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review article
drug therapy
often underreport hypomanic and manic symp- pression with melancholic features, they are less
toms, perceiving such features to be closer to well- effective than SSRIs for bipolar depression, since
being than illness. A family history of bipolar dis- they can trigger mania or hypomania.40 SSRIs ap-
order can assist in making the correct diagnosis. pear to be less effective than either tricyclic anti-
depressants or selective norepinephrine-reuptake
antidepressant medications inhibitors for depression in which physical symp-
toms or pain is prominent.41 The SSRI fluoxetine
About half of moderate-to-severe episodes of de- is the only antidepressant that has consistently
pression will improve with antidepressant treat- been shown to be effective in children and adoles-
ment.32 Classes of antidepressant agents are de- cents,42 and SSRIs may be superior to selective nor-
fined by their mechanism of action (Table 1). Many epinephrine-reuptake inhibitors in young adults
agents with effective antidepressant action amplify (18 to 24 years of age),43 although they are more
serotonin or norepinephrine signaling by inhibit- likely to trigger mania in children.44
ing reuptake at the synaptic cleft (Fig. 1A and 1B).
The several classes of drugs include SSRIs, norep- norepinephrine-reuptake inhibitors
inephrine-reuptake inhibitors, and dual-action Nortriptyline, maprotiline, and desipramine are
agents that inhibit uptake of serotonin and norepi- tricyclic norepinephrine-reuptake inhibitors with
nephrine. Monoamine oxidase inhibitors (MAOIs) anticholinergic effects.45 Reboxetine is a selective
inhibit monoamine degradation by monoamine ox- norepinephrine-reuptake inhibitor with an effec-
idase A or B. Other antidepressant agents antago- tiveness similar to that of tricyclic antidepressants
nize a2–adrenergic autoreceptors with a resultant and SSRIs,32 though it is unavailable in the United
increase in the release of norepinephrine, antago- States.
nize 5-hydroxytryptamine2A (5-HT2A) receptors,
or both. dual-action antidepressants
Serotonin–norepinephrine reuptake inhibitors such
ssri s as venlafaxine, duloxetine, and milnacipran block
Clinical trials have shown little difference in efficacy monoamine transporters more selectively than
or tolerability among various available SSRIs32-34 tricyclic antidepressants and without the cardiac-
or between SSRIs and other classes of antidepres- conduction effects that can occur with tricyclic
sants.32,35-38 However, some specific differences agents.32 Some tricyclics (imipramine and amitrip-
should be noted. tyline) inhibit both serotonin and norepinephrine
The active metabolite of fluoxetine has a half- reuptake. The dual-action antidepressant venlafax-
life that is longer than that of other SSRIs, which ine appears to demonstrate superior efficacy and
permits once-daily dosing and thereby reduces the higher rates of remission in severe depression as
effect of missed doses and mitigates the SSRI dis- compared with either SSRIs such as fluoxetine or
continuation syndrome (described below). How- tricyclic antidepressants.46-48 The efficacy of du-
ever, fluoxetine should be used with caution in pa- loxetine is similar to that of the SSRI paroxetine.49
tients with bipolar disorder or a family history of Venlafaxine and duloxetine are effective for the treat-
bipolar disorder, because an active metabolite per- ment of chronic pain50 and diabetic neuropathic
sists for weeks and may aggravate the manic state pain, respectively,51 as well as pain occurring as part
