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(Drug information on paroxetine) (up to 40 mg daily) and clonazepam(Drug information on 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(Drug information on 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(Drug information on 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.)