengalami
kualitas tidur secara keseluruhan.
peningkatan yang signifikan secara
Lichstein dan Johnson 40
total pada waktu tidur, efisiensi tidur,
menggunakan terapi relaksasi untuk
kualitas tidur, dan kantuk di siang
penghentian hipnosis, menghasilkan
hari. Beberapa penelitian lain
substansi pengurangan total (47%)
termasuk kontrol stimulis terapi
dalam penggunaan obat tidur.

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sebagai bagian dari interverensi. (CBT) menggabungkan terapi

perilaku (misalnya, relaksasi, kontrol
rangsangan, pembatasan tidur) dengan
terapi kognitif untuk membentuk
Terapi pembatasan tidur
multikomponen dan intervensi
Terapi pembatasan tidur digunakan omnibus. CBT adalah combinasi
untuk membatasi jumlah waktu sebuah terapi dengan variasi
yang dihabiskan bangun dari tempat tergantung pada metode spesifik yang
tidur. Ini dilakukan dengan digunakan. CBT sudah lama
menentukan jumlah tidur pasien digunakan untuk insomnia dan studi
secara teratur setiap harinya dan awal menunjukkan kegunaan dalam
membatasi jumlah yang diizinkan penghentian hipnosis. 47 Beberapa
berada di tempat tidur dengan jumlah penelitian selanjutnya telah dilakukan.
yang sama. Misalnya, jika seorang Banyak penelitian yang secara khusus
pasien saat ini menghabiskan 10 jam mengevaluasi penghentian
di tempat tidur per malam tetapi BZD. Baillargeon dan rekan 48
hanya tidur 6 jam, maka jumlahnya mempelajari 65 subject dengan
waktu di tempat tidur per malam akan insomnia kronis mengambil BZD
menjadi terbatas pada 6 hingga 6,5 setiap malam, mengacak subyek dan
jam, tergantung pada batasan tidur diawasi bertahap sendiri atau
spesifik Protokol yang digunakan. dikombinasikan dengan 8 minggu
Meskipun pembatasan tidur terapi CBT. Di akhir pengobatan , lebih
yang ditemukan untuk insomnia banyak subjek memiliki penghentian
secara umum, 45 Taylor and obat pada kelompok gabungan (77%)
kolega 46 melakukan satu-satunya dibandingkan dengan kelompok
ujian belajar yang dikenal efektivitas tapering saja (38%), dengan hasil
pembatasan tidur di serupa pada tindak lanjut 12 bulan
menyelesaikan penghentian (70% vs 24%). Meskipun beberapa
hipnosis. Empat puluh enam subyek penelitian lain melaporkan tidak ada
ditugaskan untuk melakukan peningkatan tingkat
pendidikan kesehatan tidur penghentian BZD denganCBT, 23,49,50
pembatasan pendidikan atau tidur ukuran kualitas tidur lainnya
dengan obat tanpa gambar. Pada umumnya membaik. Morin dan
kelompok pembatasan tidur, 52,6% rekan 25 dianggap sebagai efek
obat hipnotik yang benar-benar diferensial yang diawasi Withdrawal
dihentikan gunakan, dibandingkan BZD dan CBT dalam uji coba acak
dengan 15,4 % dalam kebersihan tidur mereka. Tujuh puluh enam subjek
kelompok. Selain itu, ada peningkatan menjalani percobaan withdrawal,
pada latensi onset tidur dan efisiensi CBT, atau keduanya. Meskipun
tidur, yang dipertahankan melalui semua kelompok memiliki
tindak lanjut 12 bulan periode. pengurangan jumlah yang signifikan
(90%) dan frekuensi (80%) dari
penggunaan BZD, pengobatan
gabungan Grup adalah yang paling
Terapi perilaku kognitif sukses di mencapai penghentian obat
Terapi kognitif adalah metode yang lengkap (85%), dengan withdrawal
menantang keyakinan pasien saat ini yang ditarik sendiri dan CBT saja
tentang tidur yang berkontribusi yang menghasilkan hasil yang kurang
terhadap insomnia. Terapi perilaku berhasil (48% dan 54% masing-
kognitif / cognitive behavioral therapy masing secara aktif). Menariknya,

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subjek di kedua kelompok yang kelompok dalam pengurangan obat,

menerima CBT melaporkan yang menurun sebesar 84% pasca
peningkatan yang lebih besar dalam perawatan, dan 66% pada tindak
kualitas tidur subjektif bila lanjut 12 bulan. Namun, hanya
dibandingkan dengan kelompok yang kelompok CBT mengalami
hanya memiliki obat yang peningkatan yang signifikan dalam
diawasi dengan gambar. Ketika tindak latensi onset tidur dan ukuran tidur
lanjut 24 bulan dilakukan 42,6% subyektif .
subyek telah melanjutkan BZD,
dengan kekambuhan yang lebih besar Peningkatan self-efficacy
pada kelompok CBT saja (69,2%) bila
Dalam beberapa analisis faktor-faktor
dibandingkan dengan gabungan
yang menyebabkan kesuksesan
(33,3%) dan withdrawal yang diawasi
penghentian hipnotis yaitu individu
(30,8%) kelompok. BzRA juga telah
self-efficacy telah berkorelasi positif
dipelajari . Zavesicka dan
dengan penghentian pengobatan.
rekan 51 melaporkan 15 tergantung
50,55 Untuk mengetahui lebih jauh efek
zolpidem subyek yang berhasil diberi
self-efficacy pada hasil pasien, Yang
sementara menerima CBT, dengan
dan rekannya 56 secara acak 48 dan
peningkatan efisiensi tidur
lama dari penggunaan hipnotis (BZD
kekurangan dan penurunan bangun
atau BzRA) ke obat tapering standar
setelah tidur serangan. Program
sendiri atau edukasi efikasi diri diikuti
tapering hipnotis 8 minggu,
oleh obat yang sama tapering. Mereka
termasuk 53 subjek yang
yang berada dalam kelompok
menggunakan BZD atau BzRA,
perlakuan memiliki yang lebih tinggi
menemukan bahwa mereka yang
persentase pengurangan dosis dari
secara acak menerima CBT miliki
pada kelompok tapering sendirian,
peningkatan efisiensi tidur dan
menunjukkan efikasi diri dapat
penurunan total waktu bangun jika
dipelajari dan dapat meningkatkan
dibandingkan dengan kontrol
penghentian hipnotik.
kelompok. 52 Namun, kedua kelompok
berhasil mengurangi penggunaan
hipnosis, tanpa tambahan signifikan
pengurangan pada kelompok Terapi Farmakologis
CBT. Sebaliknya, Morgan dan
rekan 53 menemukan bahwa CBT Beberapa penelitian telah
sangat berkurang penggunaan obat mengevaluasi kegunaan dari obat-
hipnosis sambil meningkatkan obatan untuk membantu dalam
efisiensi tidur dan mengurangi latensi penghentian BZD, meskipun
onset tidur dalam kohort 209 umumnya dalam pengaturan
pengguna hipnotis kronis. Lichstein kecemasan atau gangguan psikologis
dan kolega 54 lebih lanjut memvalidasi lainnya.
kegunaan CBT dalam hipnotis pasien Yang akan dibahas ini sudah termasuk
insomnia dependen menggunakan ondansetron, 57 imipramine, 58,59buspir
BZD, BzRA, atau obat penenang on, 58 –
antidepresan dengan mengacak subjek
60paroxetin, 61 carbamazepine, 62
menghubungkan ke CBT dengan pregabalin, 63 progesteron, 64 antihista
withdrawal obat, placebo biofeedback min, 65 dan propranolol. 66 Hanya
dengan withdrawal obat, atau obat sedikit obat-obatan untuk membantu
tanpa gambar saja. Tidak ada dalam penghentian BZD spesifik
perbedaan yang signifikan antara untuk insomnia. Ada juga beberapa

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studi tentang suplemen lain untuk menemukan itu melatonin tidak

membantu penghentian hipnotik. meningkatkan penghentian BZD. 74 -
78 Sebuah meta-analisis juga
Zopiclone menyimpulkan itu suplementasi
melatonin tidak mempengaruhi
Withdrawal dan rebound insomnia
tingkat Penghentian BZD. 79
telah terbukti lebih ringan gejalanya
dengan BzRA dibandingkan dengan Valerian
beberapa BZD. 18 Oleh karena itu,
beberapa peneliti telah mengusulkan Bukti penggunaan suplemen herbal
penggunaan BzRA sebagai valerian dalam insomnia sampai saat
menjembatani ke penghentian ini masih belum bisa disimpulkan. 80
BZD. Pat-Horenczyk dan kawan- Namun, Poyares dan rekan
kawannya 67 mempelajari 24 subyek 81 melaporkan beberapa hasil positif
yang mengambil trazepam untuk dengan penggunaan valerian dalam
insomnia. Semua menjalani 5 minggu penghentian BZD. Subjek yang
protokol withdrawal dan diikuti dirawat dengan valerian memiliki
dengan night actigraphy kualitas tidur subjektif yang lebih baik
dan polysomnograms serial selama dibandingkan kelompok plasebo,
periode withdrawal. Satu grup dengan penurunan bangun (terjaga)
dialihkan ke Zopiclone lalu setelah onset tidur di polysomnogram
berhentikan, sedangkan yang lainnya 2 minggu, meskipun dengan latensi
diberi flunitrazepam dan secara onset tidur yang lebih rendah.
langsung diberhentikan. Kedua
instrument obyektif (polisomnogram
dan aktigrafi) dan tindakan subyektif
RINGKASAN
(buku harian tidur) menunjukan hasil
lebih bagus dalam kelompok Penghentian obat hipnotis masih
zopiclone dibandingkan dengan grup menjadi sesuatu yang
flunitra-zepam. Temuan positif serupa menantang. Bukti saat ini
ditemukan dalam laporan lain. 68 menunjukkan tapering bertahap lebih
70 Dua penelitian menunjukkan itu disukai daripada penghentian
substitusi obat tiba-tiba menghasilkan mendadak karena karena rebound
respon yang lebih baik lebih dari insomnia dan gejala
substitusi bertahap. 68,70 withdrawal. Namun, tapering yang
ideal belum ditemukan. Secara klinis
Melatonin percobaan saat ini sedang berlangsung
Beberapa telah mengemukakan terapi dalam upaya untuk meningkatkan
melatonin bisa membantu dalam memahami jadwal penurunan yang
penghentian hipnosis. Di sebuah studi ideal. 31Selain tapering hipnotik,
retrospektif besar dari prolonged menyediakan pasien dengan handout
release melatonin, 31% berhenti tentang edukasi
menggunakanhipnotis (BZDs atau mungkin menyediakan beberapa
BzRA) setelah melatonin dimulai. 71 manfaat. Terapi psikologis juga
Beberapa uji coba random juga telah bermanfaat dengan bukti terbanyak
dipertimbangkan kegunaan melatonin yang mendukung yaitu dengan CBT
pada penghentian hipnotik khususnya yang bersamaan dengan
BZD. Meskipun 2 dari cobaan ini tapering. Beberapa pasien yang
menunjukkan beberapa menggunakan BZD hipnotik mungkin
keefektifan, 72,73 kebanyakan mendapat manfaat dari peralihan

128
Laras Pamekas Wicaksono (201610330311150)

penghentian obat dengan sama dapat dibuat dengan penenang

BzRA. Dalam kasus tersebut, beralih antidepresan, antihistamin, atau
mediasi ke BzRA lebih bermanfaat hipertensi lainnya. Selanjutnya,
dari penurunan langsung pada penghentian obat hipnotik pada anak-
BZD. Terapi medis lainnya belum anak masih didasarkan pada literatur
menunjukkan manfaat yang orang dewasa. Diperlukan penelitian
seragam. Lebih-lebih, karena sebagian lebih lanjut tentang penghentian
besar bukti untuk penghentian hipnotik untuk mendirikan guidelines
hipnotis dilakukan dengan BZD, tidak yang optimal pada dewasa maupun
jelas bahwa pendekatan yang anak-anak.

129
Curr Psychiatry Rep (2016) 18:78
DOI 10.1007/s11920-016-0717-y
SLEEP DISORDERS (P GEHRMAN, SECTION EDITOR)
An Update on the Use of Sedative-Hypnotic Medications
in Psychiatric Disorders
Shane Creado 1 & David T. Plante 1,2
# Springer Science+Business Media New York 2016
Abstract Sleep disturbance is a common clinical problem
experienced by patients with a wide range of psychiatric dis-
orders. Accumulating evidence has demonstrated that insom-
nia is a comorbid process that affects the course and treatment
of a number of forms of mental illness. The efficacy and safety
of sedative-hypnotic medications have largely been
established in patients who do not have comorbid psychiatric
disorders, underscoring the need for further research in this
sphere. This review summarizes pertinent findings in the re-
cent literature that have examined the role of hypnotic medi-
cation in the treatment of psychiatric illness, and highlights
potential areas that may prove fruitful avenues of future
research.
Keywords Insomnia . Sedative . Hypnotic . Sleep .
Psychiatric
Introduction
Sleep disturbance is extremely common among persons with
psychiatric disorders. Insomnia, defined as difficulty initiating
or maintaining sleep despite adequate opportunity that is as-
sociated with significant distress or impairment, is a diagnos-
tic feature of mood and anxiety disorders, and is also
This article is part of the Topical Collection on Sleep Disorders
* David T. Plante
dplante@wisc.edu
1
Department of Psychiatry, University of Wisconsin School of
Medicine and Public Health, Madison, WI, USA
2
Wisconsin Sleep, 6001 Research Park Blvd., Madison,
WI 53719, USA
frequently experienced by persons with several other forms
of psychiatric illness [1]. Insomnia shares a particularly strong
bidirectional relationship with mood disorders, as it has been
associated with increased risk of incident depression and
poorer treatment outcomes, as well as increased suicidal ide-
ation, suicide attempts, and completed suicide [2]. These re-
lationships have led to development of current nosological
perspectives that consider sleep difficulties as comorbid with,
rather than secondary to, psychiatric disorders [1, 3].
Despite these evolving views on sleep disturbance and psy-
chiatric disorders, there are several important questions that
remain unanswered, particularly in regard to the use of
sedative-hypnotic medications. First, what evidence supports
the use of specific medications in the treatment of insomnia
comorbid with psychiatric disorders? Second, does pharma-
cologic treatment of insomnia impact psychiatric symptoms
beyond specific effects on sleep disturbance? Third, how do
sedative-hypnotic medications alter the longitudinal course of
major mental illnesses? And finally, might agents designed to
improve sleep continuity have separate effects on other
spheres of neurocognitive functioning, particularly those that
have been demonstrated to be altered by sleep?
In this review, we will highlight the recent salient literature
that examines these vital areas of inquiry. We will focus our
summary predominantly on medications that were initially
developed and/or marketed for the purpose of treating insom-
nia, with inclusion of other agents used off-label to treat sleep
disturbance where pertinent. We readily acknowledge the ef-
ficacy of non-pharmacologic methods for the treatment of
insomnia [4]; however, this review will specifically focus
medications and not other cognitive-behavioral approaches.
Moreover, because several reviews have detailed the effects
and efficacy of the melatonergic antidepressant agomelatine
[5–7], this medication is considered beyond the scope of this
review. In keeping with the Current Reports format, we will
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78 Page 2 of 7
focus primarily on recent developments in the literature, and
specifically overview the use of sedative-hypnotic medica-
tions in unipolar major depressive disorder, bipolar disorder,
schizophrenia, and post-traumatic stress disorder (PTSD). Our
goal is to provide a succinct, yet critical assessment of the
recent literature on this topic, as well as underscore areas of
future research required to advance the field.
Major Depressive Disorder
Insomnia is very common in major depressive disorder
(MDD), with up to 90 % of patients experiencing difficulty
initiating or maintaining sleep during a mood episode [8].
Since their inception nearly three decades ago, specific sero-
tonin reuptake inhibitors (SSRIs) have become the mainstay
of treatment for unipolar depression. As a class, SSRIs tend
not to have significant antihistaminergic or anticholinergic
effects and thus tend to be less sedating than older tricyclic
antidepressant (TCA) medications. In this context, a research
design in which patients experiencing a major depressive ep-
isode with comorbid insomnia are co-administered an open-
label SSRI with a blinded sedative-hypnotic versus placebo
has become a useful paradigm to study the effects of sedative
hypnotics on both sleep and psychiatric symptoms within the
standard of care. Using this study design, Fava et al. [9] pre-
viously reported that eszopiclone 3 mg nightly co-
administered with fluoxetine in patients with MDD and in-
somnia not only significantly improved sleep-related symp-
toms, but also significantly improved depressive symptoms
beyond its soporific effects [measured by improvement on
the 17-item Hamilton Rating Scale for Depression (HDRS-
17) with sleep items omitted]. Building on this work, Fava
and colleagues [10•] more recently conducted a post hoc anal-
ysis that combined data from this prior study with another
randomized placebo-controlled study of patients with gener-
alized anxiety disorder treated with escitalopram and concur-
rent eszopicone 3 mg nightly versus placebo [11]. For this
study, anxious depression was defined as an HDRS-17 score
≥14 (excluding insomnia items) and an anxiety/somatization
factor score (derived from six sub-items on the HDRS-17) ≥7
[10•]. Pooled analyses demonstrated eszopiclone co-
administration significantly improved insomnia symptoms
[assessed by the change mean change from baseline on the
Insomnia Severity Index (ISI)] [10•]. Moreover, after 8 weeks
of co-therapy with eszopiclone, HDRS-17 scores decreased
from baseline, regardless of whether insomnia items were ex-
cluded; however, this effect was not observed when specifi-
cally examining anxiety/somatization [10•].
Another recent study examined an open-label SSRI
(escitalopram) with co-administration of zolpidem extended-
release (ER) 12.5 mg versus placebo in patients with MDD
and comorbid insomnia [12•]. Zolpidem ER increased self-
Curr Psychiatry Rep (2016) 18:78
reported sleep duration and continuity, as well as next day
functioning, but did not augment the antidepressant response
of escitalopram assessed by the change in HDRS-17 [12•].
Despite the divergent antidepressant effects observed in
zolpidem ER compared to eszopiclone [9, 10•, 12•], there is
not currently sufficient evidence to suggest one agent is supe-
rior to the other in the treatment of insomnia with comorbid
depression, as this would require a direct comparison.
However, it does raise important questions regarding how
different pharmacologic properties of these agents might lead
to particular effects on co-occurring depressive symptoms. In
general, although both agents are considered to be non-
benzodiazepine benzodiazepine receptor agonists (BZRAs),
they do have different affinities for the GABA-A receptor,
with zolpidem being highly selective for α1 subtype, while
eszopiclone additionally has considerable activity at GABA
receptors containing α3 and α5 subunits [13]. Whether the
different effects on comorbid depressive symptoms observed
in these studies is due to specific neuropharmacologic proper-
ties of the drugs, or some other factor, such as inadvertent
unblinding in eszopiclone studies due to very high rates of
dysgeusia [which can occur in >25 % of participants [10•]]
remains to be explained, but may prove a fruitful area of future
research.
Another vital area of investigation is how sedative-
hypnotics affect suicidal ideation in patients with comorbid
depression and insomnia. A sizeable literature has demonstrat-
ed that insomnia is an independent risk factor for suicide,
raising the possibility that treatment of insomnia with a
sedative-hypnotic might reduce suicidal risk [14]. Because
prior studies that have examined co-therapy of sedative-
hypnotics with SSRIs have excluded people at significant risk
of suicide [9, 12•], there is insufficient evidence to determine
whether sedative-hypnotics alter the risk of suicide. This is an
important area of investigation because clinicians are often
unwilling to prescribe sedative-hypnotics to patients with sui-
cidal ideation, possibly out of concern that the agent may be
utilized in overdose attempts. Also, a controlled study to ex-
amine effects of sedative-hypnotics on suicidal ideation re-
quires a very thoughtful study design to protect the safety of
research participants. To help clarify the potential role of
sedative-hypnotics in the management of suicidal ideation, a
carefully crafted, multi-site randomized clinical trial of open-
label SSRI with zolpidem ER versus placebo in depressed
adult outpatients with insomnia and suicidal ideation has been
developed and is currently recruiting participants with funding
from the National Institutes of Mental Health [15]. We eagerly
anticipate the results of this Reducing Suicidal Ideation
Through Insomnia Treatment (REST-IT) study, as it is very
likely to significantly impact the standard of care in
psychiatry.
Beyond BZRAs, there has been little recent empiric evalu-
ation of the impact of off-label sedative-hypnotics in the
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Curr Psychiatry Rep (2016) 18:78
treatment of insomnia with comorbid depressive symptoms.
Wichniak and colleagues [16] in an open-label study exam-
ined the effects of trazodone continuous-release (CR) 25–
150 mg daily in patients with primary insomnia with and
without comorbid depressive symptoms, finding that this
agent improves clinical symptoms including increased subjec-
tive sleep duration and reduced sleep onset latency.
Additionally, during the run-out phase, patients with higher
depressive symptoms [assessed using the Beck Depression
Inventory (BDI)] tended to have a deterioration of symptoms
relative to those without depressive symptoms [16]. One other
non-controlled study assessed low-dose doxepin (<25 mg/
day) in psychiatric inpatients with insomnia and MDD [17].
This retrospective case series failed to demonstrate significant
benefit of doxepin on sleep onset or maintenance in these
patients [17]. Clearly, because sedating antidepressants are
the some of the most commonly prescribed agents for insom-
nia [18], further research that clarifies the evidence for use of
these agents to treat insomnia in psychiatric illness is needed.
Bipolar Disorder
Sleep disturbance, both insomnia and hypersomnolence, is
extremely common in bipolar disorder. Insomnia frequently
occurs in all phases of the illness, including manic, depressive,
and euthymic periods [19, 20]. A sizeable circumstantial liter-
ature has suggested sleep disturbance may induce mood
switching, particularly to mania [21]. Adding to this literature,
Cretu and colleagues recently examined the role of sleep dis-
turbance in a cohort of 89 recovered patients with bipolar
disorder followed for over 1 year [22]. Notably, in this cohort,
sleep disturbance [assessed with the Pittsburgh Sleep Quality
Index (PSQI)] not only correlated significantly with residual
mood symptoms, but also predicted earlier mood episode re-
currence, even after covarying for residual mood symptoms
[22]. Additionally, these findings highlight the potential im-
portance of the treatment of sleep disturbance in bipolar dis-
order, which theoretically might provide benefit by reducing
the occurrence of mood episodes over the longitudinal course
of the disorder. However, links between treatment of insomnia
and mood stabilization have been highly speculative, and the
evidence base regarding the use of specific sedative-hypnotics
in bipolar disorder has been quite limited.
McElroy and colleagues assessed the use of ramelteon
8 mg nightly versus placebo in outpatients with bipolar disor-
der experiencing mild to moderate manic symptoms and in-
somnia [23]. During the course of the 8-week study, other
medications were continued and left unchanged (except in
instances in which a medication required dose reduction for
side effect management) [23]. In this study, ramelteon did not
demonstrate efficacy greater than placebo on the primary out-
come measure (change in insomnia assessed by 65-item
Page 3 of 7 78
Pittsburgh Insomnia Rating Scale), nor did it have differential
effects on manic symptoms or global severity of illness [23].
However, it did demonstrate improvement in global rating of
depressive symptoms, and no serious adverse events were
observed [23]. Although this study represents one of the first
attempts to conduct a randomized controlled study for insom-
nia in bipolar disorder, the small sample size (total N = 21), as
well as the fact that patients were hypomanic, may limit the
power of the study to detect benefit over placebo, as well as
the generalizability of results to the management of comorbid
insomnia in other phases of bipolar disorder.
Norris and colleagues further extended research on
ramelteon in insomnia comorbid with bipolar disorder, exam-
ining a larger number of participants (N = 83), who were
euthymic at baseline [24•]. Participants in this double-blind
investigation were randomized to either ramelteon 8 mg or
placebo, in addition to their regular psychiatric medications,
and followed for up to 24 weeks or until they experienced a
depressive or manic relapse [24•]. Remarkably, participants
receiving ramelteon had significantly and roughly twofold
lower odds of mood relapse compared to placebo. Also, par-
ticipants randomized to placebo who had most recently recov-
ered from a mixed or depressive episode had even higher odds
(odds ratio 2.67 and 3.75, respectively) of completing the 24-
week study compared to participants in the placebo group
[24•]. This improved mood stability occurred despite no sig-
nificant change in the PSQI (last observation carried forward),
although trends towards improvement in the PSQI were ob-
served from 8–20 weeks of treatment [24•]. The authors spec-
ulated that participants might not have had significant im-
provement in the PSQI with ramelteon relative to placebo
due to a ceiling effect caused by concordant sedating psycho-
tropic medications prescribed for bipolar disorder [24•]. Other
study limitations include a relatively small sample size, as well
as a duration of mood stability required for study entry of only
1 week, which is shorter than other clinical trials examining
mood stability in bipolar disorder [24•]. Despite these limita-
tions, this study suggests that ramelteon, a melatonin type 1-
and 2-receptor agonist, may alter the longitudinal course of
bipolar disorder, and clearly further research in this sphere is
indicated.
Other than the two aforementioned randomized-controlled
studies of ramelteon in bipolar disorder [23, 24•], the remain-
ing evidence base to guide the choice of sedative hypnotic
medication in bipolar disorder is largely uncontrolled.
Schaffer and colleagues performed a chart review assessing
the efficacy and safety of zolpidem (immediate and extended
release), eszopiclone, zaleplon, and ramelteon in 361 consec-
utive patients with bipolar disorder [25]. In general, they noted
about half of their of their patients required chronic daily sed-
ative-hypnotics, and that BZRAs had success rates (defined as
much or very much improved on the Clinical Global
Impression Scale-Bipolar Version) of 36–60 %, with more
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78 Page 4 of 7
limited success for ramelteon (15 %). These agents were all
generally well tolerated, and chronic sedative-hypnotic users
had not experienced unacceptable untoward events [25].
Although these uncontrolled data must be interpreted with
caution, they do provide some evidence that these agents
may be reasonable choices for the treatment of insomnia as-
sociated with bipolar disorder, including chronic use.
Another class of agents, sedating antidepressants, is fre-
quently used to treat insomnia in patients with bipolar disor-
der; however, the evidence base for these medications is lim-
ited, despite their widespread use [18]. Because previous stud-
ies have suggested that TCAs and trazodone might increase
the risk of mood switching, particularly to the manic phase
[26, 27], clarification of the safety and efficacy of these agents
in persons with bipolar disorder is an important area of study.
In the absence of controlled data, Wichniak and colleagues
recently reviewed the literature to identify case reports of se-
dating antidepressants (trazodone and mirtazapine, as well as
agomelatine) inducing manic symptoms [28]. Although the
risk of bias in this approach is substantial, they found that
trazodone and mirtazapine tended to cause mania in patients
with other risk factors for manic switching (e.g., not being on a
concomitant mood stabilizer) and tended to occur at antide-
pressant (i.e., higher) doses than the lower doses typically
prescribed off-label for insomnia [28]. Thus, if these agents
are used to treat insomnia comorbid with bipolar disorder, it
would seem most prudent to utilize these agents only in pa-
tients concurrently maintained on a mood-stabilizing medica-
tion, and with careful monitoring for increased mood
switching. Ideally, further controlled research would shed
light on the efficacy and safety of sedating antidepressants in
bipolar disorder; however, there are likely economic and eth-
ical reasons that such studies are not likely to be conducted in
the near future.
Beyond treating insomnia and potentially altering the lon-
gitudinal course of bipolar disorder, the use of sedative-
hypnotics may also provide benefit in the management of
other negative health behaviors such as smoking, which is
3.5-fold more common among patients with bipolar disorder
than the general population [29]. Since insomnia preceding
and during attempts to quit smoking have been associated
with cessation failure [30, 31], the use of adjunctive sleep-
promoting agents in patients attempting to quit smoking, par-
ticularly among high-risk patients such as those with major
mental illness, is a potentially promising line of investigation.
Forrest and colleagues performed a secondary analysis of an
RCT that examined varenicline versus placebo in patients
with bipolar disorder desirous of quitting smoking, finding
the use of concomitant hypnotic agents was associated with
a greater likelihood of cessation in these patients [32]. Despite
limitations including a small sample size (N = 60), and open-
label use of hypnotic use limiting cause and effect inferences,
these results suggest future larger controlled studies that
Curr Psychiatry Rep (2016) 18:78
include patients with bipolar disorder, as well as other psychi-
atric disorders associated with increased rates of smoking,
such as schizophrenia, are indicated.
Schizophrenia
Schizophrenia is the quintessential psychotic illness, with
symptoms that fall into three broad categories: positive, neg-
ative, and cognitive; all of which are can negatively impact
social and occupational functioning. Cognitive symptoms,
which can include poor executive functioning, attentional dif-
ficulties, and difficulty with working memory, can be partic-
ularly impairing for patients with the disorder [33]. The most
consistently identified sleep-related difficulties endured by pa-
tients with schizophrenia include difficulties falling and
staying asleep [34, 35]. Since insomnia and sleep restriction
are associated with cognitive impairment in a number of do-
mains [36, 37], treating sleep initiation and continuity difficul-
ties could theoretically result in improved cognition in these
patients.
Following this line of inquiry, Tek and colleagues exam-
ined the use of eszopiclone 3 mg nightly versus placebo in 39
clinically stable outpatients with schizophrenia or
schizoaffective disorder and comorbid insomnia [38•]. The
study included an 8-week randomized period, followed by a
single-blind 2-week placebo phase to assess durability of drug
effects. Eszopiclone demonstrated significant efficacy over
placebo on the primary outcome measure of change in ISI
score, with a between group difference of nearly four points
on the scale [38•]. During the discontinuation period, there
was no difference between eszopiclone and placebo in the
change in ISI score [38•]. Despite improvements in insomnia,
eszopiclone did not demonstrate benefit on the secondary out-
come of change in Measurement and Treatment Research to
Improve Cognition in Schizophrenia (MATRICS) Consensus
Cognitive Battery, which assesses processing speed, attention,
verbal and non-verbal working memory, verbal and visual
learning, reasoning/ problem solving, and social cognition
[38•]. Exploratory analysis suggested subscale improvement
with eszopiclone on a working memory test, the letter number
span component of MATRICS, for participants with schizo-
phrenia (but not schizoaffective disorder), which correlated
with the change in ISI score [38•]. However, improvements
in working memory observed during the double-blind phase
with eszopiclone did not persist into the single-blind placebo
phase, suggesting such changes were not durable [38•].
In addition to changes in working memory, it has been
posited that eszopiclone might lead to improved sleep-
dependent procedural memory consolidation in persons with
schizophrenia. Patients with schizophrenia have demonstrated
impairments in overnight improvement on a well-established
finger-tapping motor sequence task (MST) [39]. Because
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Curr Psychiatry Rep (2016) 18:78
patients with schizophrenia demonstrate reductions in sleep
spindles [40] and sleep-dependent improvement on the MST
correlates with these waxing-waning electroencephalographic
oscillations characteristic of non-rapid eye movement sleep
[41], examining the effects of agents such as eszopiclone,
which may increase sleep spindles through potentiation of
the GABAergic thalamic reticular nucleus (the primary site
of sleep spindle generation), is a promising line of inquiry.
Wamsley and colleagues examined both the ability of
eszopiclone to generate sleep spindles as well as its associative
effects on overnight MST performance [42•]. After screening,
21 patients with schizophrenia completed in laboratory base-
line visits, which consisted of two consecutive nights of
polysomnography, with the MST performed during the sec-
ond night of sleep. One week later, participants completed a
similar treatment visit; however, patients were randomized to
either eszopiclone 3 mg or placebo and completed the MST
using an alternate sequence compared to baseline.
Eszopiclone significantly increased the number and density
of spindles relative to baseline compared to placebo, but did
not significantly enhance overnight MST improvement [42•].
When eszopiclone and placebo groups were combined, sleep
spindle number and density correlated with overnight MST
improvement [42•]. These findings support the notion that
pharmacologic enhancement of sleep spindles may have some
benefit in patients with schizophrenia; however, further re-
search is indicated to determine what domains may be impact-
ed and whether such improvements have demonstrable clini-
cal impact on the disorder.
Post-Traumatic Stress Disorder
PTSD is among the most common psychiatric conditions,
with an overall lifetime prevalence in the USA of roughly
7 % [43]. Sleep disturbance is a core feature of PTSD, with
insomnia and nightmares both components of the diagnostic
criteria for the disorder [1]. Additionally, insomnia and night-
mares may play a role in the morbidity of the disorder, and
thus be an important target of therapy [44]. Despite this, the
evidence base for treatment of sleep disturbance in PTSD is
relatively scant. Recent review of the literature supports the
use of prazosin as a first-line agent for both insomnia and
nightmares in PTSD [45].
There is also recent evidence that suggests that eszopiclone
may provide benefit as an adjunctive agent in the treatment of
sleep disturbance in PTSD. Pollack and colleagues examined
the use of eszopiclone 3 mg nightly in patients with PTSD and
co-occurring sleep disturbance, using a randomized, double-
blind, placebo-controlled crossover design [46•]. Three weeks
of eszopiclone compared to placebo was associated with sig-
nificantly reduced sleep onset latency and improvement in
sleep quality (measured by the PSQI). Additionally, similar
Page 5 of 7 78
to benefits of co-therapy in major depression [9, 10•],
eszopiclone also significantly improved PTSD symptoms
[assessed with the clinician-administered short PTSD rating
interview (SPRINT) and the clinician-administered PTSD
scale (CAPS)], even when sleep-related items were excluded
[46•]. Although these results are promising, the study was
relatively small (N = 23), and future work replicating such
results as well as evaluating longitudinal effects beyond
short-term use are indicated. In addition, comparative effec-
tiveness studies would be helpful in determining whether
sedative-hypnotics provide benefit above other agents fre-
quently used off-label to treat insomnia in PSTD. In particular,
atypical antipsychotics, which are commonly prescribed
largely for their sedative-hypnotic properties in patients with
PTSD [47], should be compared both in efficacy on sleep and
PTSD symptoms, as well as side-effect profile, given the neg-
ative health consequences (e.g., weight gain, metabolic syn-
drome, etc.) associated with second generation antipsychotics.
Conclusions
Because sleep plays an integral role in the presentation
and course of many psychiatric disorders, research that
examines the use of sedative-hypnotics in mental illness
is likely to significantly impact the delivery of care in
clinical psychopharmacology. However, despite recent in-
roads made by the investigations described in this review,
the evidence base for the use of hypnotic medications in
psychiatric illness remains relatively limited. There are
myriad factors that influence the use of sedative-
hypnotics by both primary care and behavioral health pro-
viders, and their optimal use remains controversial [48,
49]. However, it is crucial that the field overcomes the
stigma surrounding these medications to empirically de-
termine how and under what circumstances these agents
can be most helpful for patients with psychiatric illness.
Such inquiry is particularly important since management
of sleep disturbance has the potential to reduce the mor-
bidity and mortality associated with psychiatric disorders,
as well as prevent major illness episodes, which are prin-
cipal goals in the care of patients with mental illness.
Compliance with Ethical Standards
Conflict of Interest Shane Creado declares no conflict of interest.
David T. Plante has received and is supported by grants from the
National Institute of Mental Health (K23MH099234), Brain and
Behavior Research Foundation and American Sleep Medicine
Foundation.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
134
78 Page 6 of 7
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Papers of particular interest, published recently, have been
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Pembaruan tentang penggunaan obat penenang-hipnotis pada gangguan kejiwaan

Shane Creado , MD 1 dan David T. Plante , MD 1
Informasi penulis Hak cipta dan Informasi lisensi Penafian
Versi edit terakhir penerbit untuk artikel ini tersedia di Curr Psychiatry Rep

Abstrak
Go to:

pengantar

Gangguan tidur sangat umum di antara orang dengan gangguan kejiwaan. Insomnia,
didefinisikan sebagai kesulitan memulai atau mempertahankan tidur walaupun ada kesempatan
yang memadai yang berhubungan dengan tekanan atau gangguan yang signifikan, adalah fitur
diagnostik gangguan mood dan kecemasan, dan juga sering dialami oleh orang dengan beberapa
bentuk penyakit kejiwaan lainnya ( 1 ). Insomnia berbagi hubungan dua arah yang sangat kuat
dengan gangguan suasana hati, karena telah dikaitkan dengan peningkatan risiko insiden depresi
dan hasil pengobatan yang lebih buruk, serta peningkatan ide bunuh diri, upaya bunuh diri, dan
bunuh diri total ( 2 ). Hubungan-hubungan ini telah menyebabkan perkembangan perspektif
nosologis saat ini yang menganggap kesulitan tidur sebagai komorbiditas dengan, bukannya
sekunder, gangguan kejiwaan ( 1 , 3 ).

