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NCDEU Report Part I: Antipsychotic for Bipolar, Benzodiazepine for OCD

NCDEU Report Part I: Antipsychotic for Bipolar, Benzodiazepine for OCD

Three reports on olanzapine (Zyprexa) as a possible treatment for bipolar affective disorder, presented at a National Institute of Mental Health-sponsored meeting in June, reflected pursuit of this indication-despite the initial "nonapprovable" letter from the U.S. Food and Drug Administration that was issued October 1998. Eli Lilly and Company had sought FDA approval for this indication based on only one clinical trial. Additional data have since been gathered by Lilly researchers and were reported at the New Clinical Drug Evaluation Unit Program (NCDEU) meeting, which was held in June in Boca Raton, Fla.

The data indicate the utility of olanzapine for manic patients with and without psychotic features and for patients with schizoaffective disorder, bipolar type. In addition, a separate study examined the health-related quality of life of olanzapine-treated patients with bipolar disorder.

Kimberly Spencer reported on the study conducted by Gary Tollefson, M.D., Ph.D., and colleagues at Lilly Research Laboratories of long-term olanzapine treatment in manic patients. In the 49-week, open-label, extension phase (conducted after a three-week, double-blind study of olanzapine versus placebo in manic or mixed episode bipolar I patients), 113 patients (82% manic, 46% without psychotic features) received 5 mg to 20 mg olanzapine daily (average dose 13.8 mg) for an average of 201 days.

The investigators found a statistically significant improvement in manic symptoms not correlated to presence or absence of psychotic features. Patients also demonstrated significant improvement in cognitive functioning on the Positive and Negative Syndrome Scale (PANSS) Cognitive component and Hostility factor.

Another study comprised a subpopulation of 177 patients with schizoaffective disorder, bipolar type. In this large double-blind trial comparing olanzapine to haloperidol (Haldol), Fan Zhang, Ph.D., reported finding that significantly more patients in the olanzapine group (28.7%) than in the haloperidol group (10.7%) improved by 40% or more on the Brief Psychiatric Rating Scale (BPRS) mania total score. On the PANSS Cognitive component, 20% of olanzapine-treated patients versus 7.1% of those receiving haloperidol showed the same significant percentage of improvement. In addition, analysis of the Montgomery-Asberg Depression Rating Scale (MADRS) revealed that patients with depression had improved during olanzapine treatment, with an average reduced score of 8.57; those receiving haloperidol increased this score by an average of 6.63.

"Overall," these investigators concluded, "results indicate that olanzapine appears to have mood stabilizing properties in this patient population."

Delving beyond the treatment effect on core symptoms of bipolar affective disorder, Madhav Namjoshi, Ph.D., and colleagues at Lilly conducted a study to assess changes in health-related quality of life (QOL). In a 49-week, open-label extension of olanzapine treatment after a three-week, placebo-controlled investigation with 139 patients, eight QOL dimensions were assessed with the Medical Outcomes Study-Short Form 36. In the acute phase, the investigators found significantly greater improvement in physical functioning in olanzapine-treated patients than in those given placebo. In the olanzapine extension phase, significant improvement over baseline was demonstrated in social functioning, role-emotional and general health. However, some decrement occurred in the vitality score over this extension period. The researchers concluded that olanzapine positively impacted "several dimensions of health-related quality of life in patients with bipolar disorder."

The newer antipsychotic agents have fewer extrapyramidal symptoms (EPS) and, since patients with bipolar affective disorder are at particular risk for EPS, other antipsychotics are expected to be studied for this indication. A preliminary open-label study of quetiapine (Seroquel) in patients with "neuroleptic dependent" mood disorders was conducted by Martha Sajatovic, M.D., of the North Coast Behavioral Health Care Systems, in Cleveland. Sixteen patients with bipolar or schizoaffective disorder who had required at least six months of neuroleptic medication in addition to a mood-stabilizing agent were provided with an average dose of 155 mg quetiapine daily for an average of 10.8 weeks, while the previous neuroleptic regimen was tapered and discontinued.

"Overall, patients did very well on quetiapine therapy with significant improvement in BPRS score, YMRS [Young Mania Rating Scale], and HAM-D [Hamilton Depression Rating Scale] score compared to previous antipsychotic medication therapy," the investigators stated. Consequently, the researchers recommended that larger, controlled trials be undertaken to explore these preliminary findings.

Medication combinations undergo less rigorous evaluation than the single-agent regimens, despite being commonly used in clinical practice. However, at NCDEU, two studies of combinations with clonazepam (Klonopin) were presented in the treatment of panic and obsessive-compulsive disorders.

John Worthington, M.D., of the Massachusetts General Hospital in Boston, reported on his group's comparison of clonazepam and paroxetine (Paxil) to paroxetine alone in treating panic disorder. While noting that selective serotonin reuptake inhibitor antidepressants like paroxetine have become first-line treatment for panic disorder, the investigators observed that the high-potency benzodiazepines like clonazepam and alprazolam (Xanax) are frequently prescribed concomitantly. They estimate that as many as 50% of patients with panic disorder receive a benzodiazepine along with an SSRI.

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