bipolar disorder in adults - treating major depression with second-generation antipsychotics.pdf

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Official reprint from UpToDate

www.uptodate.com2013 UpToDate

AuthorsWilliam V Bobo, MD, MPH

Richard C. Shelton, MD

Section EditorPaul Keck, MD

Deputy EditorDavid Solomon, MD

Bipolar disorder in adults: Treating major depression with second-generation antipsychotics

Disclosures

All topics are updated as new evidence becomes available and ourpeer review process is complete.

Literature review current through:Oct 2013. | This topic last updated:Jun 8, 2013.

INTRODUCTION Although manic, hypomanic, and mixed episodes are diagnostic hallmarks for bipolar disorder,

depressive episodes predominate the lifetime course of illness and result in greater disability and risk of suicide

[1,2]. Bipolar major depression is often treated with antidepressants, but their use is controversial because these

drugs may not be effective and may cause switches from depression to mania as well as rapid cycling. Otherdrugs that are widely used for bipolar depression include second-generation antipsychotics [3].

This topic reviews the efficacy, safety, and tolerability of second-generation antipsychotics for bipolar major

depression. Choosing a medication regimen for bipolar major depression, mania, mixed episodes, hypomania, and

the maintenance treatment of bipolar disorder are discussed separately, as is the efficacy and safety of

antidepressants for bipolar major depression:

(See "Bipolar disorder in adults: Pharmacotherapy for acute depression".)

(See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania".)

(See "Bipolar disorder in adults: Maintenance treatment".)

(See "Bipolar disorder in adults: Treating major depression with antidepressants".)

DEFINITION OF BIPOLAR DISORDER Bipolar disorder is a mood disorder that is characterized by episodes of

mania (table 1), hypomania (table 2), and major depression (table 3), as well as mixed episodes (major depression

concurrent with mania) [4]. The subtypes of bipolar disorder include bipolar I and bipolar II. Patients with bipolar I

disorder experience manic and mixed episodes, and nearly always experience major depressive and hypomanic

episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode,

and the absence of manic and mixed episodes. Additional information about the clinical features and diagnosis of

bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Clinical features"and "Bipolar disorder in

adults: Assessment and diagnosis", section on 'Diagnosis'.)

EFFICACY For outpatients with bipolar major depression and no comorbid substance use disorders,

randomized trials have established the efficacy ofquetiapineand olanzapine[5-8]. By contrast, multiple trials havefound no benefit in using aripiprazoleand ziprasidone[9,10]. Other second-generation antipsychotics that may

possibly be helpful include asenapine, clozapine, lurasidone, and risperidone, but their benefit has yet to be

established. (See 'Other second-generation antipsychotics'below.)

In addition, second-generation antipsychotics are often used as monotherapy or in combination with other drugs for

mania, as well maintenance treatment of patients with bipolar disorder. (See "Bipolar disorder in adults:

Pharmacotherapy for acute mania, mixed episodes, and hypomania"and "Bipolar disorder in adults: Maintenance

treatment".)

Quetiapine Quetiapinemonotherapy is efficacious for bipolar major depression, based upon multiple

meta-analyses of randomized trials [5,11]. As an example, one meta-analysis of five homogeneous trials (3057

patients treated for eight weeks) compared quetiapine with placebo (limited use of lorazepamand hypnotics was

allowed for the first three to four weeks); the primary findings were as follows [ 7]:

Remission occurred in more patients who received quetiapinethan placebo (61 versus 42 percent)

olar disorder in adults: Treating major depression with second-gener... http://www.uptodate.com/contents/bipolar-disorder-in-adults-treating-...

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Reduction of anxiety symptoms was greater with quetiapine

Remission was comparable forquetiapine300 mg per day and 600 mg per day

Improvement in quality of life (satisfaction) was superior with quetiapinethan placebo

Remission rates were lower for patients with more severe depressive episodes

However, meta-analyses of the same five trials found that discontinuation of treatment because of side effects

occurred in more patients who received quetiapinethan placebo (24 versus 6 percent), and was greater for

quetiapine 600 mg per day than 300 mg per day [5,7]. Adverse effects that occurred more often with quetiapine

than placebo included:

Sedation

Weight gain

Dry mouth

Headache

Dizziness

Nausea

Constipation

Extrapyramidal symptoms

Additional information about quetiapineside effects (table 4and table 5) is discussed separately. (See "Second-

generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on

'Quetiapine'.)

