Diagnostic criteria, random parallel placebo-controlled study design, and appropriate clinical assessment for both safety and efficacy are all among the essential requirements for the evaluation of a new antidepressant agent. Paroxetine and imipramine were compared for efficacy and safety in a large multicentre, randomized, placebo-controlled, double-blind, parallel design study in the USA. The study involved 717 outpatients with major depressive disorder; after a one-week washout period they were treated for 6 weeks, being assessed at weekly intervals. The results from all six participant centres combined showed that both active drugs were statistically superior to placebo by week 2 and that the antidepressant response was significant for both. Paroxetine was better tolerated than imipramine with fewer dropouts from side effects. This combined study clearly indicated that paroxetine was an effective and well-tolerated antidepressant.