Management of Bipolar Disorder

By | March 27, 2015

Antipsychotics are frequently used in the treatment of bipolar disorder. Most patients started on antipsychotics as adjunctive treatment for manic episodes continue these agents beyond 6 months, even in the absence of conclusive data on the long-term efficacy of most antipsychotics in maintenance treatment.

Typical antipsychotics are effective antimanic agents but appear less effective than lithium, valproate, and carbamazepine in the maintenance treatment of bipolar disorder. Long-term treatment with typical antipsychotics can precipitate depressive episodes. These data and the greater risk of tardive dyskinesia in affective disorder limit the role of typical antipsychotics for maintenance treatment.

Atypical or novel antipsychotics have a more benign adverse effect profile, and emerging evidence suggests that they may be important options in the treatment of bipolar disorder. These agents as a class appear to be effective in acute mania, with olanzapine, risperidone, quetiapine, ziprasidone, and aripiprozole having received FDA indications for acute mania. In addition, as described in site, the combination of olanzapine and fluoxetine has been approved by the FDA for the treatment of bipolar depression. Moreover, olanzapine has received FDA approval for maintenance treatment in bipolar disorder, and emerging data suggest that aripiprazole may have efficacy in maintenance therapy. Taken together, this evidence suggests that atypical antipsychotics may ultimately prove to have roles in managing not only acute mania but also acute depression and maintenance therapy in patients with bipolar disorders.

Olanzapine has received an FDA indication not only as an antimanic agent but also for maintenance therapy. Multicenter, randomized, double-blind, placebo-controlled trials indicate that olanzapine as maintenance monotherapy for bipolar disorders after acute manic episodes was superior to placebo and comparable (and on some measures superior) with lithium. In these studies, olanzapine tended to robustly prevent mania and more modestly prevent depression. Mean olanzapine dosages in these monotherapy maintenance trials after acute manic episodes were approximately 12-16 mg/day, and sedation and weight gain were the main adverse effects. There are only limited data regarding the efficacy of olanzapine as continuation and maintenance therapy after acute depressive episodes in bipolar disorders. In a 52-week continuation study, approximately three-quarters of patients who remitted in an 8-week acute depression study who were placed on open olanzapine monotherapy required addition of open fluoxetine, and even with this intervention allowed, about 45% relapsed (primarily into depression). As noted earlier, in an active-comparator trial, olanzapine monotherapy compared with divalproex monotherapy was somewhat more poorly tolerated due to sedation and weight gain but somewhat more effective on some secondary outcome measures.

Sedation and weight gain are the main adverse effects seen with olanzapine. These difficulties are particularly challenging during maintenance therapy. Increasing concerns have been raised regarding the risks of obesity and diabetes with olanzapine and other newer antipsychotics. Indeed, the FDA has stipulated changes in the product information for not only olanzapine but also other newer antipsychotics to reflect these risks, suggesting a class effect for such problems. In contrast, the report of a recent consensus development conference on antipsychotics and obesity, diabetes, and hyperlipidemia emphasized differences between agents, with clozapine and olanzapine being the most, risperidone and quetiapine being less, and ziprasidone and aripiprazole being the least implicated (American Diabetes Association).

Like other newer antipsychotics, aripiprazole appears effective in acute mania. Multicenter, randomized, double-blind, placebo-controlled trials indicate that aripiprazole monotherapy is effective for acute manic and mixed episodes, and it received such an indication in 2004. In addition, in a recent 26-week double-blind, placebo-controlled trial, aripiprazole was effective as continuation/maintenance treatment in patients with recent manic or mixed episodes, with anxiety and nervousness being the main adverse effects. Indeed, aripiprazole received a maintenance indication in early 2005.

To date, there are no controlled trials of risperidone for maintenance therapy in bipolar disorders. However, in a 6-month multicenter study in 541 patients (430 completers) with bipolar disorders or schizoaffective disorder bipolar type, open adjunc-tive risperidone (mean dosage approximately 4 mg/day) was generally well tolerated, with sedation, weight gain, and extra-pyramidal symptoms being the main adverse events. In this study, extrapyramidal symptom ratings decreased from baseline to endpoint, and there were no new cases of tardive dyskinesia. Also, in an uncontrolled trial, open risperidone showed benefits when added to patients’ medication regimen in treatment that lasted an average of 6 months.

To date, there are no double-blind, placebo-controlled trials of quetiapine maintenance therapy in bipolar disorders, although small longer-term open treatment trials suggest that open quetiapine is well tolerated in bipolar disorders.

To date, there are no controlled trials of ziprasidone for acute bipolar depression or maintenance treatment in bipolar disorders. However, open continuation/maintenance studies suggest that ziprasidone is well tolerated and lacks substantial sedation, weight gain, or cardiac problems.

Clozapine may have utility in bipolar disorder patients. An open, randomized study suggested that adjunctive clozapine was effective in the maintenance treatment of patients with treatment-resistant bipolar and schizoaffective disorder. However, the risks of sedation, weight gain, and aplastic anemia, and the inconvenience of frequent blood monitoring for blood dyscrasias, suggest clozapine ought to be held in reserve for patients with treatment-resistant bipolar disorders.

Taken together, these data suggest a possible emerging role for the use of atypical antipsychotics in the maintenance treatment of patients with bipolar disorders. These drugs do not appear to entail as much risk of tardive dyskinesia or exacerbation of depression as seen with typical antipsychotics. However, at least some atypical antipsychotics have been associated with problematic sedation, weight gain, and metabolic disturbances. In addition, further studies are needed to establish whether or not atypical antipsychotics as a class have efficacy in the maintenance treatment of patients with bipolar disorders. Patients whose bipolar disorder is resistant to mood stabilizers or combinations thereof are reasonable candidates for ongoing treatment with atypical antipsychotics, as noted in the 2002 revision of the American Psychiatric Association’s practice guideline for bipolar disorders (American Psychiatric Association 2002). Additional controlled studies are needed to clarify the role(s) of atypical antipsychotics in maintenance treatment in patients with bipolar disorders. In the interim, careful assessment of the risks and benefits is indicated before long-term treatment with these agents is pursued.