Clinical and Research News
Are Atypicals Missing Link In Bipolar Treatment?
Psychiatric News
Volume 37 Number 13 page 22-23

A substantial volume of current reports, including a number of presentations at APA’s 2002 annual meeting in May, support the use of atypical antipsychotic drugs in the medication management of bipolar disorder and treatment-resistant depression. Indeed, a seemingly burning question during the annual meeting centered on what moniker the drugs in the class should really carry, given their expanding use beyond psychosis.

New research presented during annual meeting seminars, symposia, and new research poster presentations demonstrated the effectiveness of olanzapine (Eli Lilly’s Zyprexa), risperidone (Janssen Pharmaceutica’s Risperdal), and aripiprazole (Bristol-Myers Squibb’s new "atypical-atypical," currently under review by the FDA; Psychiatric News, June 21) as adjunctive therapy (and in the case of olanzapine, as effective monotherapy) in the treatment of bipolar disorder. The annual meeting reports coincided with journal reports on the same topic and support the newly revised recommendation of APA’s Practice Guideline for the Treatment of Bipolar Disorder, which was released earlier this year (Psychiatric News, January 4).


"The goal of therapy in patients with bipolar disorder is to control symptoms to prevent relapse and manage complications such as mixed episodes," said Paul Keck, M.D., a professor and vice chair of research at the University of Cincinnati College of Medicine. Keck was a member of the work group on bipolar disorder helping to revise APA’s practice guideline.

"Often, a mood stabilizer is not enough to adequately control all phases of the illness and maintain remission, so doctors may need to consider appropriate additional medication to stabilize mood," Keck explained in a prepared statement accompanying the annual meeting release of data on olanzapine’s effectiveness in the disorder.

Annual meeting sessions detailed reports of clinical trials funded by Lilly in which olanzapine was found to be effective as an adjunct to either lithium or valproate, extending the time to relapse and prolonging remission in patients with bipolar disorder. One study found specifically that those patients taking olanzapine and either lithium or valproate remained free of symptoms of mania for an average of 362 days, versus 63 days for those patients taking only lithium or valproate. Rates of relapse for patients with a mood stabilizer plus olanzapine were 15.2 percent, versus 35.4 percent for those taking only a mood stabilizer.

A second Lilly-funded report detailed a comparison of olanzapine with the company’s combined olanzapine and fluoxetine formulation (OFC). The company has been looking at OFC as a treatment for bipolar disorder as well as treatment-resistant depression and psychotic depression and hopes to file a new drug application with the FDA for the combined product later this year.

The comparison study found that olanzapine alone not only controlled the mania phase of bipolar disorder, but also improved depressive symptoms as well. The efficacy and rapid onset of the actions of OFC, however, were significantly greater than olanzapine alone.

In these studies the most frequently reported adverse events for olanzapine alone were weight gain, increased appetite, headache, and dry mouth. For patients treated with OFC, the most common adverse event reported was somnolence, followed by less-frequent reports of diarrhea, weight gain, dry mouth, headache, and increased appetite.

New research presented at the annual meeting, supported by Janssen Pharmaceutica, looked at the efficacy of adding risperidone to either lithium or valproate in patients with rapid-cycling bipolar disorder. The small study—only 25 patients—indicated that patients receiving risperidone in addition to a mood stabilizer experienced statistically greater improvement in scores on the Beck Depression Inventory and the Global Assessment of Functioning. However, scores on the Hamilton Depression Rating Scale and the Young Mania Rating Scale did not statistically differ from placebo.

A second new research report detailed a 15-month head-to-head comparison of adding either risperidone or olanzapine to a primary mood stabilizer (again lithium or valproate). In this study, funded by Janssen’s sister company, Johnson and Johnson Pharmaceutical Research and Development, both drugs were found to be equally effective at improving outcomes over monotherapy with only the mood stabilizer. Side-effect profiles for both the atypicals did not differ statistically except for a very significant increase in the number of patients gaining a "clinically significant amount" of weight on olanzapine versus those on risperidone (four times as many).


The June American Journal of Psychiatry contains the results of a Lilly-sponsored, three-week, double-blind, head-to-head comparison of olanzapine and divalproex (Depakote, marketed by Abbott Laboratories) for the treatment of acute mania.

The report comes from Mauricio Tohen, M.D., D.P.H., a Lilly clinical research fellow and associate clinical professor of psychiatry at Harvard and McLean, and his extensive list of colleagues at Lilly Research, Harvard Medical School and McLean Hospital, the University of California at Los Angeles Neuropsychiatric Institute, and the National Institute of Mental Health.

Zyprexa, incidentally, is only the third brand-name drug to gain approval from the Food and Drug Administration—in March 2000—for the treatment of acute mania. Lithium has been approved since 1972; it was more than 20 years before the second brand-name drug, Depakote, was approved.

Tohen’s team followed just under 250 patients hospitalized for acute bipolar manic or mixed episodes. Patients were randomly assigned to receive either olanzapine or divalproex at starting doses consistent with the approved labeling of both medications. The researchers were free to adjust the dosing of either drug, based on clinical outcome and adverse events, as well as blood levels for patients randomized to divalproex. Patients randomized to olanzapine also had blood drawn, although no analysis was performed because no standard blood levels have been shown to be clinically valuable for olanzapine. Olanzapine dosing ranged from 5 mg to 20 mg per day, and divalproex dosing ranged from 500 mg to 2500 mg per day.

The patients taking olanzapine at the end of the three-week protocol showed a mean improvement in the Young Mania Rating Scale (YMRS) total score of 13.4 points, while the group taking divalproex showed an average improvement of 10.4 points. The three-point difference was statistically significant. Indeed, observations over the three weeks showed olanzapine to be statistically significantly better at improving mania on days 2, 14, and 21 of the study.

However, the mean improvement seen in the olanzapine group was statistically significant in only three YMRS items: increased motor activity, sleep, and language-thought disorder.

The percentage of each group achieving a "clinical response," defined as a greater than or equal to 50-percent improvement in the YMRS total score, was not significantly different. The olanzapine group, however, responded more quickly than the patients taking divalproex.

Similarly, the difference in the percentage of each medication group achieving remission (with a YMRS total score at the end of the study equal to or below 12) did not reach statistical significance either. But again, the olanzapine group achieved remission more quickly—in three days, compared with six days for the subjects taking divalproex.

Tohen’s team got a surprising result when it compared the response of subjects with and without psychosis. The patients without psychotic features experienced statistically greater improvement while taking olanzapine as compared with divalproex. In the group of patients who did exhibit psychotic features, no statistically significant difference was found between the two drugs. The finding was contrary to what would have been assumed, knowing olanzapine’s well-documented efficacy in treating symptoms of psychosis, the authors wrote.

"Often," Keck said, "patients with bipolar disorder require complex treatment regimens to manage all phases of their illness, creating a compliance challenge for patients and a management challenge for clinicians. These studies suggest that physicians may be able to use olanzapine as a foundation to simplify patients’ treatment regimens, and the combination of olanzapine and fluoxetine could be an effective treatment choice." ▪

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