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Antipsychotic Drug Treatment for Patients with Schizophrenia: Theoretical

Background, Clinical Considerations and Patient Preferences

Article  in  Clinical Medicine: Therapeutics · January 2009

DOI: 10.4137/CMT.S2175 · Source: DOAJ

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Clinical Medicine: Therapeutics

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Antipsychotic Drug Treatment for Patients with Schizophrenia:

Theoretical Background, Clinical Considerations and Patient
Preferences

René Ernst Nielsen and Jimmi Nielsen

Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, Aalborg, Denmark.
Email: ren@rn.dk

Abstract: The cornerstone in treatment of psychosis is antipsychotic drugs. Treatment options have increased over the years; newer
antipsychotic drugs with a proposed increased efficacy regarding negative and cognitive symptoms, but also a shift in side-effects
from neurological side-effects to metabolic side-effects have arisen as the new challenge. The basis of successful pharmacological
treatment is a fundamental understanding of the mechanisms of action, the desired effects and side-effects of antipsychotic drugs,
a good relationship with the patient and a thorough monitoring of the patient before and during treatment. The clinically relevant
aspects of antipsychotic drug treatment are reviewed; mechanism of antipsychotic drug action, clinical considerations in treatment,
switching antipsychotic drugs, polypharmacy, safety and patient preference.

Keywords: schizophrenia, treatment, antipsychotic, atypical, interaction

Clinical Medicine: Therapeutics 2009:1 1053–1068

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Clinical Medicine: Therapeutics 2009:1 1053

Nielsen and Nielsen
Introduction
The basis of successful pharmacological treatment is a
fundamental understanding of the mechanisms of action,
the desired effects and side-effects of antipsychotic
drugs, a good relationship with the patient and a
thorough monitoring of the patient before and during
treatment. The treatment of psychotic symptoms should
not solely be based on psychotropics, but also include
psychosocial and psychotherapeutic interventions.1
The introduction of chlorpromazine by Laborit,
Delay and Deniker in 1952 changed the treatment
of psychosis dramatically,2,3 and initiated the
development of several new antipsychotic drugs, all
with a dopaminergic receptor antagonism in common.4
A promising new class of antipsychotic drugs appeared
in the 1990s with a proposed increased efficacy regarding
negative and cognitive symptoms, but also a shift
in side-effects from neurological side-effects to
metabolic side-effects as the new challenge.5–7 After
more than ten years with atypical antipsychotic drugs,
the gloss is wearing off and studies now suggest the
clinical differences are small and the side-effects
troublesome.8
The authors hope that this clinical overview will
throw light on the different antipsychotic drugs,
desired effects, side-effects, safety concerns and
the importance of patient preferences, and by that
improve the treatment of patients with psychosis.
Mechanism of Action
Dopamine hypothesis
The dopamine hypothesis attributes disturbed dopamine
neurotransmission as an explanation for symptoms
in schizophrenia.9 Patients with schizophrenia have an
increased activity in the mesolimbic dopamine receptor
systems which is believed to be responsible for the
psychotic or positive symptoms, e.g. hallucinations and
delusions.4 The level of dopamine in the prefrontal
cortex is lower compared to healthy controls, probably
causing negative and cognitive symptoms.9 The reduced
striatal dopamine receptor activity, as a result of
treatment with dopamine D2 blocking agents, causes
extra pyramidal side-effects (EPS).9 The antagonistic
dopaminergic effect on the pituitary gland causes
hyperprolactinemia.
Since the advent of chlorpromazine, the
dopaminergic system has had a core role in our
1054 Clinical Medicine: Therapeutics 2009:1
understanding of how antipsychotic drugs work.10
Newer neuroimaging binding studies show that
blocking the dopamine D2 receptors more than
60%–70% corresponds to the antipsychotic effect
whereas blocking more than 75% increases the risk
of EPS.11,12 This theory is questioned by the fact
that clozapine, the antipsychotic drug with the
highest efficacy,5,13 only has a dopamine D2 receptor
blockage of 40% in clinical relevant dosages11 which
suggests that antipsychotic effect is more than pure
dopamine D2 receptor antagonism.
The glutamate hypothesis
Glutamate functions as the main excitatory neuro-
transmitter in the brain, and is involved in many functions
e.g. cognition and perception.14 The glutamate receptors
are divided into ionotropic and metabotropic receptors
consisting of several subunits,15 where the ionotropic
N-methyl-D-aspartate (NMDA) receptors is of special
interest in schizophrenia research and treatment.16
The glutamate hypothesis presumes hypofunction
of the glutamatergic system causing symptoms of
schizophrenia,16 partly by increasing dopaminergic
tone in the mesolimbic system secondary as a result
of the aforementioned glutamatergic hypofunction.16
NMDA receptors in particulary have been implicated
in the pathogenesis, but their role is not fully elucidated,
although trials with e.g. ketamine and phencyclicine
(PCP) that antagonize the NMDA receptor has
been shown to induce symptoms mimicking the
positive and negative symptoms of schizophrenia in
healthy volunteers, and worsen symptoms in patients
with schizophrenia.15 Data on brain morphology
postmortem and NMDA receptors has been gathered,
but no clear conclusions has been drawn.15 There
has also been focus on genes coding for the NMDA
receptor, both in studies of animals with knock-out
genes but also in humans with gene-mapping;16 but
again no clear conclusions can be drawn.16
The use of glutamate NMDA receptor agonists in
combination with dopamine blocking antipsychotic
drugs have only been used in trials, and no compounds
have reached the market yet.17 The trials have generally
been small, on treatment refractory patients and have
not been conclusive;17 further research is still needed.
This review will focus on drugs marketed and used
for treating patients with psychosis and experimental
drugs will not be discussed further.
 Antipsychotic drug treatment for patients with schizophrenia