Meskipun pandangan yang berkembang tentang gangguan tidur dan gangguan kejiwaan ini, ada
beberapa pertanyaan penting yang tetap tidak terjawab, terutama dalam hal penggunaan obat
penenang-hipnosis.Pertama, bukti apa yang mendukung penggunaan obat tertentu dalam
pengobatan komorbiditas insomnia dengan gangguan kejiwaan? Kedua, apakah pengobatan
farmakologis insomnia berdampak gejala kejiwaan di luar efek khusus pada gangguan
tidur? Ketiga, bagaimana cara obat penenang-hipnotis mengubah perjalanan longitudinal
penyakit mental utama? Dan akhirnya, bisakah agen yang dirancang untuk meningkatkan
kontinuitas tidur memiliki efek terpisah pada bidang fungsi neurokognitif lainnya, terutama yang
telah terbukti diubah oleh tidur?

Dalam ulasan ini, kami akan menyoroti literatur penting terbaru yang meneliti bidang-bidang
penting penyelidikan ini. Kami akan memfokuskan ringkasan kami terutama pada obat-obatan
yang pada awalnya dikembangkan dan / atau dipasarkan untuk tujuan mengobati insomnia,
dengan memasukkan agen lain yang digunakan di luar label untuk mengobati gangguan tidur di
tempat yang bersangkutan. Kami siap mengakui kemanjuran metode non-farmakologis untuk
pengobatan insomnia ( 4 ), namun, ulasan ini akan secara khusus memfokuskan obat dan bukan
pendekatan kognitif-perilaku lainnya. Selain itu, karena beberapa ulasan telah merinci efek dan
kemanjuran agomelatine antidepresan melatonergik ( 5 - 7 ), obat ini dianggap di luar cakupan
ulasan ini. Sesuai dengan format Laporan Saat Ini , kami akan fokus terutama pada

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perkembangan terbaru dalam literatur, dan secara khusus meninjau penggunaan obat penenang-
hipnotik pada gangguan depresi mayor unipolar, gangguan bipolar, skizofrenia, dan gangguan
stres pascatrauma (PTSD). Tujuan kami adalah untuk memberikan penilaian ringkas, namun
kritis dari literatur terbaru tentang topik ini, serta menggarisbawahi bidang penelitian masa depan
yang diperlukan untuk memajukan bidang ini.

Go to:

Gangguan Depresif Utama

Insomnia sangat umum terjadi pada gangguan depresi mayor (MDD), dengan hingga 90% pasien
mengalami kesulitan memulai atau mempertahankan tidur selama episode suasana hati
( 8 ). Sejak awal mereka hampir tiga dekade lalu, inhibitor reuptake serotonin spesifik (SSRI)
telah menjadi pengobatan utama untuk depresi unipolar. Sebagai kelas, SSRI cenderung tidak
memiliki efek antihistaminergik atau antikolinergik yang signifikan, dan dengan demikian
cenderung kurang sedasi daripada obat trisiklik antidepresan (TCA) yang lebih tua. Dalam
konteks ini, desain penelitian di mana pasien yang mengalami episode depresi mayor dengan
komorbid insomnia bersama-sama memberikan label terbuka SSRI dengan obat penenang-
hipnotis versus plasebo, telah menjadi paradigma yang berguna untuk mempelajari efek hipnotik
sedatif pada keduanya. gejala tidur dan kejiwaan dalam standar perawatan. Menggunakan desain
penelitian ini, Fava et al. ( 9 ) sebelumnya melaporkan bahwa eszopiklon 3mg setiap malam
diberikan bersama dengan fluoxetine pada pasien dengan MDD dan insomnia tidak hanya secara
signifikan memperbaiki gejala yang berhubungan dengan tidur, tetapi juga secara signifikan
meningkatkan gejala depresi di luar efek soporifiknya [diukur dengan peningkatan pada 17-item
Hamilton Rating Skala untuk Depresi (HDRS-17) dengan item tidur dihilangkan]. Membangun
pada pekerjaan ini, Fava dan rekan ( 10 ) baru-baru ini melakukan analisis post hoc yang
menggabungkan data dari penelitian sebelumnya dengan penelitian terkontrol plasebo acak lain
dari pasien dengan gangguan kecemasan umum yang diobati dengan escitalopram dan
eszopicone 3mg bersamaan setiap malam dibandingkan dengan plasebo ( 11 ). Untuk penelitian
ini, depresi cemas didefinisikan sebagai skor HDRS-17 ≥ 14 (tidak termasuk item insomnia) dan
skor faktor kecemasan / somatisasi (berasal dari 6 sub-item pada HDRS-17) ≥ 7 ( 10 ). Analisis
yang dikumpulkan menunjukkan pemberian bersama eszopiclone secara signifikan
meningkatkan gejala insomnia [dinilai oleh perubahan rata-rata perubahan dari awal pada
Insomnia Severity Index (ISI)] ( 10 ).Selain itu, setelah 8 minggu terapi dengan eszopiklon, skor
HDRS-17 menurun dari awal, terlepas dari apakah item insomnia dikeluarkan, namun efek ini
tidak diamati ketika secara khusus memeriksa kecemasan / somatisasi ( 10 ).

Penelitian terbaru lainnya meneliti label terbuka SSRI (escitalopram) dengan pemberian bersama
zolpidem extended-release (ER) 12.5mg dibandingkan dengan plasebo pada pasien dengan MDD
dan komorbid insomnia ( 12 ). Zolpidem ER meningkatkan durasi dan kontinuitas tidur yang
dilaporkan sendiri, serta fungsi hari berikutnya, tetapi tidak tetapi tidak menambah respons
antidepresan escitalopram yang dinilai oleh perubahan HDRS-17 ( 12 ). Meskipun efek

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antidepresan divergen diamati pada zolpidem ER dibandingkan dengan eszopiklon ( 9 , 10 , 12 ),

saat ini tidak ada bukti yang cukup untuk menyarankan satu agen lebih unggul dari yang lain
dalam pengobatan insomnia dengan depresi komorbiditas, karena ini akan membutuhkan
langsung perbandingan. Namun, hal ini menimbulkan pertanyaan penting mengenai bagaimana
sifat farmakologis yang berbeda dari agen ini dapat menyebabkan efek tertentu pada gejala
depresi yang terjadi bersamaan. Secara umum, meskipun kedua agen dianggap sebagai non-
benzodiazepine benzodiazepine agonis reseptor (BZRAs), mereka memiliki afinitas yang
berbeda untuk reseptor GABA-A, dengan zolpidem yang sangat selektif untuk subtipe α1,
sementara eszopiklon juga memiliki aktivitas yang cukup besar pada reseptor GABA.
mengandung subunit α3 dan α5 ( 13 ). Apakah efek yang berbeda pada gejala depresi komorbid
yang diamati dalam penelitian ini adalah karena sifat neurofarmakologis spesifik dari obat, atau
faktor lain, seperti ketidaksengajaan unblinding dalam penelitian eszopiklon karena tingkat
disgeusia yang sangat tinggi [yang dapat terjadi pada> 25% dari peserta ( 10 )] masih harus
dijelaskan, tetapi dapat membuktikan bidang yang bermanfaat dari penelitian masa depan.

Daerah penting lain dari penyelidikan adalah bagaimana sedatif-hipnotis mempengaruhi ide
bunuh diri pada pasien dengan depresi komorbiditas dan insomnia. Sebuah literatur yang cukup
besar telah menunjukkan bahwa insomnia adalah faktor risiko independen untuk bunuh diri,
meningkatkan kemungkinan bahwa pengobatan insomnia dengan obat penenang-hipnotis dapat
mengurangi risiko bunuh diri ( 14 ). Karena penelitian sebelumnya yang telah memeriksa
koterapi sedatif-hipnotik dengan SSRI telah mengecualikan orang dengan risiko bunuh diri yang
signifikan ( 9 , 12 ), ada bukti yang tidak cukup untuk menentukan apakah sedatif-hipnotik
mengubah risiko bunuh diri. Ini adalah area investigasi penting karena dokter sering tidak mau
meresepkan obat penenang-hipnotik untuk pasien dengan ide bunuh diri, mungkin karena
kekhawatiran bahwa agen dapat digunakan dalam upaya overdosis. Juga, sebuah studi terkontrol
untuk menguji efek sedatif-hipnotik pada ide bunuh diri membutuhkan desain penelitian yang
sangat bijaksana untuk melindungi keamanan peserta penelitian. Untuk membantu memperjelas
peran potensial obat penenang-hipnotik dalam pengelolaan ide bunuh diri, percobaan klinis acak
multi-situs yang dibuat dengan hati-hati dari label terbuka SSRI dengan zolpidem ER versus
plasebo pada pasien rawat jalan dewasa yang depresi dengan insomnia dan ide bunuh diri telah
dikembangkan, dan saat ini merekrut peserta dengan dana dari National Institutes of Mental
Health ( 15 ). Kami dengan bersemangat mengantisipasi hasil dari Pengurangan Ide Bunuh Diri
Melalui Pengobatan Insomnia (REST-IT) ini, karena sangat mungkin berdampak signifikan
terhadap standar perawatan di psikiatri.

Di luar BZRA, ada sedikit evaluasi empiris baru-baru ini tentang dampak obat penenang-
hipnotik off-label dalam pengobatan insomnia dengan gejala depresi co-morbid. Wichniak dan
rekan ( 16 ) dalam sebuah studi label terbuka meneliti efek trazodone continuous-release (CR)
25-150mg setiap hari pada pasien dengan insomnia primer dengan dan tanpa gejala depresi co-
morbid, menemukan bahwa agen ini meningkatkan gejala klinis termasuk peningkatan durasi
tidur subjektif dan latensi onset tidur berkurang.Selain itu, selama fase run-out, pasien dengan

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gejala depresi yang lebih tinggi [dinilai menggunakan Beck Depression Inventory (BDI)],
cenderung mengalami penurunan gejala relatif dibandingkan dengan mereka yang tidak memiliki
gejala depresi ( 16 ). Satu penelitian lain yang tidak terkontrol menilai doxepin dosis rendah
(<25mg / hari) pada pasien rawat inap psikiatrik dengan insomnia dan MDD ( 17 ). Seri kasus
retrospektif ini gagal menunjukkan manfaat signifikan doxepin pada onset tidur atau
pemeliharaan pada pasien ini ( 17 ). Jelas, karena obat penenang antidepresan adalah beberapa
agen yang paling sering diresepkan untuk insomnia ( 18 ), penelitian lebih lanjut yang
mengklarifikasi bukti untuk menggunakan agen ini untuk mengobati insomnia pada penyakit
kejiwaan diperlukan.

Go to:

Gangguan Bipolar

Gangguan tidur, baik insomnia dan hipersomnensi, sangat umum terjadi pada gangguan
bipolar. Insomnia sering terjadi pada semua fase penyakit, termasuk periode manik, depresi, dan
eutimik ( 19 , 20 ). Literatur tidak langsung yang cukup besar menyatakan bahwa gangguan tidur
dapat menyebabkan perubahan suasana hati, terutama pada mania ( 21 ). Menambah literatur ini,
Cretu dan rekan baru-baru ini meneliti peran gangguan tidur dalam kohort dari delapan puluh
sembilan pasien yang pulih dengan gangguan bipolar yang diikuti selama lebih dari satu tahun
( 22 ). Khususnya, dalam kohort ini, gangguan tidur [dinilai dengan Indeks Kualitas Tidur
Pittsburgh (PSQI)] tidak hanya berkorelasi secara signifikan dengan gejala mood residual, tetapi
juga memprediksi kekambuhan episode mood sebelumnya, bahkan setelah mengelompokkan
gejala mood residual ( 22 ). Selain itu, temuan ini menyoroti pentingnya pengobatan gangguan
tidur pada gangguan bipolar, yang secara teoritis dapat memberikan manfaat dengan mengurangi
terjadinya episode suasana hati selama perjalanan longitudinal dari gangguan tersebut. Namun,
hubungan antara pengobatan insomnia dan mood-stabilization sangat spekulatif, dan basis bukti
mengenai penggunaan obat penenang-hipnotik spesifik pada gangguan bipolar sangat terbatas.

McElroy dan rekan menilai penggunaan ramelteon 8mg setiap malam dibandingkan dengan
plasebo pada pasien rawat jalan dengan gangguan bipolar yang mengalami gejala manik ringan
dan insomnia ( 23 ).Selama studi 8 minggu, obat lain dilanjutkan dan dibiarkan tidak berubah
(kecuali dalam kasus di mana obat memerlukan pengurangan dosis untuk manajemen efek
samping) ( 23 ). Dalam penelitian ini, ramelteon tidak menunjukkan kemanjuran yang lebih
besar daripada plasebo pada ukuran hasil primer (perubahan insomnia dinilai oleh 65-item
Pittsburgh Insomnia Rating Scale), juga tidak memiliki efek diferensial pada gejala manik atau
keparahan penyakit global ( 23 ). Namun, itu menunjukkan peningkatan peringkat global dari
gejala depresi, dan tidak ada efek samping serius yang diamati ( 23 ). Meskipun penelitian ini
merupakan salah satu upaya pertama untuk melakukan studi terkontrol secara acak untuk
insomnia pada gangguan bipolar, ukuran sampel yang kecil (total N = 21), serta fakta bahwa
pasien hipomanik, dapat membatasi kekuatan penelitian untuk mendeteksi manfaat dibandingkan

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plasebo, serta generalisasi hasil untuk pengelolaan insomnia komorbid pada fase lain gangguan
bipolar.

Norris dan rekannya melanjutkan penelitian lebih lanjut tentang ramelteon pada insomnia
comorbid dengan gangguan bipolar, memeriksa sejumlah besar peserta (N = 83), yang euthymic
pada awal ( 24 ). Peserta dalam penelitian double-blind ini diacak untuk ramelteon 8mg atau
plasebo, di samping obat-obatan psikiatrik reguler mereka, dan diikuti hingga 24 minggu atau
sampai mereka mengalami kekambuhan depresi atau manik ( 24 ). Hebatnya, peserta yang
menerima ramelteon memiliki kemungkinan dua kali lipat lebih rendah mengalami penurunan
mood dibandingkan dengan plasebo. Juga, peserta yang secara acak menggunakan plasebo yang
baru saja pulih dari episode campuran atau depresi memiliki peluang yang lebih tinggi (rasio
odds 2,67 dan 3,75, masing-masing) untuk menyelesaikan studi 24 minggu dibandingkan dengan
peserta dalam kelompok plasebo ( 24 ). Stabilitas mood yang meningkat ini terjadi meskipun
tidak ada perubahan signifikan pada PSQI (pengamatan terakhir yang dilakukan), meskipun tren
peningkatan PSQI diamati dari 8-20 minggu perawatan ( 24 ). Para penulis berspekulasi bahwa
peserta mungkin tidak memiliki peningkatan yang signifikan dalam PSQI dengan ramelteon
relatif terhadap plasebo karena efek langit-langit yang disebabkan oleh obat psikotropika
penenang yang diresepkan yang diresepkan untuk gangguan bipolar ( 24 ). Keterbatasan
penelitian lain termasuk ukuran sampel yang relatif kecil, serta durasi stabilitas suasana hati yang
diperlukan untuk masuknya studi hanya satu minggu, yang lebih pendek dari uji klinis lain yang
memeriksa stabilitas suasana hati pada gangguan bipolar ( 24 ).Terlepas dari keterbatasan ini,
penelitian ini menunjukkan bahwa ramelteon, suatu agonis reseptor tipe 1 dan 2 melatonin, dapat
mengubah perjalanan longitudinal dari gangguan bipolar, dan jelas penelitian lebih lanjut dalam
bidang ini diindikasikan.

Selain dari dua studi ramelteon terkontrol acak yang disebutkan sebelumnya pada gangguan
bipolar ( 23 , 24 ), basis bukti yang tersisa untuk memandu pilihan obat hipnotik sedatif pada
gangguan bipolar sebagian besar tidak terkendali. Schaffer dan koleganya melakukan tinjauan
bagan yang menilai kemanjuran dan keamanan zolpidem (pelepasan langsung dan lama),
eszopiklon, zaleplon, dan ramelteon pada 361 pasien berturut-turut dengan gangguan bipolar
( 25 ). Secara umum, mereka mencatat sekitar setengah dari pasien mereka memerlukan hipnotik
sedatif kronis setiap hari, dan bahwa BZRA memiliki tingkat keberhasilan (didefinisikan sebagai
banyak atau sangat jauh meningkat pada Clinical Global Impression Scale-Bipolar Version) dari
36-60%, dengan semakin terbatasnya kesuksesan ramelteon (15%). Agen-agen ini umumnya
ditoleransi dengan baik, dan pengguna obat penenang-hipnotis kronis tidak mengalami kejadian
yang tidak diinginkan yang tidak dapat diterima ( 25 ). Meskipun data yang tidak terkontrol ini
harus ditafsirkan dengan hati-hati, mereka memberikan beberapa bukti bahwa agen ini mungkin
merupakan pilihan yang masuk akal untuk pengobatan insomnia yang terkait dengan gangguan
bipolar, termasuk penggunaan kronis.

Kelas lain dari agen, penenang antidepresan, sering digunakan untuk mengobati insomnia pada
pasien dengan gangguan bipolar; Namun, basis bukti untuk obat-obatan ini terbatas, meskipun

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digunakan secara luas ( 18 ). Karena penelitian sebelumnya telah menyarankan bahwa TCA dan
trazodone dapat meningkatkan risiko perubahan suasana hati, terutama ke fase manik ( 26 , 27 ),
klarifikasi keamanan dan kemanjuran agen ini pada orang dengan gangguan bipolar adalah
bidang studi yang penting. Dengan tidak adanya data yang terkontrol, Wichniak dan rekannya
baru-baru ini meninjau literatur untuk mengidentifikasi laporan kasus antidepresan penenang
(trazodone dan mirtazapine, serta agomelatine) yang menginduksi gejala manik ( 28 ). Meskipun
risiko bias dalam pendekatan ini sangat besar, mereka menemukan bahwa trazodone dan
mirtazapine cenderung menyebabkan mania pada pasien dengan faktor risiko lain untuk manic
switching (misalnya, tidak menggunakan penstabil mood bersamaan), dan cenderung terjadi pada
antidepresan (yaitu lebih tinggi) daripada dosis yang lebih rendah yang biasanya diresepkan
untuk insomnia ( 28 ). Dengan demikian, jika agen-agen ini digunakan untuk mengobati
komorbiditas insomnia dengan gangguan bipolar, tampaknya paling bijaksana untuk
menggunakan agen-agen ini hanya pada pasien yang secara bersamaan dirawat dengan obat yang
menstabilkan suasana hati, dan dengan pemantauan yang cermat untuk meningkatkan perubahan
suasana hati. Idealnya, penelitian terkontrol lebih lanjut akan menjelaskan kemanjuran dan
keamanan obat penenang antidepresan dalam gangguan bipolar; Namun, ada kemungkinan
alasan ekonomi dan etika bahwa studi tersebut tidak mungkin dilakukan dalam waktu dekat.

Selain mengobati insomnia dan berpotensi mengubah perjalanan longitudinal dari gangguan
bipolar, penggunaan obat penenang-hipnotik juga dapat memberikan manfaat dalam pengelolaan
perilaku kesehatan negatif lainnya seperti merokok, yang 3,5 kali lipat lebih umum di antara
pasien dengan gangguan bipolar daripada umum populasi ( 29 ). Karena insomnia sebelum dan
selama upaya untuk berhenti merokok telah dikaitkan dengan kegagalan penghentian ( 30 , 31 ),
penggunaan agen penunjang tidur tambahan pada pasien yang berusaha berhenti merokok,
terutama di antara pasien berisiko tinggi seperti pasien dengan penyakit mental berat, adalah
jalur investigasi yang berpotensi menjanjikan. Forrest dan rekannya melakukan analisis sekunder
dari RCT yang meneliti varenicline versus plasebo pada pasien dengan gangguan bipolar yang
ingin berhenti merokok, menemukan penggunaan agen hipnosis bersamaan dikaitkan dengan
kemungkinan penghentian yang lebih besar pada pasien ini ( 32 ). Meskipun terdapat
keterbatasan termasuk ukuran sampel yang kecil (N = 60), dan penggunaan label terbuka dari
hipnotis penggunaan yang membatasi sebab dan akibat kesimpulan, hasil ini menyarankan studi
terkontrol yang lebih besar di masa depan yang mencakup pasien dengan gangguan bipolar, serta
gangguan kejiwaan lainnya yang terkait dengan peningkatan tingkat merokok, seperti
skizofrenia, diindikasikan.

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Skizofrenia

Skizofrenia adalah penyakit psikotik klasik, dengan gejala yang jatuh ke dalam tiga kategori
besar: positif, negatif, dan kognitif, yang semuanya dapat berdampak negatif pada fungsi sosial
dan pekerjaan. Gejala kognitif, yang dapat mencakup fungsi eksekutif yang buruk, kesulitan

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atensi, dan kesulitan dengan memori kerja, dapat sangat mengganggu bagi pasien dengan
gangguan tersebut ( 33 ). Kesulitan terkait tidur yang paling konsisten diidentifikasi yang dialami
oleh pasien dengan skizofrenia termasuk kesulitan tidur dan tetap tidur ( 34 , 35 ). Karena
insomnia dan pembatasan tidur dikaitkan dengan gangguan kognitif di sejumlah domain
( 36 , 37 ), mengobati inisiasi tidur dan kesulitan kontinuitas secara teoritis dapat menghasilkan
peningkatan kognisi pada pasien ini.

Mengikuti penelitian ini, Tek dan rekannya meneliti penggunaan eszopiklon 3mg setiap malam
dibandingkan dengan plasebo pada 39 pasien rawat jalan yang stabil secara klinis dengan
skizofrenia atau gangguan skizoafektif dan insomnia komorbiditas ( 38 ). Penelitian ini termasuk
periode acak 8 minggu, diikuti oleh fase plasebo 2 minggu single-blind untuk menilai daya tahan
efek obat. Eszopiclone menunjukkan kemanjuran yang signifikan dibandingkan plasebo pada
ukuran hasil utama dari perubahan skor ISI, dengan perbedaan antara kelompok hampir 4 poin
pada skala ( 38 ). Selama periode penghentian, tidak ada perbedaan antara eszopiklon dan
plasebo dalam perubahan skor ISI ( 38 ). Meskipun ada peningkatan insomnia, eszopiklon tidak
menunjukkan manfaat pada hasil sekunder dari perubahan dalam MATRICS Consensus
Cognitive Battery, yang menilai kecepatan pemrosesan, perhatian, memori kerja verbal dan
nonverbal, pembelajaran verbal dan visual, penalaran / pemecahan masalah, dan kognisi sosial
( 38 ). Analisis eksplorasi menyarankan perbaikan subskala dengan eszopiklon pada tes memori
yang bekerja, komponen rentang nomor surat MATRICS, untuk peserta dengan skizofrenia
(tetapi bukan gangguan skizoafektif), yang berkorelasi dengan perubahan skor ISI ( 38 ). Namun,
perbaikan dalam memori kerja diamati selama fase double-blind dengan eszopiklon tidak
bertahan ke fase plasebo single-blind, menunjukkan perubahan tersebut tidak tahan lama ( 38 ).

Selain perubahan dalam memori kerja, telah dikemukakan bahwa eszopiklon dapat menyebabkan
peningkatan konsolidasi memori prosedural tergantung tidur pada orang dengan
skizofrenia. Pasien dengan skizofrenia menunjukkan penurunan dalam perbaikan semalam pada
tugas sekuens motorik jari-tapping (MST) ( 39 ). Karena pasien dengan skizofrenia menunjukkan
penurunan spindel tidur ( 40 ) dan peningkatan tergantung tidur pada MST berkorelasi dengan
karakteristik osilasi elektroensefalografik yang semakin berkurang dari tidur gerakan mata yang
tidak cepat ( 41 ), meneliti efek agen seperti eszopiklon, yang dapat meningkatkan spindel tidur
melalui potensiasi nukleus reticular thalamic GABAergic (situs utama generasi spindle tidur),
adalah jalur penelitian yang menjanjikan. Wamsley dan rekannya meneliti baik kemampuan
eszopiklon untuk menghasilkan kumparan tidur maupun efek asosiatifnya pada kinerja MST
semalam ( 42 ). Setelah skrining, dua puluh satu pasien dengan skizofrenia menyelesaikan
kunjungan awal di laboratorium, yang terdiri dari dua malam berturut-turut polisomnografi,
dengan MST dilakukan pada malam kedua tidur. Satu minggu kemudian, peserta menyelesaikan
kunjungan pengobatan yang serupa, namun, pasien secara acak diberikan eszopiklon 3mg atau
plasebo, dan menyelesaikan MST menggunakan urutan alternatif dibandingkan dengan
awal. Eszopiclone secara signifikan meningkatkan jumlah dan kepadatan spindle relatif terhadap
baseline dibandingkan dengan plasebo, tetapi tidak secara signifikan meningkatkan peningkatan

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MST semalam ( 42 ). Ketika kelompok eszopiklon dan plasebo digabungkan, jumlah spindel
tidur dan kepadatan berkorelasi dengan peningkatan MST semalam ( 42 ).Temuan ini
mendukung gagasan bahwa peningkatan farmakologis gelendong tidur mungkin memiliki
beberapa manfaat pada pasien dengan skizofrenia, namun, penelitian lebih lanjut diindikasikan
untuk menentukan domain apa yang mungkin terkena dampak dan apakah perbaikan tersebut
memiliki dampak klinis yang dapat dibuktikan pada gangguan tersebut.

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Gangguan Stres Pascatrauma

PTSD adalah salah satu kondisi kejiwaan yang paling umum, dengan prevalensi seumur hidup
secara keseluruhan di Amerika Serikat sekitar 7% ( 43 ). Gangguan tidur adalah fitur inti dari
PTSD, dengan insomnia dan mimpi buruk kedua komponen kriteria diagnostik untuk gangguan
tersebut ( 1 ). Selain itu, insomnia dan mimpi buruk dapat memainkan peran dalam morbiditas
gangguan, dan dengan demikian menjadi target terapi yang penting ( 44 ). Meskipun demikian,
basis bukti untuk perawatan gangguan tidur pada PTSD relatif sedikit. Ulasan literatur terbaru
mendukung penggunaan prazosin sebagai agen lini pertama untuk insomnia dan mimpi buruk di
PTSD ( 45 ).

Ada juga bukti terbaru yang menunjukkan bahwa eszopiklon dapat memberikan manfaat sebagai
agen tambahan dalam pengobatan gangguan tidur di PTSD. Pollack dan rekannya meneliti
penggunaan eszopiclone 3mg setiap malam pada pasien dengan PTSD dan gangguan tidur yang
terjadi bersamaan, menggunakan desain crossover terkontrol plasebo terkontrol secara acak,
double-blind, terkontrol plasebo ( 46 ). Eszopiklon tiga minggu dibandingkan dengan plasebo
dikaitkan dengan latensi onset tidur yang berkurang secara signifikan dan peningkatan kualitas
tidur (diukur oleh PSQI). Selain itu, mirip dengan manfaat koterapi pada depresi berat ( 9 , 10 ),
eszopiklon juga secara signifikan meningkatkan gejala PTSD [dinilai dengan wawancara
Peringkat pendek PTSD (SPRINT) yang dikelola dokter dan Skala PTSD yang Diurus oleh
Dokter (CAPS)], bahkan ketika item yang berhubungan dengan tidur dikeluarkan
( 46 ).Meskipun hasil ini menjanjikan, penelitian ini relatif kecil (N = 23), dan pekerjaan di masa
depan mereplikasi hasil tersebut serta mengevaluasi efek longitudinal di luar penggunaan jangka
pendek ditunjukkan. Selain itu, studi efektivitas komparatif akan membantu dalam menentukan
apakah obat penenang-hipnotik memberikan manfaat di atas agen lain yang sering digunakan di
luar label untuk mengobati insomnia di PSTD. Secara khusus, antipsikotik atipikal, yang
umumnya diresepkan sebagian besar untuk sifat obat penenang-hipnotis pada pasien dengan
PTSD ( 47 ), harus dibandingkan baik dalam kemanjuran pada gejala tidur dan PTSD, serta
profil efek samping, mengingat konsekuensi kesehatan yang negatif. (misalnya kenaikan berat
badan, sindrom metabolik, dll.) yang terkait dengan antipsikotik generasi kedua.

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Kesimpulan

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Firda Auliya Ciptaning Kinasih (20610330311164)

Karena tidur memainkan peran integral dalam presentasi dan perjalanan dari banyak gangguan
kejiwaan, penelitian yang meneliti penggunaan obat penenang-hipnotik dalam penyakit mental
kemungkinan besar akan berdampak signifikan pada pemberian perawatan di psikofarmakologi
klinis. Namun, meskipun terobosan baru-baru ini dibuat oleh investigasi yang dijelaskan dalam
ulasan ini, dasar bukti untuk penggunaan obat hipnotik pada penyakit kejiwaan masih relatif
terbatas. Ada banyak sekali faktor yang mempengaruhi penggunaan obat penenang-hipnotik oleh
perawatan primer dan penyedia kesehatan perilaku, dan penggunaan optimalnya masih
kontroversial ( 48 , 49 ). Namun, sangat penting bahwa bidang mengatasi stigma seputar obat-
obatan ini untuk secara empiris menentukan bagaimana dan dalam keadaan apa agen ini dapat
sangat membantu bagi pasien dengan penyakit kejiwaan. Penyelidikan tersebut sangat penting
karena manajemen gangguan tidur memiliki potensi untuk mengurangi morbiditas dan mortalitas
yang terkait dengan gangguan kejiwaan, serta mencegah episode penyakit utama, yang
merupakan tujuan utama dalam perawatan pasien dengan penyakit mental.

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Ucapan Terima Kasih

Dr. Plante telah menerima dan didukung oleh hibah dari National Institute of Mental Health
(K23MH099234), Yayasan Riset Otak dan Perilaku dan American Sleep Medicine Foundation.

Go to:

Catatan kaki
Kepatuhan dengan Pedoman Etika

Konflik kepentingan:

Creado Melaporkan tidak ada konflik kepentingan.

Hak Asasi Manusia dan Hewan dan Persetujuan Diinformasikan:

Artikel ini tidak mengandung studi dengan subyek manusia atau hewan yang dilakukan oleh
penulis.

Go to:

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Curr Psychiatry Rep . Naskah penulis; tersedia di PMC 2017 1 September.

Diterbitkan dalam bentuk yang diedit akhir sebagai:
Curr Psychiatry Rep. 2016 Sep; 18 (9): 78.
doi: 10.1007 / s11920-016-0717-y
PMCID : PMC4980146
NIHMSID: NIHMS807994
PMID: 27417512

Pembaruan tentang penggunaan obat penenang-hipnotis pada gangguan kejiwaan

Shane Creado , MD 1 dan David T. Plante , MD 1
Informasi penulis Hak cipta dan Informasi lisensi Penafian
Versi edit terakhir penerbit untuk artikel ini tersedia di Curr Psychiatry Rep

Abstrak
Go to:

pengantar

Gangguan tidur sangat umum di antara orang dengan gangguan kejiwaan. Insomnia,
didefinisikan sebagai kesulitan memulai atau mempertahankan tidur walaupun ada kesempatan
yang memadai yang berhubungan dengan tekanan atau gangguan yang signifikan, adalah fitur
diagnostik gangguan mood dan kecemasan, dan juga sering dialami oleh orang dengan beberapa
bentuk penyakit kejiwaan lainnya ( 1 ). Insomnia berbagi hubungan dua arah yang sangat kuat

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dengan gangguan suasana hati, karena telah dikaitkan dengan peningkatan risiko insiden depresi
dan hasil pengobatan yang lebih buruk, serta peningkatan ide bunuh diri, upaya bunuh diri, dan
bunuh diri total ( 2 ). Hubungan-hubungan ini telah menyebabkan perkembangan perspektif
nosologis saat ini yang menganggap kesulitan tidur sebagai komorbiditas dengan, bukannya
sekunder, gangguan kejiwaan ( 1 , 3 ).

