Exaggerated intracellular calcium responses to challenges with serotonin (5-HT) have been reported in depression. In our studies, consistent with previous reports, patients with depression exhibited an exaggerated increase in 5-HT-stimulated intracellular calcium concentration ([Ca++]i). Basal cytosolic calcium was elevated in both calcium-free and 1 mM calcium media in depressed patients. the increased responsiveness to 5-HT was seen in both conditions. Patients with schizophrenia and substance abuse did not differ from normal controls. The 5-HT response was correlated with diastolic blood pressure (r = 0.33, p = 0.02): however, this association did not fully account for the exaggerated [Ca++]i responses in the depressed group. These findings suggest that exaggerated increases in [Ca++]i in response to serotonin are a characteristic of depressed patients not shared with schizophrenic and substance abuse patients. The relationship of depression to hypertension, two conditions that share abnormalities of calcium homeostasis, warrants further study.