The Difficulties of Managing Bipolar Depression

by Kara Gobron, PhD

Depression is typically the predominant clinical state in bipolar disorder, and it accounts for the majority of the morbidity, mortality, disability, and cost.(1-3) Bipolar depression is also associated with rates of suicide estimated to be 50 times the average rate.(4) Effective management of this phase of bipolar illness is considered a major unmet medical need.

The management of depression in bipolar disorder can be challenging, but recently studies have begun to explore the use of atypical antipsychotics for bipolar depression. Recent evidence(5) has suggested that antidepressants are not effective in the treatment of bipolar depression, although this finding still remains controversial and unresolved.

The use of atypical antipsychotics for bipolar depression has been explored in recent studies. However, to date, only quetiapine and combination therapy with olanzapine/fluoxetine have specific FDA approval for acute bipolar depression. Olanzapine and aripiprazole are the only FDA-approved atypical antipsychotics for use in maintenance therapy for bipolar disorder but are not specifically indicated for bipolar depression.

The FDA approval of quetiapine for the treatment of bipolar depression was based in large part on the results of the BOLDER studies(6,7), which were randomized controlled trials in more than 1,000 outpatients with bipolar disorder. Quetiapine (300 mg or 600 mg once daily) produced significantly greater improvement in depressive symptoms when compared to placebo 1 week after treatment initiation. This benefit was sustained throughout the 8 weeks of the study, although no additional benefit was observed at the 600 mg dose relative to the 300 mg dose. In the BOLDER studies, quetiapine was well-tolerated, with the most frequent adverse events including dry mouth, sedation, somnolence, dizziness, and constipation.

Olanzapine/fluoxetine combination therapy has also shown rapid and robust symptom relief in controlled clinical trials.(8-10) It has been suggested as a first-option treatment for acute bipolar depression.(11) A large, randomized, double-blind, 8-week trial evaluated the efficacy of olanzapine (n = 370), an olanzapine/fluoxetine combination (n = 86), and placebo (n = 377) in bipolar I depression.(10) The primary outcome measure was the Montgomery Asberg Depression Rating Scale (MADRS) total score. Both olanzapine and olanzapine/fluoxetine resulted in significant improvement in MADRS scores over the entire study. However, from week 4 onward, the olanzapine/fluoxetine combination resulted in significant improvement over olanzapine alone.

The efficacy of olanzapine/fluoxetine in bipolar I depression was also evaluated in a randomized, double-blind, 7-week comparison to lamotrigine (n = 205 per treatment group).(8) Treatment with olanzapine/fluoxetine was associated with a modest but significantly greater change from baseline than lamotrigine throughout the treatment period, using MADRS scores (p = .002). Olanzapine/fluoxetine was also associated with a significantly lower incidence of the adverse events of suicidal and self-injurious behavior (0.5% vs. 3.4% for lamotrigine, p = .037).

The choice of atypical antipsychotic must take into account the iatrogenic effects of the drug in terms of cardiometabolic risk factors, as most patients with bipolar disorder have other risk factors for cardiovascular disease such as hypertension, high cholesterol, smoking, obesity, and diabetes. Advances in our understanding of bipolar depression and its treatment are necessary to further the advancement of safe and effective therapies. Some atypical antipsychotics have improved the management of bipolar depression, but more studies are necessary to allow physicians to fully weigh the risk/benefit ratio of treating bipolar depression.

To learn more about this topic, neuroscienceCME encourages you to participate in this week‘s live satellite TV broadcast titled Bipolar Depression: Individualizing Treatment to Prevent Relapse and Recurrence. Moderator Roger S. McIntyre, MD, and faculty Susan L. McElroy, MD, will incorporate the latest evidence-based diagnosis and treatment strategies to provide early detection, intervention, and long-term maintenance opportunities with the goal of improving outcomes for patients with bipolar depression. Visit www.neuroscienceCME.com/CC320 to register and for details about the various participation options.

Do you have feedback for the author? Click here to send us an email.

References

1. Calabrese JR, Hirschfeld RM, Frye MA, Reed ML. Impact of depressive symptoms compared with manic symptoms in bipolar disorder: results of a U.S. community-based sample. J Clin Psychiatry 2004;65:1499-1504.
2. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;60:261-269.
3. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002;59:530-537.
4. Baldessarini RJ, Pompili M, Tondo L. Suicide in bipolar disorder: risks and management. CNS Spectr 2006;11:465-471.
5. Ghaemi SN, Rosenquist KJ, Ko JY, Baldassano CF, Kontos NJ, Baldessarini RJ. Antidepressant treatment in bipolar versus unipolar depression. Am J Psychiatry 2004;161:163-165.
6. 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.
7. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol 2006;26:600-609.
8. Brown EB, McElroy SL, Keck PE, Jr., et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry 2006;67:1025-1033.
9. Shelton RC. Olanzapine/fluoxetine combination for bipolar depression. Expert Rev Neurother 2006;6:33-39.
10. 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.
11. Practice Guideline for the Treatment of Patients with Bipolar Depression: Second Edition. 2002.