Meskipun pandangan yang berkembang tentang gangguan tidur dan gangguan kejiwaan ini, ada
beberapa pertanyaan penting yang tetap tidak terjawab, terutama dalam hal penggunaan obat
penenang-hipnosis.Pertama, bukti apa yang mendukung penggunaan obat tertentu dalam
pengobatan komorbiditas insomnia dengan gangguan kejiwaan? Kedua, apakah pengobatan
farmakologis insomnia berdampak gejala kejiwaan di luar efek khusus pada gangguan
tidur? Ketiga, bagaimana cara obat penenang-hipnotis mengubah perjalanan longitudinal
penyakit mental utama? Dan akhirnya, bisakah agen yang dirancang untuk meningkatkan
kontinuitas tidur memiliki efek terpisah pada bidang fungsi neurokognitif lainnya, terutama yang
telah terbukti diubah oleh tidur?

Dalam ulasan ini, kami akan menyoroti literatur penting terbaru yang meneliti bidang-bidang
penting penyelidikan ini. Kami akan memfokuskan ringkasan kami terutama pada obat-obatan
yang pada awalnya dikembangkan dan / atau dipasarkan untuk tujuan mengobati insomnia,
dengan memasukkan agen lain yang digunakan di luar label untuk mengobati gangguan tidur di
tempat yang bersangkutan. Kami siap mengakui kemanjuran metode non-farmakologis untuk
pengobatan insomnia ( 4 ), namun, ulasan ini akan secara khusus memfokuskan obat dan bukan
pendekatan kognitif-perilaku lainnya. Selain itu, karena beberapa ulasan telah merinci efek dan
kemanjuran agomelatine antidepresan melatonergik ( 5 - 7 ), obat ini dianggap di luar cakupan
ulasan ini. Sesuai dengan format Laporan Saat Ini , kami akan fokus terutama pada
perkembangan terbaru dalam literatur, dan secara khusus meninjau penggunaan obat penenang-
hipnotik pada gangguan depresi mayor unipolar, gangguan bipolar, skizofrenia, dan gangguan
stres pascatrauma (PTSD). Tujuan kami adalah untuk memberikan penilaian ringkas, namun
kritis dari literatur terbaru tentang topik ini, serta menggarisbawahi bidang penelitian masa depan
yang diperlukan untuk memajukan bidang ini.

Go to:

Gangguan Depresif Utama

Insomnia sangat umum terjadi pada gangguan depresi mayor (MDD), dengan hingga 90% pasien
mengalami kesulitan memulai atau mempertahankan tidur selama episode suasana hati
( 8 ). Sejak awal mereka hampir tiga dekade lalu, inhibitor reuptake serotonin spesifik (SSRI)
telah menjadi pengobatan utama untuk depresi unipolar. Sebagai kelas, SSRI cenderung tidak
memiliki efek antihistaminergik atau antikolinergik yang signifikan, dan dengan demikian
cenderung kurang sedasi daripada obat trisiklik antidepresan (TCA) yang lebih tua. Dalam
konteks ini, desain penelitian di mana pasien yang mengalami episode depresi mayor dengan

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komorbid insomnia bersama-sama memberikan label terbuka SSRI dengan obat penenang-
hipnotis versus plasebo, telah menjadi paradigma yang berguna untuk mempelajari efek hipnotik
sedatif pada keduanya. gejala tidur dan kejiwaan dalam standar perawatan. Menggunakan desain
penelitian ini, Fava et al. ( 9 ) sebelumnya melaporkan bahwa eszopiklon 3mg setiap malam
diberikan bersama dengan fluoxetine pada pasien dengan MDD dan insomnia tidak hanya secara
signifikan memperbaiki gejala yang berhubungan dengan tidur, tetapi juga secara signifikan
meningkatkan gejala depresi di luar efek soporifiknya [diukur dengan peningkatan pada 17-item
Hamilton Rating Skala untuk Depresi (HDRS-17) dengan item tidur dihilangkan]. Membangun
pada pekerjaan ini, Fava dan rekan ( 10 ) baru-baru ini melakukan analisis post hoc yang
menggabungkan data dari penelitian sebelumnya dengan penelitian terkontrol plasebo acak lain
dari pasien dengan gangguan kecemasan umum yang diobati dengan escitalopram dan
eszopicone 3mg bersamaan setiap malam dibandingkan dengan plasebo ( 11 ). Untuk penelitian
ini, depresi cemas didefinisikan sebagai skor HDRS-17 ≥ 14 (tidak termasuk item insomnia) dan
skor faktor kecemasan / somatisasi (berasal dari 6 sub-item pada HDRS-17) ≥ 7 ( 10 ). Analisis
yang dikumpulkan menunjukkan pemberian bersama eszopiclone secara signifikan
meningkatkan gejala insomnia [dinilai oleh perubahan rata-rata perubahan dari awal pada
Insomnia Severity Index (ISI)] ( 10 ).Selain itu, setelah 8 minggu terapi dengan eszopiklon, skor
HDRS-17 menurun dari awal, terlepas dari apakah item insomnia dikeluarkan, namun efek ini
tidak diamati ketika secara khusus memeriksa kecemasan / somatisasi ( 10 ).

Penelitian terbaru lainnya meneliti label terbuka SSRI (escitalopram) dengan pemberian bersama
zolpidem extended-release (ER) 12.5mg dibandingkan dengan plasebo pada pasien dengan MDD
dan komorbid insomnia ( 12 ). Zolpidem ER meningkatkan durasi dan kontinuitas tidur yang
dilaporkan sendiri, serta fungsi hari berikutnya, tetapi tidak tetapi tidak menambah respons
antidepresan escitalopram yang dinilai oleh perubahan HDRS-17 ( 12 ). Meskipun efek
antidepresan divergen diamati pada zolpidem ER dibandingkan dengan eszopiklon ( 9 , 10 , 12 ),
saat ini tidak ada bukti yang cukup untuk menyarankan satu agen lebih unggul dari yang lain
dalam pengobatan insomnia dengan depresi komorbiditas, karena ini akan membutuhkan
langsung perbandingan. Namun, hal ini menimbulkan pertanyaan penting mengenai bagaimana
sifat farmakologis yang berbeda dari agen ini dapat menyebabkan efek tertentu pada gejala
depresi yang terjadi bersamaan. Secara umum, meskipun kedua agen dianggap sebagai non-
benzodiazepine benzodiazepine agonis reseptor (BZRAs), mereka memiliki afinitas yang
berbeda untuk reseptor GABA-A, dengan zolpidem yang sangat selektif untuk subtipe α1,
sementara eszopiklon juga memiliki aktivitas yang cukup besar pada reseptor GABA.
mengandung subunit α3 dan α5 ( 13 ). Apakah efek yang berbeda pada gejala depresi komorbid
yang diamati dalam penelitian ini adalah karena sifat neurofarmakologis spesifik dari obat, atau
faktor lain, seperti ketidaksengajaan unblinding dalam penelitian eszopiklon karena tingkat
disgeusia yang sangat tinggi [yang dapat terjadi pada> 25% dari peserta ( 10 )] masih harus
dijelaskan, tetapi dapat membuktikan bidang yang bermanfaat dari penelitian masa depan.

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Daerah penting lain dari penyelidikan adalah bagaimana sedatif-hipnotis mempengaruhi ide
bunuh diri pada pasien dengan depresi komorbiditas dan insomnia. Sebuah literatur yang cukup
besar telah menunjukkan bahwa insomnia adalah faktor risiko independen untuk bunuh diri,
meningkatkan kemungkinan bahwa pengobatan insomnia dengan obat penenang-hipnotis dapat
mengurangi risiko bunuh diri ( 14 ). Karena penelitian sebelumnya yang telah memeriksa
koterapi sedatif-hipnotik dengan SSRI telah mengecualikan orang dengan risiko bunuh diri yang
signifikan ( 9 , 12 ), ada bukti yang tidak cukup untuk menentukan apakah sedatif-hipnotik
mengubah risiko bunuh diri. Ini adalah area investigasi penting karena dokter sering tidak mau
meresepkan obat penenang-hipnotik untuk pasien dengan ide bunuh diri, mungkin karena
kekhawatiran bahwa agen dapat digunakan dalam upaya overdosis. Juga, sebuah studi terkontrol
untuk menguji efek sedatif-hipnotik pada ide bunuh diri membutuhkan desain penelitian yang
sangat bijaksana untuk melindungi keamanan peserta penelitian. Untuk membantu memperjelas
peran potensial obat penenang-hipnotik dalam pengelolaan ide bunuh diri, percobaan klinis acak
multi-situs yang dibuat dengan hati-hati dari label terbuka SSRI dengan zolpidem ER versus
plasebo pada pasien rawat jalan dewasa yang depresi dengan insomnia dan ide bunuh diri telah
dikembangkan, dan saat ini merekrut peserta dengan dana dari National Institutes of Mental
Health ( 15 ). Kami dengan bersemangat mengantisipasi hasil dari Pengurangan Ide Bunuh Diri
Melalui Pengobatan Insomnia (REST-IT) ini, karena sangat mungkin berdampak signifikan
terhadap standar perawatan di psikiatri.

Di luar BZRA, ada sedikit evaluasi empiris baru-baru ini tentang dampak obat penenang-
hipnotik off-label dalam pengobatan insomnia dengan gejala depresi co-morbid. Wichniak dan
rekan ( 16 ) dalam sebuah studi label terbuka meneliti efek trazodone continuous-release (CR)
25-150mg setiap hari pada pasien dengan insomnia primer dengan dan tanpa gejala depresi co-
morbid, menemukan bahwa agen ini meningkatkan gejala klinis termasuk peningkatan durasi
tidur subjektif dan latensi onset tidur berkurang.Selain itu, selama fase run-out, pasien dengan
gejala depresi yang lebih tinggi [dinilai menggunakan Beck Depression Inventory (BDI)],
cenderung mengalami penurunan gejala relatif dibandingkan dengan mereka yang tidak memiliki
gejala depresi ( 16 ). Satu penelitian lain yang tidak terkontrol menilai doxepin dosis rendah
(<25mg / hari) pada pasien rawat inap psikiatrik dengan insomnia dan MDD ( 17 ). Seri kasus
retrospektif ini gagal menunjukkan manfaat signifikan doxepin pada onset tidur atau
pemeliharaan pada pasien ini ( 17 ). Jelas, karena obat penenang antidepresan adalah beberapa
agen yang paling sering diresepkan untuk insomnia ( 18 ), penelitian lebih lanjut yang
mengklarifikasi bukti untuk menggunakan agen ini untuk mengobati insomnia pada penyakit
kejiwaan diperlukan.

Go to:

Gangguan Bipolar

Gangguan tidur, baik insomnia dan hipersomnensi, sangat umum terjadi pada gangguan
bipolar. Insomnia sering terjadi pada semua fase penyakit, termasuk periode manik, depresi, dan

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eutimik ( 19 , 20 ). Literatur tidak langsung yang cukup besar menyatakan bahwa gangguan tidur
dapat menyebabkan perubahan suasana hati, terutama pada mania ( 21 ). Menambah literatur ini,
Cretu dan rekan baru-baru ini meneliti peran gangguan tidur dalam kohort dari delapan puluh
sembilan pasien yang pulih dengan gangguan bipolar yang diikuti selama lebih dari satu tahun
( 22 ). Khususnya, dalam kohort ini, gangguan tidur [dinilai dengan Indeks Kualitas Tidur
Pittsburgh (PSQI)] tidak hanya berkorelasi secara signifikan dengan gejala mood residual, tetapi
juga memprediksi kekambuhan episode mood sebelumnya, bahkan setelah mengelompokkan
gejala mood residual ( 22 ). Selain itu, temuan ini menyoroti pentingnya pengobatan gangguan
tidur pada gangguan bipolar, yang secara teoritis dapat memberikan manfaat dengan mengurangi
terjadinya episode suasana hati selama perjalanan longitudinal dari gangguan tersebut. Namun,
hubungan antara pengobatan insomnia dan mood-stabilization sangat spekulatif, dan basis bukti
mengenai penggunaan obat penenang-hipnotik spesifik pada gangguan bipolar sangat terbatas.

McElroy dan rekan menilai penggunaan ramelteon 8mg setiap malam dibandingkan dengan
plasebo pada pasien rawat jalan dengan gangguan bipolar yang mengalami gejala manik ringan
dan insomnia ( 23 ).Selama studi 8 minggu, obat lain dilanjutkan dan dibiarkan tidak berubah
(kecuali dalam kasus di mana obat memerlukan pengurangan dosis untuk manajemen efek
samping) ( 23 ). Dalam penelitian ini, ramelteon tidak menunjukkan kemanjuran yang lebih
besar daripada plasebo pada ukuran hasil primer (perubahan insomnia dinilai oleh 65-item
Pittsburgh Insomnia Rating Scale), juga tidak memiliki efek diferensial pada gejala manik atau
keparahan penyakit global ( 23 ). Namun, itu menunjukkan peningkatan peringkat global dari
gejala depresi, dan tidak ada efek samping serius yang diamati ( 23 ). Meskipun penelitian ini
merupakan salah satu upaya pertama untuk melakukan studi terkontrol secara acak untuk
insomnia pada gangguan bipolar, ukuran sampel yang kecil (total N = 21), serta fakta bahwa
pasien hipomanik, dapat membatasi kekuatan penelitian untuk mendeteksi manfaat dibandingkan
plasebo, serta generalisasi hasil untuk pengelolaan insomnia komorbid pada fase lain gangguan
bipolar.

Norris dan rekannya melanjutkan penelitian lebih lanjut tentang ramelteon pada insomnia
comorbid dengan gangguan bipolar, memeriksa sejumlah besar peserta (N = 83), yang euthymic
pada awal ( 24 ). Peserta dalam penelitian double-blind ini diacak untuk ramelteon 8mg atau
plasebo, di samping obat-obatan psikiatrik reguler mereka, dan diikuti hingga 24 minggu atau
sampai mereka mengalami kekambuhan depresi atau manik ( 24 ). Hebatnya, peserta yang
menerima ramelteon memiliki kemungkinan dua kali lipat lebih rendah mengalami penurunan
mood dibandingkan dengan plasebo. Juga, peserta yang secara acak menggunakan plasebo yang
baru saja pulih dari episode campuran atau depresi memiliki peluang yang lebih tinggi (rasio
odds 2,67 dan 3,75, masing-masing) untuk menyelesaikan studi 24 minggu dibandingkan dengan
peserta dalam kelompok plasebo ( 24 ). Stabilitas mood yang meningkat ini terjadi meskipun
tidak ada perubahan signifikan pada PSQI (pengamatan terakhir yang dilakukan), meskipun tren
peningkatan PSQI diamati dari 8-20 minggu perawatan ( 24 ). Para penulis berspekulasi bahwa
peserta mungkin tidak memiliki peningkatan yang signifikan dalam PSQI dengan ramelteon

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relatif terhadap plasebo karena efek langit-langit yang disebabkan oleh obat psikotropika
penenang yang diresepkan yang diresepkan untuk gangguan bipolar ( 24 ). Keterbatasan
penelitian lain termasuk ukuran sampel yang relatif kecil, serta durasi stabilitas suasana hati yang
diperlukan untuk masuknya studi hanya satu minggu, yang lebih pendek dari uji klinis lain yang
memeriksa stabilitas suasana hati pada gangguan bipolar ( 24 ).Terlepas dari keterbatasan ini,
penelitian ini menunjukkan bahwa ramelteon, suatu agonis reseptor tipe 1 dan 2 melatonin, dapat
mengubah perjalanan longitudinal dari gangguan bipolar, dan jelas penelitian lebih lanjut dalam
bidang ini diindikasikan.

Selain dari dua studi ramelteon terkontrol acak yang disebutkan sebelumnya pada gangguan
bipolar ( 23 , 24 ), basis bukti yang tersisa untuk memandu pilihan obat hipnotik sedatif pada
gangguan bipolar sebagian besar tidak terkendali. Schaffer dan koleganya melakukan tinjauan
bagan yang menilai kemanjuran dan keamanan zolpidem (pelepasan langsung dan lama),
eszopiklon, zaleplon, dan ramelteon pada 361 pasien berturut-turut dengan gangguan bipolar
( 25 ). Secara umum, mereka mencatat sekitar setengah dari pasien mereka memerlukan hipnotik
sedatif kronis setiap hari, dan bahwa BZRA memiliki tingkat keberhasilan (didefinisikan sebagai
banyak atau sangat jauh meningkat pada Clinical Global Impression Scale-Bipolar Version) dari
36-60%, dengan semakin terbatasnya kesuksesan ramelteon (15%). Agen-agen ini umumnya
ditoleransi dengan baik, dan pengguna obat penenang-hipnotis kronis tidak mengalami kejadian
yang tidak diinginkan yang tidak dapat diterima ( 25 ). Meskipun data yang tidak terkontrol ini
harus ditafsirkan dengan hati-hati, mereka memberikan beberapa bukti bahwa agen ini mungkin
merupakan pilihan yang masuk akal untuk pengobatan insomnia yang terkait dengan gangguan
bipolar, termasuk penggunaan kronis.

Kelas lain dari agen, penenang antidepresan, sering digunakan untuk mengobati insomnia pada
pasien dengan gangguan bipolar; Namun, basis bukti untuk obat-obatan ini terbatas, meskipun
digunakan secara luas ( 18 ). Karena penelitian sebelumnya telah menyarankan bahwa TCA dan
trazodone dapat meningkatkan risiko perubahan suasana hati, terutama ke fase manik ( 26 , 27 ),
klarifikasi keamanan dan kemanjuran agen ini pada orang dengan gangguan bipolar adalah
bidang studi yang penting. Dengan tidak adanya data yang terkontrol, Wichniak dan rekannya
baru-baru ini meninjau literatur untuk mengidentifikasi laporan kasus antidepresan penenang
(trazodone dan mirtazapine, serta agomelatine) yang menginduksi gejala manik ( 28 ). Meskipun
risiko bias dalam pendekatan ini sangat besar, mereka menemukan bahwa trazodone dan
mirtazapine cenderung menyebabkan mania pada pasien dengan faktor risiko lain untuk manic
switching (misalnya, tidak menggunakan penstabil mood bersamaan), dan cenderung terjadi pada
antidepresan (yaitu lebih tinggi) daripada dosis yang lebih rendah yang biasanya diresepkan
untuk insomnia ( 28 ). Dengan demikian, jika agen-agen ini digunakan untuk mengobati
komorbiditas insomnia dengan gangguan bipolar, tampaknya paling bijaksana untuk
menggunakan agen-agen ini hanya pada pasien yang secara bersamaan dirawat dengan obat yang
menstabilkan suasana hati, dan dengan pemantauan yang cermat untuk meningkatkan perubahan
suasana hati. Idealnya, penelitian terkontrol lebih lanjut akan menjelaskan kemanjuran dan

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keamanan obat penenang antidepresan dalam gangguan bipolar; Namun, ada kemungkinan
alasan ekonomi dan etika bahwa studi tersebut tidak mungkin dilakukan dalam waktu dekat.

Selain mengobati insomnia dan berpotensi mengubah perjalanan longitudinal dari gangguan
bipolar, penggunaan obat penenang-hipnotik juga dapat memberikan manfaat dalam pengelolaan
perilaku kesehatan negatif lainnya seperti merokok, yang 3,5 kali lipat lebih umum di antara
pasien dengan gangguan bipolar daripada umum populasi ( 29 ). Karena insomnia sebelum dan
selama upaya untuk berhenti merokok telah dikaitkan dengan kegagalan penghentian ( 30 , 31 ),
penggunaan agen penunjang tidur tambahan pada pasien yang berusaha berhenti merokok,
terutama di antara pasien berisiko tinggi seperti pasien dengan penyakit mental berat, adalah
jalur investigasi yang berpotensi menjanjikan. Forrest dan rekannya melakukan analisis sekunder
dari RCT yang meneliti varenicline versus plasebo pada pasien dengan gangguan bipolar yang
ingin berhenti merokok, menemukan penggunaan agen hipnosis bersamaan dikaitkan dengan
kemungkinan penghentian yang lebih besar pada pasien ini ( 32 ). Meskipun terdapat
keterbatasan termasuk ukuran sampel yang kecil (N = 60), dan penggunaan label terbuka dari
hipnotis penggunaan yang membatasi sebab dan akibat kesimpulan, hasil ini menyarankan studi
terkontrol yang lebih besar di masa depan yang mencakup pasien dengan gangguan bipolar, serta
gangguan kejiwaan lainnya yang terkait dengan peningkatan tingkat merokok, seperti
skizofrenia, diindikasikan.

Go to:

Skizofrenia

Skizofrenia adalah penyakit psikotik klasik, dengan gejala yang jatuh ke dalam tiga kategori
besar: positif, negatif, dan kognitif, yang semuanya dapat berdampak negatif pada fungsi sosial
dan pekerjaan. Gejala kognitif, yang dapat mencakup fungsi eksekutif yang buruk, kesulitan
atensi, dan kesulitan dengan memori kerja, dapat sangat mengganggu bagi pasien dengan
gangguan tersebut ( 33 ). Kesulitan terkait tidur yang paling konsisten diidentifikasi yang dialami
oleh pasien dengan skizofrenia termasuk kesulitan tidur dan tetap tidur ( 34 , 35 ). Karena
insomnia dan pembatasan tidur dikaitkan dengan gangguan kognitif di sejumlah domain
( 36 , 37 ), mengobati inisiasi tidur dan kesulitan kontinuitas secara teoritis dapat menghasilkan
peningkatan kognisi pada pasien ini.

Mengikuti penelitian ini, Tek dan rekannya meneliti penggunaan eszopiklon 3mg setiap malam
dibandingkan dengan plasebo pada 39 pasien rawat jalan yang stabil secara klinis dengan
skizofrenia atau gangguan skizoafektif dan insomnia komorbiditas ( 38 ). Penelitian ini termasuk
periode acak 8 minggu, diikuti oleh fase plasebo 2 minggu single-blind untuk menilai daya tahan
efek obat. Eszopiclone menunjukkan kemanjuran yang signifikan dibandingkan plasebo pada
ukuran hasil utama dari perubahan skor ISI, dengan perbedaan antara kelompok hampir 4 poin
pada skala ( 38 ). Selama periode penghentian, tidak ada perbedaan antara eszopiklon dan
plasebo dalam perubahan skor ISI ( 38 ). Meskipun ada peningkatan insomnia, eszopiklon tidak

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menunjukkan manfaat pada hasil sekunder dari perubahan dalam MATRICS Consensus
Cognitive Battery, yang menilai kecepatan pemrosesan, perhatian, memori kerja verbal dan
nonverbal, pembelajaran verbal dan visual, penalaran / pemecahan masalah, dan kognisi sosial
( 38 ). Analisis eksplorasi menyarankan perbaikan subskala dengan eszopiklon pada tes memori
yang bekerja, komponen rentang nomor surat MATRICS, untuk peserta dengan skizofrenia
(tetapi bukan gangguan skizoafektif), yang berkorelasi dengan perubahan skor ISI ( 38 ). Namun,
perbaikan dalam memori kerja diamati selama fase double-blind dengan eszopiklon tidak
bertahan ke fase plasebo single-blind, menunjukkan perubahan tersebut tidak tahan lama ( 38 ).

Selain perubahan dalam memori kerja, telah dikemukakan bahwa eszopiklon dapat menyebabkan
peningkatan konsolidasi memori prosedural tergantung tidur pada orang dengan
skizofrenia. Pasien dengan skizofrenia menunjukkan penurunan dalam perbaikan semalam pada
tugas sekuens motorik jari-tapping (MST) ( 39 ). Karena pasien dengan skizofrenia menunjukkan
penurunan spindel tidur ( 40 ) dan peningkatan tergantung tidur pada MST berkorelasi dengan
karakteristik osilasi elektroensefalografik yang semakin berkurang dari tidur gerakan mata yang
tidak cepat ( 41 ), meneliti efek agen seperti eszopiklon, yang dapat meningkatkan spindel tidur
melalui potensiasi nukleus reticular thalamic GABAergic (situs utama generasi spindle tidur),
adalah jalur penelitian yang menjanjikan. Wamsley dan rekannya meneliti baik kemampuan
eszopiklon untuk menghasilkan kumparan tidur maupun efek asosiatifnya pada kinerja MST
semalam ( 42 ). Setelah skrining, dua puluh satu pasien dengan skizofrenia menyelesaikan
kunjungan awal di laboratorium, yang terdiri dari dua malam berturut-turut polisomnografi,
dengan MST dilakukan pada malam kedua tidur. Satu minggu kemudian, peserta menyelesaikan
kunjungan pengobatan yang serupa, namun, pasien secara acak diberikan eszopiklon 3mg atau
plasebo, dan menyelesaikan MST menggunakan urutan alternatif dibandingkan dengan
awal. Eszopiclone secara signifikan meningkatkan jumlah dan kepadatan spindle relatif terhadap
baseline dibandingkan dengan plasebo, tetapi tidak secara signifikan meningkatkan peningkatan
MST semalam ( 42 ). Ketika kelompok eszopiklon dan plasebo digabungkan, jumlah spindel
tidur dan kepadatan berkorelasi dengan peningkatan MST semalam ( 42 ).Temuan ini
mendukung gagasan bahwa peningkatan farmakologis gelendong tidur mungkin memiliki
beberapa manfaat pada pasien dengan skizofrenia, namun, penelitian lebih lanjut diindikasikan
untuk menentukan domain apa yang mungkin terkena dampak dan apakah perbaikan tersebut
memiliki dampak klinis yang dapat dibuktikan pada gangguan tersebut.

Go to:

Gangguan Stres Pascatrauma

PTSD adalah salah satu kondisi kejiwaan yang paling umum, dengan prevalensi seumur hidup
secara keseluruhan di Amerika Serikat sekitar 7% ( 43 ). Gangguan tidur adalah fitur inti dari
PTSD, dengan insomnia dan mimpi buruk kedua komponen kriteria diagnostik untuk gangguan
tersebut ( 1 ). Selain itu, insomnia dan mimpi buruk dapat memainkan peran dalam morbiditas
gangguan, dan dengan demikian menjadi target terapi yang penting ( 44 ). Meskipun demikian,

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basis bukti untuk perawatan gangguan tidur pada PTSD relatif sedikit. Ulasan literatur terbaru
mendukung penggunaan prazosin sebagai agen lini pertama untuk insomnia dan mimpi buruk di
PTSD ( 45 ).

Ada juga bukti terbaru yang menunjukkan bahwa eszopiklon dapat memberikan manfaat sebagai
agen tambahan dalam pengobatan gangguan tidur di PTSD. Pollack dan rekannya meneliti
penggunaan eszopiclone 3mg setiap malam pada pasien dengan PTSD dan gangguan tidur yang
terjadi bersamaan, menggunakan desain crossover terkontrol plasebo terkontrol secara acak,
double-blind, terkontrol plasebo ( 46 ). Eszopiklon tiga minggu dibandingkan dengan plasebo
dikaitkan dengan latensi onset tidur yang berkurang secara signifikan dan peningkatan kualitas
tidur (diukur oleh PSQI). Selain itu, mirip dengan manfaat koterapi pada depresi berat ( 9 , 10 ),
eszopiklon juga secara signifikan meningkatkan gejala PTSD [dinilai dengan wawancara
Peringkat pendek PTSD (SPRINT) yang dikelola dokter dan Skala PTSD yang Diurus oleh
Dokter (CAPS)], bahkan ketika item yang berhubungan dengan tidur dikeluarkan
( 46 ).Meskipun hasil ini menjanjikan, penelitian ini relatif kecil (N = 23), dan pekerjaan di masa
depan mereplikasi hasil tersebut serta mengevaluasi efek longitudinal di luar penggunaan jangka
pendek ditunjukkan. Selain itu, studi efektivitas komparatif akan membantu dalam menentukan
apakah obat penenang-hipnotik memberikan manfaat di atas agen lain yang sering digunakan di
luar label untuk mengobati insomnia di PSTD. Secara khusus, antipsikotik atipikal, yang
umumnya diresepkan sebagian besar untuk sifat obat penenang-hipnotis pada pasien dengan
PTSD ( 47 ), harus dibandingkan baik dalam kemanjuran pada gejala tidur dan PTSD, serta
profil efek samping, mengingat konsekuensi kesehatan yang negatif. (misalnya kenaikan berat
badan, sindrom metabolik, dll.) yang terkait dengan antipsikotik generasi kedua.

Ucapan Terima Kasih

Dr. Plante telah menerima dan didukung oleh hibah dari National Institute of Mental Health
(K23MH099234), Yayasan Riset Otak dan Perilaku dan American Sleep Medicine Foundation.

Go to:

Catatan kaki
Kepatuhan dengan Pedoman Etika

Konflik kepentingan:

Creado Melaporkan tidak ada konflik kepentingan.

Hak Asasi Manusia dan Hewan dan Persetujuan Diinformasikan:

Artikel ini tidak mengandung studi dengan subyek manusia atau hewan yang dilakukan oleh
penulis.
Go to:

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Firda Auliya Ciptaning Kinasih (20610330311164)

Kesimpulan
Karena tidur memainkan peran integral dalam presentasi dan perjalanan dari banyak gangguan
kejiwaan, penelitian yang meneliti penggunaan obat penenang-hipnotik dalam penyakit mental
kemungkinan besar akan berdampak signifikan pada pemberian perawatan di psikofarmakologi
klinis. Namun, meskipun terobosan baru-baru ini dibuat oleh investigasi yang dijelaskan dalam
ulasan ini, dasar bukti untuk penggunaan obat hipnotik pada penyakit kejiwaan masih relatif
terbatas. Ada banyak sekali faktor yang mempengaruhi penggunaan obat penenang-hipnotik oleh
perawatan primer dan penyedia kesehatan perilaku, dan penggunaan optimalnya masih
kontroversial. Namun, sangat penting bahwa bidang mengatasi stigma seputar obat-obatan ini
untuk secara empiris menentukan bagaimana dan dalam keadaan apa agen ini dapat sangat
membantu bagi pasien dengan penyakit kejiwaan. Penyelidikan tersebut sangat penting karena
manajemen gangguan tidur memiliki potensi untuk mengurangi morbiditas dan mortalitas yang
terkait dengan gangguan kejiwaan, serta mencegah episode penyakit utama, yang merupakan
tujuan utama dalam perawatan pasien dengan penyakit mental

164
 Review

Emerging drugs for the treatment

of anxiety
James W Murrough†, Sahab Yaqubi, Sehrish Sayed & Dennis S Charney
†
1. Background Icahn School of Medicine at Mount Sinai, Department of Psychiatry, Mood and Anxiety Disorders
Program, New York, NY, USA
2. Medical need
3. Existing treatment Introduction: Anxiety disorders are among the most prevalent and disabling
4. Current research goals psychiatric disorders in the United States and worldwide. Basic research has
provided critical insights into the mechanism regulating fear behavior in ani-
5. Scientific rationale
mals and a host of animal models have been developed in order to screen
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15

6. Competitive environment compounds for anxiolytic properties. Despite this progress, no mechanistically
7. Potential development issues novel agents for the treatment of anxiety have come to market in more than
8. Conclusion two decades.
9. Expert opinion Areas covered: The current review will provide a critical summary of current
pharmacological approaches to the treatment of anxiety and will examine
the pharmacotherapeutic pipeline for treatments in development. Anxiety
and related disorders considered herein include panic disorder, social anxiety
disorder, generalized anxiety disorder and post-traumatic stress disorder. The
glutamate, neuropeptide and endocannabinoid systems show particular
promise as future targets for novel drug development.
Expert opinion: In the face of an ever-growing understanding of fear-related
For personal use only.

behavior, the field awaits the translation of this research into mechanistically
novel treatments. Obstacles will be overcome through close collaboration
between basic and clinical researchers with the goal of aligning valid endo-
phenotypes of human anxiety disorders with improved animal models. Novel
approaches are needed to move basic discoveries into new, more effective
treatments for our patients.