Bipolar II major depression Randomized trials for bipolar disorder often exclude patients with bipolar II

disorder or combine them with bipolar I patients in the analyses. However, several trials of quetiapinemonotherapy

included bipolar II patients with major depression and found that the drug was effective for this subgroup:

Two randomized trials, each lasting eight weeks, compared quetiapine(300 or 600 mg at bedtime) with

placebo in patients with bipolar major depression [12]. A pooled analysis of the subgroup of 321 patients

with bipolar II depression found that remission was greater with quetiapine 300 or 600 mg/day, compared

with placebo (39 and 38 versus 20 percent). This was consistent with the finding that both doses of

quetiapine were superior in the total sample of bipolar patients [13]. Among patients with bipolar II

depression, discontinuation of treatment due to adverse effects of quetiapine 300 mg/day and 600 mg/day

and placebo were 16, 23, and 2 percent; common side effects of quetiapine included dry mouth, sedation,

fatigue, and dizziness.

An eight week randomized trial compared quetiapine(300 or 600 mg at bedtime) with placebo in patients

with bipolar major depression [14]. In the subgroup of 208 patients with bipolar II disorder, symptoms

improved more with both doses of quetiapine than placebo; this was consistent with the finding that

quetiapine was superior in patients with bipolar I disorder.

Compared with other drugs Although head to head randomized trials seem to suggest that quetiapine

monotherapy is superior to lithiummonotherapy orparoxetinemonotherapy for bipolar major depression, the

comparative benefit of quetiapine is not clear due to methodologic problems:

One eight week trial assigned patients to quetiapine300 mg per day (N = 255), quetiapine 600 mg per day

(N = 263), orlithium(target serum concentration 0.6 to 1.2 mEq/L [0.6 to 1.2 mmol/L]; N = 136) [15].

Although symptoms improved more with either dose of quetiapine than with lithium, the study was

underpowered for lithium [16]. In addition, the mean serum concentration of lithium was 0.61 mEq/L (0.61

mmol/L), and more than a third of the patients treated with lithium had a median serum concentration


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Olanzapine For patients with bipolar major depression, randomized trials have demonstrated the efficacy of

olanzapinemonotherapy [17]:

One six week trial compared olanzapine(5 to 20 mg per day) with placebo in 514 patients; use of

concomitant medication was not reported. Remission occurred in more patients who received olanzapine

than placebo (38 versus 29 percent), and discontinuation of treatment due to adverse effects was

comparable (9 and 8 percent) [8].

One eight week trial compared olanzapine(5 to 20 mg per day) with placebo in 706 patients;benzodiazepines and anticholinergic drugs were allowed as well. Remission occurred in more patients who

received olanzapine than placebo (33 versus 25 percent) [6]. In the subgroup (N = 311) with comorbid

anxiety symptoms, remission occurred more often with olanzapine. However, in the entire sample (N = 706),

discontinuation of treatment due to adverse effects occurred in more patients who received olanzapine than

placebo (9 versus 5 percent).

Olanzapinecan cause serious weight gain and may also cause diabetes mellitus [18-20]. In the randomized trials

that compared olanzapine with placebo in patients with bipolar major depression, the following adverse effects

occurred more often with olanzapine [6,8]:

SedationWeight gain

Increased appetite

Dry mouth

Weakness

Hypercholesterolemia

Hypertriglyceridemia

Hyperglycemia

Alanine aminotransferase abnormally high

Aspartate aminotransferase abnormally high

Gamma glutamyl transpeptidase abnormally high

Hyperprolactinemia

Neutropenia

Additional information about olanzapineside effects (table 4and table 5) is discussed separately. (See "Second-

generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on

'Olanzapine'.)

Olanzapine plus fluoxetine The combination ofolanzapineand fluoxetinecan help patients with bipolar

major depression. In one eight-week trial that compared olanzapine plus fluoxetine (6 and 25, 6 and 50, or 12 and

50 mg per day), olanzapine monotherapy (5 to 20 mg per day), and placebo in 833 patients, remission occurred in

more patients who received olanzapine plus fluoxetine than olanzapine alone or placebo (49 versus 33 and 25

percent) [6]. However, side effects of the combination included weight gain, increased appetite, dry mouth,weakness, and diarrhea. Additional information about the efficacy of olanzapine plus fluoxetine is discussed

separately, as is the risk of switching from depression to mania. (See "Bipolar disorder in adults: Treating major

depression with antidepressants".)

