Bipolar Disorder in Adults - Treating Major Depression With Second-Generation Antipsychotics PDF

Bipolar disorder in adults: Treating major depression with second-gener...
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Bipolar disorder in adults: Treating major depression with second-generation antipsychotics Authors William V Bobo, MD, MPH Richard C. Shelton, MD Disclosures All topics are updated as new evidence becomes available and our peer 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. Other drugs 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 (See "Bipolar (See "Bipolar (See "Bipolar disorder disorder disorder disorder in adults: in adults: in adults: in adults: Pharmacotherapy for acute depression".) Pharmacotherapy for acute mania, mixed episodes, and hypomania".) Maintenance treatment".) Treating major depression with antidepressants".) Section Editor Paul Keck, MD Deputy Editor David Solomon, MD
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 of quetiapine and olanzapine [5-8]. By contrast, multiple trials have found no benefit in using aripiprazole and 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 Quetiapine monotherapy 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 lorazepam and hypnotics was allowed for the first three to four weeks); the primary findings were as follows [7]: Remission occurred in more patients who received quetiapine than placebo (61 versus 42 percent)
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Reduction of anxiety symptoms was greater with quetiapine Remission was comparable for quetiapine 300 mg per day and 600 mg per day Improvement in quality of life (satisfaction) was superior with quetiapine than 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 quetiapine than 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 quetiapine side effects (table 4 and table 5) is discussed separately. (See "Secondgeneration 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 quetiapine monotherapy 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 lithium monotherapy or paroxetine monotherapy for bipolar major depression, the comparative benefit of quetiapine is not clear due to methodologic problems: One eight week trial assigned patients to quetiapine 300 mg per day (N = 255), quetiapine 600 mg per day (N = 263), or lithium (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 <0.6 mEq/L (<0.6 mmol/L). One eight week trial assigned patients to quetiapine 300 mg per day (N = 229), quetiapine 600 mg per day (N = 232), or paroxetine 20 mg per day (N = 118) [14]. Although symptoms improved more with either dose of quetiapine than with paroxetine, the study was underpowered for paroxetine. In addition, the paroxetine dose was at the low end of the dose range that is usually used to treat major depression (table 6).
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Olanzapine For patients with bipolar major depression, randomized trials have demonstrated the efficacy of olanzapine monotherapy [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). Olanzapine can 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]: Sedation Weight 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 olanzapine side effects (table 4 and table 5) is discussed separately. (See "Secondgeneration antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Olanzapine'.) Olanzapine plus fluoxetine The combination of olanzapine and fluoxetine can 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 of olanzapine monotherapy (table 4 and table 5) and fluoxetine monotherapy (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 either lurasidone 20 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 lithium or 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 valproate and randomly assigned the patients to receive adjunctive risperidone, paroxetine, or risperidone plus paroxetine [25]. All three groups improved. The side effects (table 4 and 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 aripiprazole or ziprasidone: 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 trials 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 4 and 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 quetiapine or olanzapine [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 secondgeneration antipsychotics, the greatest risk for metabolic effects is with olanzapine and clozapine, followed by quetiapine and risperidone (table 4) [40]. The risk of clinically significant weight gain for olanzapine monotherapy and olanzapine plus fluoxetine appears to be comparable [6,41]. Lurasidone does not cause short-term weight gain, whereas asenapine does [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, olanzapine and quetiapine often cause somnolence that leads to discontinuation of treatment [28]: In an eight week randomized trial that compared olanzapine with 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 quetiapine with 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".) Quetiapine monotherapy 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.) Olanzapine monotherapy 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.) Olanzapine plus fluoxetine is 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 aripiprazole or ziprasidone. (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 4 and table 5). (See 'Side effects' above.) Among second-generation antipsychotics, the greatest risk for metabolic effects (eg, weight gain, hyperlipidemia, and hyperglycemia) is with olanzapine and clozapine, followed by quetiapine and risperidone (table 4). The risk of clinically significant weight gain appears to be comparable for olanzapine monotherapy and olanzapine plus fluoxetine. Lurasidone does not cause short-term weight gain, whereas asenapine does. (See 'Metabolic effects' above.) Among patients with bipolar major depression, olanzapine and quetiapine often 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.) Use of UpToDate is subject to the Subscription and License Agreement. 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 children and 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 specific plan, 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, or psychomotor retardation.
Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. American Psychiatric Association, Washington, DC 2000.
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Selected adverse effects of antipsychotic medications for schizophrenia

