ATLANTA— Depression is now regarded as the more serious phase of bipolar disorder. Patients with bipolar disorder generally spend much more time depressed than in a manic state, and depression is viewed as being more likely than mania to impair the patient’s ability to function at home, work, and socially, according to Keming Gao, MD, PhD, a Bipolar Research Fellow at the Case Western Reserve University School of Medicine in Cleveland. However, the treatment options for this phase are limited and present an unmet need. Atypical antipsychotics have begun to show potential in the acute treatment of depressive symptoms in patients with bipolar disorder, he noted. Dr. Gao discussed the use of these drugs in bipolar depression at the 158th Annual Meeting of the American Psychiatric Association.

THE EVIDENCE

In an eight-week, double-blind, placebo-controlled study by Tohen and colleagues, olanzapine alone or in combination with fluoxetine significantly improved depressive symptoms in patients with bipolar depression when compared with placebo. This multicenter study involved more than 800 inpatients and outpatients with minimal moderate severity of depression at the study entry. “The combination therapy did significantly better than monotherapy from week 4 to week 8,” said Dr. Gao.

Although the switching to mania is generally considered a risk associated with antidepressants in patients with bipolar disorder, the study did not associate olanzapine/fluoxetine combination therapy with an increased likelihood of treatment-emergent mania, relative to olanzapine or placebo. Nonetheless, Keck and his colleagues recommended that bipolar patients receiving olanzapine and fluoxetine be monitored for signs or symptoms of emerging mania due to the cyclic nature of bipolar disorder.

Olanzapine also improved bipolar depression in several open-label and double-blind maintenance studies, but these studies indicated that the drug more effectively prevents bipolar mania relapse than depression relapse. “This suggests that olanzapine works more like lithium than lamotrigine,” Dr. Gao remarked.

• Studies of risperidone have focused mainly on efficacy during the manic phase of bipolar disorder. Like other atypical antipsychotic agents, this drug is FDA approved for the short-term treatment of bipolar mania. However, risperidone “also shows some efficacy to reduce depressive symptoms in some open-label short- and long-term mania studies,” said Dr. Gao. This is consistent with the results of a recent small, randomized, double-blind comparison study of risperidone, paroxetine, or a combination of both drugs for bipolar depression.

In this study, Shelton and Stahl reported that a 12-week addition of risperidone, paroxetine, or the combination to a mood stabilizer provided moderate relief from bipolar depression; there was no difference in efficacy among the three treatments. The study included 30 patients with bipolar I or II disorder who had been treated with a mood stabilizer but continued having moderate depression. “Using another SSRI in the combined condition could have produced a more robust effect and should be tested,” the authors recommended.

• Quetiapine’s effect on bipolar depression has been evaluated in a large, multicenter, randomized, double-blind, placebo-controlled study by Calabrese and his colleagues. “The study showed that quetiapine was efficacious in reducing depressive symptoms in patients with bipolar I or II depression,” claimed Dr. Gao.

The study was an eight-week trial of quetiapine for depression in patients with bipolar I or II disorder of at least moderate severity. It was published in the July American Journal of Psychiatry. Compared with placebo, quetiapine significantly reduced not only depressive symptoms in these patients but also anxiety. It also improved sleep quality and global quality of life.

Quetiapine may therefore eventually emerge as a first-line treatment for bipolar depression. However, further trials must first confirm the existence of its apparently robust antidepressant properties in that setting, Dr. Gao added.

SAFETY AND TOLERABILITY

All atypical antipsychotics are relatively well tolerated by patients with bipolar disorder. Patients are seemingly more sensitive to antipsychotic treatment when they are in depressive phases than when they are in manic phases. A slower titration or a lower dose may be needed for patients when they are in a depressive phase, said Dr. Gao. Somnolence/ sedation is a commonly reported side effect of all atypical antipsychotics in the treatment of bipolar disorder. But their effects on body weight, lipids, blood glucose levels, prolactin levels, liver function, and blood pressure, as well as their extrapyramidal side effects varied substantially, Dr. Gao added. He recommended that clinicians monitor these side effects closely regardless of which drug is prescribed.

EXPERT RECOMMENDATIONS

After polling 47 international experts in the treatment of bipolar disorder, a consensus guideline had been formulated in 2004. The consensus had reached more than 90% agreement on the 1,282 options in the different phase treatments of bipolar disorder. For the acute treatment of bipolar depression, lamotrigine monotherapy was recommended as a first-line agent for every presentation except for psychotic depression. Lithium plus lamotrigine or an antidepressant received first-line rating for severe nonpsychotic depression. However, experts overwhelmingly agreed that the combination of an atypical antipsychotic and an antidepressant, lithium, or lamotrigine should be the first-line treatment for psychotic depression. The combination of an atypical antipsychotic and an antidepressant or a mood stabilizer received second-line rating for nonpsychotic depression. However, this survey was conducted before the results of the quetiapine depression study became available, Dr. Gao added.

—Timothy Begany

Suggested Reading
Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351-1360.
Keck PE Jr, Corya SA, Altshuler LL, et al. Analyses of treatment-emergent mania with olanzapine/fluoxetine combination in the treatment of bipolar depression. J Clin Psychiatry. 2005;66:611-616.
Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry. 2004;65:1715-1719.
Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088.
Yatham LN. Atypical antipsychotics for bipolar disorder. Psychiatr Clin North Am. 2005;28:325-347.

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