Study design consisted of 24 weeks of open treatment with imipramine followed by a 12-month controlled discontinuation/maintenance phase for those patients who met operationalized response criteria at both the 16- and 24-week assessments. The selection of the original sample of 110 patients with panic disorder and agoraphobia who started open treatment; the procedure of administering 4 identical-looking tablets throughout the study that were composed of either 10 mg, 25 mg, 50 mg, or 75 mg of imipramine or placebo; the rationale for the target, stable dose of 2.25 mg/kg per day; and the characterization of treatment response have been described in a previous publication.12 Briefly, all subjects gave informed consent for both the open and placebo-controlled experimental phases of the study. They were selected from the pool of patients, aged 18 to 65 years, who contacted the Phobia and Anxiety Disorders Clinic, The Ohio State University Medical Center, Columbus, either through clinical referrals or in response to media coverage or advertisement. In addition to meeting Structured Clinical Interview DSM-III-R13 diagnostic criteria for panic disorder with agoraphobia of at least moderate severity and 3 months' duration, patients must have been experiencing active, recurrent panic attacks at the time of initial evaluation. Additionally, fear of panicking or losing control must have been the primary motivation for their escape or avoidance behaviors. Exclusion criteria included evidence of organic mental disorders; psychotic, bipolar, and obsessive-compulsive disorders; primary or current major depression with melancholia; and suicidal intention or a score of 18 or higher on the 17-item Hamilton Depression Rating Scale.14 Other exclusionary criteria included posttraumatic stress disorder, somatization disorder, severe personality disorders (borderline, schizotypal), and substance abuse disorder (current or in remission for <6 months). In addition, patients had to be in good general health, have no contraindications for the use of imipramine because of illness or because of treatment necessary for the illness, and demonstrate compliance during an initial, 2-week, single-blind placebo run-in. Finally, although the expectation was to have patients free of all psychotropic drugs for 14 days before treatment began, an exception was made in the case of patients who were unable to stop using benzodiazepines initially. This was done with the understanding that these drugs, administered by research personnel, should be taken on a regular, not as needed, basis and that they would be tapered off gradually, starting at week 4 of open imipramine treatment and completely discontinued by the week 16 assessment, to qualify for randomization to the maintenance study. No additional treatments, in particular no encouragement or instructions for self-directed exposure to phobic situations or other coping strategies, were given during the open phase of the study. Patients identified as nonresponders at week 16 were dropped from the study and offered alternative, clinically appropriate treatment. Participation in all treatment phases of the study was free.