Weight gain/diabetes mellitus
First generation agents Chlorpromazine Fluphenazine Haloperidol Loxapine Perphenazine Pimozide Thioridazine* Thiothixene Trifluoperazine +++ + + ++ ++ + ++ ++ ++ +++ + + ND ND ND ND ND ND + +++ +++ ++ ++ +++ + +++ +++ ++ +++ +++ ++ ++ ++ +++ ++ ++ +++ + ++ ++ ++ + +++ + +
Hypercholesterolemia
EPS/TD
Prolactin elevation
Sedation
Second generation agents [1] 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 requiring regular blood cell count monitoring. Adapted from: 1. Treatment Guidelines from The Medical Letter, August 2010; Vol. 8 (96):61. www.medicalletter.org.
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Selected adverse effects of atypical antipsychotic medications

Acute
Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Seizures Prolonged QT, dystonia Seizures, dystonia Seizures, dystonia Prolonged QT, dystonia Gastrointestinal (vomiting)
Chronic
NMS, Agranulocytosis, Myocarditis EPS, TD, NMS EPS, TD, NMS, Agranulocytosis EPS, TD, NMS EPS
NMS: neuroleptic malignant syndrome; TD: tardive dyskinesia; EPS: extrapyramidal side effects.
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Unipolar depression in adults: Antidepressant doses*

Usual total starting dose per day (mg) Usual total dose per day (mg) Extreme daily dose range (mg)
Drug
Selective serotonin reuptake inhibitors Citalopram Escitalopram Fluoxetine Fluvoxamine Fluvoxamine CR Paroxetine Paroxetine CR Sertraline 20 10 20 50 100 20 25 50 20 to 40 10 to 20 20 to 60 50 to 200 100 to 200 20 to 40 25 to 50 50 to 200 10 to 40 5 to 30 10 to 80 25 to 300 100 to 300 10 to 50 12.5 to 62.5 25 to 300
Serotonin-norepinephrine reuptake inhibitors Desvenlafaxine Duloxetine Milnacipran Venlafaxine Venlafaxine XR Atypical agents Agomelatine (not available in United States) Bupropion Bupropion SR 12 hour Bupropion XL 24 hour 200 150 300 (maximum single dose 150 mg) 300 (maximum single dose 200 mg) 300 100 to 450 150 to 400 25 25 to 50 25 to 50 50 30 to 60 12.5 37.5 to 75 37.5 50 30 to 120 100 to 200 75 to 375 75 to 225 50 to 400 30 to 120 50 to 300 75 to 450 75 to 375
150
150 to 450 (United States) 150 to 300 (Europe)
Bupropion hydrobromide 24 hour Mirtazapine Serotonin modulators Nefazodone Trazodone Trazodone ER Vilazodone
174
348
174 to 522
15
15 to 45
7.5 to 60
200 100 150 10
300 to 600 200 to 500 375 40
50 to 600 100 to 600 150 to 375 10 to 40
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Tricyclics and tetracyclics Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Maprotiline Nortriptyline Protriptyline Trimipramine 25 25 25 25 25 25 25 25 10 25 150 to 300 200 to 300 100 to 250 150 to 300 150 to 300 150 to 300 100 to 225 50 to 150 15 to 60 150 to 300 10 to 300 25 to 400 25 to 300 25 to 300 25 to 300 10 to 300 25 to 225 10 to 150 5 to 60 25 to 300
Monamine oxidase inhibitors Isocarboxazid Phenelzine Selegiline transdermal Tranylcypromine 10 10 15 6 mg/24 hour patch 10 to 40 15 to 90 6 to 12 mg/24 hour patch 30 to 60 10 to 60 7.5 to 90 6 to 12 mg/24 hour patch 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 Lexicomp drug monographs included with UpToDate. Lower end doses may be useful for initiating or maintaining elderly, medically compromised (eg, renal or hepatic illness), or drug sensitive patients, as well as patients with a low body mass index. High doses may be 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 more information refer to the UpToDate topic on unipolar depression in adults and selective serotonin reuptake inhibitors. 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 mg per 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 cyclic antidepressants and monoamine oxidase inhibitors for treatment of adults with depression. Data from: 1. The American Psychiatric Publishing Textbook of Psychopharmacology, 4th edition. Schatzberg AF, Nemeroff CB (eds); American Psychiatric Publishing, Inc. Washington, D.C. (2009). 2. Labbate LA, Fava M, Rosenbaum JF, Arana GW. Drugs for the treatment of depression. In: Handbook of Psychiatric Drug Therapy, 6th ed, Lippincott Williams and Wilkins, Philadelphia 2010. p.54. 3. Gartlehner G, Thaler K, Hill S, Hansen RA. How should primary care doctors select which antidepressants to administer? Curr Psychiatry Rep 2012; 14:360. 4. Lexicomp Online. Copyright 1978-2013 Lexicomp, Inc. All Rights Reserved.
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Side effects of antidepressant medications