Types of antipsychotic drugs Receptors and Antipsychotic Drugs

Antipsychotics are usually divided into typical/first Dopamine receptors
generation, or atypical/second generation antipsychotics.18 The dopaminergic system consists of five receptors
No clear terminology or definitions exist. In this overview named D1 to D5 divided into two families, the D1-like
the terms typical and atypical antipsychotic drugs will receptor family consists of the D1 and D5 receptors,
be used. and the D2-like receptor family consists of the D2
What makes atypical antipsychotic drugs to D4 receptors.9,36 As described earlier, the dopamine
atypical is not clearly defined, but a low tendency D2 receptor is essential in the pathophysiology of
to produce EPS and a low frequency of sustained psychotic disorders. The effects of the remaining
increased levels of prolactin are often used in the receptors are not fully elucidated, e.g. the D1
definition.19–21 The atypical antipsychotic drugs are and D4 receptors, are probably involved in the
listed in Figure 1. mechanism of cognitive symptoms in patients with
EPS was a common side-effect when treating psychotic schizophrenia.9,37
symptoms in patients with typical antipsychotic
drugs.22 This side-effect was not seen as frequent with Serotonin receptors
atypical antipsychotic drugs,23 due to either a more The serotonergic (5-HT) receptor system is also
selective mesolimbic dopaminergic blockade,24,25 involved in the mechanism of action of antipsychotic
a powerful serotonergic antagonism on the 5-HT2A drugs, as most atypical antipsychotic drugs have
receptor26 a 5-HT1A agonism, or a rapid dissociation an antagonistic effect on the 5-HT2A receptor and
from the dopamine D2 receptor.7,19 a partial agonistic effect on the 5-HT1A receptor.26
The atypical antipsychotic drugs gave hope for This mechanism is probably responsible for an
better compliance due to fewer side-effects,18 but time increase in nigrostriatal and prefrontal cortex
has shown that atypical antipsychotic drugs do not release of dopamine resulting in lower levels of
improve compliance compared to typical antipsychotic EPS and perhaps fewer cognitive side effects,
drugs,27–31 and although EPS is no longer the most respectively.26 The D2/5-HT2A ratio seems to be
troublesome side-effect,22,23 other side-effects have more important for an anti-EPS profile than the
arisen, e.g. weight gain, dyslipidemia and decreased absolute 5-HT2A affinity.26 The 5-HT2C receptor has
insulin sensitivity.18,32–34 been associated with increased appetite, especially
All antipsychotic drugs have the dopamine D2 in combination with affinity for the histaminergic H1
receptor blockade in common,4,35 but variations in receptor26,38,39 as described later. A genetic variation
other receptor affinities differentiate the side-effects of on the 5-HT2C receptor could also be involved in
antipsychotic drugs. A short description of clinically the pathogenesis of antipsychotic drug induced
relevant receptors will follow. weight gain.40

Amisulpride Aripiprazole Clozapine lloperidone Olanzapine Paliperidone Quetiapine Risperidone Sertindole Ziprasidone
Anticholinergic
Autonomic
EPS
Metabolic
Sedation
Prolactin

Side-effect occurs only rarely

Side-effect occurs, but treatment can be initiated in patient with decreased sensitivity
Side-effect is common and severe, but treatment can be initiated in patients with decreased sensitivity if special circumstances points toward treatment

Receptor affinities Amisulpride Aripiprazole Clozapine lloperidone Olanzapine Paliperidone Quetiapine Risperidone Sertindole Ziprasidone
Dopamine (+++) (+++) (+) (+++) (++) (+++) (+) (+++) (+++) (++)
Muscarine (−) (−) (+++) (−) (+++) (−) (−) (−) (−) (−)
Adrenergic (−) (+) (+++) (+++) (++) (+++) (+++) (+++) (+++) (++)
Histaminergic (−) (−) (+++) (−) (+++) (+) (+++) (+) (−) (+)
T½ 12 hours 3–4 days 12 hours* 18 hours 30 hours 23 hours 7 hours 24 hours** 2–4 days 6–8 hours

Figure 1.
#
Adapted from the Danish Society of Clinical Psychopharmacology.
*Metabolism is biphasic with great interindividual variation (T½ = between 6–26 hours).
**Metabolism of the risperidone molecule has a T½ of 2–4 hours, but 9-hydroxy risperidone has T½ of 24 hours.

