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Olanzapine/Fluoxetine Combination Treats Bipolar Depression Without Triggering Mania: Presented at ECNP

By Paula Moyer

PRAGUE, CZECH REPUBLIC -- October 14, 2003 -- Patients with bipolar disorder can achieve effective relief of depression with a combination of olanzapine (Zyprexa) and fluoxetine (Prozac), while being spared the treatment-emergent mania that such patients often get on antidepressant monotherapy, according to researchers speaking here September 22^nd at the 16^th Congress of the European College of Neuropsychopharmacology.

"When bipolar patients do not have a mood stabiliser, treatment of their depressive phases… with an antidepressant often triggers mania," said Sara Corya, MD, senior research physician, Eli Lilly and Company, Indianapolis, Indiana. "We found that this combination was no more associated with mania than was placebo."

Dr. Corya and her colleagues wanted to see whether particular treatment strategies were less likely to induce treatment-emergent mania in bipolar patients experiencing depression. In a double-blind study, they randomised 833 such patients to one of three groups: a combination of olanzapine and fluoxetine, olanzapine monotherapy, or placebo. The study period was 8 weeks.

The patients' baseline scores on the Montgomery-Asberg Depression Rating Scale (MADRS) were more than 20. Among these patients, 86 were in the combination group and were treated with one of three daily dosing regimens: 6 mg of olanzapine and 25 mg of fluoxetine, 6 mg of olanzapine and 50 mg of fluoxetine, or 12 mg of olanzapine and 50 mg of fluoxetine. The 370 patients in the olanzapine monotherapy group received 5 to 20 mg daily of olanzapine. There were 377 patients in the placebo group.

After the double-blind period, 562 subjects also participated in an optional open-label extension phase, 6 months in duration, in which either olanzapine monotherapy or the olanzapine/fluoxetine combination therapy could be given at any time.

The investigators monitored patients for treatment-emergent mania using the Young Mania Rating Scale (YMRS). All patients had a baseline YMRS score of less than 15. The investigators defined treatment-emergent mania as a YMRS score exceeding 15 at any subsequent visit. The rates of treatment-emergent mania during the 8-week phase were 6.4% in the combination group, 5.7% in the monotherapy group, and 6.7% in the placebo group -- rates that were statistically similar, Dr. Corya said.

Subjects in the combination group had YMRS decreases averaging 1.38 (+5.59 SD); similarly, the olanzapine monotherapy scores decreased 0.55 (+5.91 SD). These reductions were more marked than were the YMRS decreases in the placebo group, which had an average YMRS decrease of 0.57 (+6.09 SD; P=0.027 and P<0.001, respectively).

In the extension phase, 404 patients were on combination therapy. Treatment-emergent mania occurred in 19 (4.7%) of these patients at any point in the extension; by the study's end, 16 patients (4.0%) met the criteria for treatment-emergent mania. The change in YMRS score from baseline was a mean increase of 0.03 among combination-therapy patients, an increase that was similar to the 158 monotherapy patients and also not statistically significant, Dr. Corya said.

"The findings show that neither combination therapy nor olanzapine monotherapy was more likely than placebo to cause treatment-emergent mania," Dr. Corya said. "Because the rate of treatment-emergent mania for [combination therapy] was low during the extension period, we conclude that this treatment regimen does not present a risk of treatment-emergent mania in bipolar patients with depression."


[Study title: Analysis Of Treatment-Emergent Mania With Olanzapine/Fluoxetine Combination. Abstract P1-089]

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