Keywords: anxiety, anxiolytic, clinical trial, endocannabinoid, glutamate, neuropeptide, panic

disorder, posttraumatic stress disorder

Expert Opin. Emerging Drugs [Early Online]

1. Background

Anxiety disorders are among the most prevalent and disabling psychiatric disorders
in the United States [1,2]. Approximately one in four adults will suffer from an anx-
iety disorder at some point in their lives. Patients with anxiety disorders experience
substantial physical and emotional discomfort and have elevated rates of substance
use and medical illnesses. Co-occurring anxiety disorders in the context of other
psychiatric disorders, for example major depressive disorder (MDD) or bipolar dis-
order, are associated with a more chronic and treatment refectory course and these
patients are at an elevated risk for suicide [3,4]. The combination of high prevalence
and high functional disability associated with anxiety disorders leads to a particu-
larly high economic and social cost.
The core feature of anxiety disorders is excessive fear and anxiety and related
behavioral disturbances. The diagnostic schema for anxiety disorders in the United
States was revised with the publication of the Diagnostic and Statistical Manual of
Mental Disorders -- Fifth Edition (DSM-V) [5]. The DSM-V recognizes the follow-
ing anxiety disorders: separation anxiety disorder, selective mutism, specific phobia
(SP), social anxiety disorder (SAD), panic disorder, agoraphobia, generalized anxi-
ety disorder (GAD), substance/medication-induced anxiety disorder and anxiety

10.1517/14728214.2015.1049996 © 2015 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 1

All rights reserved: reproduction in whole or in part not permitted
165
 J. W. Murrough et al.
disorder due to another medication condition. There are two
residual categories for presentations that do not fit any of the
preceding categories: other specific anxiety disorder and
unspecified anxiety disorder. Separation anxiety disorder and
selective mutism are expressed primarily in childhood and
will not be discussed here further. In DSM-V, agoraphobia
has been added as a new diagnosis and post-traumatic stress
disorder (PTSD) and obsessive compulsive disorder (OCD)
have been moved elsewhere in the diagnostic schema. PTSD
is a disorder of excessive fear and anxiety and is appropriately
retained in considerations of the biology and treatment of
anxiety disorders. OCD may be distinctive compared to the
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15
anxiety disorders and PTSD in terms of clinical presentation,
biology and treatment.
The current review will provide a critical summary of cur-
rent pharmacological approaches to the treatment of anxiety
and will examine the pharmacotherapeutic pipeline for anxi-
ety treatments in development. The current review focuses
on therapeutic agents that are in early- or late-phase human
testing for anxiety disorders at the time of this writing. For
an in-depth review of anxiolytic development from a preclin-
ical perspective, the reader is directed to several recent
reviews [6,7].
For personal use only.
2. Medical need
Substantial progress has been made in neurobiological
research aimed at uncovering the molecular and neurocircuit
alterations that lead to anxiety. Basic research has provided
critical insights into the mechanism regulating fear behavior
in animals and a host of animal models have been developed
in order to screen compounds for anxiolytic properties.
Despite this progress, no mechanistically novel agents for
the treatment of anxiety have come to market in more than
two decades. The validity of current animal models of human
anxiety disorders is limited, thereby imposing a major chal-
lenge to drug discovery in this area. For a thorough discussion
of animal models of anxiety and their utility, please see [7].
There is an urgent need for mechanistically novel, more
effective treatments for anxiety. As touched on above, anxiety
disorders are associated with substantial functional
impairment [2] and patient and family burden [8]. These disor-
ders are associated with increased utilization of health care
services [9] and reduced work productivity [10]. Current treat-
ments fall short of what is needed to meet this large public
health burden. For example, recent large meta-analyses were
unable to support the efficacy of benzodiazepines [11] or aza-
pirones (e.g., buspirone) for panic disorder [12]. PTSD,
GAD and SAD likewise are only partially responsive to
currently available treatments, including serotonin selective
reuptake inhibitors (SSRIs) [13,14]. Troublingly, a report
from the Institute of Medicine concluded that the available
evidence was inadequate to support the efficacy of SSRIs or
other pharmacotherapy in PTSD [15]. Clearly, the discovery
2 Expert Opin. Emerging Drugs (2015) 20(3)
of novel pharmacotherapeutic treatments for anxiety repre-
sents a large unmet medical need.
3. Existing treatment
3.1 First-line treatments
Agents with current US FDA approval for the treatment of
anxiety disorders are summarized in Table 1. Multiple ran-
domized controlled trials (RCTs) support the efficacy of
SSRIs and serotonin norepinephrine reuptake inhibitors
(SNRIs) as first-line treatments for GAD, SAD, panic disor-
der and PTSD [13,16-18]. An analysis of 12 RCTs in panic dis-
order found a mean effect size for SSRIs relative to placebo of
0.55 [19]. In the case of GAD, response rates for SSRIs of
between 60 and 75% are generally reported in RCTs, com-
pared to response rates between 40 and 60% for placebo [17].
Data suggest that PTSD may be less amenable to current
pharmacotherapy compared to other anxiety disorders.
A Cochrane review of pharmacotherapy for PTSD including
35 RCTs and 4597 participants did support the use of SSRIs
as first-line medication treatment [13].
3.2Second-line and other treatments for anxiety
disorder
Tricyclic antidepressants (TCAs) and monoamine oxidase
inhibitors (MAOIs) have reasonable efficacy data in anxiety
disorders but are usually reserved for second-line treatment
due to safety and tolerability issues. The benzodiazepines
play an important role in the treatment of some anxiety
disorders; however these agents too are usually reserved for
second-line or adjunctive use due to tolerability and abuse lia-
bility issues. These agents have the advantage of a rapid onset
of action, inviting their use early in the course of treatment
prior to the onset of efficacy of a co-administered SSRI/
SNRI. Data supporting the longer-term efficacy of benzodia-
zepines is more limited. For example, Goddard et al. showed
that co-administration of clonazepam with sertraline in the
treatment of panic disorder resulted in a significantly greater
proportion of responders in the sertraline/clonazepam
group at the end of one week, but not at study end [20]. Anti-
convulsants, including gabapentin and pregabalin, have mixed
data to support efficacy in certain anxiety disorders. The data
for second-generation antipsychotics (SGAs) in anxiety disor-
ders is likewise mixed and will be reviewed in greater detail
below.
4. Current research goals
As a group, anxiety disorders represent a heterogeneous group
of illnesses that have excessive fear and anxiety as their core
phenomenology. Psychiatry has struggled to determine the
appropriate nosological classification of these disorders and
the newest version of the DSM presents yet another configu-
ration, as noted above. The changing diagnostic landscape
and uncertain boundaries between anxiety disorders create
166
 Emerging drugs for the treatment of anxiety

Table 1. Current FDA-approved treatments for anxiety disorders.

Pharmacologic Examples Molecular FDA-approved Dose range Common adverse Pregnancy

class target(s) indications effects category

SSRI Escitalopram SERT GAD 10 -- 20 mg Nausea, Diarrhea, C

daily Headache, Insomnia,
Somnolence, Sexual
dysfunction
Fluoxetine SERT OCD, PD 20 -- 60 mg As above C
daily
Fluvoxamine SERT OCD, SAD 100 -- 300 mg As above C
daily
Paroxetine SERT GAD, OCD, PD, 20 -- 50 mg As above D
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PTSD, SAD daily

Sertraline SERT OCD, PD, PTSD, 50 -- 200 mg As above C
SAD daily
SNRI Duloxetine SERT, NET GAD 60 -- 120 mg As above, plus C
daily Hypertension
Venlafaxine SERT, NET GAD, PD, SAD 75 -- 225 mg As above C
daily
BZD Alprazolam GABA-AR Anxiety 1 -- 4 mg daily Somnolence, Cognitive D
(non-specific), PD problems, Appetite
change, Fatigue (Class
Effects)
Chlordiazepoxide GABA-AR Anxiety 15 -- 40 mg As above C
(non-specific), daily
Clonazepam GABA-AR PD 1 -- 4 mg daily As above D
Diazepam GABA-AR Anxiety 2 -- 10 mg As above D
For personal use only.

(non-specific) daily
Lorazepam GABA-AR Anxiety 1 -- 6 mg daily As above D
(non-specific)
Oxazepam GABA-AR Anxiety 30 -- 120 mg As above C
(non-specific) daily
TCA Clomipramine SERT, NET, mACh, OCD, PD 25 -- 250 mg Dry mouth, Constipation, C
A1R, H1R daily Urinary retention,
Somnolence, Dizziness,
Weight gain, Sexual
dysfunction, Orthostasis
(Class Effects)
Doxepine SERT, NET, Anxiety 75 -- 300 mg As above C
mAChR, A1R, H1R (non-specific) daily
Imipramine SERT, NET, PD 100 -- 200 mg As above C
mAChR, A1R, H1R daily
MAOI Phenelzine MAO PD 45 -- 90 mg Dry mouth, Constipation, ?
daily Orthostasis, Weight gain,
Sexual dysfunction,
Somnolence, Dizziness,
Headache
Antihistamine Hydroxyzine H1R Anxiety 200 -- 400 mg Sedation, Dry mouth, C
(non-specific) daily Dizziness, Headache
Other Buspirone 5-HT1AR Anxiety 20 -- 60 mg Nausea, Dizziness, B
(non-specific) daily Headache

5-HT: 5-hydroxy-tryptamine; 5HT1AR: 5-HT 1A receptor; A1R: a-adrenergic 1 receptor; BZD: Benzodiazepines; GABA-AR: GABA A receptor; GAD: Generalized
anxiety disorder; H1R: Histamine 1 receptor; MAO: Monoamine oxidase; MAOI: MAO inhibitor; mAChR: Muscarinic acetylcholine receptor; NET: Norepinephrine
transporter; OCD: Obsessive-compulsive disorder; PD: Panic disorder; SERT: Serotonin transporter; SAD: Social anxiety disorder; SNRI: Serotonin norepinephrine
reuptake inhibitor; SSRI: Selective serotonin reuptake inhibitor; TCA: Tricyclic antidepressant.

challenges for drug development, compounding other hurdles
noted above. In response to these challenges, some major
pharmaceutical companies have either substantially reduced
their investment in CNS research or else eliminated their
CNS programs altogether. This concerning development
compels changes in the approach to anxiety drug development
by academia and industry.
Most recently, investigators and government agencies have
advocated for a dimensional approach to the study and treat-
ment of anxiety [21]. This approach relies on breaking down

Expert Opin. Emerging Drugs (2015) 20(3) 3

167
 J. W. Murrough et al.
disorders into phenotypic dimensions that cut across tradi-
tional diagnostic boundaries and then mapping these pheno-
types onto discrete perturbations at the neurocircuit and
molecular level. For example, factor analytic studies suggest
that PTSD is best represented by the five symptom clusters
of re-experiencing, avoidance, numbing, dysphoric arousal,
and anxious arousal [22] and recent neuroimaging findings
have linked amygdala volume specifically to the dimension
of anxious arousal [23]. Current research goals, therefore,
including developing novel pharmacological agents that may
target specific dimensions of the anxious phenotype based
on a refined understanding of underlying neurobiology.
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5. Scientific rationale
The rational development of therapeutics for anxiety disorders
is based on a solid understanding of underlying pathophysiol-
ogy and on the development and application of valid animal
models. As noted above, there are currently important limita-
tions regarding both of these fundamental points. The GABA
system has historically been the primary focus of anxiolytic
drug discovery. More recently, the SSRIs and SNRIs -- first
developed for the treatment of depression -- have become
the mainstay of anxiolytic treatment. The incomplete effec-
For personal use only.
tiveness of current treatment and the burdening neuroscience
of fear-related behavior, however, compel the search for novel,
more effective treatments. In the section below, we provide a
critical review of the current landscape of drug development
for anxiety disorders. Organized by neurochemistry, we begin
by reviewing agents that act on the serotonin, melatonin,
norepinephrine and dopamine systems. We then review prog-
ress in the clinical development of agents, the target, the glu-
tamate and GABA systems, neuropeptide systems and the
endocannabinoid system. The glutamate, neuropeptide and
endocannabinoid systems may show particular promise as
target for novel drug development.
6. Competitive environment
See Table 2 for a summary of investigational and emerging
treatments for anxiety disorders.
6.1 Serotonin
6.1.1 Vortioxetine
Vortioxetine is a serotonergic compound developed by
Lundbeck and is approved by the U.S. FDA and European
Medicines Agency (EMA) for treatment of MDD [24]. Vorti-
oxetine is a serotonin transporter (SERT) inhibitor with
additional effects as a 5-HT1A receptor (full) agonist, a
5-HT1B receptor (partial) agonist, and a 5-HT1D, 5-HT3,
and 5-HT7 receptor antagonist. Vortioxetine increases extra-
cellular levels of serotonin, dopamine, noradrenaline, acetyl-
choline and histamine within ventral hippocampus and
prefrontal cortex (PFC) and modulates GABA and glutamate
neurotransmission in preclinical studies [25].
4 Expert Opin. Emerging Drugs (2015) 20(3)
To date, three separate RCTs of vortioxetine have been
conducted in patients with GAD and have produced equivo-
cal results [26-28]. In one study, patients with GAD were ran-
domized to 8 weeks of vortioxetine 5 mg per day (n = 150)
versus placebo (n = 151); total HAM-A score was lower in
the vortioxetine group (-14.30 vs -10.49, p < 0.001) [26].
The results of two other RCTs in GAD, however, were nega-
tive [27,28]. Most common side effects reported in the vortiox-
etine groups were nausea, headache, dizziness, and dry
mouth [26-29]. Taken together, the clinical trial data to date
is suggestive of a benefit of vortioxetine in GAD but addi-
tional studies may be required to confirm these findings.
6.1.2 Vilazodone
Vilazodone was developed by Merck and was approved by the
U.S. FDA for the treatment of MDD in 2011 [30]. In addition
to functioning as an SSRI, vilazodone acts as a 5-HT1A recep-
tor partial agonist, similar to buspirone. Preclinical studies
show that activation of presynaptic 5-HT1A autoreceptors
function to delay the anti-anxiety and antidepressant effects
of SSRIs [31]. Through simultaneous blockade of the SERT
and activation of the 5-HT1A receptor, vilazodone may
overcome this delay. This dual mechanism of action can
potentially shorten the delay of anti-depressive action,
decrease side-effects related to serotonin reuptake inhibition
in SSRI, and alleviate anxiety symptoms [31]. The true clinical
implication of this pharmacodynamics profile, however,
remains unclear.
To date, there are no published RTCs examining vilazo-
done in patients with anxiety disorders. A post-hoc analysis
of two Phase III RCTs involving patient with MDD sug-
gested vilazodone could be beneficial in treatment of MDD
with anxious features [32]. Following 8 weeks of treatment,
patients in the active arm showed significant improvement
in somatic and psychic symptoms of anxiety compared to
placebo. Some data suggest a lower sexual dysfunction with
vilazodone compared to SSRIs. However, more studies
needed to be done to clarify this [32,33]. Overall, more studies
are required in order to fully evaluate the potential of vilazo-
done for patients with anxiety disorders.
6.2 Melatonin
6.2.1 Agomelatine
Agomelatine is a mechanistically unique melatonin receptor
(MT1, MT2) agonist and a 5-HT2C receptor antagonist [34].
The agent is approved for the treatment of MDD in Europe
but has no indications in the US Molecular and cellular
studies show that agomelatine’s synergistic effects on the mel-
atonin and serotonin systems can enhance neuroplasticity,
including enhancing neurogenesis in the adult hippocam-
pus [35]. Preclinical studies also show that agomelatine reduces
stress-induced increases in glutamate release within the PFC
and synchronizes circadian rhythm by stimulating melatoner-
gic and serotonergic receptors in suprachiasmatic nucleus
(SCN) of the hypothalamus [34]. There is some overlap
168
 Emerging drugs for the treatment of anxiety

Table 2. Investigational and emerging treatments for anxiety disorders.

Mechanistic Compound Molecular target/pharmacodynamics Disorder Manufacturer Phase of

class development

5-HT Vortioxetine SERT; 5-HT1AR (full) agonist; 5-HT1BR (partial) agonist; GAD Lundbeck Phase III
5-HT1DR, 5-HT3R and 5-HT7R antagonist
Vilazodone SERT; 5-HT1AR partial agonist GAD Merck Phase III
PRX-03140 5-HT4R partial agonist PTSD EPIX Phase II
Melatonin Agomelatine M1 and M2 agonist, 5-HT2CR antagonist GAD, Servier Phase III
OCD Phase II
NE/ Guanfacine A2R agonist GAD, Shire Phase II
Dopamine SAD
Nepicastat DBH inhibitor PTSD Roche Phase II
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SGA Aripiprazole D2R partial agonist; 5-HT2AR antagonist PTSD Otsuka Phase II
Brexpiprazole D2/D3R partial agonist PTSD Otsuka Phase III
Glutamate/ Pregabalin VDCC SAD Pfizer Phase III
GABA
Ketamine NMDAR antagonist PTSD Generic N/A
Ganaxolone GABA-AR PAM PTSD Purdue Phase II
Pharma
Neuropeptide Itriglumide CCK-BR antagonist GAD, PD Rottapharma Phase II
Madaus
Verucerfont CRF-1 antagonist PTSD Neurocrine Phase II
Biosciences

5-HT: 5-hydroxy-tryptamine; A1R: a-adrenergic 1 receptor; CCK: Cholecystokinin; CRF: Corticotrophin releasing factor (CRF); DBH: Dopamine b-hydroxylase;
GAD: Generalized anxiety disorder; M: Melatonin; NET: Norepinephrine transporter; NMDA: N-methyl-D-aspartate; mGlu: Metabotropic glutamate receptor;
For personal use only.

OCD: Obsessive compulsive disorder; PAM: Positive allosteric modulator; PD: Panic disorder; PTSD: Posttraumatic stress disorder; R: Receptor; SAD: Social anxiety
disorder; SERT: Serotonin transporter; SGA: Second generation antipsychotic; VDCC: Voltage-dependent calcium.

between the neural effects of agomelatine and conventional
antidepressants and it is currently unclear to what extent the
unique molecular effects of agomelatine contribute to its
mechanism of action.
Two RCTs of agomelatine have been completed in patients
with GAD [36,37]. In a Phase III, 12-week, 3-arm RCT includ-
ing escitalopram as an active comparator, agomelatine showed
significant reduction in HAM-A scores over placebo [37]. Esci-
talopram and agomelatine had similar efficacy. The results of
a second RCT, which included a 42-week open-label period
(25 -- 50 mg/d) followed by a 6 months double-blind period,
showed a significantly lower relapse rate in agomelatine vs
placebo group (19.5 vs 30.7%; p = 0.045) [38]. A meta-
analysis that included six RCTs in patients with MDD with
anxieties features provides support for the efficacy of agomela-
tine for the treatment of anxiety symptoms [39]. A few case
reports and open-label trials have shown the efficacy of ago-
melatine augmentation in treatment of OCD [40]. The result
of recent Phase II trial investigating the efficacy of agomela-
tine in OCD has not yet been published (NCT01108393).
6.3 Norepinephrine and dopamine
Noradrenergic hyperactivity has been established as a critical
component of the stress response and abnormal noradrenergic
signaling has been consistently implicated in anxiety-related
behavior [41-43]. Elevated catecholamine activity during the
stress, which can impair PFC function, has been linked to
PTSD and other anxiety disorders in both clinical and
preclinical studies [44]. Cerebrospinal fluid (CSF) levels of
norepinephrine have been found to be significantly higher in
patients with PTSD compared to healthy volunteers [45].
Translational research in particular supports inhibition of
the a-1 receptor and/or stimulation of the a-2 receptor as
pharmacological strategies in PTSD or other anxiety
disorders [46].
6.3.1 Guanfacine
Guanfacine is a noradrenergic a-2 receptor agonist that is
approved in an extended release form for Attention Deficit
Hyperactivity Disorder (ADHD) [47]. Agonist activity at a-2
presynaptic auto-receptors reduces aberrant noradrenergic sig-
naling, which is hypothesized to lead to attenuation of anxiety
and trauma-related symptoms [46]. To date, two small double-
blind RCTs have not provided clear evidence of guanfacine’s
efficacy to ameliorate PTSD symptoms in adults [48,49]. There
is open-label evidence showing the efficacy of this agent in
treatment of PTSD symptoms and PTSD-related nightmares
in a child and adolescent population [50]. There are currently
no RCTs of guanfacine in other anxiety disorders. Although
the clinical trial data to date does not support the efficacy of
guanfacine in PTSD, studies are ongoing in other anxiety
disorders, including GAD, SP and SAD (NCT01470469).
6.3.2Nepicastat
Nepicast is a selective dopamine b-hydroxylase (DBH)
inhibitor, currently under investigation as a treatment for

Expert Opin. Emerging Drugs (2015) 20(3) 5

169
 J. W. Murrough et al.
PTSD (NCT00659230, NCT00641511). Inhibition of
b-hydroxylase reduces the conversion of dopamine to norepi-
nephrine, thereby reducing noradrenergic synaptic signaling.
Interestingly, this agent has been shown to be effective in
attenuating cocaine and alcohol-related behaviors in animal
studies [51]. Much more research will be required to determine
if this interesting class of drugs has potential efficacy in PTSD
or other anxiety disorders.
6.4 Second-generation antipsychotics
Numerous RCTs have been conducted to evaluate the efficacy
of SGAs for the treatment of anxiety disorders, including
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risperidone, ziprasidone, olanzapine, aripiprazole and quetia-
pine. The potential efficacy of SGAs in GAD and PTSD
has received the most attention.
6.4.1 Aripiprazole
Aripiprazole is approved by the FDA for schizophrenia, bipo-
lar disorder, MDD (adjunct), autistic disorder and Tourette’s
syndrome. Aripiprazole has a unique pharmacodynamic
profile as a partial agonist at the D2 receptor, along with
antagonist activity at the 5-HT1A and 5-HT2A receptors.
Two small RCTs of aripiprazole have been conducted in
OCD with promising preliminary results [52,53]. In addition,
For personal use only.
open-label trials of aripiprazole have been conducted in
GAD, panic disorder [54], MDD with anxious features [55]
and PTSD [56] with initial encouraging results. Additional
randomized controlled data are required to further character-
ize the efficacy of aripirazole in anxiety disorders.
6.4.2 Other SGAs
Several large RCTs support the efficacy of quetiapine in
GAD [57,58]. There is mixed evidence for the efficacy of risper-
idone in GAD [59,60] and there is comparatively less support
for olanzapine and ziprasidone. A large multi-site RCT of ris-
peridone as augmentation in PTSD in a Veteran Affairs pop-
ulation was negative [61]. As SGAs are associated with
significant adverse effects in some cases (e.g., metabolic syn-
drome and motor disturbances), the clinician must weigh
the risks and benefits of SGAs in the treatment of anxiety.
Given the limited data supporting efficacy, these agents may
be reserved for third- or fourth-line treatments in certain
cases.
6.4.3Brexpiprazole
Brexpiprazole is a D2/D3 receptor partial agonist currently
under investigation as an adjunctive treatment in PTSD
and in MDD with anxious features (NCT02013531,
NCT02196506).
6.5 Glutamate and GABA
6.5.1 Pregabalin
Pregabalin, 3-isobutyl-GABA, was initially developed by
Pfizer for the treatment of epilepsy and neuropathic pain
and was approved by the European Medicines Agency for
6 Expert Opin. Emerging Drugs (2015) 20(3)
treatment of GAD in 2006 [62]. There is no FDA approval
for this compound for anxiety in the USA. Pregabalin is a
chemical analog of GABA, though with no activity on
GABA receptors. The drug binds to the a-2-b subunit of pre-
synaptic voltage-dependent calcium channels, resulting in
reduced Ca2+ influx and reduced release of glutamate and nor-
epinephrine into the synaptic cleft [62]. The inhibitory effect
of pregabalin on excitatory neuronal pathways, hypothesized
to be overactive in anxiety disorders, may contribute to its
anxiolytic effect [25].
Pregabalin has demonstrated efficacy in several RCTs in
GAD [63,64], although the FDA ultimately determined that
there was insufficient evidence of efficacy to grant approval.
A meta-analysis in patient with GAD showed equal efficacy
between pregabalin and the other comparators studied:
duloxetine, ecitalopram, paroxetine, and venlafaxine [65]. Pre-
gabaline was also similarly effective in GAD compared to
alprazolam and lorazepam [63,66]. There is limited evidence
showing the efficacy of pregabalin augmentation with SSRI
in OCD or PTSD [67,68]. Of note, pregabalin is recommended
as a first line of treatment in comorbid GAD and epilepsy [69].
6.5.2 Ketamine
Ketamine is a noncompetitive glutamate NMDA receptor
antagonist currently FDA approved as an anesthetic agent [70].
Over the last decade, several small RCTs have provided evi-
dence that ketamine results in a rapid antidepressant effect
(e.g., within one day), even in patients with treatment-
resistant depression (TRD) [71-74]. In the largest study of
ketamine conducted to date in patients with TRD (n = 73),
ketamine was associated with a higher antidepressant response
rate compared to midazolam (used as a psychoactive control
condition) at the 24-h primary outcome time point (64 and
28%, respectively; odds ratio: 2.18) [72]. Most recently, keta-
mine has been examined for potential efficacy in PTSD [75]
and OCD.
A recently published RCT is the first study to examine the
efficacy of ketamine in PTSD [75]. In this study, ketamine was
administered as a single intravenous (IV) infusion in a double-
blind, randomized crossover study in 41 patients with chronic
PTSD and symptom change at 24 h post-treatment was the
primary outcome measure. Ketamine was associated with a
significant reduction in symptom severity measured using
the impact of event scale, compared to midazolam (mean dif-
ference score: 12.7, p = 0.02). The treatment was generally
well tolerated. Future studies examining the safety and
efficacy of repeated treatments of ketamine in PTSD will be
required in order to more completely evaluate the potential
for this therapy in chronic or treatment-refractory PTSD.
Two small clinical trials of ketamine have been conducted
in patients with OCD, yielding mixed results [76,77]. In the
first study, ketamine administered IV in an open-label fashion
was not associated with symptom improvement in 10 patients
with treatment refractory OCD [76]. In a second small RCT
involving 15 patients with OCD, ketamine was associated
170

with significant symptom improvement, with 50% of the
sample meeting response criteria following ketamine com-
pared to 0% following placebo [77]. Clearly, more data is
needed to evaluate the potential efficacy of ketamine in OCD.
6.5.3 Glutamate metabotropic receptor modulators
Preclinical studies have demonstrated a key role for glutamate
in the regulation of fear and anxiety, in addition to depressive
behaviors [78]. Metabotropic glutamate receptor (mGluR)
modulators, particularly mGluR1, mGluR2/3 and mGluR5,
have been shown to modulate anxiety and fear in preclinical
studies [7,79]. A small RCT investigating the effects of the
mGluR2/3 agonist LY354740/LY544344 in patients with
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15
GAD was halted due to concerns regarding the potential for
convulsions [80]. A separate mGluR2/3 agonist failed to
demonstrate benefit in panic disorder within the context of
an RCT [81]. An ongoing study is being conducted to evaluate
the safety and efficacy of another mGluR2/3 receptor agonist,
pomaglumetad methionil, in treatment of PTSD
(NCT02234687).
Other glutamate metabotropic receptor modulator includ-
ing, mGluR1 and mGluR5 antagonist, has shown positive
results in the animal model of anxiety [78]. Although there
have been some initial setbacks, mGluR modulators yet
For personal use only.
represent a promising area for future treatment development
for anxiety.
D-Cycloserine and drug-augmentation of
6.5.4
psychotherapy
There has been growing interest in designing rational combi-
nations of medication with psychotherapy -- based on mecha-
nisms of fear learning and extinction -- as a novel approach to
the treatment of anxiety disorders (see [82] for a recent review).
Among the strategies studied, the combination of the NMDA
receptor modulator d-cycloserine (DCS) with specific forms
of cognitive behavioral therapy (CBT) has received the most
attention. DCS is a partial agonist at the glycine site on the
NMDA receptor and was originally used as an antimicrobial
agent. Systemic infusion of DCS enhances fear extinction in
animal models [83] and multiple clinical trials in human pop-
ulations now support the hypothesis that DCS can enhance
the efficacy of CBT for anxiety disorders [84-86]. In an early
proof of concept study, patients with SP (e.g., acrophobia)
were randomized to receive behavioral exposure therapy plus
placebo or behavioral exposure therapy plus DCS [85]. Patients
randomized to therapy plus DCS had significantly reduced
symptoms at both 1 week and 3 months following treatment.
To date, positive trials have been reported in PTSD, SP, SAD,
panic disorder and OCD. Negative studies have also been
reported [82].
6.6 Neuropeptides
6.6.1 Corticotrophin-releasing factor
Corticotrophin-releasing factor (CRF) or hormone (CRH) is
a 41-amino-acid neuropeptide first isolated in the 1980s.
Expert Opin. Emerging Drugs (2015) 20(3)
Emerging drugs for the treatment of anxiety
A large body of literature indicates that stress-related anxiety
is associated with chronically elevated activity of CNS circuits
that utilize CRF. CRF is involved in mediating the neuroen-
docrine, immune, autonomic, and behavioral responses to
stress [87]. The identification of CRF was followed by the
discovery of three CRF paralogs (urocortins 1, 2, and 3) and
two CRF/urocortin receptors CRF1 and CRF2 [88].
Acute and chronic centrally administered CRF produces
anxiety-like responses such as sleep disturbances, loss of appe-
tite and anhedonia in numerous animal models of anxiety dis-
orders [89]. CRF1 antagonist demonstrates anxiolytic activity
in multiple animal models [90,91]. Preclinical studies have spe-
cifically implicated CRF1 receptor located within the amyg-
dala as mediating the fear-related behaviors in the context of
stress [92]. Clinical studies show increased CSF concentrations
of CRF in PTSD [93,94]. Given this confluence of data, CNS-
penetrant CRF1 receptor antagonists have been developed
and have undergone extensive testing by the pharmaceutical
industry [95].
Unfortunately, no CRF1 receptor antagonist to date has
successfully demonstrated safety and efficacy in Phase III clin-
ical testing for a stress-related psychiatric disorder. In one
case, a large multicenter RCT in GAD failed to show superi-
ority of the selective CRF-1 receptor antagonist pexacerfont,
compared with placebo [96]. Clinical trials involving the
CRF-1 receptor antagonists verucerfont and emicerfont in
SAD have been completed with undisclosed results [97].
A large NIH-supported multi-site study involving the
CRFR1 antagonist GSK561679 (GlaxoSmithKline) in
PTSD has been recently completed and results are likewise
pending [98].
Despite a large amount of preclinical and mechanistic data
implicating the CRF system in fear-related behaviors and anx-
iety disorders, the field still awaits positive results from clinical
trials.
6.6.2 Neuropeptide Y
Neuropeptide Y (NPY) is a 36-amino-acid peptide, belonging
to the pancreatic polypeptide family and is co-localized and
released with neurons containing norepinephrine. In addition
to being the most abundant peptide known, most mammals
have identical NPY sequences, making NPY one of the most
evolutionary conserved peptides. NPY was first isolated and
sequenced in 1982 and since its discovery several functions
were discovered, linking NPY to the regulation of energy bal-
ance, stress responses [99], sleep and food intake. High expres-
sion levels of NPY are found in brain regions implicated in
the control of anxiety such as the amygdala, hippocampus,
brainstem, nucleus accumbens, locus coeruleus, and the hypo-
thalamus, where the highest concentrations are present [100].
NPY exerts its action by binding to the G-protein coupled
NPY receptors, consisting of Y1-Y5. The Y1 and Y2 receptors
in particular have been shown to mediate anti-anxiety and
antidepressant actions of NPY [101,102]. Recently, researchers
have identified NPY-related mechanisms that may underlie
7
171
 J. W. Murrough et al.
the development of early life anxiety using a nonhuman pri-
mate model of anxious temperament [103]. Their findings sug-
gest higher levels of Y1 and Y5 receptors in the amygdala are
associated with reduced anxiety. Genetic manipulation of the
NPY system provides additional evidence implicating Y1 and
Y5 receptors in reducing anxiety and increasing stress
resilience.
Preclinical research supports the potent anxiolytic actions
of NPY in a wide range of animal model, including fear-
potentiated startle, social interaction, conflict paradigms and
the elevated plus maze [104]. In a recent preclinical study,
rats were infused with intranasal NPY or placebo before
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15
exposure to a single prolonged stress (a model of PTSD)
and compared to untreated controls. The findings revealed
that intranasal NPY infusion attenuates development of
PTSD-like symptoms in rats and even 7 days later rats dis-
played lower depressive like behavior and reduced
anxiety [105].
The role of NPY in behavioral effects of stress has also been
clinically demonstrated in human studies. Plasma NPY
responses to yohimbine, an a-2 receptor antagonist, and pla-
cebo were measured in a group of combat veterans with
PTSD compared to healthy control subjects. The authors
found the PTSD patients had lower baseline plasma NPY
For personal use only.
and blunted yohimbine-stimulated increases in plasma
NPY [106]. Higher plasma NPY levels were also observed in
combat-exposed veterans without PTSD compared with vet-
erans presently reporting PTSD, implying the role of NPY
in resilience and coping [107]. Of note, it is unclear the extent
to which peripheral NPY levels correlate with central func-
tioning. Cerebrospinal fluid (CSF) levels of NPY are also sig-
nificantly lower in combat-related PTSD compared with
healthy, non-combat exposed controls [108,109]. Clearly, the
NPY system is a promising target for novel anxiety therapeu-
tics. Pharmacotherapeutic strategies focusing on increasing
NPY signaling in the CNS may represent a promising avenue
for future research.
6.6.3 The substance P/neurokinin system
The substance P/neurokinin system has been extensively
studied in mood and anxiety disorder research since its discov-
ery in the 1930s. Basic research in neuropeptides sparked fol-
lowing a positive clinical trial for aprepitant (MK-869), a
synthetic neurokinin receptor antagonist, in a placebo-
controlled trial in patients with MDD [110]. Substance P is
an 11-amino-acid peptide, belonging to a group of proteins
called tachykinins, mediating its biological actions through
G-protein coupled tachykinin receptors including neurokinin
1 receptor (NK1). Substance P and NK1 are broadly
distributed in brain regions implicated in stress including
the hypothalamus basolateral amygdala, hippocampus,
nucleus accumbens, and frontal cortex [111,112].
Although preclinical testing has demonstrated robust
antidepressant effects, inconsistent results have been demon-
strated in the anxiolytic profiles of NK1 antagonists in a
8 Expert Opin. Emerging Drugs (2015) 20(3)
number of animal models [113,114]. Significantly elevated sub-
stance P concentrations in CSF are observed in PTSD [115],
providing translational evidence for the role of substance P
and NK1 receptor in stress-related behaviors and anxiety
disorders.
A 12-week, multicenter RCT was conducted to assess the
efficacy and safety of the NK1 antagonist orvepitant
(60 mg/day) compared to placebo in subjects with PTSD.
This Phase IIb trial had to be terminated before completion
owing to the occurrence of isolated events of seizures [101].
A Phase IIa, proof-of-concept randomized, double-blind,
placebo-controlled trial was conducted to evaluate the
NK1 antagonist GR205171 in patients with chronic
PTSD [116]. Although there was significant improvement in
the mean CAPS total score across all patients over time, no
significant difference was found between GR205171 and pla-
cebo. Interestingly, an exploratory analysis showed that
GR205171 treatment was associated with significant
improvement compared to placebo on the CAPS hyperarousal
symptom cluster.
Several trials with inconsistent results have been conducted
to test the efficacy of NK1 receptor antagonist in SAD. In an
initial proof-of-concept study in SAD of AV608, an
NK1 receptor antagonist developed by Avera Pharmaceuti-
cals, results were suggestive of efficacy; however these findings
were not replicated in subsequent RCTs [101]. A Phase IIa
RCT of LY68601, an NK1 receptor antagonist developed
by also failed to demonstrate efficacy in SAD [117].
Given the negative data to date, the potential for neuroki-
nin modulators as novel anti-anxiety drugs remains uncertain.
6.6.4 Cholecystokinin
Cholecystokinin (CCK) is a 115-amino acid pre-hormone
originally described in the gastrointestinal (GI) tract and
subsequently observed to be abundant throughout the
CNS. The two primary CCK receptors -- CCK-A and
CCK-B -- are G-protein coupled receptors and are localized
to both the CNS and the GI system, with CCK-B being
predominant in the brain. CCK tends to potentiate anxiety
in animal models, for example in the context of the elevated
plus maze and the open field test [118]. Building on these
studies, it was observed that infusion of CCK caused anxiety
in healthy adults and panic attacks in patients with panic
disorder [119]. Interestingly, recent work has shown a close
relationship between CCK and the endocannabinoid system
in extinction learning and fear-potentiated startle [120].
These results encouraged significant interest in the CCK
system for treatment development and several non-peptide
selective CCK receptor antagonists have been developed.
Clinical trials of CCK receptor antagonists in GAD and
panic disorder have yielded negative results and future treat-
ment development focused on the CCK system is
uncertain [101].
172