Clinical Medicine: Therapeutics 2009:1 1055

Nielsen and Nielsen
Adrenergic receptors
Animal studies have shown that a central α-1
receptor antagonism has a stabilizing effect on
dopamine release in the mesocorticolimbic part of
the brain, which is the proposed mechanism behind
antipsychotic effect.41,42 The central α-1 receptor
antagonism is not only believed to be involved in
the mechanism of antipsychotic effect but also in
sedation,41 which is evident in patients treated with,
e.g. clozapine.41,42
The α-2 receptor antagonistic effect of many
antipsychotic drugs is not fully understood, but the
combination of α-2 receptor antagonism and dopamine
D2 antagonism has been proposed as mediating
antipsychotic effect at lower D2 occupancies.41
The peripheral effects of adrenoreceptor blockade
are discussed in the safety paragraph of this
overview.
Muscarinic receptors
The cholinergic system consists of nicotinergic and
muscarinergic receptors but antipsychotic drugs mostly
affect the muscarine system. The muscarinic receptor
system consists of 5 receptors named M1 to M5.43
A muscarinic antagonism, or anticholinergic effect,
is especially seen in the older high dose/low potency
antipsychotic drugs, e.g. chlorpromazine, but also
seen to a lesser extent in some of the atypical drugs,
e.g. olanzapine and clozapine.43 The anticholinergic
effect reduces EPS through the M4 receptor antagonism,
but increases the risk of confusion, seizures,
constipation, urinary retention, sinus tachycardia and
cognitive deficits.43–46 The muscarinic receptor system
modulates the dopaminergic system when used in
the treatment of EPS, through M4 antagonism that
increases the dopaminergic load in the nigrostriatal
area.43 Muscarinic agonism has been proposed
as mediating decreased dopaminergic tone in the
mesolimbic area, and thereby decreasing psychotic
symptoms.43
The antagonistic effect of some antipsychotic
drugs on the muscarinic M3 receptor has been
implicated in the development of diabetes by a direct
inhibitory effect of the pancreatic β-cells insulin
release.38,47
The nicotinergic receptor agonistic drugs have
shown promise in the treatment of negative and
cognitive symptoms in patients with schizophrenia.48
1056 Clinical Medicine: Therapeutics 2009:1
Histamine receptors
The histaminergic receptor system consists of four
receptors labeled H1 to H4 with the H4 receptor primarily
located peripherally.49 Both the atypical and typical
antipsychotic drugs exert antagonistic properties
on the histamine receptors, especially, olanzapine,
quetiapine and clozapine.50 The histaminergic receptor
antagonism on the H1 receptor is involved in the
changed feeding patterns, increased appetite and
decreased satiety, mediating the antipsychotic drug
induced weight gain.33,49,50 Sedation and decreased
arousal are also linked to the H1 receptor and,
moreover, sedation decreases cognitive functioning.
As a consequence, histamine receptor agonists are
targets for future cognitive enhancing drugs.49,51
Treatment with Antipsychotics
Efficacy vs. effectiveness
Two concepts are important when discussing the effects
of antipsychotic drugs: Efficacy and effectiveness.
Efficacy is defined as “the ability to produce the
desired beneficial effect in expert hands and under ideal
circumstances” and is derived from double-blinded
randomized clinical trials. In these trials, rating scales for
measuring psychopathology and side-effects are used.
In- and exclusion criteria for these trials are often very
stringent, and participants eligible for these trials often
differ from the patients everyday clinical psychiatrists
treat as substance abuse, somatic comorbidity,
compulsory measures, etc are not allowed.52
Effectiveness is defined as “the ability of an
intervention to produce the desired beneficial effect
in actual use” and consist of four domains: Efficacy,
tolerability and safety, function and acceptability.53
An example of effectiveness as outcome measure
is time to any cause of discontinuation as used in
the CATIE trial that compared several atypical
antipsychotic drugs and one typical antipsychotic
drug.8 This outcome measure might treat some drugs
unfairly because patients are more likely to drop-out
early due to acute side-effects such as EPS or sedation
whereas e.g. weight gain occur over time and is less
likely to cause early discontinuation.
Meta-analysis suggests that some of the atypical
antipsychotic drugs are more efficacious than
others.1354 Besides clozapine, olanzapine, amisulpride,
risperidone and zotepine seem to be more efficacious
than typical and other atypical antipsychotic drugs.13
 Antipsychotic drug treatment for patients with schizophrenia
Clozapine has shown superiority in treatment-resistant
patients, but this unique effect has not been found in
non-treatment-resistant patients.55
Clinical recommendations
Antipsychotic drugs should ideally not be used until a
proper physical examination has been performed, but
this might not be possible due to lack of cooperation
from the patient. For the typical antipsychotics, the
dose-response relationship seems to be an inverted
u-curve,56 suggesting excessive high dosages cause
side-effects such as sedation and EPS which often are
misinterpreted as negative symptoms. Similar is not
found with the atypical antipsychotics which might
be due to lesser tendency to cause EPS.57 Therefore,
patients should always receive the lowest effective
dosage in order to get the optimum treatment of their
symptoms with as few side-effects as possible. The
optimum dosage is differentiated with higher dosage
in the acute phase, and after stabilization an effort to
reduce the dosage in the maintenance phase should
be done. Today, atypical antipsychotic drugs are
considered first line drugs and typical antipsychotic
drugs should be reserved for patients not responding
to atypical antipsychotic drugs due to an increased
risk of developing TD.58 Even though, meta-analysis
support some difference in efficacy between the
atypical antipsychotic drugs, so far clinical response
has been highly individual and unpredictable59
suggesting that choice of antipsychotic drugs should
be based on prior response to treatment, side-effect
profile and the patient’s preference. In case of non-
or partial response more efficacious drugs, even
with a less tolerable metabolic profile, should be
used. Clozapine should be reserved for patients not
responding to at least two antipsychotic drugs, or
patients with schizophrenia having tardive dyskinesia
or severe suicidal ideations.60 In cases of persistent
aggression in schizophrenia clozapine might be of
value due to a special antiaggressive effect.61
Depot formulations
of antipsychotic drugs
Antipsychotic drug treatment is associated with a
lower risk of relapse compared to placebo treatment,62
but non-adherence to treatment is common when
treating patients with schizophrenia.63 Reasons for
non-adherence are many, but cognitive difficulties or
Clinical Medicine: Therapeutics 2009:1 1057
lack of a daily routine for medication are common.30,64
The clinical assessment of adherence is difficult and
sometimes inaccurate, which can delay intervention.63
When using long-acting injectable antipsychotic drugs
adherence to treatment is known, and it is possible to
intervene at an earlier stage, if the patient discontinues
treatment.64 The assortment of atypical long-acting
injectable antipsychotic drugs is increasing, as drugs
are in pipeline for marketing.
Time to onset of antipsychotic drug effect
It has been assumed that the antipsychotic effect
occurred after several weeks of treatment.65 The
delay in treatment response was explained by the
“depolarization block” theory; this theory arose
from animal studies that showed continued firing
from the dopamine neurons for three weeks after
the antipsychotic drug treatment was initiated.66,67
Newer studies have shown an earlier effect,68–70 some
with effect in the initial 24 hours.68 Other studies
have shown the greatest improvement in psychotic
symptoms within the first two weeks compared