in the event of a switch from depression to mania. of primary or secondary depression.52,53 Bupropi-
At higher doses, paroxetine and sertraline also on, which inhibits both norepinephrine and dopa-
block dopamine reuptake, which may contribute mine reuptake, has no direct action on the seroto-
to their antidepressant action. nin system and is generally similar in efficacy to
SSRIs can be helpful in patients who do not tricyclic antidepressants32 and SSRIs.54 Bupropion
have a response to tricyclic antidepressants, an is associated with less nausea, diarrhea, somno-
older class of drugs, and appear to be better toler- lence, and sexual dysfunction than are SSRIs54 and
ated with lower rates of discontinuation32,36,37,39 constitutes an effective alternative, or adjunctive
and fewer cardiovascular effects.39 Although tricy- therapy, for patients who do not have a response to
clic antidepressants may have greater efficacy than SSRIs.55,56
SSRIs in severe major depressive disorder or de-
Nausea or
Insomnia Anticholinergic Gastrointestinal Sexual
and Agitation Sedation Hypotension Effects† Effects Dysfunction Weight Gain
mg/day
Reuptake inhibitors
Selective serotonin- reuptake inhibitors
The
(SSRIs)
Fluoxetine (Prozac) 20 20–40 Low Moderate None or mild None or mild None or mild Moderate Moderate Mild
Paroxetine (Paxil) 20 20–40 Low Moderate None or mild None or mild Mild Moderate Moderate Mild
Sertraline (Zoloft) 50 50–150 Low Moderate None or mild None or mild None or mild Moderate Moderate Mild
www.nejm.org
new england journal
inhibitors (NRIs)
of
october 27 , 2005
Maprotiline (Ludiomil) 75 75–200 High Mild None or mild Mild Mild None or mild Mild Moderate
Mixed or dual-action reuptake inhibitors
Older agents (TCAs)
Amitriptyline (Elavil) 25–50 100–300 High None or mild Moderate Moderate Severe None or mild Mild Moderate
Dothiepin (Dothep)‡ 25–50 100–300 High None or mild Moderate Moderate Moderate None or mild Mild Moderate
Clomipramine (Anafranil) 25–50 100–250 High Mild Moderate Moderate Moderate Mild Mild Moderate
Imipramine (Tofranil) 25–50 100–300 High Moderate Mild Moderate Moderate None or mild Mild Moderate
Downloaded from www.nejm.org at UNIVERSITY OF ILLINOIS on August 26, 2010. For personal use only. No other uses without permission.
Newer agents (non-TCAs)
Venlafaxine (Effexor) (NRI plus SRI) 37–75 75–225 Moderate Moderate None or mild None or mild None or mild Moderate Moderate None or mild
Milnacipran (Ixel) (NRI plus SRI)‡ 50–100 100–200 Low Moderate None or mild None or mild None or mild Moderate Moderate None or mild
Bupropion (Wellbutrin) (NRI plus 150 150–300 Low Moderate None or mild None or mild Mild Mild None or mild None or mild
DRI)
Duloxetine (Cymbalta) (NRI plus 30 30–90 Low None or mild Mild None or mild Mild Mild None or mild None or mild
SRI)
MAOIs
Irreversible agents
Phenelzine (Nardil) 15 30–90 High Moderate Mild Moderate Mild Mild Moderate Mild
Tranylcypromine (Parnate) 10 20–60 High Moderate Mild Moderate Mild Mild Moderate Mild
www.nejm.org
drug therapy
Mirtazapine (Remeron) (5-HT2 plus 5-HT3 30 30–60 Low None or mild Severe Mild None or mild None or mild None or mild Severe
plus a2-adrenergic receptors)
Mianserin (Bolvidon) (5-HT2 plus a1- and 30 60–120 Low None or mild Moderate Mild Mild None or mild None or mild Mild
a2-adrenergic receptors)‡
Downloaded from www.nejm.org at UNIVERSITY OF ILLINOIS on August 26, 2010. For personal use only. No other uses without permission.
1823
The new england journal of medicine
A B
Autoreceptor
a2 5-HT1A
blockade
Noradrenergic Neuron Serotonergic Neuron
5-HT1B Autoreceptor
blockade
5-HT1D
NE Serotonin
b1 5-HT
post-synaptic a1
5-HT1A other?
