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.

With little data on this common practice, Worthington and colleagues sought to "provide critical information through the first systematic evaluation of [this] pharmacologic treatment strategy."

The investigators treated 69 panic disorder patients with 12 weeks of either paroxetine (up to 40 mg daily) and clonazepam (up to 2 mg daily) or paroxetine and placebo in a double-blind, randomized design. In one of the combination treatment arms, clonazepam was administered acutely over five weeks and then tapered; in the other, it was maintained during the entire 12-week course. Treatment response was defined by a Clinical Global Impression (CGI)-Severity score of 1 or 2 with an absence of panic attacks.

In their analysis of the first 21 patients completing treatment, therapeutic response was achieved by 14% of patients on paroxetine plus placebo, 50% of those on paroxetine plus continued clonazepam and 65% of those on paroxetine plus acute-phase clonazepam with taper. Dropout rates for the first three weeks were highest among the paroxetine plus placebo group (43%), compared to the two benzodiazepine groups (7%). Although there were a similar number of drug side effects in each of the treatment arms, the investigators considered the combination treatment better tolerated and more effective than the SSRI alone for panic disorder.

In an assessment of the possible benefit of adding clonazepam to sertraline (Zoloft) for the treatment of OCD, Barbara Crockett, M.D., and colleagues at Duke University Medical Center in Durham, N.C., compared this combination to sertraline with placebo in 35 patients in a double-blind, randomized design. The investigators had anticipated that the combination would prove to be beneficial because, in their estimation, only 38% to 43% of patients with OCD respond to SSRIs, and because of "both the marked anxiolytic effects of clonazepam as well as its serotonergic effects."

Despite this rationale, there was no significant difference between the groups in the interim analysis of measures with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) or the Hamilton Anxiety Rating Scale. With some trend on the CGI-Severity scale favoring the combination, however, the investigators considered further study to be warranted.

Other studies of medication for panic disorder reported at NCDEU included a 12-week, acute treatment study with nefazodone (Serzone), and a long-term, 80-week trial with sertraline. Ronald Marcus, M.D., of Bristol-Myers Squibb Co., reported on a multisite, international, double-blind comparison of nefazodone and placebo for panic disorder. At the 10-week endpoint, a mean 453 mg daily dose of nefazodone was associated with significantly greater improvement than placebo on the Panic Attack Response analysis, the mean reduction in number of panic attacks from baseline and the percentage of patients with no panic attacks. Most patients tolerated the agent well, with only 4% of nefazodone patients discontinuing due to adverse events, compared to 7% of those receiving placebo.

Mark Rapaport, M.D., of the University of California, San Diego, and colleagues followed up on short-term studies of sertraline effectiveness for panic disorder, with a long-term evaluation of its safety. In the 80-week study, the most common adverse events included headache, insomnia and malaise. They found that the severity of most adverse events was considered mild to moderate. "The adverse events tended to occur early in treatment," they observed, "with occurrence of both new and previously reported adverse events markedly decreased with increasing duration of treatment." The long-term effectiveness of sertraline for panic disorder in this study was reported by Wayne Goodman, M.D., of the University of Florida College of Medicine, Gainesville.

A combined analysis of placebo-controlled trials of sertraline for OCD was described by John Greist, M.D., of Health-care Technology Systems in Madison, Wis., and colleagues. They found that data from 908 patients in five multicenter trials consistently indicated sertraline superior to placebo on all measures, including Y-BOCS, CGI-Severity and CGI Improvement, and the National Institute of Mental Health-Obsessive Compulsive Disorder Symptoms scale. Significant symptom reduction was measurable in some cases, according to investigators, after two weeks of treatment.

Although such rating scales are essential to gauge the effect of sertraline on symptoms of OCD compared to placebo, Jean Endicott, Ph.D., of the New York State Psychiatric Institute, pointed out, "truly favorable treatment outcome requires accurate assessment of broader domains of change and improvement." Accordingly, this group assessed QOL from a range of studies of sertraline treatment for mood and anxiety disorders. The investigators reported that sertraline was not only associated with improved core symptoms of mood and anxiety disorders, but with an improved QOL across a wide range of patient types. They encouraged other investigators to include QOL measures in their trials, suggesting the Quality of Life Enjoyment & Satisfaction Questionnaire as a suitable instrument to differentiate QOL factors in responders to comparative treatments and between drug and placebo responders.

(Additional assessments of clinical research methodology and recommendations for clinical trial designs offered at the NCDEU will follow in Part II of this report-Ed.)