The side effects ofolanzapinemonotherapy (table 4and table 5) and fluoxetinemonotherapy (table 7) are

discussed elsewhere. (See 'Olanzapine'above and "Selective serotonin reuptake inhibitors: Pharmacology,

administration, and side effects".)

Other second-generation antipsychotics Low quality evidence (eg, indirect outcome, lack of placebo or other

control, or small sample), as well as unpublished studies, suggests that monotherapy with other second-generation

antipsychotics may possibly be useful for treating bipolar major depression:

Asenapine A pooled analysis of two randomized trials, each lasting three weeks, compared asenapine (5

or 10 mg twice per day) with placebo in a subgroup of 173 patients with mixed episodes (major depression

concurrent with mania) [21]. Remission occurred in more patients treated with asenapine than placebo (45


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versus 24 percent); this was consistent with the finding that asenapine was superior in the total sample of

patients with mania or mixed episodes. However, among patients with mixed episodes, sedation, dizziness,

extrapyramidal symptoms, and weight gain occurred more often with asenapine than placebo.

Clozapine A retrospective observational study of 326 patients treated with adjunctive clozapine (mean

dose 307 mg per day) for up to two years found that the number of hospitalizations and number of days in

the hospital were lower during clozapine treatment than the same period of time immediately prior to use of

clozapine [22]

Lurasidone Unpublished, six week randomized trials have found the following:

In one trial, response (reduction of baseline symptoms 50 percent) occurred in more patients who

received monotherapy with eitherlurasidone20 to 60 mg per day or lurasidone 80 to 120 mg per day,

compared with placebo (53 and 51 versus 30 percent) [23]. In addition, discontinuation of treatment due

to adverse effects was comparable for the three groups (7 and 6 and 6 percent).

In the second trial, patients resistant to lithiumor divalproex monotherapy received adjunctive lurasidone

or placebo; improvement was greater with lurasidone [24]

Risperidone One trial enrolled 30 patients with an incomplete response to carbamazepine, lithium, or

valproateand randomly assigned the patients to receive adjunctive risperidone, paroxetine, or risperidoneplus paroxetine [25]. All three groups improved.

The side effects (table 4and table 5) of these drugs are discussed separately. (See "Second-generation

antipsychotic medications: Pharmacology, administration, and comparative side effects".)

Drugs with little to no benefit For patients with bipolar major depression, multiple randomized trials indicate

that there is little to no benefit in using aripiprazoleorziprasidone:

Aripiprazole Two eight-week trials compared aripiprazole (5 to 30 mg per day) with placebo in a total of

749 patients; a pooled analysis found that the benefits of aripiprazole and placebo were comparable [9]

Ziprasidone Two six-week tr ials compared ziprasidone (20 to 80 mg twice daily) with placebo in a total of

856 patients; in each trial, ziprasidone demonstrated no advantage [10,26]

Rapid cycling bipolar disorder The efficacy of second-generation antipsychotics to treat bipolar major

depression in rapid cycling patients is discussed separately. (See "Rapid cycling bipolar disorder in adults:

Treatment of major depression", section on 'Treatment'.)

Geriatric bipolar disorder The efficacy of second-generation antipsychotics to treat bipolar major depression

in geriatric patients is discussed separately. (See "Geriatric bipolar disorder: Acute treatment", section on

'First-line treatment'.)

SAFETY AND TOLERABILITY

Side effects Side effects associated with second-generation antipsychotics include weight gain, hyperglycemia,

type 2 diabetes mellitus, hyperlipidemia, sedation, hyperprolactinemia, neuroleptic malignant syndrome, orthostatic

hypotension, sudden death, and an increased risk of mortality when used to treat psychiatric symptoms associated

with dementia in elderly patients (table 4and table 5). Second-generation antipsychotics can also cause

extrapyramidal symptoms and tardive dyskinesia, but at rates lower than first-generation drugs. These side effects

and their management are described separately. (See "Second-generation antipsychotic medications:

Pharmacology, administration, and comparative side effects"and "Pharmacotherapy for schizophrenia: Side effect

management"and "Causes of hyperprolactinemia"and "Neuroleptic malignant syndrome"and "Acquired long QT

syndrome"and "Tardive dyskinesia: Clinical features and diagnosis"and "Tardive dyskinesia: Prevention and

treatment".)