6.6.5 The endocannabinoid system
A growing body of preclinical work demonstrates an impor-
tant role for the endocannabinoid system in anxiety and
fear-related behavior [7]. Endocannabinoid signaling modu-
lates multiple behavioral processes, including sleeping, appe-
tite, pain, and emotional memory [121]. The system consists
of polyunsaturated fatty acid endogenous ligands (ananda-
mide [AEA] and 2-arachidonoylglycerol [2-AG]) and two G
protein-coupled receptors, cannabinoid receptors 1 (CB1)
and 2 (CB2) [122]. The CB1 receptor is widely distributed in
the CNS, including the frontal cortex, amygdala, basal gan-
glia, hippocampus, and periaqueductal gray. CB2 receptors
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15
are likewise widely distributed [123]. A recent positron emis-
sion tomography (PET) study utilizing the CB1-selective
radioligand [11C]OMAR found abnormally elevated binding
of CB1 in individuals with PTSD compared to healthy
volunteers [124].
To date, there is paucity of data examining the effects of
agents that target the endocannabinoid system in anxiety
disorder populations. A recent small open study of oral
delta-9-THC (a primary active ingredient in cannabis)
showed encouraging results in PTSD [125]. A second study
found evidence for a beneficial effect of cannabidiol for public
speaking in SAD [126]. Of note, concerns regarding side effects
For personal use only.
of direct CB1 agonist or antagonist compounds -- including
depression, anxiety and psychotic symptoms -- may serve to
limit the utility of direct CB receptor modulators [127,128]. In
contrast, agents acting to inhibit one of the primary enzymes,
fatty acid amide hydrolase (FAAH), have yielded positive
results in preclinical models of fear and anxiety [129].
A recent study utilized a genetic knock-in mouse model of a
common variant in the human FAAH as well as human neu-
roimaging to show that reduced FAAH signaling is associated
with enhanced PFC-amygdala connectivity and fear extinc-
tion [130]. A clinical trial utilizing an FAAH inhibitor
(PF-04457845) is currently being conducted in the context
of fear conditioning in humans (NCT01665573).
7. Potential development issues
Key development issues already alluded to in this review are:
i) the changing landscape of anxiety disorder definitions;
ii) uncertainty regarding the fundamental pathophysiology
of anxiety disorders; and iii) the less-than-optimal validity of
current models for anxiety disorders. Please see Griebel and
Holmes for a recent discussion of these development issues [7].
One approach to address these issues involves identifying reli-
able intermediate phenotypes for anxiety disorders that may
facilitate translational research between preclinical and clinical
studies. Human in vivo neuroimaging applied to anxiety dis-
order populations has revealed relatively consistent abnormal-
ities within brain systems that detect and regulate fear,
including the amygdala, hippocampus and medial PFC. For
example, patients with PTSD evidence exaggerated neural
Expert Opin. Emerging Drugs (2015) 20(3)
Emerging drugs for the treatment of anxiety
response to threat within the amygdala and a parallel reduc-
tion in responses within the PFC [131]. Similarly, abnormal
fear learning or fear extinction has been demonstrated in
PTSD and may facilitate translational drug discovery as these
behaviors can be studies with high fidelity in animals [132]. It is
hoped that the continued refinement of the clinical nosology
of anxiety disorders in close tandem with an evolving
knowledge base of the mechanisms of fear regulation and
the optimization of animal models of anxiety will converge
on accelerated and more efficient treatment development.
8. Conclusion
Anxiety disorders are common and are associated with signif-
icant levels of subjective suffering, functional impairment and
poor treatment outcome. Currently available first-line treat-
ments for anxiety disorders include SSRI and SNRI medica-
tion, with benzodiazepines best suited for short-term and
adjunctive anxiolytic treatment. TCAs and MAOIs are effec-
tive but tolerability issues limit their use. Other available
treatments with comparatively less data may be indicated in
certain cases and include anticonvulsants and SGAs. Com-
pounds currently in clinical development for anxiety disorders
include new monoaminergic agents and SGAs. Encourag-
ingly, mechanistically novel compounds targeting glutamate,
neuropeptide and endocannabinoid systems are also in devel-
opment. Beyond the compounds covered in the current
review, other potentially promising areas for future research
include neurotrophic signaling systems, the renin-angiotensin
system, the acetylcholine system and even components of the
opioid system [6]. Combining target selective agents with
psychotherapy based on a growing appreciation of the mech-
anisms of fear regulation is another promising avenue. The
clear medical need for new, more effective treatments compels
a continued vigorous drug discovery effort for anxiety
disorders.
9. Expert opinion
Anxiolytic drug discovery may be at a tipping point. Thanks
to an explosion of research in the past 10 years, our under-
standing of fear-related behavior is among the most developed
knowledge area in behavioral neuroscience. On the other
hand, these discoveries have yet to lead to mechanistically
novel, more effective treatments for disorders of fear and anx-
iety in humans. As noted above, important obstacles in the
drug development process for anxiety include continued
gaps in our understanding of the pathophysiology of anxiety
disorders and limitations in current animal models of anxiety.
The shifting diagnostic boundaries of anxiety disorders and an
absence of valid, reliable human biomarkers has further
hindered the drug development process.
A close collaboration between basic and clinical researchers
will be required to move the field closer towards its treatment
discovery goals. Valid endophenotypes for human anxiety
9
173
 J. W. Murrough et al.

disorders must be identified and mapped onto preclinical
models. These endophenotypes have the potential to increase
the fidelity and efficiency of early-phase clinical research by
providing biological targets as surrogate endpoints for novel
compounds. For example, candidate compounds could be
screened quickly for their capacity to modulate human
amygdala responses to threat using functional MRI in an
early-phase clinical trial. The time is ripe to use translational
approaches to move basic discoveries into new, more effective
treatments for our patients.
Declaration of interest
Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Nyu Medical Center on 05/28/15
at Mount Sinai), and Icahn School of Medicine at Mount
Sinai has been named on a use patent on ketamine for the
treatment of depression. The Icahn School of Medicine has
entered into a licensing agreement for the use of ketamine as
therapy for treatment-resistant depression. DS Charney and
Icahn School of Medicine at Mount Sinai could potentially
benefit if ketamine were to gain approval for the treatment
of depression. DS Charney is named on a patent pending
for ketamine as a treatment for PTSD and for neuropeptide
Y as a treatment for mood and anxiety disorders; he has
received funding from the U.S. Department of Defense,
NIH, NIH/NIMH, NARSAD, USAMRAA; he has severed

In the past 3 years, JW Murrough has served on advisory
boards for Janssen Research and Development and Genen-
tech, has provided consultation services for ProPhase, LLC
and Impel Neuropharma and has received research support
from Janssen and Avanir Pharmaceuticals; he is named on a
patent pending for neuropeptide Y as a treatment for mood
and anxiety disorders; he is named on a patent pending for
lithium as a method to maintain the antidepressant response
to ketamine. DS Charney (Dean of Icahn School of Medicine
on the scientific advisory board for the Institute of Medicine
Committee on DHS Workforce Resilience and on the
editorial board of CNS Spectrums. JW Murrough is sup-
ported by NIH grant K23MH094707 and by the Doris
Duke Charitable Foundation. The authors have no other
relevant affiliations or financial involvement with any organi-
zation or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manu-
script apart from those disclosed.

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Affiliation
James W Murrough†1,2,3 MD,
Sahab Yaqubi4 MD, Sehrish Sayed1 MPH &
Dennis S Charney1,2,3,5 MD
†
Author for correspondence
1
Icahn School of Medicine at Mount Sinai,
Department of Psychiatry, Mood and Anxiety
Disorders Program, One Gustave L. Levy Place,
Box 1230, New York, NY 10029, USA
Tel: +1 212 241 7574;
Fax: +1 212 241 3354;
E-mail: james.murrough@mssm.edu
2
Icahn School of Medicine at Mount Sinai,
Fishberg Department of Neuroscience,
New York, NY, USA
3
Friedman Brain Institute, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
4
Icahn School of Medicine at Mount Sinai/
Elmhurst Hospital Center, Department of
Psychiatry, New York, NY, USA
5
Icahn School of Medicine at Mount Sinai,
Department of Pharmacology and Systems
Therapeutics, New York, NY, USA
178
Irma Rahmawati Madrik (201610330311030)

Kemunculan Obat untuk Terapi Ansietas

James W Murrough, Sahab Yaqubi, Sehrish Sayed & Dennis S Charney Icahn School of
Medicine at Mount Sinai, Department of Psychiatry, Mood and Anxiety Disorders Program,
New York, NY, USA

Pendahuluan: Gangguan kecemasan adalah salah satu gangguan kejiwaan yang paling umum
di Amerika Serikat dan di seluruh dunia. Penelitian dasar tentang pengetahuan kritis dalam
mekanisme yang mengatur perilaku takut pada hewan telah dikembangkan untuk
mendapatkan senyawa anxiolytic. Terlepas dari kemajuan ini, tidak ada obat baru yang secara
mekanis mengatasi kecemasan muncul di pasaran dalam lebih dari dua dekade. Area yang
dicakup: Ulasan saat ini akan memberikan ringkasan penting dari pendekatan farmakologis
terkini pada pengobatan kecemasan dan akan memeriksa farmakoterapi untuk perawatan
dalam pengembangan. Kecemasan dan gangguan terkait gangguan panik, gangguan
kecemasan sosial, gangguan kecemasan umum dan gangguan stres pasca-trauma. Sistem
glutamat, neuropeptida, dan endocannabinoid menunjukkan harapan untuk pengembangan
obat baru. Pendapat ahli: Dalam menghadapi pemahaman yang terus berkembang tentang
perilaku yang berhubungan dengan rasa takut, bidang penelitian ini terus memperbarui cara
perawatan secara mekanis. Hambatan kolaborasi erat antara peneliti dasar dan klinis dengan
tujuan menyelaraskan endofenotipe gangguan kecemasan manusia yang valid dengan model
hewan yang ditingkatkan. Diperlukan pendekatan baru untuk memindahkan penemuan dasar
menjadi terapi baru yang lebih efektif untuk pasien.

Kata kunci: kegelisahan, ansiolitik, uji klinis, endocannabinoid, glutamat, neuropeptida,

gangguan panik, gangguan stres pasca trauma

1. Latar Belakang
Gangguan kecemasan adalah salah satu gangguan kejiwaan yang paling umum di Amerika
Serikat [1,2]. Sekitar satu dari empat orang menderita gangguan kecemasan di dalam hidup
mereka. Pasien dengan gangguan kecemasan mengalami ketidaknyamanan fisik dan
emosional yang substansial dan memiliki tingkat penggunaan narkoba dan penyakit medis
yang meningkat. Gangguan kecemasan yang terjadi bersamaan dalam konteks gangguan
kejiwaan lainnya, misalnya gangguan depresi mayor (MDD) atau gangguan bipolar, dikaitkan
dengan gangguan makan yang lebih kronis. pasien-pasien berisiko tinggi untuk bunuh diri
[3,4] . Kombinasi prevalensi tinggi dan kecacatan fungsional yang tinggi berkaitan dengan
gangguan kecemasan menyebabkan masalah ekonomi dan sosial yang sangat tinggi. inti dari
gangguan kecemasan adalah rasa takut dan kecemasan yang berlebihan dan gangguan
perilaku yang terkait. Skema diagnostik untuk gangguan kecemasan di Amerika Serikat
direvisi dengan publikasi Manual Diagnostik dan Statistik Gangguan Mental - Edisi Kelima
(DSM-V) [5]. DSM-V menyatakan bahwa gangguan kecemasan yaitu gangguan kecemasan
parsial, mutisme selektif, fobia spesifik (SP), gangguan kecemasan sosial (SAD), gangguan
panik, agorafobia, gangguan kecemasan umum (GAD), gangguan kecemasan yang
disebabkan oleh obat

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. Ada dua kategori yang tidak sesuai dengan kategori sebelumnya: gangguan kecemasan
spesifik dan gangguan kecemasan yang tidak diketahui. Gangguan kecemasan parsial dan
mutisme selektif diekspresikan terutama pada masa kanak-kanak tidak akan dibahas lebih
lanjut di sini. Dalam DSM-V, agorafobia ditambahkan sebagai diagnosis baru dan gangguan
stres pasca-trauma (PTSD) dan gangguan obsesif kompulsif (OCD) dipindahkan ke tempat
lain dalam skema diagnostik. PTSD adalah gangguan rasa takut dan kecemasan yang
berlebihan dan dipertahankan dengan tepat dalam pertimbangan biologi dan pengobatan
gangguan kecemasan. OCD mungkin berbeda dibandingkan dengan gangguan kecemasan
dan PTSD dalam hal presentasi klinis, biologi dan pengobatan. Ulasan saat ini akan
memberikan ringkasan penting dari pendekatan farmakologis saat ini untuk pengobatan
kecemasan dan akan memeriksa farmakoterapi untuk perawatan kecemasan dalam
pengembangannya. Tinjauan saat ini berfokus pada agen terapeutik yang berada dalam
pengujian manusia untuk gangguan kecemasan pada saat penulisan ini. Untuk ulasan
mendalam tentang perkembangan anxiolytic dari perspektif praklinis, pembaca diarahkan ke
beberapa ulasan terbaru [6,7].

2. Kebutuhan medis

Kemajuan substansial dibuat untuk penelitian neurobiologis yang bertujuan untuk

mengungkap perubahan molekul dan neurocircuit yang mengarah pada kecemasan. Penelitian
dasar telah memberikan wawasan kritis dalam mekanisme yang mengatur perilaku ketakutan
pada hewan. dan sejumlah hewan telah dikembangkan untuk membuat senyawa untuk sifat
anxiolytic. Terlepas dari kemajuan ini, tidak ada agen baru yang secara mekanis untuk
mengatasi kecemasan muncul di pasaran dalam lebih dari dua dekade. Validitas model hewan
saat dan gangguan kecemasan manusia terbatas, sehingga memberikan tantangan besar dalam
penemuan obat. Untuk diskusi menyeluruh tentang model kecemasan hewan dan
kegunaannya, silakan lihat [7]. Ada kebutuhan mendesak akan perawatan mekanis yang baru
dan lebih efektif untuk mengatasi kecemasan. Seperti disinggung di atas, gangguan
kecemasan berhubungan dengan gangguan fungsional substansial [2] dan beban pasien dan
keluarga [8]. Gangguan ini terkait dengan peningkatan pemanfaatan layanan perawatan
kesehatan [9] dan penurunan produktivitas kerja [10]. Perawatan saat ini tidak memenuhi apa
yang dibutuhkan serta menambah beban kesehatan masyarakat. Sebagai contoh, meta-analisis
besar baru-baru ini tidak dapat mendukung kemanjuran benzodiazepin [11] atau azapirones
(misalnya, buspirone) untuk gangguan panik [12]. PTSD, GAD dan SAD juga hanya
sebagian obat responsif terhadap perawatan yang tersedia saat ini, termasuk serotonin
selective reuptake inhibitor (SSRIs) [13,14]. Masalahnya, sebuah laporan dari Institute of
Medicine menyimpulkan bahwa bukti yang tersedia tidak memadai untuk mendukung
kemanjuran SSRI atau farmakoterapi lainnya di PTSD [15]. Jelas, penemuan

perawatan farmakoterapi baru untuk kegelisahan mewakili kebutuhan medis besar yang tidak
terpenuhi.

3. Perawatan yang adaPerawatan

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3.1lini pertama Agen dengan persetujuan FDA AS saat ini untuk pengobatan gangguan
kecemasan dirangkum dalam Tabel 1. Beberapa uji coba terkontrol acak (RCT) mendukung
kemanjuran SSRI dan serotonin norepinefrin reuptake inhibitor (SNRI) sebagai yang
pertama- pengobatan lini untuk GAD, SAD, gangguan panik dan PTSD [13,16-18]. Analisis
12 RCT pada gangguan panik menemukan ukuran efek rata-rata untuk SSRI relatif terhadap
plasebo 0,55 [19]. Dalam kasus GAD, tingkat respons untuk SSRI antara 60 dan 75%
umumnya dilaporkan dalam RCT, dibandingkan dengan tingkat respons antara 40 dan 60%
untuk plasebo [17]. Data menunjukkan bahwa PTSD mungkin kurang menerima
farmakoterapi saat ini dibandingkan dengan gangguan kecemasan lainnya. Ulasan Cochrane
dari farmakoterapi untuk PTSD termasuk 35 RCT dan 4.597 peserta mendukung penggunaan
SSRI sebagai pengobatan lini pertama [13].
3.2 Perawatan lini kedua dan lainnya untuk gangguan kecemasan Antidepresan trisiklik
(TCA) dan inhibitor monoamine oksidase (MAOI) memiliki data efikasi yang wajar dalam
gangguan kecemasan tetapi biasanya dicadangkan untuk pengobatan lini kedua karena
masalah keamanan dan tolerabilitas. Benzodiazepin memainkan peran penting dalam
pengobatan beberapa gangguan kecemasan; namun agen ini juga biasanya dicadangkan untuk
penggunaan lini kedua atau tambahan karena masalah toleransi dan penyalahgunaan. Agen-
agen ini memiliki keuntungan dari onset aksi yang cepat, mengundang penggunaannya pada
awal pengobatan sebelum onset efikasi SSRI / SNRI yang diberikan bersama. Data yang
mendukung kemanjuran jangka panjang benzodiazepin lebih terbatas. Misalnya, Goddard et
al. menunjukkan bahwa pemberian clonazepam dengan sertraline dalam pengobatan
gangguan panik menghasilkan proporsi responden yang secara signifikan lebih besar pada
kelompok sertraline / clonazepam pada akhir satu minggu, tetapi tidak pada akhir studi [20].
Antikonvulsan, termasuk gabapentin dan pregabalin, memiliki data campuran untuk
mendukung kemanjuran pada gangguan kecemasan tertentu. Data untuk antipsikotik generasi
kedua (SGA) pada gangguan kecemasan juga dicampur dan akan ditinjau lebih rinci di bawah
ini.

4. Sasaran penelitian saat ini

Sebagai sebuah kelompok, gangguan kecemasan mewakili kelompok penyakit yang

heterogen yang memiliki ketakutan dan kecemasan berlebihan sebagai fenomenologi inti
mereka. Psikiatri telah berjuang untuk menentukan klasifikasi nosologis yang tepat untuk
gangguan ini dan versi terbaru DSM menghadirkan konfigurasi lain, seperti disebutkan di
atas. Perubahan lanskap diagnostik dan batas-batas yang tidak pasti antara gangguan
kecemasan menciptakantantangan untuk pengembangan obat, menambah rintangan lain yang
disebutkan di atas. Menanggapi tantangan ini, beberapa perusahaan farmasi besar telah secara
substansial mengurangi investasi mereka dalam penelitian SSP atau menghilangkan program
SSP mereka sama sekali. Perkembangan menyangkut ini
memaksa perubahan dalam pendekatan pengembangan obat kecemasan oleh akademisi dan
industri. Baru-baru ini, para penyelidik dan lembaga pemerintah telah menganjurkan
pendekatan dimensional untuk studi dan pengobatan kecemasan [21]. Pendekatan ini
bergantung pada memecah

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gangguan menjadi dimensi fenotipik yang melintasi batas diagnostik tradisional dan
kemudian memetakan fenotip ini ke gangguan diskrit di tingkat neurocircuit dan molekul.
Sebagai contoh, studi analitik faktor menunjukkan bahwa PTSD paling baik diwakili oleh
lima kelompok gejala yang mengalami kembali, penghindaran, mati rasa, gairah dysphoric,
dan gairah cemas [22] dan temuan neuroimaging baru-baru ini telah mengaitkan volume
amigdala khusus dengan dimensi gairah gelisah. [23]. Tujuan penelitian saat ini, oleh karena
itu, termasuk mengembangkan agen farmakologis baru yang dapat menargetkan dimensi
spesifik dari fenotip cemas berdasarkan pada pemahaman yang disempurnakan dari
neurobiologi yang mendasarinya.

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5.pemikiran ilmiah

DasarPengembangan rasional terapi untuk gangguan kecemasan didasarkan pada pemahaman

yang kuat tentang patofisiologi yang mendasari dan pada pengembangan dan penerapan
model hewan yang valid. Seperti disebutkan di atas, saat ini ada batasan penting mengenai
kedua poin mendasar ini. Sistem GABA secara historis menjadi fokus utama dari penemuan
obat ansiolitik. Baru-baru ini, SSRI dan SNRI - yang pertama kali dikembangkan untuk
pengobatan depresi - telah menjadi andalan pengobatan ansiolitik. Namun, efektivitas yang
tidak lengkap dari perawatan saat ini dan membebani neuroscience dari perilaku yang
berhubungan dengan rasa takut, memaksa pencarian untuk mencari pengobatan baru yang
lebih efektif. Pada bagian di bawah ini, kami memberikan tinjauan kritis dari lanskap
perkembangan obat saat ini untuk gangguan kecemasan. Diatur oleh neurokimia, kami mulai
dengan meninjau agen yang bekerja pada sistem serotonin, melatonin, norepinefrin, dan
dopamin. Kami kemudian meninjau kemajuan dalam pengembangan klinis agen, target,
sistem glutamat dan GABA, sistem neuropeptida dan sistem endocannabinoid. Sistem
glutamat, neuropeptida, dan endocannabinoid dapat menunjukkan harapan khusus sebagai
target untuk pengembangan obat baru.

6. Lingkungan yang kompetitif

Lihat Tabel 2 untuk ringkasan perawatan yang sedang diselidiki dan muncul untuk gangguan
kecemasan.
6.1 Serotonin 6.1.1 Vortioxetine Vortioxetine adalah senyawa serotonergik yang
dikembangkan oleh Lundbeck dan disetujui oleh US FDA dan European Medicines Agency
(EMA) untuk pengobatan MDD [24]. Vortioxetine adalah penghambat serotonin transporter
(SERT) dengan efek tambahan sebagai agonis reseptor 5-HT1A (penuh), agonis reseptor 5-
HT1B (parsial), dan antagonis reseptor 5-HT1D, 5-HT3, dan 5-HT7. Vortioxetine
meningkatkan kadar ekstraseluler serotonin, dopamin, noradrenalin, asetilkolin dan histamin
dalam hippocampus ventral dan korteks prefrontal (PFC) dan memodulasi transmisi
neurotransmisi GABA dan glutamat dalam studi praklinis [25].
Sampai saat ini, tiga RCT terpisah vortioxetine telah dilakukan pada pasien dengan GAD dan
telah menghasilkan hasil samar-samar [26-28]. Dalam satu studi, pasien dengan GAD secara
acak sampai 8 minggu vortioxetine 5 mg per hari (n = 150) dibandingkan plasebo (n = 151);
total skor HAM-A lebih rendah pada kelompok vortioxetine (-14,30 vs -10,49, p <0,001)
[26]. Hasil dua RCT lain di GAD, bagaimanapun, adalah negatif [27,28]. Efek samping
paling umum yang dilaporkan pada kelompok vortioxetine adalah mual, sakit kepala, pusing,
dan mulut kering [26-29]. Secara keseluruhan, data uji klinis hingga saat ini menunjukkan
manfaat vortioxetine pada GAD tetapi studi tambahan mungkin diperlukan untuk
mengkonfirmasi temuan ini.
6.1.2 Vilazodone Vilazodone dikembangkan oleh Merck dan disetujui oleh FDA AS untuk
pengobatan MDD pada 2011 [30]. Selain berfungsi sebagai SSRI, vilazodone bertindak
sebagai agonis parsial reseptor 5-HT1A, mirip dengan buspirone. Penelitian praklinis
menunjukkan bahwa aktivasi fungsi reseptor 5-HT1A presinaptik berfungsi untuk menunda

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efek anti-kecemasan dan antidepresan dari SSRI [31]. Melalui blokade serentak SERT dan
aktivasi reseptor 5-HT1A, vilazodone dapat mengatasi keterlambatan ini. Mekanisme kerja
ganda ini berpotensi memperpendek keterlambatan aksi anti-depresi, mengurangi efek
samping yang terkait dengan penghambatan reuptake serotonin pada SSRI, dan mengurangi
gejala kecemasan [31]. Implikasi klinis sebenarnya dari profil farmakodinamik ini,
bagaimanapun, masih belum jelas. Sampai saat ini, tidak ada RTC yang diterbitkan
memeriksa vilazodone pada pasien dengan gangguan kecemasan. Analisis post-hoc dari dua
RCT Fase III yang melibatkan pasien dengan MDD menyarankan vilazodone bisa bermanfaat
dalam pengobatan MDD dengan fitur cemas [32]. Setelah 8 minggu pengobatan, pasien
dalam kelompok aktif menunjukkan peningkatan signifikan dalam gejala kecemasan somatik
dan psikis dibandingkan dengan plasebo. Beberapa data menyarankan disfungsi seksual yang
lebih rendah dengan vilazodone dibandingkan dengan SSRI. Namun, penelitian lebih lanjut
perlu dilakukan untuk mengklarifikasi ini [32,33]. Secara keseluruhan, penelitian lebih lanjut
diperlukan untuk sepenuhnya mengevaluasi potensi vilazodone untuk pasien dengan
gangguan kecemasan.

6.2 Melatonin

6.2.1 Agomelatine Agomelatine adalah agonis reseptor melatonin yang unik secara mekanis
(MT1, MT2) dan antagonis reseptor 5-HT2C [34]. Agen ini disetujui untuk pengobatan MDD
di Eropa tetapi tidak memiliki indikasi di AS. Studi molekuler dan seluler menunjukkan
bahwa efek sinergis agomelatine pada sistem melatonin dan serotonin dapat meningkatkan
neuroplastisitas, termasuk meningkatkan neurogenesis pada hippocampus dewasa [35]. Studi
praklinis juga menunjukkan bahwa agomelatine mengurangi peningkatan pelepasan glutamat
yang disebabkan oleh stres dalam PFC dan mensinkronkan ritme sirkadian dengan
merangsang reseptor melatonergik dan serotonergik dalam nukleus suprachiasmatic (SCN)
dari hipotalamus [34]. Ada beberapa tumpang tindih

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antara efek saraf agomelatin dan antidepresan konvensional dan saat ini tidak jelas sejauh
mana efek molekuler unik agomelatin berkontribusi pada mekanisme kerjanya. Dua RCT
agomelatine telah selesai pada pasien dengan GAD [36,37]. Dalam Fase III, 12 minggu, RCT
3-lengan termasuk escitalopram sebagai pembanding aktif, agomelatine menunjukkan
penurunan yang signifikan dalam skor HAM-A dibandingkan plasebo [37]. Escitalopram dan
agomelatine memiliki khasiat yang serupa. Hasil dari RCT kedua, yang termasuk periode
label terbuka 42 minggu (25 - 50 mg / hari) diikuti oleh periode double-blind 6 bulan,
menunjukkan tingkat kekambuhan yang lebih rendah secara signifikan pada kelompok
agomelatine vs plasebo (19,5 vs 30,7%; p = 0,045) [38]. Sebuah metaanalisis yang
memasukkan enam RCT pada pasien dengan MDD dengan fitur kecemasan memberikan
dukungan untuk kemanjuran agomelatine untuk pengobatan gejala kecemasan [39]. Beberapa
laporan kasus dan uji coba label terbuka telah menunjukkan kemanjuran augmentasi
agomelatin dalam pengobatan OCD [40]. Hasil uji coba Fase II baru-baru ini yang
menyelidiki kemanjuran agomelatine dalam OCD belum dipublikasikan (NCT01108393).

6.3 Norepinefrin dan dopamin Hiperaktif noradrenergik telah ditetapkan sebagai komponen
penting dari respons stres dan pensinyalan noradrenergik yang abnormal telah secara
konsisten terlibat dalam perilaku yang berhubungan dengan kecemasan [41-43]. Peningkatan
aktivitas katekolamin selama stres, yang dapat merusak fungsi PFC, telah dikaitkan dengan
PTSD dan gangguan kecemasan lainnya dalamklinis dan
studipraklinis [44]. Kadar norebinefrin cairan serebrospinal (CSF) telah ditemukan secara
signifikan lebih tinggi pada pasien dengan PTSD dibandingkan dengan sukarelawan sehat
[45]. Penelitian translasi khususnya mendukung penghambatan reseptor a-1 dan / atau
stimulasi reseptor a-2 sebagai strategi farmakologis pada PTSD atau gangguan kecemasan
lainnya [46].

6.3.1 Guanfacine Guanfacine adalah agonis reseptor a-2 noradrenergik yang disetujui dalam
bentuk rilis yang diperpanjang untuk Attention Deficit Hyperactivity Disorder (ADHD) [47].
Aktivitas agonis pada reseptor auto presinaptik a-2 mengurangi pensinyalan noradrenergik
yang menyimpang, yang dihipotesiskan akan menyebabkan pelemahan kecemasan dan gejala
terkait trauma [46]. Sampai saat ini, dua RCT ganda ganda belum memberikan bukti yang
jelas tentang kemanjuran guanfacine untuk memperbaiki gejala PTSD pada orang dewasa
[48,49]. Ada bukti label terbuka yang menunjukkan kemanjuran agen ini dalam pengobatan
gejala PTSD dan mimpi buruk terkait PTSD pada anak dan populasi remaja [50]. Saat ini
tidak ada RCT guanfacine pada gangguan kecemasan lainnya. Meskipun data uji klinis
hingga saat ini tidak mendukung kemanjuran guanfacine di PTSD, penelitian sedang
berlangsung di gangguan kecemasan lainnya, termasuk GAD, SP dan SAD (NCT01470469).

6.3.2 Nepicastat Nepicast adalah penghambat selektif dopamin b-hidroksilase (DBH), saat ini
sedang diselidiki sebagai pengobatan untuk PTSD (NCT00659230, NCT00641511).
Penghambatan b-hidroksilase mengurangi konversi dopamin menjadi norepinefrin, sehingga
mengurangi pensinyalan sinaptik noradrenergik. Menariknya, agen ini telah terbukti efektif

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dalam melemahkan kokain dan perilaku terkait alkohol dalam penelitian pada hewan [51].
Dibutuhkan lebih banyak penelitian untuk menentukan apakah kelas obat yang menarik ini
memiliki potensi kemanjuran pada PTSD atau gangguan kecemasan lainnya.

6.4 Antipsikotik generasi kedua Banyak RCT telah dilakukan untuk mengevaluasi
kemanjuran SGA untuk pengobatan gangguan kecemasan, termasuk risperidone, ziprasidone,
olanzapine, aripiprazole dan quetiapine. Potensi kemanjuran SGA di GAD dan PTSD telah
menerima perhatian terbesar.

6.4.1 Aripiprazole Aripiprazole disetujui oleh FDA untuk skizofrenia, gangguan bipolar,
MDD (tambahan), gangguan autistik dan sindrom Tourette. Aripiprazole memiliki profil
farmakodinamik unik sebagai agonis parsial pada reseptor D2, bersama dengan aktivitas
antagonis pada reseptor 5-HT1A dan 5-HT2A. Dua RCT kecil aripiprazole telah dilakukan
dalam OCD dengan hasil awal yang menjanjikan [52,53]. Selain itu, percobaan label terbuka
aripiprazole telah dilakukan di GAD, gangguan panik [54], MDD dengan fitur cemas [55]
dan PTSD [56] dengan hasil awal yang menggembirakan. Data terkontrol acak tambahan
diperlukan untuk lebih mengkarakterisasi kemanjuran aripirazole pada gangguan kecemasan.
6.4.2 SGA lain Beberapa RCT besar mendukung kemanjuran quetiapine pada GAD [57,58].
Ada bukti beragam untuk kemanjuran risperidone pada GAD [59,60] dan ada relatif lebih
sedikit dukungan untuk olanzapine dan ziprasidone. RCT multi-situs besar risperidone
sebagai augmentasi pada PTSD dalam populasi Veteran Affairs adalah negatif [61]. Karena
SGA dikaitkan dengan efek samping yang signifikan dalam beberapa kasus (misalnya,
sindrom metabolik dan gangguan motorik), dokter harus menimbang risiko dan manfaat SGA
dalam pengobatan kecemasan. Mengingat data yang terbatas mendukung kemanjuran, agen
ini dapat dicadangkan untuk perawatan lini ketiga atau keempat dalam kasus-kasus tertentu.

6.4.3 Brexpiprazole Brexpiprazole adalah agonis parsial reseptor D2 / D3 yang saat ini
sedang diselidiki sebagai pengobatan tambahan di PTSD dan MDD dengan fitur cemas
(NCT02013531, NCT02196506).

6.5 Glutamat dan GABA

6.5.1 Pregabalin Pregabalin, 3-isobutyl-GABA, pada awalnya dikembangkan oleh Pfizer

untuk pengobatan epilepsi dan nyeri neuropatik dan telah disetujui oleh Badan Obat Eropa
untuk
perawatan GAD pada tahun 2006 [62]. Tidak ada persetujuan FDA untuk senyawa ini untuk
kecemasan di AS. Pregabalin adalah analog kimia GABA, meskipun tanpa aktivitas pada
reseptor GABA. Obat ini berikatan dengan subunit a-2-b dari saluran kalsium yang
bergantung pada tegangan presinaptik, menghasilkan penurunan Ca2 + masuknya dan
mengurangi pelepasan glutamat dan norepinefrin ke dalam celah sinaptik [62]. Efek
penghambatan pregabalin pada jalur neuron rangsang, diduga terlalu aktif dalam gangguan
kecemasan, dapat berkontribusi pada efek ansiolitiknya [25]. Pregabalin telah menunjukkan
kemanjuran dalam beberapa RCT di GAD [63,64], meskipun FDA pada akhirnya
menentukan bahwa tidak ada cukup bukti kemanjuran untuk memberikan persetujuan.

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Sebuah meta-analisis pada pasien dengan GAD menunjukkan kemanjuran yang sama antara
pregabalin dan pembanding lainnya yang diteliti: duloxetine, ecitalopram, paroxetine, dan
venlafaxine [65]. Pregabaline juga sama efektifnya dalam GAD dibandingkan dengan
alprazolam dan lorazepam [63,66]. Ada bukti terbatas yang menunjukkan kemanjuran
augmentasi pregabalin dengan SSRI pada OCD atau PTSD [67,68]. Dari catatan, pregabalin
direkomendasikan sebagai pengobatan lini pertama pada GAD komorbiditas dan epilepsi
[69].