to every two week period afterwards.65 There is an
important distinction to be made between onset of
antipsychotic drug effect and full clinical effect of the
drug. There is no doubt that time to full clinical effect
is delayed weeks to months, but the initial effect
occurs earlier, and is distinguishable from a pure
sedative effect.65,68 Agitation in the acute phase of a
psychotic breakthrough is common, and treatment
thereof by either antipsychotic drugs or tranquilizers
is important to minimize distress for the patient.71
Switching Antipsychotic Drug
Treatment
Switching antipsychotic drug treatment is common,
e.g. shown in the CATIE trial, where all cause of
discontinuation was the primary outcome.8 The study
was conducted under circumstances that resembled the
everyday clinic, and showed that 74% of participants
changed medication within 18 months.8
The most common reasons for switching
antipsychotic drug treatment are lack of efficacy or
side-effects. Before switching a balance between the
anticipated effects and side-effects should always
be thoroughly discussed with the patient,72 and the
following should be considered: Method of switch,
pharmacokinetics of the antipsychotic drugs, risks
Nielsen and Nielsen
during change and adverse events in conjunction with
switching treatment.
Switching can be done either abruptly by
discontinuing the prior treatment and initiating the
new treatment at the same time; gradual switch by
tapering off prior drug before initiating the new drug
or cross tapering by tapering off prior drug while
initiating the new drug. No evidence supports using
any specific method of switching.73
Pharmacokinetic considerations
The half life of the drugs used in the switch is
important for timing of the switch. If switching from
a drug with a long half life, e.g. depot formulation or
aripiprazole, a slow down tapering is not necessary,
as the concentration decreases slowly. In contrast,
e.g. quetiapine has a short half life, and therefore the
new drug should be initiated and titrated up, before
lowering the dosage of quetiapine.74
Below are the different important receptor systems
discussed in relation to switch of antipsychotic drug
therapy. The general description of the receptor
systems can be found in the mechanism of action
paragraph.
Dopaminergic considerations
Switch from a drug with a high affinity for the
dopaminergic receptor to a drug with a lower affinity
encompasses a risk of rebound psychosis.75 This is
probably caused by dopamine hypersensitivity in
the mesolimbic system where physiological levels
of dopamine can cause psychosis because of lower
dopaminergic antagonism. There is also a risk of
rebound tardive dyskinesia that has been hidden by EPS
on the previous drug, or caused by the hypersensitivity
of dopamine receptors.75 The occurrence of switch
emergent EPS can be seen when switching from a
drug with a low affinity for the dopamine receptor to
a drug with a higher affinity.
Histaminergic considerations
The main concern when switching between drugs with
different affinities for the histaminergic receptor is
sedation or lack hereof.75 Switching from a drug with
high histaminergic receptor affinity to a drug with
lower affinity, symptoms of histaminergic rebound can
occur, e.g. insomnia. The opposite switch can result
in massive sedation, and possibly lower adherence to
1058 Clinical Medicine: Therapeutics 2009:1
treatment, if the patient isn’t informed of the effect.
Rebound insomnia usually resolves with time, but
can be minimized with a slow cross tapering, or
with a short period of treatment with tranquilizers,
e.g. benzodiazepines.75
Muscarinergic considerations
There is risk of muscarinergic rebound when
switching from a drug with a high anticholinergic
effect to a drug with a lower or no antagonistic effect
on the muscarine receptor. The symptoms are nausea,
vomiting, diaphoresis and sometimes insomnia.75
Slow tapering off the medication usually resolves
the problem, but when an abrupt discontinuation is
necessary, e.g. agranulocytosis on clozapine treatment,
substitution with anticholinergic drugs can minimize
rebound symptoms.74
Conclusions on switching
Ideally before initiating a change in antipsychotic
drug treatment, the patient should be treated with
the initial antipsychotic drug in clinical relevant
dosages and for sufficient time to see improvement.
The patient should in general be informed about the
risks of adverse events and also the possible gains of
a switch, as to give the patient adequate information
to make an informed decision regarding treatment,
but also to prepare the patient for possible adverse
events.
The authors recommend the cross-titration method
because this method probably has the lowest risk of
relapse but the abrupt switch is necessary in cases of
severe adverse events. The physician should consider
the pharmacokinetics, receptor profiles of the drugs
and reasons for changing medication before planning
the switch. Atypical antipsychotic drugs receptor
affinities and side-effect profiles can be seen in
Figure 1.
Polypharmacy and Concomitant
Medication
Little is known about the combination of antipsychotic
drugs, and the use of concomitant medication such as
benzodiazepines, antidepressant or anticonvulsants
as described below. Antipsychotic polypharmacy
is defined as the concurrent use of two or more
antipsychotic drugs in a single patient.76,77 The use of
antipsychotic polypharmacy is common even though
 Antipsychotic drug treatment for patients with schizophrenia
the evidence is sparse and mostly indicates increased
adverse effects, with no increased symptom control.76
Polypharmacy is used in several other fields of
medicine, e.g. treatment of  hypertension, where
drugs usually have different pharmacological
mechanisms of action, e.g. beta blockers and thiazide
diuretics for hypertension. The assumed dopamine D2
blocking mechanism behind antipsychotic drug
action is universal to all antipsychotic drugs, although
differences exist in receptor affinities for other
receptors as described earlier. The theoretical reason
for combining drugs to increase the antipsychotic
effect is therefore limited.77 Polypharmacy can be
necessary in cases of, e.g. cross-titration and in the
treatment of breakthrough psychosis.76
If patients experiences antipsychotic drug induced
hyperprolactinemia, and dose reduction or change
of medication is impossible, concomitant treatment
with aripiprazole should be considered as this has
shown promise in reducing prolactin levels.78–80 The
mechanism behind this is probably a dopaminergic
agonistic effect on the pituitary gland by aripiprazole,
a partial dopamine agonist.78,80,81
Studies combining antipsychotic drugs with each
other have shown limited effect on the psychotic
symptoms in general, and in some cases even increased
the burden of side-effects.77 The augmentation of
antipsychotic drugs due to lack of efficacy should
generally not be used until treatment with clozapine
has been tried.13
In cases of partial response to clozapine,
augmentation of clozapine with anticonvulsants
has shown some promise in improving psychotic
symptoms,82,83 although the primary use of
anticonvulsants in combination with clozapine is to
lower risk of seizures during clozapine treatment.84
The combination of clozapine and atypical
antipsychotic drugs has not shown great promise in
improving antipsychotic effects, although studies
have been conducted on e.g. risperidone, amisulpride,
and aripiprazole.85–90 A meta-analysis has shown a
small but significant effect, but the clinical relevancy
of this is doubtful.91 The results of augmentation due
to reduction of side-effects seem more promising.
The combination of antipsychotic drugs and
benzodiazepines is used for treating anxiety and
agitation even though evidence is sparse.92 The
difficulties in benzodiazepine drug treatment are well
Clinical Medicine: Therapeutics 2009:1 1059
known, e.g. addiction, cognitive problems, sedation
and withdrawal symptoms.92,93