Drug Anticholinergic Drowsiness Insomnia/agitation Orthostatic hypotension
Selective serotonin reuptake inhibitors (SSRIs) Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Atypical agents Agomelatine (not available in United States) Bupropion 0 0 2+ (immediate release) 1+ (sustained release) Mirtazapine 1+ 4+ 0 0 0 0 1+ 1+ 0 0 0 0 0 1+ 0 0 0 0 1+ 1+ 0 1+ 1+ 2+ 1+ 1+ 2+ 1+ 1+ 1+ 1+ 2+ 1+
Serotonin-norepinephrine reuptake inhibitors (SNRIs) Desvenlafaxine 0 1+ 2+ 0
Duloxetine Milnacipran Venlafaxine
0 1+ 0
0 1+ 1+
2+ 0 2+
0 0 0
Serotonin modulators Trazodone 0 4+ 0 1+ (hypnotic dose) 3+ (antidepressant dose) Vilazodone Nefazodone** 0 1+ 0 2+ 2+ 0 0 1+
Tricyclic and tetracyclic antidepressants (TCAs) Amitriptyline Amoxapine Clomipramine Desipramine 4+ 2+ 4+ 1+ 4+ 2+ 4+ 4+ 0 2+ 1+ 1+ 3+ 2+ 2+ 2+
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Doxepin Imipramine Maprotiline Nortriptyline Protriptyline Trimipramine
3+ 3+ 2+ 2+ 2+ 4+
3+ 3+ 3+ 2+ 1+ 4+
0 1+ 0 0 1+ 1+
2+ 4+ 2+ 1+ 2+ 3+
Monoamine oxidase inhibitors Isocarboxazid Phenelzine Selegiline Tranylcypromine 1+ 1+ 1+ 1+ 1+ 2+ 0 1+ 2+ 1+ 1+ 2+ 2+ 3+ 1+ 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, heart disease, congenital long QT syndrome, hypokalemia or hypomagnesemia, elevated serum drug concentrations (eg, drug overdose, interacting drugs, organ failure) and combination of drugs with QTc prolonging effects. Refer to topic on acquired long QT syndrome. All SSRIs and SNRIs are associated with transient nausea and gastrointestinal discomfort upon initiation or dose increase. Based upon reports of dose related QTc prolongation and arrhythmia, the maximum recommended dose of citalopram 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. Monitor blood pressure regularly. Trazodone is associated rarely with priapism, which is considered a medical emergency. Refer to UpToDate topic 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: 1. Nelson JC. Tricyclic and tetracyclic drugs. In: The American Psychiatric Publishing Textbook of Psychopharmacology, 4th ed, Schatzberg AF, Nemeroff CB (Ed), American Psychiatric Publishing, Washington, DC 2009. p.263. 2. Lexicomp Online. Copyright 1978-2013 Lexicomp, Inc. All Rights Reserved. 3. Wenzel-Seifert K, Wittmann M, Haen E: QTc prolongation by psychotropic drugs and the risk of torsade de pointes. Dtsch Arztebl Int 2011; 108(41):687-93. 4. Serretti A, Chiesa A. Sexual side effects of pharmacological treatment of psychiatric disease. Clin Pharm Ther 2011; 89:142-7. 5. Howland RH. A benefit-risk assessment of agomelatine in the treatment of major depression. Drug Saf 2011; 34:709.
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Monitoring for metabolic side effects of antipsychotic drugs

At least every 5 years
Baseline
4 weeks
8 weeks
12 weeks
Quarterly
Annually
Personal or family history Weight (body mass index) Waist circumference Blood pressure Fasting plasma glucose Fasting lipid profile
X X X X X X X X X X X X
X X X
* For patients taking olanzapine, quetiapine, clozapine. Copyright 2004 American Diabetes Association. From Diabetes Care, Vol. 27, 2004: 596-601. Reproduced with permission.
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Abnormal involuntary movement scale
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