receptor post-synaptic
receptor post-synaptic 5-HT2A
Stimulate post-synaptic receptor Block post-synaptic
receptors Stimulate receptor
Activate signal transduction and Second messenger
second messenger pathways effects
Starting Standard
Drug Dose Dose Main Side Effects
Weight Gain Lethargy Ataxia Nausea Tremor Other
mg/day
Mood stabilizers
Lithium 600–900 450–1500 Severe Mild None or mild Moderate Severe Polyuria, fatigue, hypo-
thyroidism, cogni-
tive deficits, acne,
headache, worsens
psoriasis
Lamotrigine 25 50–300 Mild Moderate Moderate Moderate None or Dizziness, headache,
(Lamictal) mild insomnia, severe
skin reactions (e.g.,
Stevens–Johnson
syndrome)
Valproic acid 15 per kg Up to 60 per Moderate Moderate Moderate Moderate Severe Headache, ovarian
(Depakene) of body kg of body cysts
or divalproex weight weight
(Depakote)
Diabetes
or Lipid Tardive Hypoten-
Weight Gain Sedation Increase Dyskinesia sion
Antipsychotic agents
Typical
Chlorpromazine 25 75–200 Moderate Severe None or mild Severe Mild EPS, sinus tachycardia
(Thorazine)
Haloperidol 2–6 10–20 None or None or None or mild Severe Mild EPS, akathisia, sinus
(Haldol) mild mild tachycardia
Atypical
Clozapine 25 300–400 Severe Severe Moderate None or Severe Low white-cell count
(Clozaril) mild
Olanzapine 5 10–20 Severe Mild Moderate Mild Mild EPS, hepatic effects,
(Zyprexa) dizziness
Risperidone 1–2 4–6 Mild Mild None or mild Mild Mild EPS, insomnia, agitation,
(Risperdal) CVA in dementia
Quetiapine 50 300–600 Mild Mild Mild Mild Moderate Somnolence, dizziness,
(Seroquel) dyspepsia
Aripiprazole 10–15 15–30 None or Mild None or mild Mild Mild EPS, insomnia, agitation,
(Abilify) mild anxiety
Ziprasidone 40–80 80–160 None or Mild None or mild Mild Mild EPS, constipation,
(Geodon) mild fatigue, insomnia,
QT prolongation
Thyroid supplement
Thyroxin 0.05 0.05–0.1 NA NA NA NA NA None if thyroid function
(Synthroid) is monitored
* These doses are standard in psychiatric practice but may not always conform to doses recommended in the Physicians’ Desk Reference or in
drug package inserts. EPS denotes extrapyramidal syndrome, CVA cardiovascular accident, and NA not applicable.
phase of treatment of a major depressive episode in tion, delusions, and psychomotor agitation) and
a patient with major depressive disorder, on the ba- there is a risk of suicide (previous suicide attempts
sis of the current literature and treatment models, or current plan for suicide).
which were developed as part of several large-scale Antidepressants are the treatment of choice for
studies of treatment algorithms.81-83 Hospitaliza- moderate-to-severe episodes of depression. Since
tion is needed if symptoms are severe (dehydra- most antidepressants that are used for major de-
Augment treatment:
First choice, lithium
Switch to new anti- Second choice, atypical Combine two anti-
depressant from a different antipsychotic agent depressants from different
pharmacologic class Third choice, lamotrigine pharmacologic classes
Fourth choice, thyroid
hormone
Figure 2. Algorithm for the Acute Treatment Phase of a Major Depressive Episode in Major Depressive Disorder.
SSRI denotes selective serotonin-reuptake inhibitor, NRI norepinephrine reuptake inhibitor, and ECT electroconvul-
sive therapy.
pressive disorder have similar effectiveness, the diovascular disease.45,84 Depression in persons 65
choice of medication depends on depressive symp- years of age or older generally requires relatively
toms (psychotic or suicidal), the history of re- low doses of antidepressants,85 and SSRIs appear
sponses to medication (including that of first- to be preferable to nonselective norepinephrine-
degree relatives), medication tolerability, adverse reuptake inhibitors, such as tricyclic antidepres-
effects, and the likelihood of adherence. Other sants, because of the lower risk of anticholinergic
considerations are concurrent medical conditions, and cardiovascular side effects.39
use of nonpsychiatric drugs, and cost of medica- The acute treatment phase usually lasts 6 to 10
tion. Table 3 lists suggested first-line medications. weeks (Table 1). The patient should be evaluated
SSRIs and other newer antidepressant drugs weekly or twice monthly by the treating physician
with a greater safety margin constitute first-line until substantial improvement is achieved. Doses
medications for moderate-to-severe depression, should be low initially and gradually increased, de-
particularly for outpatients, for patients treated by pending on the clinical response (Table 4) and side
primary care physicians, and for patients with car- effects. The decision to increase the dose, change
Variable Medication
Patient history
Age group
Children and adolescents SSRI (fluoxetine)
Adults <65 yr SSRI, NRI, or SNRI
Adults ≥65 yr SRI
Family history of response Same medication that was effective in first-degree relative
Past response Same medication that was effective previously
Depression characteristic
Bipolar depression Mood stabilizer (lithium or lamotrigine) plus antidepressant
Psychotic depression Antidepressant plus antipsychotic (atypical)
Depression with features of obsessive–compulsive SSRI
disorder
Panic attacks SSRI
Agitated depression Sedating antidepressant
Depression with psychomotor retardation Nonsedating antidepressant (NRI, SSRI)
Medication-resistant depression Electroconvulsive therapy or combination of medications
Coexisting medical conditions
Heart disease Nontricyclic antidepressants
Stroke Caution with SNRIs or NRIs and blood pressure
Pain Duloxetine, venlafaxine
Concern regarding side effects
Gastrointestinal symptoms Nontricyclic antidepressant
Anticholinergic symptoms Nontricyclic antidepressant
Sexual dysfunction Non-SSRI antidepressant
Weight gain Avoid atypical antipsychotics
Postural hypotension NRI
Diabetes Avoid atypical antipsychotics
* SSRI denotes selective serotonin-reuptake inhibitor, SNRI serotonin–norepinephrine reuptake inhibitor, NRI norepi-
nephrine-reuptake inhibitor, and SRI serotonin-reuptake inhibitor.