6.5.2 Ketamin Ketamin adalah antagonis reseptor NMDA glutamat nonkompetitif yang saat
ini disetujui FDA sebagai agen anestesi [70]. Selama dekade terakhir, beberapa RCT kecil
telah memberikan bukti bahwa ketamin menghasilkan efek antidepresan yang cepat
(misalnya, dalam satu hari), bahkan pada pasien dengan depresi yang resisten terhadap
pengobatan (TRD) [71-74]. Dalam penelitian ketamin terbesar yang dilakukan hingga saat ini
pada pasien dengan TRD (n = 73), ketamin dikaitkan dengan tingkat respons antidepresan
yang lebih tinggi dibandingkan dengan midazolam (digunakan sebagai kondisi kontrol
psikoaktif) pada titik waktu hasil primer 24 jam (64). dan 28%, masing-masing; rasio odds:
2.18) [72]. Baru-baru ini, ketamin telah diperiksa untuk kemanjuran potensial pada PTSD
[75] dan OCD. RCT yang baru-baru ini diterbitkan adalah studi pertama yang meneliti
kemanjuran ketamin dalam PTSD [75]. Dalam penelitian ini, ketamin diberikan sebagai infus
tunggal intravena (IV) dalam studi crossover acak ganda yang dilakukan pada 41 pasien
dengan PTSD kronis dan perubahan gejala pada 24 jam pasca perawatan adalah ukuran hasil
utama. Ketamin dikaitkan dengan penurunan yang signifikan dalam keparahan gejala yang
diukur menggunakan dampak skala kejadian, dibandingkan dengan midazolam (skor
perbedaan rata-rata: 12,7, p = 0,02). Perawatan umumnya ditoleransi dengan baik. Penelitian
di masa depan yang menguji keamanan dan kemanjuran perawatan ketamin yang berulang di
PTSD akan diperlukan untuk mengevaluasi lebih lengkap potensi terapi ini pada PTSD kronis
atau refraktori yang tahan terhadap pengobatan. Dua uji klinis kecil ketamin telah dilakukan
pada pasien dengan OCD, menghasilkan hasil yang beragam [76,77]. Dalam studi pertama,
ketamine yang diberikan IV secara label terbuka tidak dikaitkan dengan perbaikan gejala
pada 10 pasien dengan OCD refraktori pengobatan [76]. Dalam RCT kecil kedua yang
melibatkan 15 pasien dengan OCD, ketamin dikaitkan dengan peningkatan gejala yang
signifikan, dengan 50% dari sampel memenuhi kriteria tanggapan setelah ketamin
dibandingkan dengan 0% setelah plasebo [77]. Jelas, lebih banyak data diperlukan untuk
mengevaluasi potensi kemanjuran ketamin dalam OCD.

6.5.3 Modulator reseptor metabotropik glutamat

Studi praklinis telah menunjukkan peran kunci glutamat dalam regulasi rasa takut dan
kecemasan, selain perilaku depresi [78]. Modulator reseptor metabotropik glutamat (mGluR),
khususnya mGluR1, mGluR2 / 3 dan mGluR5, telah terbukti memodulasi kecemasan dan
ketakutan dalam studi praklinis [7,79]. Sebuah RCT kecil yang menyelidiki efek mGluR2 / 3
agonis LY354740 / LY544344 pada pasien dengan GAD dihentikan karena kekhawatiran
mengenai potensi kejang [80]. Agonis mGluR2 / 3 yang terpisah gagal menunjukkan manfaat
pada gangguan panik dalam konteks RCT [81]. Sebuah penelitian yang sedang berlangsung
sedang dilakukan untuk mengevaluasi keamanan dan kemanjuran agonis reseptor mGluR2 / 3

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lainnya, pomaglumetad methionil, dalam pengobatan PTSD (NCT02234687). Modulator

reseptor metabotropik glutamat lainnya termasuk, antagonis mGluR1 dan mGluR5, telah
menunjukkan hasil positif dalam model kecemasan hewan [78]. Meskipun telah ada beberapa
kemunduran awal, modulator mGluR belum mewakili bidang yang menjanjikan untuk
pengembangan pengobatan masa depan untuk kecemasan.

6.5.4 D-Sikloserin dan penambahan obat dari psikoterapi

Ada minat yang semakin besar dalam merancang kombinasi obat yang rasional dengan
psikoterapi - berdasarkan mekanisme pembelajaran ketakutan dan kepunahan - sebagai
pendekatan baru dalam pengobatan gangguan kecemasan (lihat [ 82] untuk ulasan terbaru).
Di antara strategi yang dipelajari, kombinasi modulator reseptor NMDA d-cycloserine (DCS)
dengan bentuk-bentuk spesifik terapi perilaku kognitif (CBT) telah menerima perhatian
paling besar. DCS adalah agonis parsial di situs glisin pada reseptor NMDA dan pada
awalnya digunakan sebagai agen antimikroba. Infus sistemik DCS meningkatkan kepunahan
rasa takut dalam model hewan [83] dan beberapa uji klinis pada populasi manusia sekarang
mendukung hipotesis bahwa DCS dapat meningkatkan kemanjuran CBT untuk gangguan
kecemasan [84-86]. Dalam bukti awal studi konsep, pasien dengan SP (misalnya, akrofobia)
secara acak menerima terapi paparan perilaku ditambah plasebo atau terapi paparan perilaku
ditambah DCS [85]. Pasien yang diacak dengan terapi ditambah DCS telah mengurangi
gejala secara signifikan pada 1 minggu dan 3 bulan setelah perawatan. Sampai saat ini, uji
coba positif telah dilaporkan dalam PTSD, SP, SAD, gangguan panik dan OCD. Studi negatif
juga telah dilaporkan [82].

6.6 Neuropeptida
6.6.1 Faktor pelepas kortikotropin
Faktor pelepas kortikotropin (CRF) atau hormon (CRH) adalah neuropeptida asam amino 41-
asam yang pertama kali diisolasi pada 1980-an.
Sejumlah besar literatur menunjukkan bahwa kecemasan yang berhubungan dengan stres
dikaitkan dengan peningkatan aktivitas sirkuit SSP secara kronis yang memanfaatkan CRF.
CRF terlibat dalam mediasi respons neuroendokrin, imun, otonom, dan perilaku terhadap
stres [87]. Identifikasi CRF diikuti oleh penemuan tiga paralog CRF (urocortins 1, 2, dan 3)
dan dua reseptor CRF / urocortin CRF1 dan CRF2 [88]. CRF akut dan kronis yang dikelola
secara terpusat menghasilkan respons seperti kecemasan seperti gangguan tidur, kehilangan
nafsu makan dan anhedonia pada banyak model hewan gangguan kecemasan [89]. Antagonis
CRF1 menunjukkan aktivitas anxiolytic dalam beberapa model hewan [90,91]. Studi
praklinis secara khusus melibatkan reseptor CRF1 yang terletak di dalam amygdala sebagai
perantara perilaku yang berhubungan dengan rasa takut dalam konteks stres [92]. Studi klinis
menunjukkan peningkatan konsentrasi CSF CRF di PTSD [93,94]. Mengingat pertemuan
data ini, antagonis reseptor CNSpenetrant CRF1 telah dikembangkan dan telah menjalani
pengujian ekstensif oleh industri farmasi [95]. Sayangnya, hingga saat ini belum ada
antagonis reseptor CRF1 yang berhasil menunjukkan keamanan dan kemanjuran dalam uji
klinis Fase III untuk gangguan kejiwaan yang berkaitan dengan stres. Dalam satu kasus,
multicenter RCT besar pada GAD gagal menunjukkan superioritas dari antagonis reseptor

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CRF-1 selektif pexacerfont, dibandingkan dengan plasebo [96]. Uji klinis yang melibatkan
antagonis reseptor CRF-1 verucerfont dan emicerfont di SAD telah selesai dengan hasil yang
tidak diungkapkan [97]. Sebuah studi multi-situs NIH yang didukung besar yang melibatkan
antagonis CRFR1 GSK561679 (GlaxoSmithKline) di PTSD baru-baru ini selesai dan
hasilnya juga sedang tertunda [98]. Meskipun sejumlah besar data praklinis dan mekanistik
yang melibatkan sistem CRF dalam perilaku yang berhubungan dengan rasa takut dan
gangguan kecemasan, bidang ini masih menunggu hasil positif dari uji klinis.

6.6.2 Neuropeptide Y
Neuropeptide Y (NPY) adalah peptida asam 36-amino, milik keluarga polipeptida pankreas
dan dilokalisasikan dan dilepaskan dengan neuron yang mengandung norepinefrin. Selain
menjadi peptida paling melimpah yang diketahui, sebagian besar mamalia memiliki urutan
NPY yang identik, menjadikan NPY salah satu peptida yang paling evolusioner. NPY
pertama kali diisolasi dan diurutkan pada tahun 1982 dan sejak penemuannya beberapa fungsi
ditemukan, menghubungkan NPY dengan regulasi keseimbangan energi, respon stres [99],
tidur dan asupan makanan. Tingkat ekspresi NPY yang tinggi ditemukan di daerah otak yang
terlibat dalam pengendalian kecemasan seperti amigdala, hippocampus, batang otak, nucleus
accumbens, locus coeruleus, dan hipotalamus, di mana terdapat konsentrasi tertinggi [100].
NPY mengerahkan aksinya dengan mengikat reseptor NPY berpasangan G-protein, yang
terdiri dari Y1-Y5. Reseptor Y1 dan Y2 khususnya telah terbukti memediasi tindakan anti-
kecemasan dan antidepresan NPY [101.102]. Baru-baru ini, para peneliti telah
mengidentifikasi mekanisme terkait NPY yang mungkin mendasari perkembangan
kecemasan awal kehidupan menggunakan model primata non-manusia dari temperamen
cemas [103]. Temuan mereka menunjukkan tingkat reseptor Y1 dan Y5 yang lebih tinggi di
amygdala dikaitkan dengan berkurangnya kecemasan. Manipulasi genetik dari sistem NPY
memberikan bukti tambahan yang melibatkan reseptor Y1 dan Y5 dalam mengurangi
kecemasan dan meningkatkan ketahanan stres. Penelitian praklinis mendukung aksi
anxiolytic yang potensial dari NPY dalam berbagai model hewan, termasuk goncangan yang
ditakuti dengan rasa takut, interaksi sosial, paradigma konflik dan labirin plus yang
ditinggikan [104]. Dalam sebuah studi praklinis baru-baru ini, tikus diinfuskan dengan NPY
intranasal atau plasebo sebelum paparan stres berkepanjangan tunggal (model PTSD) dan
dibandingkan dengan kontrol yang tidak diobati. Temuan mengungkapkan bahwa infus NPY
intranasal melemahkan perkembangan gejala seperti PTSD pada tikus dan bahkan 7 hari
kemudian tikus menunjukkan perilaku depresi yang lebih rendah dan mengurangi kecemasan
[105]. Peran NPY dalam efek perilaku stres juga telah dibuktikan secara klinis dalam
penelitian pada manusia. Respons NPY plasma terhadap yohimbine, antagonis reseptor a-2,
dan plasebo diukur pada sekelompok veteran perang dengan PTSD dibandingkan dengan
subyek kontrol yang sehat. Para penulis menemukan bahwa pasien PTSD memiliki NPY
plasma awal yang lebih rendah dan peningkatan yang distimulasi yohimbine tumpul pada
NPY plasma [106]. Level NPY plasma yang lebih tinggi juga diamati pada veteran yang
terpapar pertempuran tanpa PTSD dibandingkan dengan veteran yang saat ini melaporkan
PTSD, menyiratkan peran NPY dalam ketahanan dan koping [107]. Dari catatan, tidak jelas
sejauh mana level NPY perifer berkorelasi dengan fungsi sentral. Tingkat cairan
serebrospinal (CSF) NPY juga secara signifikan lebih rendah pada PTSD yang terkait dengan

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pertempuran dibandingkan dengan kontrol yang sehat dan non-tempur yang terpapar
[108.109]. Jelas, sistem NPY adalah target yang menjanjikan untuk terapi kecemasan baru.
Strategi farmakoterapi yang berfokus pada peningkatan pensinyalan NPY di SSP dapat
mewakili jalan yang menjanjikan untuk penelitian di masa depan.

6.6.3 Sistem zat P / neurokinin Sistem zat P / neurokinin

telah banyak dipelajari dalam penelitian gangguan suasana hati dan kecemasan sejak
penemuannya pada 1930-an. Penelitian dasar pada neuropeptida dipicu setelah uji klinis
positif untuk aprepitant (MK-869), antagonis reseptor neurokinin sintetik, dalam uji coba
terkontrol plasebo pada pasien dengan MDD [110]. Substansi P adalah 11-amino-asam
peptida, yang termasuk dalam kelompok protein yang disebut tachykinin, memediasi aksi
biologisnya melalui reseptor tachykinin berpasangan G-protein termasuk reseptor neurokinin
1 (NK1). Substansi P dan NK1 didistribusikan secara luas di daerah otak yang terlibat dalam
stres termasuk hipotalamus basolateral amigdala, hippocampus, nucleus accumbens, dan
frontal cortex [111.112]. Meskipun pengujian praklinis telah menunjukkan efek antidepresan
yang kuat, hasil yang tidak konsisten telah ditunjukkan dalam profil ansiolitik antagonis NK1
dalam sejumlah model hewan [113.114]. Konsentrasi P substansi yang meningkat secara
signifikan dalam CSF diamati di PTSD [115], memberikan bukti translasional untuk peran
reseptor zat P dan NK1 dalam perilaku yang berhubungan dengan stres dan gangguan
kecemasan. 12 minggu, multicenter RCT dilakukan untuk menilai kemanjuran dan keamanan
antagonis NK1 orvepitant (60 mg / hari) dibandingkan dengan plasebo pada subjek dengan
PTSD. Uji coba Fase IIb ini harus dihentikan sebelum penyelesaian karena kejadian kejang
yang terisolasi [101].

Fase IIa, uji coba konsep acak, double-blind, terkontrol plasebo dilakukan untuk
mengevaluasi antagonis NK1 GR205171 pada pasien dengan PTSD kronis [116]. Meskipun
ada peningkatan yang signifikan dalam skor total CAPS di semua pasien dari waktu ke
waktu, tidak ada perbedaan signifikan yang ditemukan antara GR205171 dan plasebo.
Menariknya, analisis eksplorasi menunjukkan bahwa pengobatan GR205171 dikaitkan
dengan peningkatan yang signifikan dibandingkan dengan plasebo pada cluster gejala
hiperousous CAPS. Beberapa percobaan dengan hasil yang tidak konsisten telah dilakukan
untuk menguji kemanjuran antagonis reseptor NK1 pada SAD. Dalam studi bukti-konsep
awal di SAD AV608, antagonis reseptor NK1 yang dikembangkan oleh Avera
Pharmaceuticals, hasilnya menunjukkan keampuhan; namun temuan ini tidak direplikasi
dalam RCT berikutnya [101]. Fase IIa RCT pada LY68601, sebuah antagonis reseptor NK1
yang dikembangkan oleh juga gagal menunjukkan kemanjuran pada SAD [117]. Mengingat
data negatif sampai saat ini, potensi modulator neurokinin sebagai obat anti-kecemasan baru
tetap tidak pasti
.
6.6.4 Cholecystokinin
Cholecystokinin (CCK) adalah pra-hormon asam amino 115 yang awalnya dijelaskan dalam
saluran gastrointestinal (GI) dan kemudian diamati berlimpah di seluruh SSP. Dua reseptor
CCK primer - CCK-A dan CCK-B - adalah reseptor berpasangan G-protein dan terlokalisasi
untuk sistem SSP dan GI, dengan CCK-B yang dominan di otak. CCK cenderung
mempotensiasi kecemasan pada model hewan, misalnya dalam konteks labirin plus tinggi dan

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uji lapangan terbuka [118]. Berdasarkan studi ini, diamati bahwa infus CCK menyebabkan
kecemasan pada orang dewasa yang sehat dan serangan panik pada pasien dengan gangguan
panik [119]. Menariknya, penelitian terbaru menunjukkan hubungan yang erat antara CCK
dan sistem endocannabinoid dalam pembelajaran kepunahan dan rasa takut yang berpotensi
meningkat [120]. Hasil ini mendorong minat yang signifikan dalam sistem CCK untuk
pengembangan pengobatan dan beberapa antagonis reseptor CCK selektif non-peptida telah
dikembangkan. Uji klinis antagonis reseptor CCK pada GAD dan gangguan panik telah
menghasilkan hasil negatif dan pengembangan pengobatan di masa depan yang berfokus
pada sistem CCK tidak pasti [101].

6.6.5 Sistem endocannabinoid

Semakin banyak pekerjaan praklinis yang menunjukkan peran penting untuk sistem
endocannabinoid dalam kecemasan dan perilaku yang berhubungan dengan ketakutan [7].
Pensinyalan Endocannabinoid memodulasi berbagai proses perilaku, termasuk tidur, nafsu
makan, rasa sakit, dan memori emosional [121]. Sistem ini terdiri dari ligan endogen asam
lemak tak jenuh ganda (anandamide [AEA] dan 2-arachidonoylglycerol [2-AG]) dan dua
reseptor berpasangan protein G, reseptor cannabinoid 1 (CB1) dan 2 (CB2) [122]. Reseptor
CB1 didistribusikan secara luas di SSP, termasuk korteks frontal, amigdala, ganglia basal,
hippocampus, dan abu-abu periaqueductal. Reseptor CB2 juga didistribusikan secara luas
[123]. Penelitian positron emission tomography (PET) yang memanfaatkan radioligand
selektif-CB1 [11C] OMAR menemukan pengikatan CB1 yang meningkat secara abnormal
pada individu dengan PTSD dibandingkan dengan sukarelawan sehat [124]. Sampai saat ini,
ada kekurangan data yang meneliti efek agen yang menargetkan sistem endocannabinoid
pada populasi gangguan kecemasan. Sebuah penelitian terbuka kecil terbaru dari delta-9-
THC oral (bahan aktif utama dalam ganja) menunjukkan hasil yang menggembirakan dalam
PTSD [125]. Sebuah studi kedua menemukan bukti untuk efek menguntungkan dari
cannabidiol untuk berbicara di depan umum dalam SAD [126]. Dari catatan, kekhawatiran
tentang efek samping dari agonis CB1 langsung atau senyawa antagonis - termasuk depresi,
kecemasan dan gejala psikotik - dapat berfungsi membatasi kegunaan modulator reseptor CB
langsung [127.128]. Sebaliknya, agen yang bertindak untuk menghambat salah satu enzim
utama, asam lemak amida hidrolase (FAAH), telah menghasilkan hasil positif dalam model
praklinis ketakutan dan kecemasan [129]. Sebuah studi baru-baru ini menggunakan model
tikus knock-in genetik dari varian umum pada FAAH manusia serta neuroimaging manusia
untuk menunjukkan bahwa berkurangnya pensinyalan FAAH dikaitkan dengan peningkatan
konektivitas PFC-amigdala dan kepunahan rasa takut [130]. Sebuah uji klinis menggunakan
FAAH inhibitor (PF-04457845) saat ini sedang dilakukan dalam konteks pengkondisian rasa
takut pada manusia (NCT01665573).

7. Masalah-masalah perkembangan potensial Isu-isu perkembangan

utama yang telah disinggung dalam ulasan ini adalah: i) lanskap perubahan definisi gangguan
kecemasan; ii) ketidakpastian mengenai patofisiologi dasar gangguan kecemasan; dan iii)
validitas yang kurang optimal dari model saat ini untuk gangguan kecemasan. Silakan lihat
Griebel dan Holmes untuk diskusi terbaru tentang masalah-masalah perkembangan ini [7].
Salah satu pendekatan untuk mengatasi masalah ini melibatkan mengidentifikasi fenotipe
menengah yang dapat diandalkan untuk gangguan kecemasan yang dapat memfasilitasi
penelitian translasi antara studi praklinis dan klinis. Neuroimaging pada manusia yang
diterapkan pada populasi gangguan kecemasan telah mengungkapkan kelainan yang relatif
konsisten dalam sistem otak yang mendeteksi dan mengatur rasa takut, termasuk amigdala,
hippocampus, dan medial PFC. Sebagai contoh, pasien dengan bukti PTSD membesar-
besarkansaraf

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responsterhadap ancaman dalam amigdala dan pengurangan paralel dalam respons dalam
PFC [131]. Demikian pula, belajar rasa takut yang abnormal atau kepunahan rasa takut telah
ditunjukkan dalam PTSD dan dapat memfasilitasi penemuan obat translasi karena perilaku ini
dapat menjadi studi dengan kesetiaan yang tinggi pada hewan [132]. Diharapkan bahwa
penyempurnaan berkelanjutan dari nosologi klinis gangguan kecemasan bersama-sama
dengan basis pengetahuan yang berkembang dari mekanisme regulasi ketakutan dan
optimalisasi model hewan dari kecemasan akan menyatu pada percepatan dan pengembangan
pengobatan yang lebih efisien.

8. Kesimpulan
Gangguan kecemasan sering terjadi dan berhubungan dengan tingkat penderitaan subjektif
yang signifikan, gangguan fungsi dan hasil perawatan yang buruk. Saat ini pengobatan lini
pertama yang tersedia untuk gangguan kecemasan termasuk pengobatan SSRI dan SNRI,
dengan benzodiazepin paling cocok untuk pengobatan ansiolitik jangka pendek dan
tambahan. TCA dan MAOI efektif tetapi masalah tolerabilitas membatasi penggunaannya.
Perawatan lain yang tersedia dengan data yang relatif lebih sedikit dapat diindikasikan dalam
kasus-kasus tertentu dan termasuk antikonvulsan dan SGA. Senyawa saat ini dalam
pengembangan klinis untuk gangguan kecemasan termasuk agen monoaminergik baru dan
SGA. Menggembirakan, senyawa novel mekanis yang menargetkan sistem glutamat,
neuropeptida, dan endocannabinoid juga sedang dikembangkan. Di luar senyawa yang
tercakup dalam ulasan saat ini, daerah lain yang berpotensi menjanjikan untuk penelitian di
masa depan termasuk sistem pensinyalan neurotropik, sistem renin-angiotensin, sistem
asetilkolin dan bahkan komponen sistem opioid [6]. Menggabungkan agen selektif target
dengan psikoterapi berdasarkan apresiasi yang berkembang dari mekanisme regulasi rasa
takut adalah jalan lain yang menjanjikan. Kebutuhan medis yang jelas akan perawatan baru
yang lebih efektif memaksa upaya penemuan obat yang kuat untuk gangguan kecemasan.

9. Pendapat ahli
Penemuan obat ansiolitik mungkin berada pada titik kritis. Berkat ledakan penelitian dalam
10 tahun terakhir, pemahaman kami tentang perilaku yang berhubungan dengan rasa takut
adalah salah satu bidang pengetahuan yang paling berkembang dalam ilmu saraf perilaku. Di
sisi lain, penemuan-penemuan ini belum mengarah pada perawatan mekanis yang baru dan
lebih efektif untuk gangguan rasa takut dan kecemasan pada manusia. Seperti disebutkan di
atas, hambatan penting dalam proses pengembangan obat untuk kecemasan termasuk
kesenjangan yang berlanjut dalam pemahaman kita tentang patofisiologi gangguan
kecemasan dan keterbatasan dalam model kecemasan hewan saat ini. Batas-batas diagnostik
yang berubah dari gangguan kecemasan dan tidak adanya biomarker manusia yang valid dan
andal telah semakin menghambat proses pengembangan obat. Kolaborasi yang erat antara
peneliti dasar dan klinis akan diperlukan untuk memindahkan bidang ini lebih dekat ke tujuan
penemuan pengobatannya. Endofenotip yang valid untukkecemasan manusia gangguanharus
diidentifikasi dan dipetakan ke model praklinis. Endofenotip ini memiliki potensi untuk
meningkatkan kesetiaan dan efisiensi penelitian klinis fase awal dengan menyediakan target
biologis sebagai titik akhir pengganti untuk senyawa baru. Sebagai contoh, kandidat senyawa
dapat disaring dengan cepat untuk kapasitas mereka untuk memodulasi respon amigdala
manusia untuk ancaman menggunakan MRI fungsional dalam uji klinis fase awal. Waktunya
sudah matang untuk menggunakan pendekatan translasi untuk memindahkan penemuan dasar
menjadi perawatan baru yang lebih efektif untuk pasien Deklarasi kepentingan Dalam 3 tahun
terakhir, JW Murrough telah melayani di dewan penasihat untuk Penelitian dan
Pengembangan Janssen dan Genentech, telah menyediakan layanan konsultasi untuk
ProPhase, LLC dan Impel Neuropharma dan telah menerima dukungan penelitian dari

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Janssen dan Avanir Pharmaceuticals; ia dinamai berdasarkan paten yang tertunda untuk
neuropeptide Y sebagai pengobatan untuk gangguan mood dan kecemasan; ia disebutkan
pada paten yang tertunda untuk lithium sebagai metode untuk mempertahankan respon
antidepresan terhadap ketamin. DS Charney (Dekan Fakultas Kedokteran Icahn
di Gunung Sinai), dan Fakultas Kedokteran Icahn di Gunung Sinai telah dinamai berdasarkan
paten penggunaan ketamin untuk pengobatan depresi. Fakultas Kedokteran Icahn telah
menandatangani perjanjian lisensi untuk penggunaan ketamin sebagai terapi untuk depresi
yang kebal terhadap pengobatan. DS Charney dan Fakultas Kedokteran Icahn di Gunung
Sinai berpotensi mendapat manfaat jika ketamine mendapat persetujuan untuk perawatan
depresi. DS Charney dinamai berdasarkan paten yang tertunda untuk ketamin sebagai
pengobatan untuk PTSD dan untuk neuropeptida Y sebagai perawatan untuk gangguan mood
dan kecemasan; dia telah menerima dana dari Departemen Pertahanan AS, NIH, NIH /
NIMH, NARSAD, USAMRAA; dia telah memutuskan di dewan penasihat ilmiah untuk
Institute of Medicine Committee on DHS Workforce Resilience dan di dewan editorial CNS
Spectrums. JW Murrough didukung oleh hibah NIH K23MH094707 dan oleh Yayasan Amal
Doris Duke. Para penulis tidak memiliki afiliasi atau keterlibatan keuangan lain yang relevan
dengan organisasi atau entitas apa pun yang memiliki kepentingan finansial atau masalah
keuangan dengan materi atau materi yang dibahas dalam naskah.

193
 Medical Group

Archives of Depression and Anxiety

DOI http://doi.org/10.17352/2455-5460.000029 ISSN: 2455-5460 CC By

Michel Bourin*
Review Article
Neurobiology of anxiety and mood disorders,
University of Nantes, 98, rue Joseph Blanchart,
44100 Nantes, France Clinical pharmacology of anxiolytics
Received: 11 January, 2018
Accepted: 10 February, 2018
Published: 12 February, 2018
Abstract
*Corresponding author: Michel Bourin, Neurobiology
of anxiety and mood disorders, University of Nantes, It is increasingly difficult to define what an anxiolytic is, since anxiety is multiple although many
98, rue Joseph Blanchart, 44100 Nantes, France, symptoms are common. On the other hand the most used drugs in different forms of anxiety were first
Email: used as antidepressants. This article tries to put together the different effective anxiolytics used and
describe their pharmacology.
Keywords: anxiolytics, antidepressants,
benzodiazepines,

https://www.peertechz.com -social anxiety disorder (SAD)

- Panic disorder (PD)

Introduction
Anxiety is one of the most common reasons for consultation
in both general practice and psychiatry. Epidemiological studies
have shown that generalized anxiety affects about 5 percent of
populations regardless of latitude. While the various types of
disabling anxiety disorders affected more than 10 percent of
the general population. The problem posed to the practitioner
is to know when anxiety becomes a pathological phenomenon.
Indeed, anxiety is one of the components of mental activity
and can be considered as part of the defense of species. It is
when she becomes “suffering” or disability that she deserves
to be treated. The different presentations of anxiety can be
summarized by:
- Anxiety attacks resulting in a set of neuro-vegetative
disorders. Panic attacks, although close to
symptomatology, differ only in the sensation of
imminent death and the psychopathological terrain on
which they originate; this type of anxiety is referred to
as a panic disorder.
- Subacute or chronic disorders that may affect a vital
function as sleep, food intake, sexuality, physic activity
(asthenia or hypomanic state).
The prescription of an anxiolytic should only be considered
when the disorder has been clarified by appreciating: level of
free anxiety, effectiveness of the defenses, character of the
disorder more or less invalidating for the subject [1].
These clinical signs belong to the different types of anxiety
of DSM 5:
-generalized anxiety disorder (GAD)
-post-traumatic stress disorder (PTSD)
The prescription of a drug in this first case being limited
to the anxiety episode; in the case of chronic anxiety,
supportive therapies, social assistance, and even elucidation
psychotherapy may be advised.
However, the demand of the patient can be so important
that the doctor is resolved to use anxiolytics that will often
have the disadvantage of being prescribed for life.
Benzodiazepines
Pharmacological properties: These derivatives share
common properties: anticonvulsant, sedative, myorelaxant
and anxiolytic.
this
Benzodiazepine receptors: In 1977, benzodiazepine-
specific acceptor sites belonging to a macromolecular complex
including GABA receptors surrounding a chlorine ionophore
and other acceptor sites were identified. Benzodiazepines are
allosteric modulators of the GABA A receptor. In addition to
these “central” receptors, there are peripheral receptors for
which certain benzodiazepines have a high affinity and which
are present in the liver, kidney and other peripheral tissues as
well although in the brain. Benzodiazepines cause a “down-
regulation” of GABA A receptors, which leads to a lower efficacy
after two months of continuous use. At the central level,
benzodiazepines mainly bind to the nanomolar BZ2 site while
imidazopyridines (zolpidem, see above) bind more affinity to
the BZ1 site [2].
Pharmacokinetics: Benzodiazepines are a group of drugs
that are well-individualized in their chemical structure and
possess homogeneous pharmacological properties. They are

021

Citation: Bourin M (2018) Clinical pharmacology of anxiolytics. Arch Depress Anxiety 4(1): 021-0025. DOI: http://doi.org/10.17352/2455-5460.000029