General principles regarding the safety and tolerability of second-generation antipsychotics in bipolar major

depression include the following:


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Patients with bipolar depression may be more sensitive to side effects than patients with mania [27,28]

The risk of extrapyramidal side effects and tardive dyskinesia is thought to be higher in bipolar disorder than

schizophrenia [29,30]

Treatment emergent mania does not occur in patients who are treated with quetiapineorolanzapine[6-8,31]

In addition, adverse effects can lead to poor adherence [32].

Metabolic effects The risk of metabolic side effects (eg, weight gain, hyperlipidemia, and hyperglycemia) is

increased with some second-generation antipsychotics [33]; this is important given the increased risk of metabolic

syndrome [34] as well as cardiovascular morbidity and mortality in patients with bipolar disorder relative to the

general population [35-37]. Although most studies of second-generation antipsychotics and metabolic effects

involve schizophrenia [33], comparable effects have been found in bipolar disorder [ 5,31,38,39]. Among second-

generation antipsychotics, the greatest risk for metabolic effects is with olanzapineand clozapine, followed by

quetiapineand risperidone(table 4) [40]. The risk of clinically significant weight gain for olanzapine monotherapy

and olanzapine plus fluoxetineappears to be comparable [6,41]. Lurasidonedoes not cause short-term weight

gain, whereas asenapinedoes [42].

Prior to initiating treatment with second-generation antipsychotics, we ask patients about their personal and family

history of obesity, diabetes, dyslipidemia, hypertension, cardiovascular disease, and family history of sudden

cardiac death [40].

Sedation Among patients with bipolar major depression, olanzapineand quetiapineoften cause somnolence

that leads to discontinuation of treatment [28]:

In an eight week randomized trial that compared olanzapinewith placebo in 706 patients, discontinuation of

treatment due to adverse effects occurred in more patients treated with olanzapine than placebo (9 versus 5

percent) [6]. Among patients who discontinued olanzapine because of side effects, the most frequent cause

was sedation.

A meta-analysis of five randomized trials (2477 patients treated for eight weeks) that compared quetiapinewith placebo found that discontinuation of treatment due to somnolence was nearly five times more likely in

patients who received quetiapine [7]

Monitoring Bipolar patients who are treated with second-generation antipsychotics should be assessed for

[40,43]:

Metabolic side effects at baseline and periodically thereafter (table 8)

Extrapyramidal symptoms at baseline and subsequently at every visit. Patients should also be monitored for

tardive dyskinesia at baseline, quarterly in the first year, and annually thereafter, using the Abnormal

Involuntary Movement Scale (AIMS) (form 1).

Orthostatic hypotension at baseline and periodically thereafter

Prolactin elevation at baseline and periodically thereafter

In addition, patients may need to be monitored for QT prolongation. Additional information about assessing patients

for metabolic side effects, extrapyramidal symptoms, orthostasis, hyperprolactinemia, and QT prolongation is

discussed further in the context of schizophrenia. (See "Pharmacotherapy for schizophrenia: Side effect

management".)

SUMMARY

Medications regimens for bipolar patients are selected according to the phase of illness. (See "Bipolar

disorder in adults: Pharmacotherapy for acute depression"and "Bipolar disorder in adults: Pharmacotherapy

for acute mania, mixed episodes, and hypomania"and "Bipolar disorder in adults: Maintenance treatment".)

Quetiapinemonotherapy is efficacious for short term treatment of bipolar major depression; however the


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drug can cause sedation, weight gain, dry mouth, headache, dizziness, nausea, constipation, and

extrapyramidal symptoms. (See 'Quetiapine'above.)

Olanzapinemonotherapy is efficacious for short term treatment of bipolar major depression; however, the

drug can cause serious weight gain and may also cause diabetes mellitus. Other adverse effects include

sedation, increased appetite, dry mouth, weakness, hypercholesterolemia, hypertriglyceridemia,

hyperglycemia, abnormally high liver functions tests, hyperprolactinemia, and neutropenia. (See 'Olanzapine'

above.)

Olanzapineplus fluoxetineis efficacious for short term treatment of bipolar major depression; however, the

combination can cause weight gain, increased appetite, dry mouth, weakness, and diarrhea. (See

'Olanzapine plus fluoxetine'above.)

