Efforts to elucidate the pathophysiology of obsessive-compulsive disorder (OCD) have largely focused on the function of the neurotransmitter serotonin. Pharmacological trials with serotonin reuptake inhibitors (SSRI) have provided the most compelling evidence of a serotonergic role in OCD, suggesting a central 5-HT dysfunction. Pharmacological challenge tests with serotonin agonists were applied to characterize central nervous system serotonergic function in OCD and to assess behavioral and neuroendocrine responses. These tests are based on the assumption that the 5-HT system exerts in the hypothalamus-pituitary axis an excitatory influence on the release of ACTH, prolactin and probably growth hormone, and that the extent of release of these hormones following a challenge with a 5-HT agonist provides an index of central 5-HT activity. Intravenous injection of clomipramine (CMI) elicits a rise in cortisol in healthy subjects (Laakmann 1984, Golden 1989). The cortisol response to CMI challenge test was blunted in depressed patients in comparison to healthy subjects (Golden et al. 1990). However, Saiz et al. (1992) found no significant rise during the CMI challenge test in OCD patients.In the present study we investigated the neuroendocrine effects of i.v. administration of CMI on serum cortisol in patients who met DSM-III-R criteria for OCD and healthy subjects. Twenty drug-free, age and sex-matched OCD outpatients (mean age [plusmn] SD: 33 [plusmn] 10.2 years) with a duration of illness of 20.5 [plusmn] 9 (mean [plusmn] SD) years and 20 sex-matched healthy subjects. The Yale Brown Obsessive Compulsive Scale (Y-BOCS) was used to quantify the severity of the obsessive and compulsive behavior; the overall total score was 25 [plusmn] 6.05 (mean [plusmn] SD). The Hamilton Depression Rating Scale was used to rate depressive symptoms (mean score [plusmn] SD: 21 [plusmn] 6.05). At 9:00 a.m. a bolus of 10 ml saline, containing 25 mg CMI, was intravenously administered. Blood samples were obtained at -- 30, 0, 5, 15, 30, 60, 90 and 120 min for the determination of the cortisol concentrations. Our data suggest that the response to the CMI challenge test was not significantly different in OCD patients compared to healthy controls.