Depression occurs in patients with schizophrenia,
and treatment depends on the phase of the psychotic
disease. The dose of antipsychotic drugs should be
increased when dealing with psychotic patients.
Antidepressants should be reserved for patients with
psychotic symptoms under control.94 One of the major
problems with diagnosing depression in patients with
schizophrenia is the existence of negative symptoms,
e.g. anhedonia, decreased range of expressed
emotion and lack of motivation, which can imitate
depression.95 The Calgary Depression Scale for
Schizophrenia can help to diagnose depression in
patients with schizophrenia differentiating depressive
from negative symptoms.95
Safety
Safety and side-effects
The side-effects of antipsychotic drugs are many but
most side-effects can be linked to a single receptor
whereas the mechanisms of others are more complex
or remain unknown. Antipsychotic drugs are often
used in patient populations where e.g. taking
overdose, substance misuse and increased burden of
cardiovascular risk factors are common. This increases
the demands of monitoring safety when treating with
antipsychotic drugs. Patients with schizophrenia
have a reduced lifespan of approximately 15 years,
even when controlling for suicide and accidental
deaths, with cardiovascular disease as main cause of
death. The exact contribution of medication remains
unknown.96
Cardiovascular and metabolic
side-effects
From the very beginning of the antipsychotic era,
antipsychotic drugs have been associated with
sudden death.97 Sudden death in otherwise healthy
people is probably related to cardiac arrhythmia
secondary to electrophysiological changes of ion
channels in the heart.98 Prolongation of the QT
interval to more than 500 ms has been associated with
an increased risk of developing the potential fatal
cardiac arrhythmia Torsade de Pointes (TdP).99,100
However, this mechanism only accounts for a minor
part of the increased mortality seen in patients
with schizophrenia.101 The antipsychotic-induced
Nielsen and Nielsen
metabolic changes such as weight gain, increased risk
of developing diabetes and dyslipidemia are far more
important.102,103 Clozapine, olanzapine and quetiapine
account for the antipsychotic drugs that cause the
worst metabolic changes but results from studies
in first-episode psychosis suggest that drugs prior
considered as weight neutral such as ziprasidone are
associated with a moderate weight gain.104,105 Most
trials comparing antipsychotic drug effects on weight
gain are limited by the fact that patients are receiving
antipsychotic drugs at baseline, i.e. patients switched
from a drug with high weight gain potentials to a drug
with lower weight gain potentials would gain less
weight or perhaps even lose weight on the new drug
and vice versa. The mechanism of antipsychotic drug
induced diabetes is probably related to decreased
insulin sensitivity which is worsened further by
weight gain and central adiposity.106 For olanzapine
and clozapine, a direct diabetogenic effect regardless
of weight gain has been established.102 Diabetic
ketoacidosis can occur as an acute complication of
antipsychotic treatment.107 Olanzapine and clozapine
seem to have the highest prevalence but most cases are
reversible when discontinuing the offending drug.108
Glycosylated hemoglobin (HbA1c) is often elevated in
these patients,107 and a decreased HDL and increased
triglycerides are associated with an increased risk
of insulin resistance.38 It should be mentioned that
estimating the contribution of the drug to metabolic
status might be difficult due to other factors such as a
sedentary lifestyle.109
Dyslipidemia increases the risk of cardiovascular
disease due to arteriosclerosis. Atypical antipsychotic
drugs affect both triglyceride and cholesterols.38
Results from the CATIE trials suggest that of the
atypical antipsychotic drugs clozapine, olanzapine and
quetiapine affect triglyceride and cholesterols the most.8
Patients with antipsychotic-induced dyslipidemia
might benefit from life-style interventions or switch
to a more metabolic tolerable antipsychotic drug, but
in many cases treatment with statins is necessary.
Several antipsychotic drugs function as antagonists
at the α1 noradrenergic receptors causing venous
vasodilatation and a drop in blood pressure. To maintain
the same cardiac output, an increase in the heart rate,
called reflex tachycardia, occurs.110 Drugs with potent
α1 antagonism cause orthostatic hypotension but
tolerance to this side-effect usually develops after a
1060 Clinical Medicine: Therapeutics 2009:1
few weeks and can be minimized by up-titrating the
dose slowly. Especially, elderly and pregnant women
are vulnerable to α1 induced side-effects. Increases in
heart rate during treatment with antipsychotic drugs
can also occur due to blocking of the cholinergic
receptors.110
Extrapyramidal side-effects
Extrapyramidal side-effects (EPS) occur due to
blocking of more than 75% of the dopamine receptors
in the striatum as described in the mechanism of
action paragraph. Atypical antipsychotic drugs cause
less EPS than typical antipsychotic drugs but a dose-
dependent relationship exist meaning that virtually
all antipsychotic drugs are capable of causing EPS,
even the atypical antipsychotic drugs.111 Clozapine
and quetiapine have lower affinities for the dopamine
receptors resulting in a rare association with EPS.112
Monitoring of  EPS is important because EPS has
been associated with poor compliance, reduced
quality of life, increased suicide rate and avoiding
acute EPS symptoms decreases the risk of tardive
dyskinesia.113 EPS consists of  the four following
domains: Parkinsonism, dystonia, akathisia and
dyskinesia.113
Parkinsonism is manifested as bradykinesia,
tremor, rigidity and postural instability. Bradykinesia
can easily be misdiagnosed as the negative symptoms
of schizophrenia or major depression. Management
of Parkinsonism includes reducing the antipsychotic
drug dose or switching to a drug with lesser tendency
to cause EPS. Anticholinergic drugs are effective for
treating antipsychotic drug induced Parkinsonism,
but due to side-effects e.g. dry mouth, cognitive
impairment, and tachycardia they should be reserved
for emergent situations.43
Dystonia occurs most frequently after intramuscular
injections of conventional antipsychotic drugs and
younger male patients seem to be at higher risk.114
It can affect several muscle groups leading to
oculogyric crisis (extraocular), blepharospasm (eyelid),
buccolingual crisis (face, jaw, and tongue), opisthotonus
(paravertebrals), retrocollis, anterocollis, torticollis
involving neck, tortipelvic crisis (trunk and pelvis),
or laryngeal-pharyngeal dystonia. Acute laryngeal
dystonia is a potential fatal condition.115 Administration
of intravenous anticholinergic drugs and subsequent
dose reduction of the offending antipsychotic drug
 Antipsychotic drug treatment for patients with schizophrenia
often resolves the problem. A rare variant of dystonia
called tardive dystonia which has a poor outcome
and no response to anticholinergic drugs can occur.113
Botulinum toxin might help these patients.116
Akathisia is an inner feeling of restlessness
often located in the lower limbs presented in the
clinic as an inability to sit or stand calmly. It can
be misdiagnosed as agitation with the risk of
worsening the situation by increasing the dose of the
offending antipsychotic drug to treat the agitation.117
Treatment includes reducing the antipsychotic drug
dose or switching to a drug with less tendency to
cause akathisia. Anticholinergic drugs are seldom
effective in resolving akathisia, unless Parkinsonism
is present, whereas propranolol or benzodiazepines
often are more effective.113
Dyskinesia is most common in its tardive forms
and consists of involuntary movements and a specific
syndrome called buccolinguomasticatory (BLM)
syndrome which is one of the most common types.
Tardive dyskinesia usually occurs after several years
of treatment with typical antipsychotic drugs and
