Bipolar disorder in adults: Pharmacotherapy for acute depression

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Bipolar disorder in adults: Pharmacotherapy for acute depression Author Jeffrey Stovall, 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: Jan 15, 2013. INTRODUCTION Bipolar disorder is an illness characterized by periods of pathologic mood elevation. Patients with bipolar I disorder have manic episodes or mixed (concurrent mood elevation and depression) episodes, and nearly always experience depressive episodes. The clinical course in patients with bipolar II disorder is characterized by one or more episodes of major depression, with at least one hypomanic episode. Recognition of bipolar disorder is important for at least two reasons: it is associated with substantial morbidity and mortality if untreated, and treatment differs from that of unipolar depression. Bipolar disorder is often misdiagnosed, especially when patients present with symptoms of depression [1]. A careful history, including information from family members, may find evidence of prior manic, mixed, or hypomanic episodes. The treatment of acute bipolar depression is reviewed here. Treatment of acute mania, mixed states, hypomania; maintenance treatment; and the epidemiology, clinical manifestations, and diagnosis of bipolar disorder are discussed elsewhere. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania" and "Bipolar disorder in adults: Maintenance treatment" and "Bipolar disorder in adults: Epidemiology and pathogenesis".) STAGE OF ILLNESS The goals for treating for bipolar depression are based upon the patient's current stage of illness, generally categorized as three phases [2]: The acute phase of treatment focuses upon managing the patients safety and the presenting symptoms. Patients in the acute phase may be suicidal, psychotic, and display such poor judgment as to pose an imminent risk to themselves. Hospitalization is often necessary until the severity of symptoms lessens. The continuation phase lasts weeks to months, during which remission of symptoms and restoration of functioning is preserved with ongoing treatment. The goal is to prevent relapse of the mood episode. The maintenance phase of treatment lasts months to years after recovery from the mood episode, and aims to prevent recurrence of a new mood episode. Long-term or lifetime maintenance is recommended for patients who have suffered one manic episode [3,4]. Maintenance treatment is discussed separately. (See "Bipolar disorder in adults: Maintenance treatment".) GENERAL PRINCIPLES Treatment of bipolar depression begins with the clinical assessment for risk of suicide, aggressiveness, and violence to others [3,4]. Patients should reduce their use of alcohol, and other substance use disorders should also be evaluated and treated. In addition, clinicians should address current psychosocial problems when patients are amenable. Patients who experience a breakthrough depressive episode while on maintenance therapy should be assessed for adherence to treatment, and initially managed by optimizing their current medication dose [5]. Although depressive episodes occur more frequently than manic episodes, and have greater impact on the quality of life, treatment of bipolar depression has not been as extensively studied [6-8]. Treatment of depressive syndromes is based upon what has been established for bipolar I disorder, even though bipolar II disorder is more prevalent. Section Editor Paul Keck, MD Deputy Editor David Solomon, MD

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Bipolar disorder in adults: Pharmacotherapy for acute depression