Other second-generation antipsychotics that may possibly be useful for treating bipolar major depression

include asenapine, clozapine, lurasidone, and risperidone. (See 'Other second-generation antipsychotics'

above.)

For patients with bipolar major depression, there is little to no benefit in using aripiprazoleorziprasidone.

(See 'Drugs with little to no benefit'above.)

Side effects associated with second-generation antipsychotics include weight gain, hyperglycemia, type 2

diabetes mellitus, hyperlipidemia, sedation, hyperprolactinemia, extrapyramidal symptoms, tardive

dyskinesia, neuroleptic malignant syndrome, orthostatic hypotension, sudden death, and an increased risk of

mortality when used to treat psychiatric symptoms associated with dementia in elderly patients (table 4and

table 5). (See 'Side effects'above.)

Among second-generation antipsychotics, the greatest risk for metabolic effects (eg, weight gain,

hyperlipidemia, and hyperglycemia) is with olanzapineand clozapine, followed by quetiapineand risperidone

(table 4). The risk of clinically significant weight gain appears to be comparable for olanzapine monotherapy

and olanzapine plus fluoxetine. Lurasidonedoes not cause short-term weight gain, whereas asenapinedoes.

(See 'Metabolic effects'above.)

Among patients with bipolar major depression, olanzapineand quetiapineoften cause somnolence that leads

to discontinuation of treatment. (See 'Sedation'above.)

Bipolar patients who are treated with second-generation antipsychotics should be monitored for metabolic

side effects (table 8), extrapyramidal symptoms, tardive dyskinesia (form 1), orthostatic hypotension, and

prolactin elevation. In addition, patients may need to be monitored for QT prolongation. (See 'Monitoring'

above.)

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Topic 16693 Version 2.0


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GRAPHICS

DSM-IV-TR diagnostic criteria for mania

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting

at least 1 week (or any duration if hospitalization is necessary).

B. During the period of mood disturbance, three (or more) of the following symptoms have

persisted (four if the mood is only irritable) and have been present to a significant degree:1) Inflated self-esteem or grandiosity

2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep)

3) More talkative than usual or pressure to keep talking

4) Flight of ideas or subjective experience that thoughts are racing

5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli)

6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor

agitation

7) Excessive involvement in pleasurable activities that have a high potential for painful consequences

(eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C. The symptoms do not meet criteria for a mixed episode.

D. The mood disturbance 1) is sufficiently severe to cause marked impairment in occupational

functioning, usual social activities, or relationships with others, 2) necessitates hospitalization to

prevent harm to self or others, or 3) has psychotic features.

E. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of

abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism).

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision,Fourth Edition (Copyright 2000). American Psychiatric Association.


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DSM-IV-TR diagnostic criteria for hypomania

A.A distinct period of persistently elevated, expansive, or irritable mood, lasting at least 4 days,

that is clearly different from the usual nondepressed mood.

B.During the period of mood disturbance, three (or more) of the following symptoms have

persisted (four if the mood is only irritable) and have been present to a significant degree:

1) Inflated self-esteem or grandiosity

2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep)

3) More talkative than usual or pressure to keep talking

4) Flight of ideas or subjective experience that thoughts are racing

5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli)

6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor

agitation

7) Excessive involvement in pleasurable activities that have a high potential for painful consequences

(eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C.The episode is associated with an unequivocal change in functioning that is uncharacteristic of

the person when not symptomatic.

D.The disturbance in mood and the change in functioning are observable by others.

E.The episode 1) is not severe enough to cause marked impairment in social or occupational

functioning, 2) does not necessitate hospitalization, and 3) does not have psychotic features.

F.The symptoms are not due to the direct physiological effects of a substance (eg, a drug of

abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism).

Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (eg,

medication, ECT, light therapy) should not count toward a diagnosis of bipolar II disorder.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision,

Fourth Edition (Copyright 2000). American Psychiatric Association.


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DSM-IV-TR diagnostic criteria for major depression

A. Five (or more) of the following symptoms have been present during the same 2-week

period, and represent a change from previous functioning. At least one of the symptoms is either

depressed mood or loss of interest or pleasure.

(Note: Do not include symptoms that are clearly due to a general medical condition, or

mood-incongruent delusions or hallucinations.)