the medication, or add another medication is mod- global judgment of the treating clinician on the ba-
eled in Figure 2. Outpatients at risk for suicide sis of patient and family reports. The best predic-
should not be given large supplies of antidepres- tors of outcome are improvements in anhedonia
sant drugs that could be lethal in the case of an (loss of pleasure), psychomotor retardation, and
overdose (Table 1). loss of interest, which are assessed by asking ques-
tions that go beyond “depressed mood.” Suicidal
monitoring treatment response ideation or risk of suicide, pessimism, guilt, and
The response of patients to treatment requires sys- other changes in cognition may take longer to im-
tematic monitoring. A practical set of criteria in- prove than vegetative symptoms, such as altera-
clude nonresponse, a decrease in baseline severity tions in sleep or appetite.86 If initial treatment is
of 25 percent or less; partial response, a 26 to 49 not tolerated or the response is unsatisfactory (<50
percent decrease in baseline severity; partial remis- percent improvement), a change in medication or
sion, a 50 percent or greater decrease in baseline approach is indicated. Thirty to 50 percent of pa-
severity (residual symptoms); and remission, an ab- tients have substantial residual symptoms after ad-
sence of symptoms. Options for the evaluation of equate first-line treatment (Table 3).87 If there has
the response include rating scales (Table 4) and the been no improvement after four weeks of treat-
than 6 months and psychotic depression require a tected early. Patient and family education reduces
longer continuation phase, up to 12 months.88 The treatment attrition and improves the outcome.
same medications and doses used to achieve relief
in the acute phase are used during the continuation nonpharmacologic therapie s
phase.45
ect
discontinuation of treatment Remission rates with ECT are 60 to 80 percent in
If there is no recurrence or relapse during contin- severe major depressive disorder,105 though lower
uation therapy, gradual discontinuation may be success rates are reported in community settings.106
planned for most patients after at least six months The maximum response is typically achieved with-
of treatment. Early discontinuation is associated in three weeks. ECT can be a first-line treatment for
with a 77 percent higher risk of relapse as com- patients who have severe major depressive disorder
pared with continuation treatment.98 The tapering with psychotic features, psychomotor retardation,
of medication over several weeks also permits de- or medication resistance.45 ECT offers rapid relief
tection of returning symptoms that require reinsti- for patients who are suicidal or pregnant.45 A
tution of a full medication dose for another three to course of ECT usually consists of 6 to 12 treat-
six months. It also minimizes the discontinuation ments, rarely exceeds 20 treatments, and is admin-
syndrome, which otherwise may last days or long- istered two or three times a week, preferably by an
er and consists of physical symptoms of imbal- experienced psychiatrist. Side effects include tran-
ance, gastrointestinal and influenza-like symptoms, sient postictal confusion and anterograde and ret-
and sensory and sleep disturbances, as well as psy- rograde memory impairment; the latter generally
chological symptoms such as anxiety, agitation, improves in days or weeks.107 After ECT, it is im-
crying spells, and irritability.99 The discontinua- portant to start prophylactic treatment with an anti-
tion syndrome is sometimes called the withdrawal depressant medication combined with an augment-
syndrome, erroneously implying drug dependence. ing medication such as lithium, because the relapse
rate is more than 50 percent.108
maintenance phase
Maintenance treatment for 12 to 36 months reduc- psychotherapy
es the risk of recurrence by two thirds.100 This ap- Brief, structured psychotherapy techniques — such
proach is indicated for patients with episodes that as cognitive behavioral therapy, interpersonal ther-
occur yearly, who have impairment because of mild apy, and certain problem-solving therapies — ap-
residual symptoms, who have chronic major de- pear to be effective in acute-phase treatment and to
pression or dysthymia, or who have extremely se- delay relapse during continuation treatment of mild
vere episodes with a high risk of suicide.8,45,97 The to moderately severe depression.45,109,110 Psycho-