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Drug classes commonly used to treat patients with acute depressive episodes include: Antidepressants Lithium Anticonvulsants Second-generation antipsychotics The goal of treatment is full remission of the depressive syndrome. However, some patients may not fully remit with any of the currently available medications, and it is important to maintain realistic expectations and avoid unhelpful polypharmacy. Persistent efforts to achieve full remission may be one reason that a study of 4035 bipolar patients, treated at 22 mood disorder specialty clinics, found use of three or more medications occurred in 40 percent of the patients, while 18 percent of patients received four or more medications. In addition, clinicians may need to consider other treatment options, such as psychotherapy. SPECIFIC TREATMENTS Antidepressants Fluoxetine plus olanzapine efficaciously treats bipolar depression [9-11]. As an example, a randomized trial (833 patients with bipolar I depression) found that remission occurred in significantly more patients who received fluoxetine plus olanzapine, compared with olanzapine alone or placebo alone (49 versus 33 and 25 percent) [9]. However, the evidence is mixed whether adjunctive antidepressants in general are efficacious [12]. The efficacy and risks of using antidepressants to treat bipolar major depression are discussed separately (see "Bipolar disorder in adults: Treating major depression with antidepressants"). Lithium Multiple placebo-controlled trials, many completed prior to 1980, have evaluated lithium therapy in patients with bipolar depression. A review of these older studies, involving 160 patients, found that the "unequivocal" lithium response rate (ie, a good or moderate response to lithium, and subsequent relapse with placebo) was approximately 36 percent [13]. Onset of the antidepressant effect of lithium, at six to eight weeks, is much later than the onset of its antimanic effect. Use of lithium to treat acute bipolar manic and mixed episodes is discussed separately. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania", section on 'Lithium' and "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects".) Lamotrigine Lamotrigine is efficacious for treating bipolar depression [14,15]. Evidence for the efficacy of lamotrigine includes a meta-analysis of five randomized trials (1072 patients with bipolar major depression) that compared lamotrigine (100 to 400 mg per day) with placebo [16]. Response (improvement from baseline on the depression rating scale 50 percent) occurred in significantly more patients who received lamotrigine than placebo (44 versus 35 percent). A planned subgroup analysis found that lamotrigine was superior to placebo for severe depression at baseline, but not for moderate depression. Discontinuation of treatment was comparable for lamotrigine and placebo. Therapy usually begins with a dose of 25 mg/day for two weeks, then 50 mg/day for two weeks. The dose can be titrated by 50 mg per week thereafter as clinically indicated; the usual maximum daily dose is 200 mg. Lamotrigine interacts with valproate and carbamazepine, such that valproate increases lamotrigine serum levels and carbamazepine decreases lamotrigine levels. There is more evidence supporting use of a lithium-lamotrigine combination, compared with combinations of lamotrigine with either valproate or carbamazepine. Systemic side effects of lamotrigine include rash and nausea. A rash may develop in up to 10 percent of patients during the initial one to two months of therapy, and necessitates discontinuation of the drug. The risk of developing a life-threatening rash such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or angioedema is approximately 1 in 1000 adults. Lamotrigine plus lithium Evidence for the efficacy of lamotrigine plus lithium includes an eight week, randomized trial that compared lamotrigine (200 mg per day) plus lithium (target serum concentration 0.6 to 1.2 mEq/L [0.6 to 1.2 mmol/L]) with placebo plus lithium in 124 patients with bipolar major depression [17]. Response (improvement from baseline on the depression rating scale 50 percent) occurred in significantly more patients who received adjunctive lamotrigine than placebo (52 versus 32 percent). The incidence of specific adverse events (including benign rash) did not differ significantly between the two groups; one case of serious rash developed with placebo.

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Bipolar disorder in adults: Pharmacotherapy for acute depression

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Valproate (Divalproex) A meta-analysis of four controlled trials (142 patients) found divalproex was efficacious for treating bipolar depression [18]. Remission occurred in significantly more patients who received divalproex compared with patients who received placebo (41 versus 24 percent). Use of valproate to treat acute bipolar manic and mixed episodes is discussed separately. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania, mixed episodes, and hypomania".) Second-generation antipsychotics Quetiapine and olanzapine are each efficacious as monotherapy for treating bipolar depression [9,19-22]. By contrast, aripiprazole monotherapy and adjunctive ziprasidone are not [23,24]. Quetiapine Evidence for the efficacy of quetiapine in patients with bipolar major depression includes the following randomized trials: A trial compared quetiapine with placebo in 666 patients, and found that remission occurred in more patients who received quetiapine 600 or 300 mg once per day, compared with placebo (70 and 70 versus 55 percent) [19] A trial compared quetiapine with placebo in 618 patients, and found that remission occurred in more patients who received quetiapine 600 mg daily compared with placebo (69 versus 55 percent) [20]. A pooled analysis of two eight-week trials that compared quetiapine with placebo in 694 patients [25]. Remission occurred in significantly more patients who received quetiapine 300 or 600 mg per day than placebo (54 and 55 versus 32 percent). The most common adverse effects of quetiapine included weight gain, dry mouth, sedation, dizziness, and constipation. Quetiapine is typically started at 50 mg once daily at bedtime. The dose is then increased every day by 50 to 100 mg to reach the target dose of 300 to 600 mg per day within one to two weeks of starting the medication. Olanzapine Olanzapine monotherapy and olanzapine plus fluoxetine were compared with placebo in a randomized trial of 833 bipolar I patients [9]. Both monotherapy and combination therapy were superior to placebo, and the combination was superior to monotherapy. Remission rates for olanzapine plus fluoxetine, olanzapine monotherapy, and placebo were 49, 37, and 25 percent respectively. Adverse events that occurred significantly more often with either the combination, or olanzapine alone, compared with placebo included weight gain, increased appetite, dry mouth, and weakness. Treatment emergent mania did not differ significantly between fluoxetine plus olanzapine, olanzapine alone, and placebo (6 and 6 and 7 percent). Fluoxetine is usually started at 20 mg once daily in the morning. For patients who do not respond within two to four weeks, the dose is increased by 10 to 20 mg per day, depending upon how well the medication is tolerated. Patients who remain unresponsive to treatment should receive additional increases of 10 to 20 mg per day every two to four weeks as tolerated, to an effective dose. The maximum dose is 60 mg per day. Olanzapine is typically started at 5 mg once daily at bedtime. For patients who do not respond within one week, the dose is increased by 5 mg per day. Patients who remain unresponsive to treatment should receive additional increases of 5 mg per day every week as tolerated, to an effective dose. The maximum dose is 15 to 20 mg per day, depending upon tolerability. Electroconvulsive therapy (ECT) Electroconvulsive therapy (ECT) remains one of the more reliable and effective treatments for refractory or life-threatening depression [26]. An overview of ECT, the technique for performing it, and medical consultation for ECT are discussed separately. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Technique for performing electroconvulsive therapy (ECT) in adults" and "Medical consultation for electroconvulsive therapy".) Omega 3 fatty acids Dietary supplementation with omega 3 fatty acids from fish oils may have modest to moderate benefits for bipolar depression. Of five randomized trials that were identified by a systematic review, analysis of the one trial that met inclusion criteria found that improvement of depression was superior with adjunctive omega 3 fatty acid (eicosapentaenoic acid), compared with placebo [27]. A subsequent meta-analysis of five, modestly to moderately heterogeneous randomized trials (291 patients with bipolar depression), using less

