We employed a neuroendocrine challenge paradigm to study the effects of antidepressant treatment on serotonergic systems in depressed patients. We compared the maximum prolactin response to intravenous clomipramine (CMI) in depressed patients who responded to antidepressant treatment to that of nonresponders. Pretreatment baseline prolactin concentrations and pretreatment prolactin responses to clomipramine challenge were not different in responders compared to non-responders. However, following antidepressant treatment, the 6 responders demonstrated a significant change in their clomipramine challenge test results, as indicated by an increase in prolactin responses. In contrast, the 7 nonresponders did not demonstrate a change in their prolactin response to clomipramine challenge following treatment. These data support the hypothesis that serotonergic system dysfunction, as manifested by blunted prolactin response to clomipramine challenge, tends to normalize after successful treatment for depression, and that abnormal serotonergic function may be a state-dependent characteristic.