A concatenation of data indicates that the pathogenesis of depression is related to an increased production and secretion of corticotropin-releasing hormone (CRH). Benzodiazepines profoundly suppress the basal and stress-related activation of the hypothalamic-pituitary-adrenocortical (HPA) system and discontinuation of these drugs results in rebound activation. We therefore investigated whether the extent of HPA system dysregulation is related to the severity of benzodiazepine withdrawal in patients with depression. We performed the combined dexamethasone/CRH test before benzodiazepine discontinuation (taper-off max. 5 mg diazepam-equivalents/week) in 14 depressed patients (13 f, 1 m, mean age 54.6 +/- 14.6) who responded to the antidepressant treatment. The severity of withdrawal symptoms was measured using the Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) questionnaire. The depressive psychopathology was monitored using the Hamilton Depression Rating Scale, Montgomery Asberg Depression Rating Scale and Beck Depression Inventory. Patients with more severe benzodiazepine withdrawal (CIWA-B-increase > 14 pts; n = 7) showed a significant higher cortisol and ACTH response in the dexamethasone/CRH test preceding the discontinuation of benzodiazepines than patients displaying less severe withdrawal symptoms (CIWA-B-increase <14 pts.; n = 7) (ANCOVA, p < 0.05). Both groups did not differ in the pre-taper psychopathology ratings and their basal neuroendocrine activity. In view of the GABAergic inhibition of HPA system activity and the anxiogenic effect of CRH, benzodiazepine withdrawal symptoms may be partly due to a disinhibition of the HPA system during discontinuation of benzodiazepines.