To the Editor: Bipolar depression is a challenge in the management of bipolar disorder. The study by Mauricio Tohen, M.D., Dr.P.H., and colleagues published in Archives of General Psychiatry(1) found that, compared with placebo, olanzapine and olanzapine plus fluoxetine were associated with a higher decrease in symptoms of depression measured by self-reported scales. This trial had a major impact in medical literature, leading a series of review articles and even the Guideline Watch for the Treatment of Patients with Bipolar Disorder to claim the efficacy associated with olanzapine or olanzapine plus fluoxetine in the treatment of bipolar depression. This combination has also received the approval from the Food and Drug Administration for the treatment of bipolar depression (2–4).
Our letter is to raise doubt on whether this study can be used to prove an antidepressant effect associated with olanzapine and its clinical significance. In this study, after 8 weeks, the Montgomery-Asberg Depression Rating Scale scores were reduced by 11.9 (SD=0.8) points in the placebo group, 15.0 (SD=0.7) points in the olanzapine group, and 18.6 (SD=1.3) points in the olanzapine-fluoxetine group. These differences were statistically significant, but it is at least questionable whether these differences should be considered clinically meaningful. This 3-point difference between placebo and olanzapine represents only about 10% of the baseline Montgomery-Asberg Depression Rating Scale score.
The conclusions of the study by Tohen and colleagues become even more doubtful if we consider that 20% of the overall score of the Montgomery-Asberg Depression Rating Scale is given by items that can represent an improvement in depressive symptoms as well as a side effect associated with olanzapine. Namely, the two most frequent side effects of olanzapine described in this study were somnolence (28.1% in intervention versus 12.5% in control) and weight gain (17.3% versus 2.7%), when in fact the Montgomery-Asberg Depression Rating Scale consists of 10 items, two of them being “reduced sleep” and “reduced appetite” as symptoms of depression. Both items were among the only three items in which the olanzapine group had a statistically significant higher decrease than the placebo group; the other item was “inner tension.” None of these items are core depressive symptoms, and all of them could be reduced by the well known sedative and increased appetite side effects of olanzapine.
These facts above raise suspicion as to whether these differences in Montgomery-Asberg Depression Rating Scale scores can be truly attributed to an actual antidepressant property of olanzapine and whether they have any clinical significance.
1.Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A: Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003; 60:1079–10882.Gao K, Calabrese JR: Newer treatment studies for bipolar depression. Bipolar Disord 2005; 7(suppl)5:13–233.Mann JJ: The medical management of depression. N Engl J Med 2005; 353:1819–18344.Hirschfeld RMA: Guideline Watch: Practice Guideline for the Treatment of Patients With Bipolar Disorder. Arlington, Va, American Psychiatric Publishing, 2006