Dysfunction of the central serotonergic system has been associated with depression in Parkinson's disease. To evaluate central serotonergic function in Parkinson's disease in relation to depression, we examined prolactin and cortisol responses to a single-dose challenge with fenfluramine (60 mg orally), a serotonin releasing/uptake-inhibiting agent, in the course of 5 hours in 11 patients with Parkinson's disease associated with major depression (SADS-RDC), 22 nondepressed parkinsonians, and 20 age- and gender-matched healthy controls. No difference in cortisol responses were observed between the groups; however, prolactin responses to fenfluramine were significantly impaired in patients with Parkinson's disease compared to controls, and the response was significantly more blunted in parkinsonian patients with major depression in comparison with the nondepressed ones. These findings indicate that there is a diminished serotonergic responsivity in depression associated with Parkinson's disease.