Six patients (mean age 62.5 +/- 7.6 years) with major depression were treated for 2 weeks with the serotonin agonist m-chlorophenylpiperazine (m-CPP), 80 mg/day in a double-blind, placebo-controlled, crossover-design pilot study. Two patients showed clinically significant improvement in depressive symptoms during active drug treatment, whereas two others showed modest effects. All patients tolerated the drug, with no major side effects and no changes in vital signs or in liver, renal, thyroid, or hematological function. Further studies are needed to determine the characteristics of the possible antidepressant effects of m-CPP; such work may yield greater understanding of the role of serotonin in affective and other psychiatric disorders.