is often irreversible. The mechanism is not fully
understood but increased sensitivity at postsynaptic
dopamine receptors after longstanding antipsychotic
drug blockade is probably involved.118 Dose reduction
or switching to an atypical antipsychotic drug with
less affinity for the dopamine receptors is first choice
when treating tardive dyskinesia.119 Increasing
antipsychotic drug dosage might inhibit tardive
dyskinesia due to Parkinsonism but worsen the long-
term prognosis. In contrast, switching to a drug with
less affinity for the dopamine receptors might cause
a transient worsening of the tardive dyskinesia due
to less Parkinsonism. Anticholinergic drug treatment
should be discontinued as this often worsens tardive
dyskinesia. If the tardive dyskinesia does not resolve,
treatment with clozapine and/or tetrabenazine can be
initiated.119
The annual risk for developing tardive dyskinesia
is around 5% for the typical antipsychotic drugs and
around 1% for the atypical antipsychotic drugs.58
Seizures
Antipsychotic drugs lower the seizure threshold which
should be taken into account in patients at high risk
for seizures, e.g. alcohol withdrawal and epilepsy.120
Especially higher plasma levels of clozapine are
Clinical Medicine: Therapeutics 2009:1 1061
associated with seizures whereas risperidone seems
to be safer.121,122 The mechanism for antipsychotic
drug induced seizures remains speculative, but
involvement of muscarine and histamine receptors
has been suggested.120
Hyperprolactinemia
Secretion of prolactin from the pituitary gland is inhibited
by dopamine, and due to the dopamine receptor blocking
properties of antipsychotic drugs hyperprolactinemia can
occur. The symptoms are amenorrhea, gynecomastia,
galactorrhea, sexual dysfunction and osteoporosis.
Symptoms of hyperprolactinemia should always be
investigated and a probable cause found.
Increased prolactin levels have been associated
with an increase in the risk of breast cancer.123 The
lipid solubility of antipsychotic drugs is important
as high solubility facilitates easier diffusion over the
blood-brain barrier. Antipsychotic drugs with low
lipid solubility are given in higher dosages to reach
clinical relevant intrathecal concentrations, and as the
pituitary gland is located outside the blood-brain barrier
higher concentrations of dopaminergic antagonistic
drugs results in higher risk for hyperprolactinemia.124
Especially risperidone and amisulpride are associated
with symptomatic hyperprolactinemia due to their
low lipid solubility and high dopamine affinity,125,126
but paliperidone has also been implicated, but is not
as extensively studied yet.127 Quetiapine and clozapine
are not associated with hyperprolactinemia.124
Aripiprazole has due to the high affinity for
dopamine receptors and the partial dopamine agonist
mechanism the ability to reverse antipsychotic induced
hyperprolactinemia.78,128
Sedation
Several receptors e.g. muscarine M1, noradrenergic
α-1, serotonin 5-HT2A/C, GABAA and histamine are
involved in causing sedation.129 However, antipsychotic
drug sedation is mainly due to an antagonistic effect on
the histamine receptor.129 Antagonism at the dopamine
receptors can elicit anhedonia and lack of motivation,
mostly due to lack of reward and drive, but clinically
it can be difficult to distinguish from sedation induced
by antihistamine effects.130 FDA gave a black box
warning for parenteral olanzapine in combination
with benzodiazepines due to deaths probably caused
by excessive sedation.131 Same precautions should
Nielsen and Nielsen
be taken during titration of clozapine due to its
hypotensive and sedative properties, or other drugs
with similar receptor profiles.132
Neuroleptic malignant syndrome
All antipsychotic drugs are capable of inducing
neuroleptic malignant syndrome (NMS) which is a
potential fatal complication. The syndrome consists
of four symptoms: Hyperpyrexia, EPS, altered
mental state and autonomic instability, but not all are
necessarily present.133 Especially for NMS involving
atypical antipsychotics, EPS is not always present.134
Laboratory findings include elevated creatinine kinase,
leucocytosis and arterial blood gas acidosis. The
exact mechanism for NMS is unknown but dopamine
blockade is undoubtedly involved.135 In case of NMS
all antipsychotics drugs should be discontinued and
in more severe cases treatment with bromocriptine
and dantrolene is indicated.135 Benzodiazepines can
be used for treatment of mild to moderate cases,
and in controlling agitation. ECT is also effective in
treating NMS.135
Serious clozapine related side-effect
Clozapine is associated with blood dyscrasias;
approximately 0.8% develops agranulocytosis and 3%
neutropenia which elucidate the need for hematological
monitoring.136 Most cases of agranulocytosis occur
during the first six months of treatment and after a year
the risk is similar to treatment with phenothiazines.136
Olanzapine and quetiapine have also been associated
with neutropenia, but do not seem to cause
agranulocytosis.137,138
Besides the blood dyscrasias, clozapine is also
associated with myocarditis and tachycardia.
Myocarditis develops during the first months and
symptoms are: Fever, tachycardia, dyspnea and
chest pain. ECG might show ST-elevation, but the
best way to diagnose myocarditis is to do troponin
levels.139 Cardiomyopathy is a long-term side-effect
which seldom occurs until after six months of
treatment and common symptoms are: Peripheral
edema, tachycardia, exertional dyspnea and fatigue.
Cardiomyopathy is detected through ECG changes
and clinical symptoms, but should be confirmed by
echocardiography.140
Therapeutic drug monitoring (TDM) is
recommended during clozapine treatment due to the
1062 Clinical Medicine: Therapeutics 2009:1
large inter-individual variation in plasma levels and
because a therapeutic threshold at 350–420 µg/L
has been found. TDM in general has only a minor
role in dose adjustment of antipsychotic drugs,
because no concentration-response relationship has
been found for most antipsychotic drugs.141
Cognitive side-effects
Cognitive deficits are seen in patients with schizophrenia
before the onset of psychosis and initiation of
treatment,142,143 and can be linked to functional outcome,
e.g. employment and compliance to treatment.30,144
These deficits can be exacerbated or improved by
pharmacological interventions. Anticholinergic effect,
either administered as an anticholinergic drug, e.g.
biperiden, or as antagonistic effect on the muscarinergic
receptors decreases cognitive function, especially
memory and attention.46
Sedation reduces the general arousal level, and a
decreased or increased level of arousal can probably
impair cognitive functioning as suggested in the
Yerkes-Dodson law, which means that sedation,
e.g. histaminergic antagonism, can improve cognition
in hyperaroused patients and decrease cognitive
functioning in others.51
Other concomitant treatments can influence cognitive
functioning, especially treatment with benzodiazepines.
This has not yet been tested in patients with
schizophrenia, but cognitive testing on patients with
other chronic psychiatric disorders has shown
significant decreases in cognitive functioning compared
to controls, and a significant improvement after
discontinuation.93,145,146
Atypical antipsychotic drugs in comparison with
typical antipsychotic drugs show a slight advantage
in cognitive improvement in favor of the atypical
antipsychotic drugs, even though this finding is
questioned by suboptimal study designs in studies of
typical versus atypical antipsychotic drug effects on
cognitive functioning.147 This is further questioned by
findings indicating that the difference between atypical
and typical antipsychotic drugs is non-existing when
treating with optimal dosages of both drugs.147,148
Metabolism of antipsychotic drugs
The most important metabolic pathway for most
antipsychotic drugs is the cytochrome P450 (CYP450)
system149 that metabolizes drugs before they can be
 Antipsychotic drug treatment for patients with schizophrenia

