50% reduction of baseline Hamilton score) and the pretreatment values of biochemical variables was examined. Responders had a lower pretreatment platelet 5-HT (530 +/- 36 vs. 664 +/- 50 ng/109platelets, p < 0.03; N = 44 and 39, respectively). Patients with a platelet 5-HT concentration above 800 ng/109platelets had a lower response rate than those below this value (p < 0.003). This difference was maximal in the subgroup of patients treated with 5-HT uptake inhibitors (N = 49). In this subgroup, the response rates of patients with 5-HT concentrations below and above the cutoff point were, respectively, 70% and 17% (p < 0.001). A pretreatment platelet 5-HT value above 800 ng/109platelets had a predictive value for a negative response of 92%. These results suggest the presence of biochemical differences in the peripheral serotonergic system between melancholic and non-melancholic patients. The inverse relationship between the pretreatment platelet 5-HT content and clinical response may be useful in the investigation of the relationship between the 5-HT system and antidepressant response. (J Clin Psychopharmacol 1998;18:222-230)