duration of maintenance treatment will depend on therapy can be a first-line therapy for mild depres-
the natural history of the illness and may be pro- sion but not for severe depression, particularly
longed or indefinite in the case of recurrent illness. psychotic and bipolar forms, unless used in combi-
The first choice of medication for the mainte- nation with pharmacology.45,111 A combination of
nance phase is the antidepressant that brought pharmacotherapy and psychotherapy may improve
about remission.45 Lithium has no advantage over the treatment response, reduce the risk of a relapse,
antidepressants for prophylaxis69 but may reduce enhance the quality of life, and increase adherence
the risk of suicide independently of its effect on to pharmacotherapy.112 Psychotherapy should be
mood.101 Tricyclic antidepressants, SSRIs, MAOIs, considered when substantial psychosocial stres-
and the newer antidepressants (mirtazepine and sors, interpersonal difficulties, or coexisting devel-
venlafaxine) all help to prevent recurrence.69,101-104 opmental or personality disorders are present.
Medication tolerability is particularly important
during the maintenance phase, because it affects special patient populations
patients’ adherence to treatment. Stable patients
should see a psychopharmacologist at intervals of patients with bipolar disorder
three to six months while they are receiving medi- Depression in bipolar disorder carries the risk of
cation. It is important to monitor adherence and a switch into mania.113,114 Mood stabilizers with
breakthrough symptoms so that problems are de- antidepressant properties, such as lithium and la-
motrigine, help prevent mania, hypomania, and effects very carefully when using antidepressants
mixed or rapid-cycling states115,116 and are recom- in youth (www.fda.gov/cder/drug/antidepressants/
mended as initial treatments of bipolar depres- default.htm).
sion.103 For severe bipolar depression, a combina-
tion of an antidepressant (an SSRI or bupropion) pregnant women
and a mood stabilizer should be considered from Antidepressant medication should be considered
the outset.40,117,118 The atypical antipsychotic drugs for pregnant women in whom a moderately severe
olanzapine and risperidone have antidepressant major depressive disorder develops spontaneously,
and antimanic effects119 but are more effective when as well as for those at high risk for recurrence if
combined with an antidepressant.120 The Ameri- their medication is discontinued.45 Risks and ben-
can Psychiatric Association recommends mainte- efits vary greatly among patients.123 Many antide-
nance treatment after a single manic episode.103 pressants are transmitted in breast milk, and their
use is reviewed elsewhere.124
children and adolescents
Fluoxetine is the only antidepressant with demon- summary
strated efficacy in childhood and adolescent de-
pression42; other SSRIs, tricyclic agents, and oth- Major depression and bipolar disorder are generally
er new-generation antidepressants have not been recurrent episodic disorders. Antidepressant and
shown to be effective for depression in this age adjunctive medications can successfully treat de-
group.121 Fluoxetine is the only SSRI currently ap- pression and prevent future episodes.
proved for pediatric use. Future challenges include the identification of
Rates of spontaneously reported suicidal idea- antidepressants that act more quickly than those
tion and suicide attempts have been higher among currently available, which take six to eight weeks to
depressed children and adolescents receiving anti- achieve remission or substantial improvement, and
depressants than among those receiving placebo that do not require continuation and maintenance
in controlled clinical trials, but no differences were treatment. A biologic classification system of sub-
noted on weekly ratings of suicidality. This possible types of major depression is needed to facilitate the
risk needs to be weighed against the risk of un- selection of the best antidepressant for each patient.
treated depression, the most common cause of sui- Supported by Public Health Service grants (MH48514 and
MH40695) and the Stanley Medical Research Institute.
cide in youth.122 There is an FDA black-box warning I am indebted to Dr. Dianne Currier for her research and assis-
urging clinicians to monitor suicide risk and side tance in the preparation of the manuscript.
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