excreted through the kidneys, but other metabolic
pathways like the aldehyde oxidases that is involved
in the metabolism of ziprasidone exist.149
The CYP450 system consists of over 50 different
enzymes that metabolize a large number of compounds
which allows the body to function under different
conditions and adapt to new expositions.150
The CYP450 enzymes primarily responsible
for the metabolism of antipsychotic drugs are
CYP1A2, CYP3A4 and CYP2D6.149,151,152 Most
antipsychotic drugs are metabolized by several
CYP450 enzymes,151 but an inhibition or induction
of the primary CYP450 enzyme can have clinical
implications for the individual patient depending on
the width of the therapeutic index of the involved
drugs, the existence of additional metabolic pathways,
patient’s sensitivity to desired and adverse effects
and the strength of the inhibition or induction.149
In Figure 2, an overview of the most important
substrates, inhibitors and inductors are depicted.
Induction of the CYP enzymes is a process that can
take up to several weeks before maximum effect
occurs, as it is caused by an increased production
of CYP450 enzymes. In contrast, inhibition occurs
immediately and reaches maximum effect when the
inhibiting drug reaches steady state.149 As induction
is caused by an increase in the CYP450 enzyme, the
effect is also prolonged after the offending drug is
discontinued, until the CYP450 enzyme again has
reached its habitual activity.149
Amisulpride and paliperidone are not metabolized
in the liver,149,152,153 but are excreted directly through
the kidneys unchanged. This knowledge can be used
when treating patients with severe liver disease.152
Patient Preference
Treatment of patients with psychotic illness
should not only focus on ameliorating psychotic
symptoms as measured by scales, but a more
holistic approach including the patient’s subjective
experience with the treatment, e.g. desired effects,
side-effects, cultural acceptance of treatment, and

