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Combination Treatment for Bipolar Depression

Am Fam Physician. 2004 May 1;69(9):2233.

The most difficult to treat and disabling aspect of bipolar disorder is the depression phase. Patients with bipolar disorder spend more time in the depressive phase than they do in the manic phase, and it takes longer to recover from the depressive phase. In addition, patients in the depressive phase have higher rates of morbidity and mortality than those in the manic phase. The current treatment for bipolar disorder is mood stabilizers such as lithium and anticonvulsants. Another option is olanzapine, which has been effective in treating mania and was found to improve depressive symptoms in patients with schizophrenia. Tohen and colleagues evaluated the efficacy and safety of olanzapine alone or in combination with fluoxetine in the treatment of bipolar I depression.

The trial was a randomized, double-blind, parallel study of patients who met the criteria for bipolar I disorder, depressed, in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. The selected participants were randomized to receive olanzapine, in a dosage of 5 to 20 mg per day, placebo, or an olanzapine-fluoxetine combination of 6 and 25, 6 and 50, or 12 and 50 mg per day in a flexible dosing schedule. Participants were assessed at baseline and at weeks 1, 2, 3, 4, 6, and 8 of the study. The assessment included multiple depression and anxiety scales, using the Montgomery-Asberg Depression Rating Scale (MADRS) as the main outcome measure. The primary outcome evaluated the rates and times to remission, with response defined as an improvement of 50 percent or greater of the MADRS total score from baseline and completion of at least four weeks of the study. Remission was defined as a MADRS score of 12 or less at an end point and completion of at least four weeks of the study. Adverse events also were recorded at each visit.

There were 833 patients who participated in the study. The olanzapine and olanzapine-fluxetine groups showed significant improvement in all depressive symptoms compared with the placebo group. At weeks 4 and 8 of the study, the olanzapine-fluoxetine group showed more improvement in depressive symptoms compared with the olanzapine-alone group, and more patients in the former group met the remission criteria.

Across the three groups, there were no differences in the incidence of treatment-emergent mania. With regard to adverse effects, somnolence, weight gain, increased appetite, headache, dry mouth, and gastrointestinal symptoms were reported. The adverse events in the olanzapine-fluoxetine group were similar to those of the olanzapine-alone group except for more reports of nausea and diarrhea in the combination group.

The authors conclude that olanzapine alone is more effective in treating the depressive phase of bipolar disorder than placebo. Adding fluoxetine to olanzapine therapy provides these patients with an even greater benefit than olanzapine alone. These improvements occurred without increasing the risk of developing manic symptoms during the treatment phase of the study. The authors add that these results need to be followed with a long-term study.

Tohen M, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. November 2003;60:1079–88.


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