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Bipolar disorder in adults: Pharmacotherapy for acute depression

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restrictive inclusion criteria as well as data from a new study, found that improvement was significantly greater with omega 3 fatty acids than placebo during treatment lasting a mean of 13 weeks [28]. Given the limited available data, few serious adverse effects, and other health benefits, use of omega 3 fatty acids (1 to 2 grams per day) as an adjunctive treatment is reasonable in patients with bipolar depression, particularly those with increased cardiovascular risk who might also benefit from the their effects on elevated triglycerides. (See "Lipid lowering with diet or dietary supplements".) Investigational approaches Ketamine is an NMDA receptor antagonist that is used as an anesthetic and may be effective for bipolar major depression (as well as unipolar major depression [29]). A crossover trial compared a single intravenous infusion of ketamine (0.5 mg/kg) with a single infusion of saline, administered two weeks apart, in 18 patients with treatment-resistant bipolar major depression who were receiving lithium or valproate; patients were randomly assigned to the order in which they received the two adjunctive infusions [30]. Improvement of symptoms was significantly greater with adjunctive ketamine than with saline, and response (improvement from baseline on the depression rating scale 50 percent) to ketamine occurred in 71 percent and to saline in 6 percent. Transient side effects that occurred only with ketamine included dissociation; feeling strange, weird, or bizarre; dry mouth; tachycardia; and increased blood pressure. A subsequent trial using the same methods in 15 patients found that response to ketamine occurred in 79 percent and to saline in 0 percent; dissociation was the most common side effect with either treatment [31]. In addition, a report described improvement of bipolar major depression with adjunctive intramuscular ketamine that was administered for nine months in one patient and six months in another patient [32]. SUGGESTED PATIENT MANAGEMENT Bipolar depression should be treated with lithium, valproate, or lamotrigine. For patients who fail to respond to monotherapy, the addition of a second drug, including an atypical antipsychotic, may be required. Adding an antidepressant to lithium or valproate has not been shown to be effective [33,34]. Lamotrigine may be particularly effective in treating bipolar major depression and is a reasonable choice to add to another medication, such as lithium, valproate, and carbamazepine [35]. It should be noted, however, that there are significant drug interactions, such that valproate increases lamotrigine serum levels and carbamazepine decreases lamotrigine levels. ECT is a reasonable alternative in patients with suicidal ideation, psychosis, or depression during pregnancy. Medication combinations Polytherapy is frequently recommended for treatment of bipolar depression [3,36-39]. The best established medication combination is fluoxetine plus olanzapine [9-11]. Adjunctive antidepressants Fluoxetine plus olanzapine efficaciously treats bipolar depression [9-11]. However, the evidence is mixed regarding whether adjunctive antidepressants in general are efficacious [12]. The role of adjunctive antidepressants is discussed separately (see "Bipolar disorder in adults: Treating major depression with antidepressants"). Other combinations Lamotrigine may be efficacious as add-on therapy for depressed bipolar patients [17,35]. Adjunctive modafinil (or the longer lasting isomer armodafinil), pramipexole, folate, or N-acetylcysteine may also be useful. A randomized trial (124 patients treated with lithium) found remission occurred in significantly more patients who received adjunctive lamotrigine, compared with placebo (52 versus 32 percent) [17]. Two randomized trials (342 patients treated with antimanic drugs and antidepressants) each found that depressive symptoms improved significantly more with adjunctive modafinil compared with placebo [40,41]. However, the larger study (N=257) found no significant difference in remission or response rates. Two randomized trials (43 patients treated with lithium or an anticonvulsant) each found that response with adjunctive pramipexole was significantly higher compared with placebo (60 and 67 versus 9 and 20 percent) [42,43]. A randomized trial (75 patients treated with antimanic and antidepressant medications) found that remission occurred in significantly more patients who received adjunctive N-acetylcysteine compared with placebo (51