Depressed mood most of the day, nearly every day (or alternatively can be irritable mood in childrenand adolescents)

Markedly diminished interest or pleasure in all, or almost all, activities, nearly every day

Significant weight loss while not dieting, weight gain, or decrease or increase in appetite

Insomnia or hypersomnia nearly every day

Psychomotor agitation or retardation nearly every day

Fatigue or loss of energy nearly every day

Feelings of worthlessness or excessive or inappropriate guilt nearly every day

Diminished ability to think or concentrate, or indecisiveness, nearly every day

Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specificplan, or a suicide attempt or a specific plan for committing suicide

B. The symptoms do not meet criteria for a Mixed Episode.

C. The symptoms cause clinically significant distress or impairment in social, occupational, or other

important areas of functioning.

D. The symptoms are not due to the direct physiological effects of substance or a general medical

condition.

E. The symptoms are not better accounted for by Bereavement, ie, after the loss of a loved one,

the symptoms persist for longer than two months or are characterized by marked functional

impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, orpsychomotor retardation.

Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4thed, Text Revision. American Psychiatric Association, Washington, DC 2000.


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Selected adverse effects of antipsychotic medications for

schizophrenia

Weight

gain/diabetes

mellitus

Hyper-

cholesterolemiaEPS/TD

Prolactin

elevationSedati

First generation agents

Chlorpromazine +++ +++ + ++ +++

Fluphenazine + + +++ +++ +

Haloperidol + + +++ +++ ++

Loxapine ++ ND ++ ++ ++

Perphenazine ++ ND ++ ++ ++

Pimozide + ND +++ ++ +

Thioridazine* ++ ND + +++ +++

Thiothixene ++ ND +++ ++ +

Trifluoperazine ++ ND +++ ++ +

Second generation agents

Aripiprazole + +

Asenapine + + ++ ++

Clozapine +++ +++ +++

Iloperidone ++ ++ + +

Lurasidone + + ++

Olanzapine +++ +++ + ++

Paliperidone ++ + ++ +++ +

Quetiapine ++ +++ ++

Risperidone ++ + ++ +++ +

Ziprasidone + + +

Adverse effects may be dose dependent.EPS: extrapyramidal symptoms; TD: tardive dyskinesia; ND: no data.* Thioridazine is also associated with dose-dependent retinitis pigmentosa. Refer to text.

Clozapine also causes granulocytopenia or agranulocytosis in approximately 1 percent of patients requiringregular blood cell count monitoring.Adapted from:

Treatment Guidelines from The Medical Letter, August 2010; Vol. 8 (96):61. www.medicalletter.org.1.

[1]


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Selected adverse effects of atypical antipsychotic medications

Acute Chronic

Clozapine Seizures NMS, Agranulocytosis, Myocarditis

Risperidone Prolonged QT, dystonia EPS, TD, NMS

Olanzapine Seizures, dystonia EPS, TD, NMS, Agranulocytosis

Quetiapine Seizures, dystonia EPS, TD, NMS

Ziprasidone Prolonged QT, dystonia EPS

Aripiprazole Gastrointestinal (vomiting)

NMS: neuroleptic malignant syndrome; TD: tardive dyskinesia; EPS: extrapyramidal side effects.


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Unipolar depression in adults: Antidepressant doses*

Drug

Usual total

starting dose

per day

(mg)

Usual total dose

per day

(mg)

Extreme daily

dose range

(mg)

Selective serotonin reuptake inhibitors

Citalopram 20 20 to 40 10 to 40

Escitalopram 10 10 to 20 5 to 30

Fluoxetine 20 20 to 60 10 to 80

Fluvoxamine 50 50 to 200 25 to 300

Fluvoxamine CR 100 100 to 200 100 to 300

Paroxetine 20 20 to 40 10 to 50

Paroxetine CR 25 25 to 50 12.5 to 62.5

Sertraline 50 50 to 200 25 to 300

Serotonin-norepinephrine reuptake inhibitors

Desvenlafaxine 50 50 50 to 400

Duloxetine 30 to 60 30 to 120 30 to 120

Milnacipran 12.5 100 to 200 50 to 300

Venlafaxine 37.5 to 75 75 to 375 75 to 450

Venlafaxine XR 37.5 75 to 225 75 to 375

Atypical agents

Agomelatine (not

available in United

States)

25 25 to 50 25 to 50

Bupropion 200 300 (maximum single

dose 150 mg)

