Drs. Tohen and Lin Reply

To the Editor: We would like to thank Drs. Moreira-Almeida and Pietrobon for their comments. We feel extremely gratified that our study has generated interest in the field of pharmacotherapy for bipolar depression, and hopefully this interest will translate into better outcomes for patients. The depressive phase of bipolar disorder is associated with a high degree of mortality and morbidity, and patients who suffer from this condition are in need of more effective and safer treatments. It should be noted that the most important clinical finding of our study was the greater efficacy of the olanzapine-fluoxetine combination relative to both placebo and olanzapine monotherapy for the acute treatment of bipolar depression in patients with bipolar disorder. Furthermore, it was the olanzapine-fluoxetine combination but not olanzapine monotherapy that received approval from the Food and Drug Administration for the treatment of acute bipolar depression.

We concur with the observations of Drs. Moreira-Almeida and Pietrobon regarding the effectiveness of olanzapine monotherapy on a subset of depressive symptoms. In the primary publication, it was noted that analysis of individual items on the Montgomery-Asberg Depression Rating Scale indicated that the olanzapine-fluoxetine combination, but not olanzapine monotherapy, was effective at reducing core mood symptoms of depression (depressed mood/apparent sadness, diminished interest or pleasure in activities). Differences between olanzapine monotherapy and placebo in baseline-to-endpoint changes on the “apparent sadness” and “suicidal thoughts” items of the Montgomery-Asberg Depression Rating Scale approached but did not achieve statistical significance. Mean baseline-to-endpoint change in the Montgomery-Asberg Depression Rating Scale total score was significantly greater for olanzapine monotherapy relative to placebo, which suggests that there may be a “signal,” albeit modest relative to the olanzapine-fluoxetine combination (effect sizes: 0.32 and 0.68, respectively). Further studies are needed to determine if this signal translates into a true effect of olanzapine monotherapy on core depressive symptoms. As additional controlled studies evaluate the relative benefits of combined antidepressant treatment with atypical antipsychotics, lithium, or anticonvulsants, we hope to gain a greater understanding of how best to treat bipolar depression in order to improve the outcomes of patients who suffer from this devastating condition.