Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone.

Bipolar disorders, a group of serious psychiatric conditions that affect approximately 2.3 million American adults, are characterized by cycling between depressive and manic or hypomanic states. The treatment of bipolar disorder is based on the use of mood stabilizers, the most common of which are valproate (divalproex) and lithium. These drugs form the cornerstone choices among the mood stabilizers for both acute-phase and preventive treatment.

Pharmacotherapy has increasingly involved combination therapy, typically consisting of a combination of lithium and another psychotropic agent such as an antipsychotic. Historically, the use of conventional antipsychotics has been hampered by a risk of tardive dyskinesia and worsening of depression. Atypical antipsychotics hold promise in avoiding the drawbacks of conventional antipsychotics and are therefore preferred as adjuncts to mood stabilizers in the treatment of bipolar disorder.

The antipsychotic market is worth an estimated $10.7 billion and is led by Eli Lilly’s blockbuster atypical antipsychotic, Zyprexa. After 2007, the market is expected to plateau due to the genericization of Janssen’s Risperdal and Pfizer’s Geodon. However, Bristol-Myers Squibb’s dopaminergic modulator Abilify, launched in 2002. has acheived good uptake and is predicted to reach blockbuster status by 2009.

Long-term efficacy has not been well demonstrated for most currently available treatment regimens for bipolar disorder. In particular few controlled studies of atypical antipsychotics in the maintenance treatment of bipolar disorder have been conducted. In order to maximize sales of atypical antipsychotics over the next few years it will therefore be necessary to conduct such studies. In a recent study sponsored by Eli Lilly, Tohen et al have addressed this need, comparing the ability of olanzapine plus mood stabiliser with mood stabiliser alone to prevent relapse of type 1 bipolar disorder patients.

This first of its kind study, recently published in The British Journal of Psychiatry was an 18-month, multi-center double-masked study of patients with bipolar disorder who had achieved remission with olanzapine in combination with lithium or valproate. This acute phase study was designed to compare continuation of combination treatment with monotherapy. Ninety nine patients who were administered a mood stabilizer together with olanzapine and who had achieved remission in this acute study were then randomly reassigned to continue or cease receiving olanzapine.

Syndromatic relapse rate (measured using the DSM-IV criteria) was similar whether or not olanzapine was administered to patients. However when remission from either symptomatic depression or mania was evaluated, combined treatment maintained remission for significantly longer periods than if only a mood stabilizer was administered to patients. Combined treatment was particularly effective in maintaining symptomatic remission in women compared to men.

The difference between syndromatic and symptomatic remission was suggested by the authors to reflect differences in scoring systems used to measure the two outcomes with the assessment of symptomatic remission being more conservative than that of syndromatic remission. Since symptomatic remission from depression or mania is judged to be especially relevant in patients with bipolar disorder, the ability of combination therapy to delay symptomatic relapse is of particular importance.

Although symptomatic remission was prolonged in patients being treated with a combination of olanzapine and a mood stabilizer compared to patients receiving mood stabilizers alone, weight gain was prominent in the former, an adverse effect which could affect compliance. The present study represents the most direct investigation into the benefits and risks associated with adding olanzapine to mood stabilizing maintenance therapy of patients with bipolar disease. Further studies verifying these findings in larger patient populations and which allow evaluation within specific subtypes of bipolar disorder are awaited.