Efficacy, Safety, and Gradual Discontinuation of Clonazepam in Panic Disorder: A Placebo-Controlled, Multicenter Study Using Optimized Dosages

Background: The purpose of this multicenter, double-blind, placebo-controlled study was to evaluate the efficacy and safety of optimized dosages of clonazepam for the treatment of panic disorder and assess the tolerability of a schedule for gradual discontinuation.

Method: Adult patients with panic disorder with or without agoraphobia (DSM-III-R criteria) were randomly assigned to receive either placebo or clonazepam in individually adjusted doses over 3 weeks to approximate an optimal dosage, which was then maintained for an additional 3 weeks, amounting to a 6-week therapeutic phase. The daily dose range was 0.25 to 4.0 mg administered in 2 divided doses. In the following 7-week discontinuance phase, the doses were tapered gradually to cessation.

Results: At the therapeutic endpoint, clonazepam (N = 222) proved clinically and statistically superior to placebo (N = 216) in change in the number of panic attacks and in Clinical Global Impressions-Severity of Illness (CGI-S) and CGI-Change scores, Patient’s Global Impression of Change scores, amount of fear and avoidance associated with phobic symptoms, and duration of anticipatory anxiety. The gradual tapering of clonazepam was not associated with symptoms suggestive of withdrawal syndrome. Although patients taking clonazepam experienced some clinical worsening compared with the status achieved at endpoint, particularly in terms of number of panic attacks, no deterioration was observed using their condition at baseline as point of reference. No overall evidence of rebound was found. All regimens were generally well tolerated. Somnolence was the main adverse event associated with clonazepam therapy. The percentage of patients who reported adverse events was higher in the clonazepam group than in the placebo group, as was the mean number of adverse events per patient.

Conclusion: In this placebo-controlled trial, clonazepam was an efficacious and safe shortterm treatment of the symptoms of panic disorder. Discontinuance during and after slow tapering was well tolerated.