Numerous studies have established that there is increased co-morbidity of depressive symptoms among patients with panic disorder with and without agoraphobia, but questions remain as to whether the symptom pattern and clinical course are similar to that of primary depressions. The Cross-National Collaborative Panic Study was initiated to study the effects of alprazolam, a triazolobenzodiazepine, in the treatment of panic disorder. In the first phase, which included more than 500 subjects, alprazolam was compared against placebo. In the second phase, alprazolam was compared with imipramine and placebo in a double-blind, randomized, controlled trial. Results of both the first and second phases will be reviewed as they bear on the issue of drug treatment of secondary depression accompanying panic disorder. The presence of depressive symptoms does not adversely influence anti-panic and anti-phobic response to medication. Equivalent drug-placebo differences occur on multiple measures of anxiety--including the number and intensity of panic attacks, phobias, anticipatory anxiety, and overall anxiety.