substrate* Inductor Inhibitor

enzyme (causes decreased (causes increased
(A non-exhaustive list)
concentration of substrate) concentration of substrate)

Amitriptyline Caffeine Tobacco smoking Ciprofloxacine

Clomipramine Olanzapine Omeprazole Fluvoxamine**
cYp1A2 Clozapine Propranolol
Haloperidol

Amitriptyline Olanzapine Buproprion

Aripirazol Paroxetin Duloxetine
Clomipramine Perphenazine Fluoxetin**
Clozapine Risperidone Paroxetin**
cYp2D6 Fluoxetin Sertindole Terbinafine
Haloperidole Tramadol
imipramine venlafaxine
Nortriptylin Zuclopenthixol

Alprazolam Methadone Carbamazepine Clarithromycine

Amlodipine Quetiapine Hiv antivirals erythromycine
Aripiprazol Sertindole Oxcarbazepine Grapefruit concentrate
cYp3A4
Clozapine verapamil Perikum Hiv antivirals
Diazepiam Ziprasidone Phenobarbital ltraconazole
Hiv antivirals Ketoconazole

Figure 2.
#
Adapted from the Danish Society of Clinical Psychopharmacology.
*Several substrates metabolized by the same enzyme can increase plasma levels, but only if substrates surpasses enzyme capacity. This interaction is
seldom of clinical importance.
**Particularly potent inhibitors, consider alternatives.

Clinical Medicine: Therapeutics 2009:1 1063

Nielsen and Nielsen
pharmacological versus non-pharmacological
treatment should be applied.154 In the recent
years, a switch from compliance to adherence in
terminology and practice has occurred; the former
is the physician taking the major role in deciding
treatment and the latter is a patient-physician
collaboration concerning treatment.154,155
Decision to prescribe a drug is a balance between
perceived positive effects on one side and adverse
effects on the other side. This should be discussed with
the patient. The insight and awareness of symptoms
and the understanding of treatment needs increase
adherence whereas negative symptoms, cognitive
deficits and drug misuse decrease adherence.154
Insight and negative symptoms can be influenced
by information regarding the disease. A continued
discussion of pros and cons of treatment during the
entire course of the illness is important.1
The most common reported dissatisfactions
with treatment are side-effects, lack of involvement
in treatment planning, lack of information about
effects and side-effects and lack of involvement of
family members.154 The attention on side-effects
is important during any treatment and of course
also during treatment with antipsychotic drugs.
The method of inquiring about side-effects is of
significant importance.156 When using a standardized
questionnaire with open questions compared to
closed questions, a higher positive answer rate was
found.156
Not all side-effects are equally distressing to the
patient, and the differences are also seen in between
genders. In general, weight gain, depression, and
insomnia are more distressing than cognitive side
effects, sedation and sexual side-effects.154 Females
found weight gain more distressing than males, and
males found sexual side-effects more distressing
than females.154 It is the patient’s subjective feeling
of effect compared to the feeling of adverse effects
that tip towards either side resulting in better or worse
adherence to treatment.157
Adherence to treatment is important; it lays the
foundation for clinical effectiveness.154 It is of crucial
importance that the patient’s subjective feelings
of desired effect and side-effects on treatment
is noted and evaluated early and throughout the
course of the illness as these are associated with
adherence.154,156 This is important as low adherence
1064 Clinical Medicine: Therapeutics 2009:1
is associated with risk of relapse, risk of admission,
longer duration of admission and increased risk
of suicide.31,158 Good adherence to treatment is in
contrast associated with a better functional outcome
for the patient.159 The physician-rated symptom
scales can be useful in the evaluating progress
regarding symptoms, but must never stand alone in
the clinical practice.
Conclusions
Advances in treatment of psychosis have occurred
over the years including a plethora of newer
pharmacological interventions. These have come
with new challenges from side-effects, demands
for monitoring and safety measures. Up to date
psychopharmacological knowledge is therefore
essential for the physician. There has been a shift
towards greater patient involvement in treatment
decisions, and there is increased focus on the
patient’s subjective feelings regarding treatment
effects and side-effects, hopefully resulting in
better attitudes towards and greater adherence to
medication.
Disclosures
The authors report no conflicts of interest.
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