FDA Likely to Approve Drug For Bipolar Depression

A pair of recent studies provides strong evidence for the clinical practice of combining the SSRI fluoxetine (Prozac) with the second-generation antipsychotic olanzapine (Zyprexa). The combination appears to create a robust synergy with regard to the two drugs’ effectiveness without increasing adverse events.

An olanzapine-fluoxetine combination (OFC) in one pill, to be marketed by Eli Lilly and Co. as Symbyax (pronounced SIM-bee-ax), received an approvable letter earlier this year from the Food and Drug Administration (FDA) and is expected to receive final approval by mid-2004. Symbyax will be the first FDA-approved drug for the treatment of bipolar depression.

A study of OFC in patients with bipolar depression appeared in last month’s Archives of General Psychiatry. A long-term study of the use of OFC in patients with major depressive disorder, and in particular treatment-resistant depression, appeared in last month’s Journal of Clinical Psychiatry. Both clinical trials were funded by Lilly.

Response More Robust After Week 4

In the first study, Mauricio Tohen, M.D., Dr.P.H., an associate clinical professor of psychiatry at Harvard Medical School and the McLean Hospital and a clinical research fellow at Lilly, followed 833 patients with bipolar depression in an eight-week, double-blind, randomized, controlled trial. Patients received OFC, olanzapine as monotherapy, or placebo.

Patients receiving OFC or olanzapine alone showed statistically significant improvements in depressive symptoms compared with the placebo group—as early as by the end of the first week. By the midpoint of the study, at week 4, the OFC group was statistically more improved than those taking olanzapine alone. That superiority continued through the end of the study.

“This really suggests,” Tohen told Psychiatric News, “that the onset of action very much seems to be connected to the effects of olanzapine. But then, by week 4, what’s really interesting is that the combination treatment seems to have a more robust response. You see a decrease in scores on the [Montgomery-Asberg Depression Rating Scale (MADRS)] of nearly 20 points. That’s really quite significant.”

By the end of the study, 24.5 percent of patients on placebo had met remission criteria of a 50-percent reduction in symptoms (measured by the MADRS), 32.8 percent of the olanzapine group achieved remission, and 48.8 percent of the OFC group achieved remission.

The only other medication to show efficacy in published studies of bipolar depression is lamotrigine (Lamictal), which carries an FDA indication for the prevention of relapse to either mania or depression in patients with bipolar disorder. In comparison, lamotrigine is associated with response rates of 48 percent to 54 percent in published studies. Compared with the olanzapine-fluoxetine combination, lamotrigine’s speed of onset is slower. To avoid serious side effects, Lamotrigine must be started at low doses and slowly titrated upward.

The speed of onset of the combination, as well as the robustness of the two medications used together, left researchers at Lilly (including Tohen) pleasantly surprised. Researchers were also pleased by the comparative side-effect profiles.

“The one thing we were hoping to see but did not was less weight gain,” Tohen said. “But there were no additional side effects with the combination treatment, and for that matter there were more discontinuations [from the study] for [patients taking] the monotherapy than with OFC.”

Sara Corya, M.D., Lilly’s associate medical director for Symbyax and first author of the second study, agreed. She told Psychiatric News that Lilly researchers have looked into the synergistic effects. In animal studies, OFC causes a significantly larger increase in available serotonin, norepinephrine, and dopamine than does olanzapine or fluoxetine alone.

On the side-effect side, “it looks like you would expect it to,” Corya said, “with some of the side effects of olanzapine and some from fluoxetine, but then some of them sort of cancel each other out.”

OFC Effective for Major Depression

In her study, Corya followed 560 patients who met criteria for major depressive disorder for a total of 76 weeks in an open-label study.

OFC was again associated with rapid, robust improvement in depressive symptoms (measured by improvements in MADRS scores). Overall, 62 percent of patients achieved a 50 percent or greater reduction in symptoms (defined as a response), and 56 percent of those were able to maintain that reduction of symptoms long enough to achieve two consecutive MADRS scores less than or equal to 8. Only 15 percent of patients experienced a relapse.

In patients who were termed “treatment resistant”—having previously failed two different antidepressant therapies of adequate dose for an appropriate length of time—53 percent met response criteria, 44 percent met remission criteria, and 25 percent relapsed.

It is important to note that treatment resistance is not related to severity of symptoms, which is a common misconception, Corya told Psychiatric News. Treatment resistance implies that patients have not responded to adequate appropriate treatment; severity of symptoms is irrelevant. Thus, even someone with a mild depression could be treatment resistant.

Corya noted that Lilly has data on more than 2,000 patients who took OFC in clinical trials, and the side-effect profiles look fairly good. Most side effects noted in the trials tended to be transient, such as somnolence. Corya observed a slightly higher incidence of tremor in the OFC group in her study than had researchers in other clinical trials; however, the tremor was not significant, and in some patients tremor decreased with time.

Tohen noted higher incidences of postural changes in blood pressure and gastrointestinal upset in the group taking OFC than in patients taking either placebo or olanzapine as monotherapy. However, neither appeared to be clinically significant, said Tohen. He noted that no increase in falls was seen as a result of blood pressure changes.

Rapid Relief of Symptoms

Overall, Tohen and Corya agreed that OFC appears to offer rapid onset of relief for depressive symptoms, achieving a robust and prolonged response—whether patients have bipolar or unipolar depression.

For patients with bipolar disorder, however, OFC “is effective on symptoms of mania as well as symptoms of depression,” Tohen noted, “and that really is a treatment that is optimum.”

An abstract of “Efficacy of Olanzapine and Olanzapine-Fluoxetine Combination in the Treatment of Bipolar I Depression” is posted on the Web at http://archpsyc.ama-assn.org/cgi/content/abstract/60/11/1079. An abstract of “Long-Term Antidepressant Efficacy and Safety of Olanzapine/Fluoxetine Combination: A 76-Week Open-Label Study” is posted at www.psychiatrist.com/abstracts/200311/110310.htm. ▪

Arch Gen Psychiatry 2003 60 1079