194
distinguished by their pharmacokinetics and their metabolism
to a large extent; condition their use [3]. These are weak acids of
variable constant dissociation with a high lipophilicity, which
allows rapid passage through the membranes (blood-brain
and placental barriers, and passage in breast milk). Almost all
benzodiazepines are insoluble in water with the exception of
chlordiazepoxide, dipotassium clorazepate and midazolam; it
is therefore necessary to use organic solutions for parenterally
administrable forms (diazepam, flunitrazepam, clonazepam).
Resorption: The resorption rate and the peak concentration
peak height (Cmax) vary for a given molecule depending
on the dosage form used and the route of administration. It
is the rate of resorption that conditions the use of different
benzodiazepines as hypnotics (fast speed) or as anxiolytics.
Oral route: It is used for all benzodiazepines, usually
in the form of tablets or capsules. The resorption is almost
always complete because of their good liposolubility. Peak
concentrations are reached between 30 minutes and 4 hours
.The rate of resorption also depends on the dosage form; it
generally grows in the following order: tablets, capsules, drops.
The rate of resorption is slower when the drug is absorbed
in the middle of the meal or when the subject is lying down.
Antacids reduce the speed but also the resorbed amount.
Intramuscular route: Resorption is usually slower and
more unpredictable than oral. Indeed, the bioavailability is
influenced by the nature of the organic solvent required for the
dissolution of the active product.
Rectal way: It is not used for anxiolytic purposes, but for
pre-anesthesia or (suppression) for convulsions in children
[4].
Intravenous way: It gives the highest and most favorable
concentration peaks for rapid and massive passage of the
product into the CNS. Intravenous injections should be done
slowly.
Plasma protein binding: The percentage of protein binding
is still very high for all benzodiazepines and is only slightly
modified when drug concentrations increase or when protein
concentrations decrease. Thus, there is no fear of major drug
interference by a mechanism of interaction at the level of
protein binding.
Volume of distribution: It depends, as far as benzodiazepines
are concerned, on their liposolubility. Depending on the subject,
it varies according to the water / fat ratio that constitutes them.
In the elderly, the volume of distribution of benzodiazepines is
most often increased, thus contributing to the prolongation of
the half-life.
Metabolism: It is carried out in the gastrointestinal lumen
for certain molecules, (eg chlordiazepoxide). Certain derivatives
such as clorazepate, prazepam are prodrugs, that is, they are
metabolized before reaching the bloodstream. In the liver,
benzodiazepines undergo demethylation or hydroxylation and
/ or conjugation.
Elimination: Benzodiazepines are essentially eliminated
in the urine in metabolic form: hydroxylated conjugated
Citation: Bourin M (2018) Clinical pharmacology of anxiolytics. Arch Depress Anxiety 4(1): 021-0025. DOI: http://doi.org/10.17352/2455-5460.000029
metabolites. The elimination half-life is related to volume
of distribution and metabolic and renal clearance. The half-
life only very poorly reflects the duration of action since it
also depends on the dose. However, in the case of repeated
administrations, the half-life makes it possible to predict
the sequences of administration and especially the obtaining
of therapeutic plateau. Indeed, the time of appearance of the
plate is carried out after 5 half-lives. Benzodiazepines, used as
anxiolytics, must be active during the nycthemeron and long
half-lives appear to be better adapted [5].
Indications: Benzodiazepines are indicated in the following
situations [6,7]:
• Symptomatic treatment of severe and / or disabling
anxiety disorders no longer than 2 months [8].
• Prevention and treatment of delirium tremens and
other manifestations of alcohol withdrawal [9].
Side effects: Benzodiazepines are low-toxicity drugs [9].
Indeed, the doses likely to cause poisoning are much higher
than the therapeutic doses. However, these drugs have ad-
verse effects at therapeutic doses
Sedative effect: This is not always an undesirable effect, since
it is sometimes sought by the prescriber, especially in case of
anxious agitation. In most cases, this effect is troublesome and
occurs at dosages close to anxiolytic dosages. The goal of the
therapist is to prescribe the smallest non-sedative anxiolytic
dose. For some benzodiazepines, the therapeutic index (ratio
of doses inducing a sedative effect / therapeutic dose) is low.
Amnesic effect: Amnestic effects are reported after IV
or IM injections or after oral intake. Amnesia occurs in
all patients when high doses are used, the elderly being
particularly sensitive. Fast-acting, high-affinity molecules on
benzodiazepine receptors cause the most dramatic amnesia.
Cognitive disorders seem to be the major side effects of
BZD [3,6-8]. Cognitive disturbances are characterized by
anterograde amnesia, decreased recall of short-term events,
and increased memory loss. There may be confusion with the
diagnosis of a Mild Cognitive Impairment (MCI) [10].
Disinhibitory effect: In animals and humans, benzodiazepines
allow a facilitation of action that resembles that which can
be observed with ethanol. This effect is beneficial when the
anxiety no longer allows the subject to act, but it facilitates the
passage to the act in some impulsive subjects [11]: it is called
“paradoxical” effect. At high doses, this effect disappears,
replaced by the sedative effect. The disinhibiting effect can be
the cause of sometimes successful suicide attempts [12].
Dependence phenomenon: After prolonged treatments,
it is possible to observe a phenomenon of dependence that
makes weaning difficult. During weaning, clinical signs may
appear: physical fatigue, sleep disorders, headache, dizziness,
tremors, sweating, constipation, etc. It is therefore advisable
not to prescribe an anxiolytic for more than 12 weeks. It is also
recommended to gradually reduce the dosage over several days
or weeks, to avoid this type of accident [13].
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 Drug Interference: They are not important. The action
seems potentiated and / or prolonged in association with: local
or general anesthetics, opioid analgesics, antidepressants,
neuroleptics, lithium, and isoniazid as well as with ethanol.
Their action seems reduced by: carbamazepine, phenytoin,
rifampicin which are enzyme inducers. It should be recognized
that these interferences often have little clinical consequences
except for the association with ethanol which leads to a
potentiation of the sedative effect of the two substances.
Conclusion
The recommendations for the correct use of BZDs are as
follows: as soon as a treatment is started, the patient must
be told how long the treatment will last and how to stop it
gradually because of the risks described above. Before any
request for renewal, one must question the implementation of a
judgment. In any patient treated daily for more than 30 days, it
is necessary to propose a strategy of stopping the consumption
if the indication is no longer valid. When initiating a judgment,
the patient’s expectations, his degree of “attachment” to the
BZDs must be assessed to arrive at a shared decision and to
evaluate the prognostic factors, to distinguish situations
requiring a particular strategy [14].
Pregabalin
It is a [(S) -3- (aminomethyl) -5-methylhexanoic acid]
analog of gamma-aminobutyric acid. Pregabalin binds to an
auxiliary subunit (alpha2-delta protein) of voltage-gated
calcium channels in the central [15].
Absorption: Pregabalin is rapidly absorbed when
administered on an empty stomach. The oral bioavailability of
pregabalin is estimated to be ≥ 90% and is dose independent.
After repeated administration of the product, the equilibrium
state is reached within 24 to 48 hours. The rate of pregabalin
absorption decreases when administered with food during the
meal, but does not result in a clinically significant effect [16].
Distribution: Pregabalin crosses the blood-brain barrier
and is present in milk. In humans, the apparent volume
of distribution of pregabalin after oral administration is
approximately 0.56 l / kg. Pregabalin does not bind to plasma
proteins.
Biotransformation: Pregabalin is very weakly metabolized
in humans (less than 1%).
Elimination: Pregabalin is eliminated from the systemic
circulation mainly through the kidneys in unchanged form.
The elimination half-life of pregabalin is approximately 6.3
hours. The clearance of pregabalin tends to decrease with age
and a reduction in pregabalin dose may be required in patients
with impaired renal function.
Clinical efficiency: In addition to epilepsy and neuropathic
pain, pregabalin has been shown to be effective in generalized
anxiety. The dosage ranges from 150 to 600 mg daily, in
two or three doses. The need for further treatment needs to
be reassessed regularly. Treatment with pregabalin may be
initiated at a dose of 150 mg daily. Depending on the patient’s
Citation: Bourin M (2018) Clinical pharmacology of anxiolytics. Arch Depress Anxiety 4(1): 021-0025. DOI: http://doi.org/10.17352/2455-5460.000029
response and tolerance, the dose may be increased to 300
mg daily after 1 week. After an additional one week, the dose
may be increased to 450 mg daily. The maximum dose of 600
mg daily can be reached after an additional week. Efficacy of
pregabalin in the treatment of generalized anxiety disorders
has been demonstrated in 8 clinical trials compared to placebo
and reference drugs (benzodiazepines and IRS). A decrease in
scores on the Hamilton Anxiety Rating Scale was noted with
pregabalin within a week and was effective on both somatic
and psychic symptoms. In a controlled clinical trial, pregabalin
has been shown to be effective in patients over 65 years of age.
Another trial demonstrated lower relapse rates compared to
placebo when pregabalin was used for up to six months [17].
The most important side effects were drowsiness, dizziness,
headache and dry mouth.
Buspirone
It is a derivative of the azaspirodecanediones series that
cannot be chemically related to any currently used drug.
Action mechanism: Buspirone does not act on GABA
receptors but binds to 5-HT1A receptors, and antagonizes
dopamine receptors preferentially presynaptic sites [18].
Compared with benzodiazepines, buspirone has a low inhibitory
effect on motor activity and is neither anticonvulsant nor
muscle relaxant. It does not induce catalepsy.
Pharmacokinetics: Buspirone is almost completely
absorbed orally and has a significant first-pass effect. Plasma
peak is reached in less than one hour for a 10 mg dose. It is
95% bound to plasma proteins. The metabolism of buspirone is
characterized by hydroxylation and oxidative degradation that
lead to the formation of metabolites with little or no activity.
The elimination of buspirone is made by the urinary and
biliary route. The apparent elimination half-life is on average
2 to 4 hours. Repeated administrations demonstrate a linear
relationship of plasma concentrations with the administered
dose [19].
Clinical efficiency: Studies have shown the anxiolytic ef-
fect of buspirone at 1 and 4 weeks versus placebo [20]. It would
be less effective in people who have already been treated with
benzodiazepines. This product has a longer action time than
benzodiazepines.
Side effects: At therapeutic dose sedation seems less im-
portant than for some benzodiazepines, but is not negligible.
Nausea, dizziness, headache and nervousness were observed.
Withdrawal syndromes have been described during discontin-
uation of buspirone therapy, but no genuine dependence on the
product in long-term studies [21]. Some cases of akathisia have
been reported. Because of its binding to plasma proteins, cau-
tion should be exercised although no major interactions have
been observed with drugs such as digoxin and cimetidine.
Hydroxyzine: Hydroxyzine, marketed in two galenic forms
(tablet, injectable) is prescribed in the case of minor manifes-
tations of anxiety [22]. Used for premedication in the case of
general anesthesia or painful examinations, it is also indicated
in the symptomatic treatment of various allergic manifesta-
tions (spasmodic rhinitis, conjunctivitis, and urticaria).
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 Action mechanism: Hydroxyzine is a piperazine derivative
unrelated to phenothiazine’s which blocks the histaminergic
receptors. Hydroxyzine has no cortical depressant effect,
but inhibits the activity of certain subcortical regions. This
allows a sedative action on emotional tension and anxiety, and
promotes the control of emotions and certain neurovegetative
reactions [23].
Pharmacokinetics: After rapid absorption, hydroxyzine is
fully metabolized. The maximum plasma level is obtained in 2
h to 2 h 30 and the action time after taking oral is 15 to 30 min.
The duration of action, whatever the dosage form, is from 6 to
8 hours.
Side effects: They are related to the anticholinergic potential
of the molecule: dry mouth, constipation, disturbances of
accommodation and confusion especially in the elderly. A
recent warning has been issued regarding the risk of QT
prolongation [24].
Etifoxine: Etifoxine is indicated in the psychosomatic
manifestations of anxiety such as neurovegetative dystonia,
especially with cardiovascular expression. This product is the
subject of controlled studies in anxiety adjustment disorder
[25].
Action mechanism: Etifoxin hydrochloride belongs to the
chemical class of benzoxazines. It works together on the GABA
system and serotoninergic 5-HT2a receptors [26]. Studies in
animals and humans have not established a rebound effect or
potential for drug dependence as well as memory disorders.
Pharmacokinetics: Etifoxine hydrochloride is well absorbed
orally. The plasma concentration decreases slowly in three
phases and is eliminated mainly by the urinary route. Etifoxine
hydrochloride passes into the placenta.
Side effects: Most often there is a slight drowsiness at the
beginning of treatment.
Antidepressants as anxiolytic drugs
The concept of antidepressant is evolving gradually since
these molecules are used successfully to treat other mental
pathologies than depression. Moreover these are not the best
drugs of bipolar depression [27]. Clomipramine was the first
to prove an activity in the treatment of obsessive compulsive
disorder (OCD) while other imipramine’s and derivatives
are not effective. In fact, its desmethyl-clomipramine
metabolite is a potent inhibitor of serotonin reuptake but
also norepinephrine. The combined results of clomipramine
and desmethylclomipramine on the inhibition of serotonin
reuptake are much greater than those of other tricyclics. Other
selective serotonin reuptake inhibitors, such as fluoxetine,
fluvoxamine, sertraline and paroxetine, have also been shown
to be effective in the treatment of OCD. Their effectiveness
in treating this condition is clearly not related to their
antidepressant properties as these drugs reduce obsessive-
compulsive symptoms in patients who are not depressed.
As early as the 1960s, several studies have demonstrated
Citation: Bourin M (2018) Clinical pharmacology of anxiolytics. Arch Depress Anxiety 4(1): 021-0025. DOI: http://doi.org/10.17352/2455-5460.000029
the efficacy of MAOIs in anxio-phobic states, but the difficulty
of using these derivatives has led them to use them only in
severe cases or even to abandon them. These results have been
confirmed more recently and new studies have been developed
thanks to the use of potentially less toxic derivatives such as
the MAO-specific inhibitors A. Liebowitz, in 1992 [27], took
stock of the various controlled trials or not, versus placebo and
concludes that these molecules have a particularly interesting
efficacy in the treatment of social phobias.
It was Klein who first observed that imipramine was able to
prevent panic attacks; later Klein [28] showed that imipramine
was effective in the treatment of phobias with panic attacks
but not effective in pure phobias. These observations led
to the treatment of subjects with panic attacks with low
doses of imipramine for preventive purposes, the high doses
exaggerating the phenomenon. The dose is increased in steps
until, after three months; doses of imipramine are similar to
those usually used in depression.
Finally, in a study Rickels et al. [29] showed that imipramine
and trazodone were effective in the treatment of generalized
anxiety. Imipramine results in better results than trazodone
and diazepam compared to placebo after 6 and 8 weeks. This
work confirms earlier work that had been conducted in patients
with anxious-depressive pathology. Now the various SSRIs
have received their marketing authorization in generalized
anxiety and other anxiety disorders.
The fact that antidepressants are active in the treatment
of anxiety disorders led us to seek the explanation of their
mechanisms of action in these pathologies. It turns out that
the 5-HT2A receptors can participate in this activity [30-32].
It seems more and more obvious that this action would be
exercised at the amygdala, a cerebral structure that seems to
be a “filter” on the perception of emotions and which is rich in
5-HT2A receptors (Table 1).
Most of SSRIs and SNRIs can be used for treating all kind of
anxiety disorders such as-generalized anxiety disorder (GAD),
social anxiety disorder (SAD), Panic disorder (PD) and post-
traumatic stress disorder (PTSD).
Conclusion
The choice of a drug to treat an anxiety disorder depends on
the type of anxiety, the assessment of the degree of discomfort
and disability caused the desirability of treatment “acute” or
more prolonged, of the subject’s request and the available care
options (14).
Anxiolytic drugs extend well beyond the initial setting
of benzodiazepines, with a marked tendency towards
prescribing antidepressants whose spectrum of use has
expanded considerably. In addition, benzodiazepines are
expected to be infrequently prescribed in the elderly, and many
benzodiazepine-treated patients should be weaned. Other
strategies and therapies other than benzodiazepines should be
used to treat anxiety and sleep disorders in elderly patients.
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Table 1: SSRIs used as anxiolytics.
I INN Half-life Posology per day
Citalopram 33 H 20-40 mg
Escitalopram 30H 10-15mg
Fluoxétine 1-4 jours 20mg -60mg
Fluvoxamine 16 H 100mg -450mg
Paroxétine 24 H 20mg- 60mg
Sertraline 24 H 50mg -200mg
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FARMAKOLOGI KLINIS OBAT ANTIANXIOLYTIK

Bourin M (2018) Clinical pharmacology of anxiolytics. Arch Depress Anxiety
4(1): 021-0025. DOI: http://doi.org/10.17352/2455-5460.
Kecemasan adalah salah satu alasan paling umum untuk konsultasi baik dalam
praktek umum dan psikiatri. Studi epidemiologis menunjukkan bahwa kecemasan umum
mempengaruhi sekitar 5 persen dari populasi. Sedangkan berbagai jenis gangguan kecemasan
mampu mempengaruhi lebih dari 10 persen dari populasi umum. Masalah diajukan kepada
praktisi adalah untuk mengetahui kapan kecemasan menjadi fenomena patologis.
Definisi secara rigkas mengenai kecemasan, sebagai berikut :
- Tipe kecemasan berupa gangguan panic merupakan serangan kecemasan yang
mengakibatkan serangkaian gangguan neuro-vegetatif.
- Gangguan subakut atau kronis yang dapat mempengaruhi fungsi vital seperti tidur,
asupan makanan, seksualitas, aktivitas fisik (asthenia atau keadaan hypomanic).

Tanda-tanda klinis ini milik berbagai jenis kecemasan dari (menurut , DSM 5), adalah
sebagai berikut :
- Gangguan Kecemasan Umum (GKU)
- Gangguan Kecemasan Sosial (GKS)
- Gangguan panik (PD)
- Post-traumatic stress disorder (PTSD)
Resep obat dalam kasus pertama ini terbatas pada episode kecemasan; dalam kasus
kecemasan kronis yang mungkin disarankan berupa terapi suportif, bantuan sosial, dan
bahkan psikoterapi yang selanjutnya akan dijelaskan sebagai berikut :
A. Benzodiazepin
sifat farmakologi: derivatif ini berbagi sifat umum: antikonvulsan, obat penenang,
myorelaxant dan anxiolytic

Reseptor Benzodiazepine: benzodiazepin spesifik milik kompleks makromolekul

termasuk reseptor GABA yang mengelilingi ionofor klorin dan situs akseptor
lainnya diidentifikasi. Benzodiazepin adalah modulator alosterik dari reseptor
GABA A. Selain reseptor “pusat”, ada reseptor perifer yang benzodiazepin
tertentu memiliki afinitas tinggi yang ada didalam hati, ginjal dan jaringan perifer
lainnya juga meskipun di otak. Benzodiazepin menyebabkan “downregulation”

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reseptor GABA A, yang mengarah pada efisiensi yang lebih rendah setelah dua
bulan penggunaan terus menerus. Di tingkat pusat, benzodiazepin terutama
berikatan dengan situs BZ2 nanomolar sementara imidazopiridin mengikat lebih
banyak hubungan dengan situs BZ1.

Farmakokinetik: Benzodiazepin adalah sekelompok obat yang tersusun dengan

baik dalam struktur kimianya dan memiliki sifat farmakologis yang homogen.
Bersifat asam lemah dari disosiasi konstan variabel dengan lipofilisitas tinggi,
yang memungkinkan perjalanan cepat melalui membran (darah-otak dan
hambatan plasenta, dan perjalanan dalam ASI). Hampir semua benzodiazepin
tidak larut dalam air kecuali chlordiazepoxide, dipotassium clorazepate dan
midazolam; oleh karena itu perlu untuk menggunakan solusi organik untuk
bentuk yang dapat diberikan secara parenteral (diazepam, fl unitrazepam,
clonazepam).

Resorpsi: Tingkat resorpsi dan puncak tinggi konsentrasi puncak (Cmax)

bervariasi untuk molekul tertentu tergantung pada bentuk sediaan yang digunakan
dan rute pemberian. Ini adalah tingkat resorpsi yang mengkondisikan penggunaan
yang berbeda benzodiazepin sebagai hipnotik (kecepatan cepat) atau sebagai
ansiolitik.

Rute oral: Digunakan untuk semua benzodiazepin, biasanya dalam bentuk tablet
atau kapsul. Resorpsi hampir selalu lengkap karena liposolubilitasnya yang baik.
Puncak konsentrasi dicapai antara 30 menit dan 4 jam. Laju resorpsi juga
tergantung pada bentuk sediaan; umumnya tumbuh dalam urutan sebagai berikut:
tablet, kapsul, tetes. Tingkat penyerapan lebih lambat ketika obat ini diserap di
tengah-tengah makan atau ketika subjek sedang berbaring.

Rute intramuskuler: Resorpsi biasanya lebih lambat dan lebih tidak dapat
diprediksi daripada oral. Memang, bioavailabilitas dipengaruhi oleh sifat pelarut
organik yang diperlukan untuk pembubaran produk aktif.

Rute rektal: Hal ini tidak digunakan untuk tujuan anxiolytic, tapi untuk pra
anestesi atau (penekanan) untuk kejang pada anak-anak

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Rute intravena: memberikan puncak konsentrasi tertinggi dan paling

menguntungkan untuk perpindahan cepat dan masif produk ke dalam SSP.
Suntikan intravena harus dilakukan secara perlahan.

Pengikatan protein plasma: Persentase pengikatan protein masih sangat tinggi

untuk semua benzodiazepin dan hanya sedikit dimodifikasi ketika konsentrasi
obat meningkat atau ketika konsentrasi protein menurun. Dengan demikian, tidak
ada rasa takut gangguan obat utama oleh mekanisme interaksi pada tingkat
pengikatan protein.

Distribusi: Tergantung, sejauh yang menyangkut benzodiazepin, pada

liposolubilitasnya. Tergantung pada subjek, itu bervariasi sesuai dengan rasio air /
lemak yang membentuk mereka. Pada orang tua, volume distribusi
benzodiazepine paling sering meningkat, sehingga berkontribusi pada
perpanjangan waktu paruh.

Metabolisme: Hal ini dilakukan dalam lumen gastrointestinal untuk molekul

tertentu, (misalnya chlordiazepoxide). Derivatif tertentu seperti clorazepate,
prazepam adalah prodrug, yaitu mereka dimetabolisme sebelum mencapai aliran
darah. Di hati, benzodiazepin mengalami demetilasi atau hidroksilasi dan / atau
konjugasi.

Eliminasi: pada dasarnya Benzodiazepin dieliminasi dalam urin dalam bentuk

metabolik: metabolit terkonjugasi hydroxylated. Waktu paruh eliminasi
berhubungan dengan volume distribusi dan metabolisme dan pembersihan ginjal.
Waktu paruh hanya sangat buruk mencerminkan durasi tindakan karena juga
tergantung pada dosis. Namun, dalam kasus administrasi berulang, paruh
memungkinkan untuk memprediksi urutan administrasi dan terutama memperoleh
dataran tinggi terapi. Memang, waktu penampilan piring dilakukan setelah 5
paruh. Benzodiazepin, digunakan sebagai ansiolitik, harus aktif selama
nycthemeron dan waktu paruh yang lama tampaknya lebih baik diadaptasi

Indikasi: Benzodiazepin diindikasikan dalam situasi berikut:

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Pengobatan simtomatik untuk gangguan kecemasan parah dan /atau

melumpuhkan. Pengobatan simtomatik untuk gangguan kecemasan parah dan /
atau melumpuhkan tidak lebih dari 2 bulan. Pencegahan dan pengobatan delirium
tremens dan manifestasi lain dari penarikan alkohol.

Efek samping: Benzodiazepin adalah obat dengan toksisitas rendah. Memang,

dosis yang cenderung menyebabkan keracunan jauh lebih tinggi daripada dosis
terapeutik. Namun, obat-obatan ini memiliki efek buruk pada dosis terapi

 Efek sedatif: Ini merupakan efek yang tidak diinginkan, karena kadang-
kadang dicari oleh prescriber, terutama dalam kasus agitasi cemas. Dalam
kebanyakan kasus, efek ini menyusahkan dan terjadi pada dosis yang
mendekati dosis anxiolytic. Tujuan dari terapis adalah untuk meresepkan dosis
ansiolitik non-sedatif terkecil. Untuk beberapa benzodiazepin, indeks terapi
(rasio dosis yang menginduksi efek sedatif / dosis terapeutik) rendah.
 Efek amnesik: Efek amnestik dilaporkan setelah injeksi IV atau IM
atau setelah asupan oral. Amnesia terjadi pada semua pasien ketika dosis
tinggi digunakan, lansia menjadi sangat sensitif. Molekul beraksi cepat,
berafiliasi tinggi pada reseptor benzodiazepine menyebabkan amnesia paling
dramatis. Gangguan kognitif tampaknya menjadi efek samping utama BZD.
Gangguan kognitif ditandai oleh amnesia anterograde, penurunan ingatan
peristiwa jangka pendek, dan peningkatan kehilangan memori. Mungkin ada
kebingungan dengan diagnosis Mild Cognitive Impairment (MCI)
 Efek disinhibisi: Pada hewan dan manusia, benzodiazepin
memungkinkan tindakan yang menyerupai apa yang dapat diamati dengan
etanol. Efek ini bermanfaat ketika kecemasan tidak lagi memungkinkan subjek
untuk bertindak, tetapi memfasilitasi peralihan ke tindakan dalam beberapa
subjek impulsif : ini disebut efek "paradoks". Pada dosis tinggi, efek ini
menghilang, digantikan oleh efek sedatif. Efek disinhibiting dapat menjadi
penyebab upaya bunuh diri yang berhasil
 Fenomena ketergantungan: Setelah perawatan yang berkepanjangan,
adalah mungkin untuk mengamati fenomena ketergantungan yang membuat
penyapihan menjadi sulit. Selama penyapihan, tanda-tanda klinis mungkin
muncul: kelelahan fisik, gangguan tidur, sakit kepala, pusing, tremor,

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berkeringat, sembelit, dll Oleh karena itu dianjurkan untuk tidak meresepkan
anxiolytic selama lebih dari 12 minggu. Dianjurkan juga untuk mengurangi
dosis secara bertahap selama beberapa hari atau minggu, untuk menghindari
jenis kecelakaan ini

Kesimpulan
Rekomendasi untuk penggunaan yang benar dari BZDs adalah sebagai
berikut: segera setelah pengobatan dimulai, pasien harus diberitahu berapa lama
pengobatan akan berlangsung dan bagaimana menghentikannya secara bertahap
karena risiko yang dijelaskan di atas. Sebelum ada permintaan untuk pembaruan,
seseorang harus mempertanyakan implementasi putusan. Pada setiap pasien yang
dirawat setiap hari selama lebih dari 30 hari, perlu untuk mengusulkan strategi
menghentikan konsumsi jika indikasi tidak lagi berlaku. Ketika memulai
penilaian, ekspektasi pasien, derajat "kemelekatan" pada BZD harus dinilai untuk
sampai pada keputusan bersama dan untuk mengevaluasi faktor prognostik, untuk
membedakan situasi yang membutuhkan strategi tertentu

B.Pregabalin
adalah analog asam [(S) -3- (aminomethyl) -5-methylhexanoic] dari asam
gamma-aminobutyric. Pregabalin berikatan dengan subunit tambahan (protein
alpha2-delta) voltage-gated Kalsium channel di pusat

Absorpsi: Pregabalin cepat diserap jika diberikan pada waktu perut

kosong. Bioavailabilitas oral pregabalin diperkirakan 90% dan dosis independen.
Setelah pemberian berulang, keadaan ekuilibrium tercapai dalam waktu 24 hingga
48 jam. Tingkat penyerapan pregabalin menurun ketika diberikan dengan
makanan selama makan, tetapi tidak menghasilkan efek yang signifikan secara
klinis.

Distribusi: Pregabalin melintasi penghalang darah-otak dan hadir dalam

susu. Pada manusia, Volume distribusi dari pregabalin setelah pemberian oral
adalah sekitar 0,56 l / kg. Pregabalin tidak mengikat protein plasma.

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Biotransformasi:
Pregabalin sangat lemah dimetabolisme pada manusia (kurang dari 1%).

Eliminasi: Pregabalin dihilangkan dari sirkulasi sistemik terutama melalui ginjal

dalam bentuk yang tidak berubah. Waktu paruh eliminasi pregabalin adalah
sekitar 6,3 jam. Pembersihan pregabalin cenderung menurun dengan
bertambahnya usia dan pengurangan dosis pregabalin mungkin diperlukan pada
pasien dengan gangguan fungsi ginjal.

Efisiensi klinis: Selain epilepsi dan nyeri neuropatik, pregabalin telah terbukti
efektif dalam kecemasan umum. Dosisnya berkisar dari 150 hingga 600 mg setiap
hari, dalam dua atau tiga dosis. Kebutuhan untuk perawatan lebih lanjut perlu
dinilai kembali secara rutin. Pengobatan dengan pregabalin dapat dimulai dengan
dosis 150 mg sehari. Tergantung pada respon pasien dan toleransi, dosis dapat
ditingkatkan sampai 300 mg sehari setelah 1 minggu. Setelah tambahan satu
minggu, dosis dapat ditingkatkan sampai 450 mg per hari. Dosis maksimum 600
mg sehari-hari dapat dicapai setelah minggu tambahan. Efektivitas pregabalin
dalam pengobatan gangguan kecemasan umum telah dibuktikan dalam 8 uji klinis
dibandingkan dengan plasebo dan obat referensi (benzodiazepin dan IRS).
Penurunan skor pada Skala Anxiety Rating Hamilton tercatat dengan pregabalin
dalam waktu seminggu dan efektif pada gejala somatik dan psikis. Dalam uji
klinis terkontrol, pregabalin telah terbukti efektif pada pasien berusia di atas 65
tahun. percobaan lain menunjukkan tingkat kekambuhan lebih rendah
dibandingkan dengan plasebo ketika pregabalin digunakan selama enam bulan.
Efek samping yang paling penting adalah rasa kantuk, pusing, sakit kepala, dan
mulut kering

C. Buspirone
Merupakan turunan dari seri azaspirodecanediones yang secara kimia tidak
berhubungan dengan obat saat ini digunakan. Mekanisme aksi: Buspirone tidak
bekerja pada reseptor GABA tetapi mengikat reseptor 5-HT1A, dan antagonis
reseptor dopamin istimewa situs presinaptik. Dibandingkan dengan
benzodiazepin, buspirone memiliki efek penghambatan yang rendah pada aktivitas
motorik dan bukan antikonvulsan maupun relaksan otot.

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Farmakokinetik: Buspirone hampir sepenuhnya diserap secara oral dan

memiliki efek first-pass yang signifikan. Puncak plasma dicapai dalam waktu
kurang dari satu jam untuk dosis 10 mg. Hal ini 95% terikat pada protein plasma.
Metabolisme buspirone ditandai dengan hidroksilasi dan oksidatif degradasi yang
mengarah pada pembentukan metabolit. Waktu paruh eliminasi rata-rata 2 hingga
4 jam. Administrasi berulang menunjukkan hubungan linear konsentrasi plasma
dengan dosis yang diberikan

Efisiensi klinis: Penelitian telah menunjukkan efek ansiolitik buspirone

pada 1 dan 4 minggu dibandingkan dengan plasebo [20]. Ini akan menjadi kurang
efektif pada orang yang telah diobati dengan benzodiazepin. Produk ini memiliki
waktu tindakan lebih lama daripada benzodiazepin.

Efek samping: Mual, pusing, sakit kepala, dan gugup perlu diamati.
Withdrawal-sindrom telah dijelaskan selama penghentian terapi buspirone, tetapi
tidak ada ketergantungan asli pada produk dalam studi jangka panjang. Beberapa
kasus akatisia telah dilaporkan. Karena sifatnya mengikat protein plasma, harus
hati-hati meskipun tidak ada interaksi utama telah diamati dengan obat-obatan
seperti digoxin dan simetidin.

Hydroxyzine: Hydroxyzine, dipasarkan dalam dua bentuk galenic (tablet,

injeksi) diresepkan dalam kasus manifestasi kecil kecemasan [22]. Digunakan
untuk premedikasi dalam kasus anestesi umum atau pemeriksaan yang
menyakitkan, itu juga ditunjukkan dalam pengobatan simtomatik dari berbagai
manifestasi alergi (rinitis spasmodik, konjungtivitis, dan urtikaria).

Mekanisme aksi: Hydroxyzine merupakan turunan piperazine yang tidak

terkait dengan fenotiazin ini yang menghambat reseptor histaminergic.
Hydroxyzine tidak memiliki efek kortikal depresan, tetapi menghambat aktivitas
daerah subkortikal tertentu. Hal ini memungkinkan tindakan obat penenang pada
ketegangan dan kecemasan emosional, dan meningkatkan kontrol emosi dan
reaksi neurovegetatif tertentu

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Farmakokinetik: Setelah penyerapan yang cepat, hidroksizin sepenuhnya

dimetabolisme. Tingkat plasma maksimum diperoleh pada 2 jam untuk 2 jam 30
dan waktu tindakan setelah minum secara oral adalah 15 sampai 30 menit. Durasi
tindakan, apa pun bentuk sediaan, adalah 6 hingga 8 jam.

Efek samping: terkait dengan potensi antikolinergik dari molekul: mulut

kering, sembelit, gangguan akomodasi dan kebingungan terutama pada orang tua.
Sebuah penelitian terbaru telah diterbitkan mengenai risiko perpanjangan QT pada
EKG jantung.

Etifoxine: Etifoxine diindikasikan dalam manifestasi psikosomatis dari

kecemasan seperti distonia neurovegetatif, terutama dengan ekspresi
kardiovaskular. Produk ini adalah subjek penelitian terkontrol dalam gangguan
penyesuaian kecemasan

Mekanisme aksi: Etifoxin hidroklorida termasuk dalam kelas kimia

benzoksazin. Ia bekerja bersama pada sistem GABA dan reseptor serotoninergik
5-HT2a [26]. Studi pada hewan dan manusia belum menunjukkan efek
peningkatan atau potensi ketergantungan obat serta gangguan memori.

Farmakokinetik:
Etifoxine hidroklorida diserap dengan baik secara oral. Konsentrasi plasma
menurun perlahan-lahan dalam tiga tahap dan dieliminasi terutama melalui sistem
kemih. Etifoxine hidroklorida masuk ke dalam plasenta.

Efek samping: Paling sering ada rasa kantuk sedikit pada awal pengobatan.

Antidepresan Sebagai Obat Ansiolitik

Konsep antidepresan berkembang secara bertahap sejak molekul ini
berhasil digunakan untuk mengobati patologi mental lainnya dari depresi. Apalagi
ini bukan obat terbaik depresi bipolar. Clomipramine adalah yang pertama kali
membuktikan aktivitas dalam pengobatan gangguan obsesif kompulsif (OCD)
sementara imipramine dan turunan lainnya tidak efektif. Faktanya, metabolit
desmethyl-clomipramine-nya adalah inhibitor kuat serotonin reuptake tetapi juga

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norepinefrin. Hasil gabungan dari clomipramine dan desmethylclomipramine pada

penghambatan serotoninreuptake jauh lebih besar daripada yang ada pada trisiklik
lainnya. Inhibitor reuptake serotonin selektif lainnya, seperti fluoxetine,
fluvoxamine, sertraline dan paroxetine, juga telah terbukti efektif dalam
pengobatan OCD. Efektivitas mereka dalam mengobati kondisi ini jelas tidak
terkait dengan sifat antidepresan mereka karena obat ini mengurangi gejala obsesif
kompulsif pada pasien yang tidak mengalami depresi.
Fakta bahwa antidepresan aktif dalam pengobatan gangguan kecemasan
membuat kami mencari penjelasan tentang mekanisme tindakan mereka dalam
patologi ini. Ternyata reseptor 5-HT2A dapat berpartisipasi dalam aktivitas ini
[30-32]. Tampaknya lebih dan lebih jelas bahwa tindakan ini akan dieksekusi pada
amigdala, struktur otak yang tampaknya menjadi “filter” pada persepsi emosi dan
yang kaya reseptor 5-HT2A. Sebagian besar SSRI dan SNRI dapat digunakan
untuk mengobati semua jenis gangguan kecemasan seperti gangguan kecemasan
umum (GAD), gangguan kecemasan sosial (SAD), gangguan panik (PD) dan
gangguan stres pasca trauma (PTSD).

Kesimpulan
Pilihan obat untuk mengobati gangguan kecemasan tergantung pada jenis
kecemasan, penilaian tingkat ketidaknyamanan dan kecacatan yang menyebabkan
keinginan pengobatan "akut" atau lebih lama, dari permintaan pasien dan pilihan
perawatan yang tersedia.
Obat-obatan ansiolitik jauh melampaui pengaturan awal benzodiazepin,
dengan kecenderungan yang jelas terhadap resep antidepresan yang spektrum
penggunaannya telah meningkat pesat. Selain itu, benzodiazepin diperkirakan
jarang diresepkan pada orang tua, dan banyak pasien yang diobati dengan
benzodiazepin harus disapih. strategi dan terapi selain benzodiazepin lainnya
harus digunakan untuk mengobati kecemasan dan gangguan tidur pada pasien usia
lanjut.

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Antianxiety Activities Associated
with Herbal Drugs: A Review

G. Mustafa, S. H. Ansari, Z. A. Bhat, and A. S. Abdulkareim

Introduction

Anxiety is a complex progressive behavioral and physiological alteration of the

organism characterized by restlessness, easy fatigability, dificulty in concentration,
irritability, muscle tension, and sleep disorders which ultimately leads to a wide
variety of CNS disorders if remains untreated. Anxiety disorders are often associ-
ated with autonomic symptoms, including heart palpitations, sweating, elevation of
body temperature, and alterations of gastrointestinal motility. In addition to indi-
vidual genetic factors also external inluences, such as nutrition, smoking, alcohol,
socioeconomic status, and environmental conditions, can strongly contribute to its
anticipated appearance. During the whole life a human being is confronted with
social, psychological, and emotional stress. Chronic social stress is one of the most
important factors responsible for precipitation of depressive disorder in humans. In
recent years, the impact of social stress on the development of psychopathologies
has been thoroughly investigated in preclinical animal studies.
There are many anxiolytics used in clinical practice but most of them are associ-
ated with one or the other undesirable effect, which ranges from psychological
dependence to severe withdrawal symptoms. The effective anxiolytic agents should
reduce anxiety symptoms, and exert calming effect with little or no effect on motor
or mental function (Katzung 2001).

