Abnormalities in serotonin (5-HT) receptors and 5-HT receptor-mediated signal transduction systems have been widely reported in mood disorders. This study was intended to evaluate 5-HT2A receptor-coupled activation of phosphatidylinositol (PI) hydrolysis in subtypes of depression. Samples for fibroblast culture were obtained from patients with major depression with or without melancholia, and normal controls. Dose response curves were determined for 5-HT-induced PI hydrolysis. PI response was determined for bradykinin and 1-α-lysophosphatidic acid (LPA), alternative Gq-coupled receptor agonists. [125I]LSD binding for 5-HT2A also was conducted. Finally, Western blot analysis was performed for phospholipase Cβ1 (PLCβ1) and Gαq/11 proteins. The maximum PI response observed with 5-HT was significantly lower in melancholics but not nonmelancholic patients relative to controls. Activation of PI hydrolysis by bradykinin and LPA was not reduced in melancholic vs melancholics and controls; responses to both agonists actually were increased in the melancholic group. [125I]LSD binding, PLC β1, and Gαq/11 protein levels did not differ between groups. The data raise the possibility that the reduced S-HT 2A receptor-induced PI hydrolysis is intrinsic to the receptor itself or its coupling to Gq protein, and is not related to altered availability of the 5-HT2A receptor, Gq or PLC.