100 to 450

Bupropion SR 12

hour

150 300 (maximum single

dose 200 mg)

150 to 400

Bupropion XL 24

hour

150 300 150 to 450 (United

States)

150 to 300 (Europe)

Bupropion

hydrobromide 24

hour

174 348 174 to 522

Mirtazapine 15 15 to 45 7.5 to 60

Serotonin modulators

Nefazodone 200 300 to 600 50 to 600

Trazodone 100 200 to 500 100 to 600Trazodone ER 150 375 150 to 375

Vilazodone 10 40 10 to 40


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Tricyclics and tetracyclics

Amitriptyline 25 150 to 300 10 to 300

Amoxapine 25 200 to 300 25 to 400

Clomipramine 25 100 to 250 25 to 300

Desipramine 25 150 to 300 25 to 300

Doxepin 25 150 to 300 25 to 300Imipramine 25 150 to 300 10 to 300

Maprotiline 25 100 to 225 25 to 225

Nortriptyline 25 50 to 150 10 to 150

Protriptyline 10 15 to 60 5 to 60

Trimipramine 25 150 to 300 25 to 300

Monamine oxidase inhibitors

Isocarboxazid 10 10 to 40 10 to 60

Phenelzine 15 15 to 90 7.5 to 90

Selegiline

transdermal

6 mg/24 hour patch 6 to 12 mg/24 hour

patch

6 to 12 mg/24 hour

patch

Tranylcypromine 10 30 to 60 10 to 60

* Total daily oral doses shown in table may need to be given as two or three equally divided doses per day,depending on specific antidepressant and other factors. For additional detail, refer to individual Lexicompdrug monographs included with UpToDate. Lower end doses may be useful for initiating or maintaining elderly, medically compromised (eg, renal orhepatic illness), or drug sensitive patients, as well as patients with a low body mass index. High doses maybe used for medications that are well tolerated but ineffective at lower doses. Maximum recommended dose of citalopram is 20 mg for patients >60 years of age, with significant

hepatic insufficiency, or taking interacting medications that can increase citalopram levels. For moreinformation refer to the UpToDate topic on unipolar depression in adults and selective serotonin reuptakeinhibitors.Although desvenlafaxine doses up to 400 mg per day have been studied, there is no evidence that doses>50 mg per day provide any additional benefit. Although duloxetine doses up to 120 mg per day have been used, there is no evidence that doses >60 mgper day provide any additional benefit in treatment of depression. Agomelatine may be hepatotoxic and is contraindicated with any degree of liver impairment.Transaminase monitoring is required according to the product information. Caution: can cause liver failure. Not available in Europe, Canada, and several other countries. Conservative starting doses shown in table are lower than starting doses shown in some other references.For additional information, refer to UpToDate topics on unipolar depression in adults and cyclicantidepressants and monoamine oxidase inhibitors for treatment of adults with depression.Data from:

The American Psychiatric Publishing Textbook of Psychopharmacology, 4th edition. Schatzberg AF,

Nemeroff CB (eds); American Psychiatric Publishing, Inc. Washington, D.C. (2009).

1.

Labbate LA, Fava M, Rosenbaum JF, Arana GW. Drugs for the treatment of depression. In: Handbook ofPsychiatric Drug Therapy, 6th ed, Lippincott Williams and Wilkins, Philadelphia 2010. p.54.

2.

Gartlehner G, Thaler K, Hill S, Hansen RA. How should primary care doctors select whichantidepressants to administer? Curr Psychiatry Rep 2012; 14:360.

3.

Lexicomp Online. Copyright 1978-2013 Lexicomp, Inc. All Rights Reserved.4.


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Side effects of antidepressant medications

Drug Anticholinergic Drowsiness Insomnia/agitationOrthost

hypotens

Selective serotonin reuptake inhibitors (SSRIs)

Citalopram 0 0 1+ 1+

Escitalopram 0 0 1+ 1+

Fluoxetine 0 0 2+ 1+

Fluvoxamine 0 1+ 1+ 1+

Paroxetine 1+ 1+ 1+ 2+

Sertraline 0 0 2+ 1+

Atypical agents

Agomelatine

(not available in

United States)

0 1+ 1+ 0

Bupropion 0 0 2+ (immediate release)

1+ (sustained release)