G. Mustafa (*) · S. H. Ansari

Herbal Cosmetics and Immunomodulatory Lab, Department of Pharmacognosy and
Phytochemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India
Z. A. Bhat
Depatment of Pharmaceutical Sciences, University of Kashmir,
Srinagar, Jammu and Kashmir, India
A. S. Abdulkareim
Phytochemistry Research Lab, Department of Pharmacognosy and Phytochemistry, Faculty
of Pharmacy, Jamia Hamdard, New Delhi, India

© Springer Nature Switzerland AG 2019 87

M. Ozturk, K. R. Hakeem (eds.), Plant and Human Health, Volume 3,
https://doi.org/10.1007/978-3-030-04408-4_5

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Allopathic Anxiolytic Agents, Pharmacodynamics,

and Disadvantages

Benzodiazepines like diazepam, lorazepam, and oxazepam are the common allo-
pathic treatment for anxiety. Other class of compounds called barbiturates are used
and are superior to benzodiazepine. Miscellaneous agents, e.g., Buspirone which is
non-gabanergic antianxiety agent, are free from benzodiazepine side effect (CNS
depression, tolerance, dependency).
Pharmacodynamic: The benzodiazepines and barbiturates act by binding to
GABAA receptors present in the neural membrane of the CNS. (GABA) is the major
inhibitory neurotransmitter in the CNS. The benzodiazepines bind to their binding
site in the GABAA receptors. The other miscellaneous agents produce their effect by
different mechanism (partial agonist effect on the brain 5-HT1A receptors), e.g.,
Buspirone—non-gabanergic antianxiety agent.
Disadvantages and drawback: Tendency to produce psychological dependency
(not related to the blood serum concentration) known as withdrawal symptoms
characterized by restlessness, tremor, agitation and sleep disorder, amnesic effect,
synergetic depressive effect with alcohol and other CNS depressants (alcohol, anti-
depressant agents), tolerance (decrease in response with repeated exposure), and
barbiturates have narrow therapeutic index, hangover effect, and physiological
dependency (Katzung 2001).
The signiicances of studying the herbal medicines of anxiety: In addition to their
intolerance to side effects, the action of herbal formulation has been found compa-
rable with the allopathic anxiolytic agents as a result of many studies done in this
area. Wide range of safety has been ascribed to the herbal anxiolytic agents com-
pared with the severe side effect of the allopathic agents in case of long exposure
(tolerance, physiological, and psychological dependency), severe toxicity with over
dose (CNS depression, respiratory and cardiovascular system depression), in addi-
tion to the psychosocial problems associated (hangover, job impairment, depression
of the locomotor activity). 54% of anxiety and depression disorder patients use
alternative/complementary medicines out of which 38% use herbal medicines
(Brown and Gerbarg 2001).
Mechanism of action of herbal anxiolytic preparations: Inhibition of 5-HT, DA,
NE reuptake, participate in 5-HT receptors downregulation, agonist the GABA, BZ,
5-HT and glutaminergic NMDA-type receptor, block Na channels (Conner and
Davidson 2002).

Plants Having Anxiolytic Effects

Ashwagandha

Biological name: Withania somnifera, family: Solanaceae, part used: Root powder,
decoction, and leaves, active constituents responsible for the anxiolytic effect:
glycowithanolides.

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Antianxiety Activities Associated with Herbal Drugs: A Review 89

Mechanism of action: GABA mimetic activity. Researchers from George

Washington University School of Medicine and Health Sciences, the adult
Psychopharmacology program at National Institute of Mental Health, and the San
Antonio Cochrane Center reviewed all the traditional literature concerning this
Ayurvedic herb. They put this herb on clinical trials to determine its safety and it
was found to have anxiolytic and antidepressant activity. Toxicity studies didn’t
reveal any signiicant adverse effects (www.holistic.com, herb for anxiety). It
induced an anxiolytic effect, comparable to that produced by lorazepam, in the ele-
vated plus maze, social interaction, and feeding latency in an unfamiliar environ-
ment (Bhattacharya et al. 2000). Another study at Dept. of Pharmacology, University
of Texas, found GABA-like activity in Withania somnifera. These results suggest
that the W. somnifera extract contains an ingredient which has a GABA-mimetic
activity. This activity was correlated with anti-anxiolytic effect (Mehta et al. 1991).
Dosage: 150–300 mg of root extract as mentioned by the American pharmaceutical
association, 2–3 g of root powder thrice daily, and capsule of 2–5 mg of withanoloi-
des (Duke 2002).

Kava

Biological name: Piper methysticum, family: Piperaceae, part used: root, active
constituents responsible for the anxiolytic effect: Kava pyrone. Mechanism of
action: Binds to GABA receptors at benzodiazepine site (Julien 2004). Inhibits glu-
tamate. Blocks sodium channels, 5-HT agonist (Conner et al. 2002). A study was
carried out to compare the anxiolytic potential of Kava-Kava extract with diazepam.
Acute effects of diazepam and a Kava-Kava preparation, compared to their respec-
tive controls, were examined in Wistar rats using the elevated plus maze (X-maze).
The time spent on open arms, percentage of open-arm visits, and parameters
describing the risk assessment were evaluated. Kava-Kava extract (120–240 mg/kg
p.o.) affected the behavior measured in the X-maze test, inducing an anxiolytic-like
behavior similar to diazepam (15 mg/kg p.o.). These data support the use of Kava-
Kava in the treatment of anxiety (Rex et al. 2002). Dosage: As revealed by many
studies the range of dose is 70–240 mg/kg of kava pyrone. The use of kava extract
is contraindicated with other CNS depressant (benzodiazepine, l-dopa, mood-
changing drugs) (Fetroro and Avila 2000).

St. John’s-Wort

Biological name: Hypericum perforatum; family: Clusiaceae; part used: lower and
upper stem leaves; active constituents responsible for the anxiolytic effect:
hypericin.

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Mechanism of action: Participates in 5-HT receptor downregulation (Davidson

and Conner 2001). Active at GABA, benzodiazepine, and glutaminergic NMDA-
type receptors, 5-HT, DA, and NE reuptake inhibitor (Julien 2004). St. John’s-wort
extract as sublingual cap. Containing 300–500 mg has been standardized to contain
0.3% hypericin, and 250 mg capsule standardized to 0.14% hypericin (Fetroro and
Avila 2000). In a reported case study it was found that St. John’s-wort not only
alleviated GAD symptoms, buy it also helped the ability to cope with daily stresses
and dificult social interactions. In case using (900 mg bid) for 4 weeks the result is
improvements in sleep, ability to relax, worry, and coping with daily stress and
premenstrual stress with no side effects or relapse.
When used as 900 mg bid for 2 weeks the result is improvements in sleep and
ability to cope with family stresses. The same dose for 4 weeks resulted in 50%
improvement reduction in nervousness, worry, and irritability.
At an increased dose level of 1500 mg/day, dry mouth was the only side effect
(Davidson and Conner 2001).

Brahmi

Biological name: Bacopa monnieri; family name: Scrophulariaceae; part used:

whole plant; active constituents responsible for the anxiolytic effect: bacopasides.
Mechanism of action: Increases enzyme level of EROD and PROD (prophylac-
tic). In this study on rats, B. monnieri showed the potential to be effective in stress.
The response had been better in the group that was pretreated for 1  week with
20–40 mg/kg/daily of it even before exposing to stress stimuli. The level of Hsp70
increases in brain as a response to stress. After giving B. monnieri for 7 days, and
then giving stress to animals, the Hsp70 was found in lower concentration in ani-
mals pretreated with Bacopa. EROD and PROD enzyme levels in pretreated rats
were found more even before exposure to stress. Thus B. monnieri primed the brain
for stress by stockpiling these useful enzymes even before stressful conditions.
Using this medicinal herb could lower our susceptibility to stress (www.holistic.
com, herb for anxiety) (Chowdhuri et al. 2002). Research on rats as models of clini-
cal anxiety showed the anxiolytic activity of its extracts with 25% bacopasides as
comparable to lorazepam. Plus there were no side effects of lorazepam, like amne-
sia. Rather there was memory-enhancing effect. Another 1-month study on diag-
nosed anxiety neurosis patients, with syrup of this medicinal herb equivalent to 12 g
of crude powder, found signiicant reduction in anxiety symptoms, level of disabil-
ity, and fatigue. There was additional increase in immediate memory, decreased
respiratory rate, and decreased SBP or systolic blood pressure (www.holistic.com,
herb for anxiety).
Dosage: Standardized luid extract: 1:2 luid extract should be taken in 4–12 ml
for adults and 2–4  ml for children within 6–12  years of age. Standardized 20%
extract (both bacopasides A and B): 200–400 mg/day in two or three divided dos-
ages for adults and 100–200 mg/day in two or three divided dosages for children
within 6–12 years of age (www.holistic.com, herb for anxiety).

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Antianxiety Activities Associated with Herbal Drugs: A Review 91

Passionlower

Biological name: Passilora incarnata; family name: Passiloraceae; part used:

whole herb, aerial part; active constituents responsible for the anxiolytic effect: sug-
gested to be benzo-lavonoids (methanol extract).
Mechanism of action: Unrevealed. A pilot double-blind randomized control trial
with oxazepam found the Passilora extract to be an effective herb for the manage-
ment of generalized anxiety disorder. It has the added side beneit of having low
chances of job impairment found with the use of oxazepam due to morning after
side effects (Akhondzadeh et al. 2001).
A fraction derived from the methanol extract of P. incarnata has been observed
to exhibit signiicant anxiolytic activity at a dose of 10 mg/kg in mice using elevated
plus maze model of anxiety. This fraction comprises mainly two components that
are visible as blue- and turquoise-colored luorescent spots at 366 nm of the UV
light. The possibility of a phytoconstituent having benzolavone nucleus as the basic
moiety being responsible for the bioactivity of P. incarnata is highly anticipated
(Dhawan et al. 2001a).
The petroleum ether, chloroform, methanol, and water extracts of Passilora
incarnata whole plant and sorted-out plant parts have been evaluated for their anx-
iolytic activity using the elevated plus maze model in mice. The methanol extracts
of leaves, stems, lowers, and whole plant exhibited anxiolytic effects at 100, 125,
200, and 300 mg/kg, respectively. The roots were practically devoid of anxiolytic
effects. These results show that roots and lowers of P. incarnata act as natural adul-
terants by causing a signiicant increase in the anxiolytic dose. Therefore, separa-
tion of these parts is recommended prior to any pharmacological, phytochemical,
and standardization studies on P. incarnata (Dhawan et al. 2001b).
It works best in thin, nervous, and easily stressed persons. Passilora incarnata
got the oficial approval of Commission E (1985) in Germany for its role in anxiety
and insomnia. Kava and valerian have quick action but the effect of Passilora incar-
nata builds up in about a month (www.holistic.com, herb for anxiety).
Dosage: Capsule—300–450 mg twice or thrice a day. Fluid extract (1:1 in 25%
alcohol)—10–30 drops three times a day. Hot infusion or tea—pour one teaspoon
(2–5 g) of herb powder with 150 ml hot water. Strain after 10 min and use it. It can
be taken twice or thrice a day, and the last dose one or 2 h before bedtime. Tincture
(1:5  in 45% alcohols). 10–60 drops twice or thrice daily. Passionlower and the
herbal compounds containing it are standardized to contain not less than 0.8% la-
vonoids to meet the standards of German, French, and Swiss Pharmacopoeias. Low
levels of serotonin have been identiied that is used to explain its effects as a natural
calming agent, as an aid to concentration, and to elevate the mood. Maltol, another
compound, is also found to have mild sedative properties (www.holistic.com, herb
for anxiety).
To ensure uniformity and consistency of the biologic effects exhibited by plant-
derived phytopharmaceuticals, uniform standards are required globally. The mono-
graphs on P. incarnata mention standardization of the plant using any known
lavonoid as the chemical marker and the marker compound was not the one respon-

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sible for the plant’s multifarious biologic effects. The recent report of a trisubsti-
tuted benzolavone compound (BZF) as the main bioactive phytoconstituent of P.
incarnata made it feasible to resort to biologic standardization of this plant using
BZF as the biomarker compound. The biologic standardization would ensure bio-
equivalence of the medicinal preparations of P. incarnata. These studies also recom-
mend the incorporation of leaf constants, ash values, extractive values, thin-layer
chromatography proile (vital “ingerprints” speciic for a plant), and quantitative
assay by determining the bioactive BZF moiety in pharmacopoeias in order to
ensure uniform biologic results and standards of P. incarnata because the plant cur-
rently has tremendous usefulness (Dhawan et al. 2002).

Siberian Ginseng

Biological name: Eleutherococcus senticosus; family: Araliaceae; Part used: root;

active constituents responsible for the anxiolytic effect: eleutherosides and senno-
sides; mechanism of action: unrevealed.
Dosage range: 100–200 mg but the common is 200 mg (standardized extract),
2–3 times daily. A regimen of 4 weeks on 2 weeks off is recommended for maxi-
mum beneits.
Standardization: The most current available medical and scientiic literature
indicates that this dietary supplement should be standardized to 0.8% eleutherosides
B and E per dose.

Star Flower

Biological name: Echium amoenum; family: Boraginaceae; part used: lower; active
constituents responsible for the anxiolytic effect: ethanol extract of lower (50 mg/kg).
Mechanism of action: Unrevealed. Study reveals that the ethanol extract of
Echium amoenum lowers at the dose of 50 mg/kg increased the percentage of time
spent and the percentage of arm entries in the open arms of the elevated plus maze
(EPM) and decreased the percentage of time spent in the closed arms of EPM. Also,
the locomotor activity was affected but not to the same extent as observed for diaz-
epam. These results suggested that the extract of E. amoenum seems to possess anx-
iolytic effect with lower sedative activity than that of diazepam (Rabbani et al. 2004).

Ginseng

Biological name: Panax ginseng; family: Araliaceae; part used: root; active con-
stituents responsible for the anxiolytic effect: ginsenoside Rb1.

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Antianxiety Activities Associated with Herbal Drugs: A Review 93

Mechanism of action: Unrevealed. There has been investigation of the anxiolytic-

like effects of red ginseng (RG, steamed raw ginseng at 98–100 °C) and sun ginseng
(SG, heat-processed ginseng at higher temperature) in mice using the elevated plus
maze model. Furthermore, the anxiolytic-like effects of RG and SG were compared
to a known active anxiolytic drug (diazepam). The RG butanol fraction (100 mg/kg)
signiicantly increased the number of open-arm entries and the time spent on the
open arm (indicators of anxiolytic-like effects) compared with that of the saline
group. However, lower doses of the SG total extract (50 mg/kg) and the SG butanol
fraction (25 and 50 mg/kg) signiicantly increased the number of open-arm entries
and the time spent on the open arms. The RG total extract (100 mg/kg) and the SG
total extract at a lower dose (25 mg/kg) did not increase the number of open-arm
entries or the time spent on the open arm. These data indicate that ginseng has
anxiolytic-like effects, and the anxiolytic potential of SG is stronger than that of RG
in the elevated plus maze model. Ginseng saponins have been suggested to play an
important role in the anxiolytic effects of ginseng (Park et al. 2005).
Pharmacological identiication of the active constituents which give the anxio-
lytic effect has been performed on albino mice using elevated plus maze as indica-
tor, using the following, drug diazepam (0.5, 1, 1.5 mg/kg – p.o), red ginseng crude
powder (300,600 and 1200  mg/kg p.o), crude saponin and non-saponin ginseng
fraction (50, 100 and 200 mg/kg ip), and pure ginsenoside rb1 rg1 ro (2.5, 5, and
10 mg/kg ip), and it is found that the ginseng powder and the crude saponin increase
the frequency and duration of open-arm entries, but only the Rb1 shows this effect
among the ginsenoside pure fraction (Carr et al. 2006).

Salvia reuterana

Biological name: Salvia reuterana; family: Boiss; part used: whole plant; active
constituents responsible for the anxiolytic effect: hydroalcoholic extract (100 mg/
kg). Mechanism of action: Unrevealed. The anxiolytic and sedative effects of
hydroalcoholic extract (HE) of Salvia reuterana (Boiss) was evaluated in mice. The
HE of Salvia reuterana (100 mg/kg) increased the percentage of time spent and the
percentage of arm entries in the open arms of the elevated plus maze. Spontaneous
locomotor activity count measured in 15 min of the test was signiicantly decreased
in animals pretreated with diazepam and 100 mg/kg of Salvia reuterana extract.

Ginkgo

Biological name: Ginkgo biloba; family: Ginkgoaceae; part used: leaf; active con-
stituents responsible for the anxiolytic effect: ginkgolide-A (1–2 mg/kg).
Mechanism of action: Unrevealed.

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The anxiolytic-like effects of Ginkgo biloba extract (GBE) and its four terpenoid
components (ginkgolide-A, ginkgolide-B, ginkgolide-C, and bilobalide) were
assessed using the elevated plus maze test in mice. Administration of GBE as a
single oral dose (0.5 or 1 g/kg, po) caused a state of suppressed motor activity and,
thus, shortened the time spent in the open-sided arms. However, when GBE
(0.063–1 g/kg, po) was administered daily for 7 days and the plus maze test was
carried out 24 h after the inal administration, the time spent in the open-sided arms
was prolonged, with the peak anxiolytic-like effect at 0.125 g/kg. A combination of
7-day administration of GBE (0.125 g/kg) and a single dose of diazepam (1 mg/kg,
po, and 10  min before testing) enhanced the anxiolytic-like effect. Flumazenil
(0.3 mg/kg, ip, and 10 min before testing) blocked the effect of diazepam, but not of
GBE.  Daily administration of ginkgolide-A (1 or 2  mg/kg, po) resulted in an
anxiolytic-like effect by the third treatment, with the maximal effect observed after
the ifth administration. Neither ginkgolide-B, ginkgolide-C, nor bilobalide pro-
duced any anxiolytic-like effects. At doses higher than 0.5  g/kg, GBE not only
inhibited motor activity but also suppressed active avoidance behavior, reduced
caffeine-induced stimulation, and enhanced pentobarbital-induced sleep, while
ginkgolide-A (up to 20 mg/kg) did not exhibit these effects. Diazepam (1 mg/kg) is
known to enhance pentobarbital-induced sleep. These results suggest that GBE pro-
duces a signiicant anxiolytic-like effect following repeated administration and that
ginkgolide-A is most likely responsible for this effect. There are also indications
that although GBE exerts a sedative effect at comparatively higher doses, gink-
golide-A has a relatively weak tendency to produce benzodiazepine-like side effects
(Kuribara et al. 2003).

American Skullcap

Biological name: Scutellaria laterilora; family: Lamiaceae; part used: whole plant;
active constituents responsible for the anxiolytic effect: baicalin, baicalein, GABA,
and glutamine.
Mechanism of action: GABAA agonist.
The phytochemistry and biological activity of Scutellaria laterilora L. (American
skullcap) which has been traditionally used as a sedative and to treat various ner-
vous disorders such as anxiety were studied. In vivo animal behavior trials were
performed to test anxiolytic effects in rats orally administered with S. laterilora
extracts. Signiicant increases in the number of entries into the center of an “open-
ield arena,” number of unprotected head dips, number of entries, and length of time
spent on the open arms of the elevated plus maze were found. The identiication and
quantiication of the lavonoid baicalin in a 50% EtOH extract (40 mg/g) and its
aglycone baicalein in a 95% EtOH extract (33 mg/g), as well as the amino acids
GABA in H2O and EtOH extracts (approximately 1.6 mg/g) and glutamine in an
aqueous extract (31 mg/g), were performed using HPLC. These compounds may
play a role in anxiolytic activity since baicalin and baicalein are known to bind to

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Antianxiety Activities Associated with Herbal Drugs: A Review 95

the benzodiazepine site of the GABAA receptor and since GABA is the main inhibi-
tory neurotransmitter (Awad et al. 2003). The aqueous extract of American skullcap
(Scutellaria laterilora L. (S. laterilora) (Lamiaceae)) has been traditionally used
by North American Indians as a nerve tonic and for its sedative and diuretic proper-
ties. Recent reports stated that lavonoids and possibly amino acids are responsible
for the anxiolytic activity. As a part of search for environmentally friendly solvents
to extract the active components from medicinal plants, in a comparison of acceler-
ated solvent extraction (ASE) using water, and supercritical luid extraction (SFE)
using CO2 and 10% EtOH as modiier, at different temperatures, lavonoids and
amino acids were quantiied by HPLC-UV and HPLC-MS, respectively. The lavo-
noid content was compared with conventional extraction methods (hot water extrac-
tion and 70% ethanol). The use of ASE at 85 Cingrate with water as solvent gave the
best results for lavonoid glycosides and amino acids, whereas SFE gave higher
yields of lavonoid aglycones. However, the results obtained for total lavonoids
were not signiicantly superior to hot water extraction or 70% aqueous EtOH extract
(Bergeron et al. 2005).

Valerian

Biological name: Valeriana oficinalis; family: valerianaceae; part used: root;

active constituents responsible for the anxiolytic effect: valerenic acid and valepotri-
ates. Mechanism of action: GABAA agonist.
Valerian has anxiolytic, tranquilizing, and sleep-inducing effects that have been
demonstrated in both animal studies and clinical trials. Valerian or its constituents
could induce these effects by interacting with central gamma-amino butyric acid
(GABA) receptors. Early in vitro studies testing the binding of valerian extract to
GABA receptors showed that the agonist muscimol was displaced, suggesting vale-
rian binding to these receptors.
Pretreatment with valerian extract or valerenic acid decreased the brainstem
inhibitory effects produced by muscimol (both P _ 0.05), suggesting that these
compounds play an important role in the regulation of GABAminergic activity.
Data from study suggest that the pharmacological effects of valerian extract and
valerenic acid are mediated through modulation of GABAA receptor function. Thus,
valerian may potentiate the sedative effects of anesthetics and other medications
that act on GABA receptors, and presurgical valerian use may cause a valerian-
anesthetic interaction. Treatment with valerian extract or valerenic acid caused an
inhibitory effect on muscimol-sensitive NTS neurons in an in vitro brainstem prepa-
ration. It was also observed that the inhibitory activity of both valerian extract and
valerenic acid was induced via GABAA, but not GABAB, receptors. The GABA
agonistic activity of valerian and its positive modulation of GABAA receptors could
partly explain valerian’s antianxiety and sedative effects (Yuan et al. n.d.).

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96 G. Mustafa et al.

Damiana

Biological name: Turnera aphrodisiaca; family: Turneraceae; part used: whole

plant; active constituents responsible for the anxiolytic effect: mother tincture of the
plant. Mechanism of action: Not revealed.
Turnera aphrodisiaca Ward (synonym Turnera diffusa) Family (Turneraceae) is
commonly known as “Damiana.” The leaves of T. aphrodisiaca have been used
traditionally as a stimulant, aphrodisiac, tonic, diuretic, nerve tonic, and laxative,
and in kidney, menstrual, and pregnancy disorders. British Herbal Pharmacopoeia
lists speciic indications for Damiana as anxiety neurosis associated with
impotency.
Phytochemical reports on T. aphrodisiaca indicate that the plant contains tetra-
phyllin B (a cyanoglycoside); gonzalitosin I (a lavonoid); arbutin (a phenolic
glycoside); damianin; tricosan-2-one, hexacosanol (hydrocarbons); a volatile oil
containing pinene, p-cymene, and 1,8-cineole; and -sitosterol (a phytosterol)
(Kumar and Sharma 2005).

Nees

Biological name: Aniba riparia; Family: Lauraceae; part used: unripe fruit; active
constituents responsible for the anxiolytic effect: riparin III.
Mechanism of action: Not revealed.
The anxiolytic effect of riparin III from the plant Aniba riparia on mice was
tested using the elevated plus maze which has shown antianxiety effect at an oral
dose of 25–50  mg/kg and both doses show no effect on the locomotor activity
(Anonymous n.d.-a).

Safed Musli

Biological name: Chlorophytum borivilianum; part used: root; active constituents

responsible for the anxiolytic effect: butanolic fraction of alcoholic extract.
Mechanism of action: Not revealed. The acute toxicity effect studies carried out
on albino mice found that the alcoholic extract and the butanolic fraction were eval-
uated for in vivo antistress activity using cold stress model on albino rats at a dose
of 500  mg/kg. The alcoholic extract exhibited moderate activity (Anonymous
n.d.-b).

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Antianxiety Activities Associated with Herbal Drugs: A Review 97

Griseb

Biological name: Aloysia polystachya; family: Verbenaceae; part used: aerial part;
active constituents responsible for the anxiolytic effect: hydroethanolic extract of
the aerial part. Mechanism of action: Not revealed.
The hydroethanolic extract of the aerial part of the plant was tested on male mice
and found that it does not show any change on the locomotive activity and motor
coordination body temperature (advantage) at a dose 1.0, 10.0, and 100 mg/kg. The
percentage of both number of entries and time spent in the open arm of the EPZ test
was signiicantly increased with a dose range of 10–100 mg/kg (Hellión 2006).

Clary

Biological name: Salvia sclarea; family name: Lamiaceae; part used: lowering top;
active constituents responsible for the anxiolytic effect: clary (aromatic essential
oil). Mechanism of action: Not revealed.
The active constituents of the aromatic oil (clary) are obtained by steam distilla-
tion of the lowering top. The dose for anxiety disorder, depression, and mental
fatigue is two drops of the essential oil to be inhaled. Side effects: drowsiness, head-
ache, increases the menstrual bleeding and euphoria. Contraindicated with estrogen-
sensitive cancer, pregnancy, and breastfeeding (Fetoro and Avila 2000).

Mugwort

Biological name: Artemisia vulgaris; Family name: Compositae; part used: root;
active constituents responsible for the anxiolytic effect: root tincture.
Mechanism of action: Not revealed. The dose used to produce the antianxiety
effect is 5  ml of root tincture orally 30  min before bedtime. Side effects: skin
inlammation, wheezing, itching, and rash. Contraindicated with pregnancy,
bleeding disorder, and acid relux (Fetoro and Avila 2000).

Magnoliaceae

Biological name: Magnolia obovata; family: Magnoliaceae; part used: stem bark;
active constituents responsible for the anxiolytic effect: honokiol.
Honokiol (3′, 5-di-2-propenyl-1, 1′-biphenyl-2, 4′-diol) is an isomer of neolig-
nans isolated and identiied from the stem bark of Magnoliaceous plants (Magnolia
obovata). The magnolia bark has been utilized as an herbal remedy for the treatment

218
98 G. Mustafa et al.

of a wide variety of clinical disorders. Honokiol and magnolol (an isomer of

honokiol) were recently identiied as anxiolytic agents in the extracts of Saiboku-to,
an oriental herbal Chinese medicine (Kampo). Behavioral evaluation through an
elevated plus maze test demonstrated that honokiol, 0.2–2 mg/kg, p.o., for 7 days,
was at least 5000 times more potent than Saiboku-to. Honokiol has a comparatively
lower risk of causing benzodiazepine-like side effects, such as central depression,
muscle relaxation, amnesia, or physical dependence (Maruyama and Kuribara
2000).

Comparison of Anxiolytic Activity of Herbal Plant

Against Allopathic Formulations

• It’s found that the anxiolytic effect of ashwagandha (Withania somnifera) is

comparable with lorazepam using EPM and social interaction as the evaluation
parameter.
• A study on rats showed that Bacopa extract showed prophylactic property if it is
used for 1 week (20–40 mg/kg/day) before exposing to stress factors.
• It is also revealed that the extract of Bacopa containing not less than 25%
bacosides is comparable to lorazepam but have the advantages of absence of
lorazepam side effect.
• Kava root extract (120–240 mg/kg p.o) is found to be equally effective as diaz-
epam (15 mg/kg p.o) without many of their side effects.
• In a pilot double-blind randomized controlled trial it was found that passion-
lower (Passilora incarnata) is effective in the treatment of general anxiety
disorder compared with oxazepam, with advantages of absence of chances of job
impairment.
• Anxiolytic effect of (Salvia reuterana) hydroalcoholic extract of the plant
(100 mg/kg) has been found comparable to diazepam 15 mg/kg.
• The daily administration of ginkgolide-A (1–2 mg/kg p.o) (Ginkgo biloba) active
constituents to mice is equally active as the combination of Ginkgo extract
(125 mg/kg) and diazepam (1 mg/kg p.o).

Conclusion

Although evidence of the eficacy of herbal preparations in treating anxiety condi-

tions is growing, translating the results of eficacy studies into effective treatments
for patients is hampered by the chemical complexity of the products, lack of stan-
dardization of commonly available preparations, and paucity of well-controlled
studies revealing the exact mechanism of actions and safety study on human.

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Antianxiety Activities Associated with Herbal Drugs: A Review 99

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PENDAHULUAN

Kecemasan adalah perubahan perilaku dan fisiologis yang progresif kompleks dari
organisme yang ditandai dengan kegelisahan, mudah lelah, kesulitan dalam konsentrasi, lekas
marah, ketegangan otot, dan gangguan tidur yang pada akhirnya mengarah ke berbagai
gangguan CNS jika tidak diobati. Gangguan kecemasan sering dikaitkan dengan gejala
otonom, termasuk jantung berdebar, berkeringat, peningkatan suhu tubuh, dan perubahan
motilitas gastrointestinal. Selain faktor genetik individu juga pengaruh eksternal, seperti
nutrisi, merokok, alkohol, status sosial ekonomi, dan kondisi lingkungan, dapat sangat
berkontribusi pada penampilan yang diantisipasi.

Selama seumur hidup manusia dihadapkan dengan stres sosial, psikologis, dan
emosional. Stres sosial kronis adalah salah satu faktor terpenting yang menyebabkan
pengendapan gangguan depresi pada manusia. Dalam beberapa tahun terakhir, dampak
tekanan sosial pada perkembangan psikopatologi telah diselidiki secara menyeluruh dalam
studi hewan pre-klinis. Ada banyak obat anxiolytics yang digunakan dalam praktek klinis
tetapi kebanyakan dari mereka terkait dengan satu atau efek yang tidak diinginkan lainnya,
yang berkisar dari ketergantungan psikologis hingga gejala penarikan yang parah. Agen
ansiolitik yang efektif harus mengurangi gejala kecemasan, dan memberikan efek
menenangkan dengan sedikit atau tidak ada efek pada fungsi motorik atau mental (Katzung
2001).

Agen Anxiolytic Allopathic, Farmakodinamik, dan Kerugian

Benzodiazepin seperti diazepam, lorazepam, dan oxazepam adalah pengobatan

allopathic umum untuk kecemasan. Kelas senyawa lain yang disebut barbiturat digunakan
dan lebih unggul dari benzodiazepine. Agen lain-lain, mis., Buspirone yang merupakan agen
anti-kecemasan non-gabanergik, bebas dari efek samping benzodiazepin (depresi SSP,
toleransi, ketergantungan).

Farmakodinamik: Benzodiazepin dan barbiturat bekerja dengan cara mengikat

reseptor GABAA yang ada di membran saraf SSP. (GABA) adalah neurotransmitter
penghambat utama dalam SSP. Benzodiazepin berikatan dengan situs pengikatannya dalam
reseptor GABAA. Agen lain-lain menghasilkan efeknya dengan mekanisme yang berbeda
(efek agonis parsial pada reseptor 5-HT1A otak), misalnya, Buspirone — agen anti-
kecemasan non-gabanergik. Kerugian dan kelemahan: Kecenderungan untuk menghasilkan
ketergantungan psikologis (tidak terkait dengan konsentrasi serum darah) yang dikenal
sebagai gejala penarikan yang ditandai oleh kegelisahan, tremor, agitasi dan gangguan tidur,
efek amnesik, efek depresi sinergik dengan alkohol dan depresan SSP lainnya (alkohol, agen

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antidepresan) ), toleransi (penurunan respons dengan paparan berulang), dan barbiturat

memiliki indeks terapi yang sempit, efek mabuk, dan ketergantungan fisiologis (Katzung
2001).

Pentingnya mempelajari obat-obatan herbal kecemasan: Selain intoleransi mereka

terhadap efek samping, aksi formulasi herbal telah ditemukan sebanding dengan agen
anxiolytic allopathic sebagai hasil dari banyak penelitian yang dilakukan di daerah ini.
Berbagai keamanan telah dikaitkan dengan agen anxiolytic herbal dibandingkan dengan efek
samping yang parah dari agen allopathic dalam kasus paparan lama (toleransi, fisiologis, dan
ketergantungan psikologis), toksisitas parah dengan dosis berlebihan (depresi SSP, sistem
pernapasan, dan sistem kardiovaskular) depresi), selain masalah psikososial yang terkait
(mabuk, penurunan pekerjaan, depresi aktivitas alat gerak). 54% pasien dengan gangguan
kecemasan dan depresi menggunakan obat-obatan alternatif / komplementer dimana 38%
menggunakan obat-obatan herbal (Brown dan Gerbarg 2001).

Mekanisme kerja persiapan anxiolytic herbal: Penghambatan 5-HT, DA, NE reuptake,

berpartisipasi dalam downregulation reseptor 5-HT, agonis GABA, BZ, 5-HT dan
glutaminergic NMDA-type reseptor, blok saluran Na (blok Conner dan Davidson) 2002

Mekanisme aksi: aktivitas mimesis GABA. Para peneliti dari Fakultas Kedokteran
dan Ilmu Kesehatan Universitas George Washington, program dewasa Psychopharmacology
di National Institute of Mental Health, dan San Antonio Cochrane Center meninjau semua
literatur tradisional mengenai ramuan Ayurvedic ini. Mereka menempatkan ramuan ini pada
uji klinis untuk menentukan keamanannya dan ditemukan memiliki aktivitas ansiolitik dan
antidepresan. Studi toksisitas tidak mengungkapkan efek samping yang signifikan
(www.holistic.com, ramuan untuk kecemasan). Ini diinduksi efek anxiolytic, sebanding
dengan yang diproduksi oleh lorazepam, di labirin ditambah tinggi, interaksi sosial, dan
latensi makan di lingkungan yang tidak dikenal (Bhattacharya et al. 2000). Studi lain di
Departemen Farmakologi, University of Texas, menemukan aktivitas mirip GABA di
Withania somnifera.

Hasil ini menunjukkan bahwa ekstrak W. somnifera mengandung bahan yang

memiliki aktivitas mimesis GABA. Aktivitas ini berkorelasi dengan efek anti-ansiolitik
(Mehta et al. 1991). Dosis: 150-300 mg ekstrak akar seperti yang disebutkan oleh asosiasi
farmasi Amerika, 2-3 g bubuk akar tiga kali sehari, dan kapsul 2-5 mg withanoloides (Duke
2002).

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