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versus 18 percent) [44]. When combining medications, clinicians should also consider quetiapine [19-21,45], divalproex [18], or olanzapine [9], which have demonstrated efficacy as monotherapy compared with placebo for bipolar depression. TREATMENT FOR BIPOLAR II DISORDER Bipolar II disorder is diagnosed in patients who have episodes of hypomania and major depression. Hypomanic episodes can disrupt the patient's functioning, but are less severe compared with the manic episodes that occur in bipolar I disorder. The level of associated functional impairment in patients with bipolar II disorder is closely linked to the severity of the depressive episodes that predominate in bipolar II disorder [8]. Relatively little research has focused specifically on the treatment of patients with bipolar II [46,47]. Many studies either exclude patients with bipolar II disorder or lump them together with bipolar I patients in the analyses. Treatment guidelines often provide little guidance [3,6], but this has started to change [48]. We suggest patients with bipolar II disorder should be treated with the same medications used for bipolar I, until further studies are available that indicate otherwise [49]. A meta-analysis of 13 studies (including seven controlled trials) evaluated the risk of inducing mania or hypomania with antidepressant treatment in bipolar disorder and found that the risk of antidepressant-associated mania/hypomania for patients with bipolar II disorder was 50 percent less than the risk for patients with bipolar I disorder [50]. In addition, the mood elevations that were provoked in bipolar II patients were less severe than in bipolar I patients. SPECIAL CIRCUMSTANCES Elderly Treatment of geriatric bipolar major depression is discussed separately. (See "Geriatric bipolar disorder: Acute treatment", section on 'Bipolar major depression'.) Pregnancy Treatment of bipolar major depression during pregnancy, the teratogenic and postnatal risks of pharmacotherapy for bipolar disorder; the principles of teratology; preconception and prenatal maintenance pharmacotherapy for bipolar patients; and preconception counseling for patients with bipolar disorder are discussed separately. (See "Bipolar disorder in pregnant women: Treatment of major depression" and "Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy" and "Principles of teratology" and "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy" and "Bipolar disorder in women: Contraception and preconception assessment and counseling".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (See "Patient information: Bipolar disorder (The Basics)" and "Patient information: Reducing the costs of medicines (The Basics)".) Beyond the Basics topics (See "Patient information: Bipolar disorder (manic depression) (Beyond the Basics)" and "Patient information: Reducing the costs of medicines (Beyond the Basics)".) SUMMARY AND RECOMMENDATIONS Bipolar disorder is an illness characterized by periods of pathologic mood elevation. Patients with bipolar I disorder have manic episodes or mixed (concurrent mood elevation and depression) episodes, and nearly

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Bipolar disorder in adults: Pharmacotherapy for acute depression

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always experience depressive episodes. Bipolar II disorder is characterized by one or more episodes of major depression, with at least one hypomanic episode. (See 'Introduction' above.) The goals for treating bipolar depression depend upon the stage of illness. The acute phase focuses upon managing the patients safety and symptoms, the continuation phase aims to achieve full symptom remission and prevent relapse, and the maintenance phase focuses upon maintaining recovery and preventing recurrence of a new mood episode. (See 'Stage of illness' above and "Bipolar disorder in adults: Maintenance treatment".) Patients presenting with acute bipolar depression should be assessed for suicide risk and aggressiveness, and substance use disorders treated. (See 'General principles' above.) For patients with acute bipolar depression, we suggest treatment with quetiapine, lithium, lamotrigine, or valproate (Grade 2B). Olanzapine plus fluoxetine, other medication combinations, and ECT are also effective. Antidepressants have not been effective as adjunctive therapy to lithium or valproate for bipolar depression. Antidepressant monotherapy may precipitate mania, but may be effective and tolerated in some patients with bipolar II disorder. (See 'Quetiapine' above and 'Lithium' above and 'Lamotrigine' above and 'Medication combinations' above and 'Electroconvulsive therapy (ECT)' above and 'Treatment for bipolar II disorder' above.) For patients with bipolar depression, adjunctive omega 3 fatty acids (1 to 2 grams per day) are a reasonable option. (See 'Omega 3 fatty acids' above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 15267 Version 22.0

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