0

Mirtazapine 1+ 4+ 0 0

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

Desvenlafaxine 0 1+ 2+ 0

Duloxetine 0 0 2+ 0

Milnacipran 1+ 1+ 0 0

Venlafaxine 0 1+ 2+ 0

Serotonin modulators

Trazodone 0 4+ 0 1+ (hypnotidose)

3+

(antidepress

dose)

Vilazodone 0 0 2+ 0

Nefazodone** 1+ 2+ 0 1+

Tricyclic and tetracyclic antidepressants (TCAs)

Amitriptyline 4+ 4+ 0 3+

Amoxapine 2+ 2+ 2+ 2+

Clomipramine 4+ 4+ 1+ 2+

Desipramine 1+ 4+ 1+ 2+


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Doxepin 3+ 3+ 0 2+

Imipramine 3+ 3+ 1+ 4+

Maprotiline 2+ 3+ 0 2+

Nortriptyline 2+ 2+ 0 1+

Protriptyline 2+ 1+ 1+ 2+

Trimipramine 4+ 4+ 1+ 3+

Monoamine oxidase inhibitors

Isocarboxazid 1+ 1+ 2+ 2+

Phenelzine 1+ 2+ 1+ 3+

Selegiline 1+ 0 1+ 1+

Tranylcypromine 1+ 1+ 2+ 2+

Scale: 0 = none; 1+ = slight; 2+ = low; 3+ = moderate; 4+ = high; ND = inadequate data.* Risk of QTc prolongation or torsades de pointes is also elevated with advanced age, female sex, heartdisease, congenital long QT syndrome, hypokalemia or hypomagnesemia, elevated serum drug

concentrations (eg, drug overdose, interacting drugs, organ failure) and combination of drugs with QTcprolonging effects. Refer to topic on acquired long QT syndrome. All SSRIs and SNRIs are associated with transient nausea and gastrointestinal discomfort upon initiationor dose increase. Based upon reports of dose related QTc prolongation and arrhythmia, the maximum recommended dose ofcitalopram is 20 mg for patients at increased risk of elevated citalopram serum concentrations.Sertraline is associated with higher rates of diarrhea. Agomelatine may be hepatotoxic and is contraindicated with any degree of liver impairment.Transaminase monitoring is required. May cause persistent dose-related increases in blood pressure (primarily diastolic) and heart rate. Monitorblood pressure regularly. Trazodone is associated rarely with priapism, which is considered a medical emergency. Refer to UpToDatetopic on Serotonin modulators. Vilazodone is associated with higher rates of nausea, vomiting, and diarrhea.** Caution: can cause liver failure. Not available in Europe, Canada, and several other countries.

Gastrointestinal forms of anticholinergic side effects include: dry mouth, constipation, epigastric distress,decreased esophagogastric tone. Refer to "Anticholinergic" data for frequency rankings.Created with data from:

Nelson JC. Tricyclic and tetracyclic drugs. In: The American Psychiatric Publishing Textbook ofPsychopharmacology, 4th ed, Schatzberg AF, Nemeroff CB (Ed), American Psychiatric Publishing,Washington, DC 2009. p.263.

1.

Lexicomp Online. Copyright 1978-2013 Lexicomp, Inc. All Rights Reserved.2.Wenzel-Seifert K, Wittmann M, Haen E: QTc prolongation by psychotropic drugs and the risk of torsadede pointes. Dtsch Arztebl Int 2011; 108(41):687-93.

3.

Serretti A, Chiesa A. Sexual side effects of pharmacological treatment of psychiatric disease. ClinPharm Ther 2011; 89:142-7.

4.

Howland RH. A benefit-risk assessment of agomelatine in the treatment of major depression. Drug Saf2011; 34:709.

5.


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Monitoring for metabolic side effects of antipsychotic drugs

Baseline4

weeks

8

weeks

12

weeksQuarterly Annually

At

least

every

5

years

Personal or

family history

X X

Weight (body

mass index)

X X X X X

Waist

circumference

X X X

Blood

pressure

X X X

Fastingplasma

glucose

X X X

Fasting lipid

profile

X * X X

* For patients taking olanzapine, quetiapine, clozapine.

Copyright 2004 American Diabetes Association. From Diabetes Care, Vol. 27, 2004: 596-601. Reproducedwith permission.


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Abnormal involuntary movement scale


bipolar disorder in adults - treating major depression with second-generation antipsychotics.pdf

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