Bipolar maintenance: Are atypical antipsychotics really ‘mood stabilizers’?
Atypical antipsychotics are being used more frequently for bipolar maintenance. Do we know enough about their long-term efficacy and safety?
Evidence for atypicals
Olanzapine is the only atypical FDA-approved for relapse prevention in bipolar disorder. This approval is supported by several studies, most notably two 1-year, double-blind trials:
- Mean time to any mood relapse was 174 days in patients taking olanzapine, mean 12.5 mg/d (±5 mg), compared with 22 days in a placebo group (Eli Lilly and Co., data on file).
- Manic relapse rate was 14.3% in patients treated with olanzapine, ~12 mg/d, compared with 28% in patients treated with lithium, ~1,100 mg/d (mean 0.76 mEq/L). The two treatments were similarly effective in preventing depressive relapse.5
As a mood stabilizer, olanzapine was as effective as divalproex in a 47-week randomized, double-blind study of 251 adults with bipolar I disorder.6 Patients treated with olanzapine improved more rapidly and had fewer manic symptoms than those treated with divalproex, but bipolar relapse rates were similar in both treatment groups.
Risperidone appears to have a role as a potential maintenance mood stabilizer in bipolar patients, although double-blind trials are lacking.
In a 6-month, open-label investigation, relapse rates were 16% for depression and 7% for mania in bipolar patients receiving risperidone (average 4 mg/d) combined with mood-stabilizing medications.7 These relapse rates are lower than those typically reported for mood-stabilizing monotherapy.
In another 6-month, open-label study, risperidone monotherapy (average 4 mg/d) was effective for treating mania and maintaining euthymia.8
IM risperidone is a useful option for bipolar patients chronically nonadherent with oral medications; it also substantially reduces the risk of neuroleptic side effects compared with older depot antipsychotics.
Quetiapine was recently approved as an antimanic agent and may possess mood-stabilizing properties. In a preliminary study of 10 patients with bipolar disorder, adding quetiapine (mean 200 mg/d) to existing mood stabilizer therapy for 12 weeks improved psychopathology, mania, and depression rating scale scores.9
More-recent unpublished data suggest dosing quetiapine to approximately 600 mg/d as monotherapy or an adjunct to treat acute mania, though controlled maintenance studies are lacking (AstraZeneca Pharmaceuticals, data on file).
Others. Some early evidence supports using ziprasidone and aripiprazole for bipolar mania:
- Ziprasidone monotherapy, 40 to 80 mg bid, was significantly more effective than placebo in reducing acute mania symptoms in a 3-week, double-blind, randomized trial of 197 patients with bipolar I disorder.10
- Aripiprazole monotherapy, 15 to 30 mg/d, had a significantly greater effect than placebo in a 3-week, double-blind, randomized trial of 262 patients in acute manic or mixed bipolar episodes. Response rates among patients with mania were 40% with aripiprazole and 19% with placebo.11
Both ziprasidone and aripiprazole were well-tolerated in these brief trials, although their efficacy as long-term mood-stabilizers in bipolar disorder is unclear.
Using clozapine raises concerns about potentially serious adverse events, although it remains the only agent with proven efficacy in treatment-refractory mania.12,13 Clozapine also appears to reduce hospitalization and affective relapse rates and improve symptoms and quality of life.14,15
Long-term safety
Compared with conventional antipsychotics, EPS are not a major concern with the atypical agents. Except for risperidone, atypicals’ effect on prolactin levels generally is not clinically meaningful. Atypicals appear to be “mood-friendly,” whereas conventional antipsychotics seem to contribute to dysphoria or cause depression in some patients.
Sedation or other annoying side effects such as dry mouth or dizziness can occur with any atypical. Other more-serious side effects may complicate antipsychotic treatment, as we are coming to understand from using atypicals for long-term schizophrenia management.
Table 3
Weight-loss medications for bipolar patients taking atypical antipsychotics
| Drug | Dosage | Side effects | Recommendations |
|---|---|---|---|
| Metformin | 500 to 1,000 mg bid | Hypoglycemia Diarrhea Nausea/vomiting | First-line in patients with comorbid type 2 diabetes |
| Orlistat | 120 mg tid | GI distress Change in bowel habits | Second-line For patients with BMI >27 Supplement fat-soluble vitamins |
| Sibutramine | 5 to 15 mg/d | Dry mouth Anorexia Insomnia Constipation | Second-line For patients with BMI 27 to 30 Risk of serotonin syndrome if given with serotonergic drugs |
| Topiramate | 50 to 250 mg/d | Somnolence Fatigue Paresthesias | Consider first-line for its potential additive mood-stabilizing effect May help comorbid binge-eating or seizure disorders |
| Zonisamide | 100 to 600 mg/d | Somnolence Dizziness Anorexia | Consider first-line for its potential additive mood-stabilizing effect May help comorbid binge-eating or seizure disorders |
Movement disorders. Antipsychotics appear more likely to cause EPS in patients with mood disorders than with schizophrenia. In one study using conventional antipsychotics, bipolar patients were 4 to 5 times more likely than schizophrenia patients to experience acute dystonia.16
Although atypicals pose some small risk for acute EPS and TD, the risk is near placebo-level with clinically relevant and comparable dosages.17 Even so, it is important to educate patients to watch for emerging signs of TD during long-term treatment with any antipsychotic. EPS risk may be dose-dependent, particularly with risperidone.18
Weight gain and obesity. Patients with bipolar disorder are more likely to be overweight or obese (body mass index [BMI] > 30) than the general population,17,19 though the reasons are unknown. Studies suggest an obesity prevalence of 32% to 35% in bipolar patients, compared with 18% in the general population.20,21
