Lamotrigine, Olanzapine Stabilize Mood in Bipolar Disorder

May 22, 2002

NEW YORK (MedscapeWire) May 23 — Lamotrigine (Lamictal) has distinct and perhaps complementary mood-stabilizing effects for the treatment of bipolar disorder, according to presentations on May 20 and 21 at the American Psychiatric Association (APA) 155th annual meeting in Philadelphia, Pennsylvania. Other presentations suggest that olanzapine (Zyprexa) enhances the effect of either lithium or valproate, and that rapidly increasing the dose of olanzapine controls agitation in both bipolar disorder and schizophrenia.

"Lamotrigine significantly delayed time to any bipolar episode and time to treatment intervention in some of the longest maintenance studies ever conducted in bipolar disorder," lead investigator Joseph R. Calabrese, MD, professor of psychiatry at Case Western Reserve University School of Medicine in Cleveland, Ohio, said in a news release. "The results support the favorable efficacy and safety profile seen in studies of lamotrigine to date, suggesting that it may be a promising treatment for bipolar disorder patients, particularly those experiencing the devastating lows of bipolar depression."

In 2 large maintenance studies that were prospectively designed to be combined for analysis of treatment outcomes, 1315 currently or recently symptomatic bipolar I patients by DSM-IV criteria were enrolled in the preliminary phase, and 638 of these patients were stabilized and randomized to 18 months of double-blind monotherapy with lamotrigine (n=280; 50-400 mg/day fixed and flexible dose), lithium (n=167; 0.8-1.1 mEq), or placebo (n=191).

In the combined analysis, both lamotrigine and lithium significantly delayed the time to treatment intervention and time to any bipolar event. In separate analyses of manic, hypomanic, or mixed vs depressive events, lamotrigine significantly delayed time to intervention for both types of events compared with placebo.

Lithium delayed time to intervention for manic/hypomanic/mixed but not for depressive events. At 18 months of treatment, interventions for depression were needed in 43% of patients on lamotrigine, 49% of patients on lithium, and 60% of those on placebo. Adverse effects were more common in the lithium group than in the lamotrigine group.

According to the authors, these findings suggest that lamotrigine and lithium have distinct and potentially complementary mood-stabilizing properties. Lamotrigine, an antiepileptic medication, is marketed by GlaxoSmithKline and is currently under phase III investigation for the treatment of bipolar depression.

A separate study showed that adding the psychotropic olanzapine to the mood stabilizers lithium or valproate extends time to relapse and prolongs remission in patients with bipolar disorder.

"For patients, each day spent with manic or depressive symptoms can be devastating, so maintaining remission over time is vital," said study author Mauricio Tohen, MD, DrPH, from Lilly Research Laboratories. "A treatment such as olanzapine that can help patients achieve and sustain remission is valuable, because it can help patients gain control and move forward with their lives."

In this randomized study of 344 patients with mania and depression, a 6-week acute phase of treatment with olanzapine in combination with lithium or valproate led to stabilization in 99 patients, who then took part in an 18-month extension period. These patients were then rerandomized to continue receiving lithium or valproate combined with either olanzapine (5-20 mg/day) or placebo.

Among patients who experienced remission of mania, olanzapine-treated patients had a significantly longer time to mania relapse than did patients treated with monotherapy (362 vs 63 days), and rates of mania relapse were also significantly lower (15.2% vs 35.4%). Among patients who experienced remission of depression, olanzapine showed a slight advantage that was not statistically significant (155 vs 27 dayyys and 23.3% vs 39.5%, respectively). Time to relapse of either mania or depression was significantly greater for olanzapine patients (124 vs 15 days).

"The goal of therapy, as outlined in the new [APA] guidelines, is to control symptoms to prevent relapse and manage complications such as mixed episodes. 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," said Paul Keck, MD, professor and vice chairman of research at the University of Cincinnati College of Medicine. "These data suggest that olanzapine, when added to lithium or valproate, may help improve the long-term picture."

The most common adverse event of olanzapine was depression. Other common events seen with olanzapine were somnolence, weight gain, anxiety, and tremor. With lithium or valproate as monotherapy, common adverse events included depression, insomnia, diarrhea, apathy, anxiety, asthenia, and thought disorder.

In yet another randomized study, rapidly increasing doses of olanzapine helped control agitation in patients with schizophrenia or bipolar disorder. Of 148 acutely agitated inpatients with schizophrenia, schizoaffective, schizophreniform disorder, or bipolar I disorder, those treated with 4 days of double-blind oral olanzapine treatment, flexibly dosed as needed using rapid initial dose escalation, had significantly greater improvement than did those treated according to usual clinical practice. Somnolence was the most common adverse effect, but the drug was generally well tolerated.

"Physicians often need to use higher doses of medication to effectively control agitation but are restricted in their treatment choices because of the side effects that can occur," said author Gerald Maguire, MD, from the University of California, Irvine. "Our study supports a growing body of evidence that shows high doses of olanzapine can control symptoms of agitation more rapidly without increased side effects, giving physicians more flexibility when choosing a therapy."

APA Annual Meeting. Presented May 20-21, 2002.

Reviewed by Gary D. Vogin, MD

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