The effect of amitriptyline upon hypothalamic‐pituitary‐adrenal [HPA]‐system‐regulating neuropeptides (corticotropin‐releasing hormone [CRH], vasopressin, somatostatin) was studied in a group of depressed elderly patients and controls. A first lumbar puncture was performed in 37 depressed in‐patients. This was followed by a 6‐week medication phase with amitriptyline. Upon its completion a second cerebrospinal fluid (CSF) sample was obtained in 18 of these 37 patients. In 25 healthy controls a first lumbar puncture was done; eleven of these individuals agreed to take 75 mg/d amitriptyline for 6 weeks and to participate in the follow‐up CSF study. Within the group of depressed patients amitriptyline led to a significant decrease of CSF CRH in treatment responders only (F_1,16 = 5.2; P < 0.02). Also, in normal controls CSF CRH concentration tended to decrease with amitriptyline treatment (t‐test; P < 0.09). No effects of amitriptyline upon vasopressin or somatostatin were observed. In normal controls (r = 0.4; P < 0.02) and in patients (r = 0.4; P < 0.03) age correlated positively with baseline CSF somatostatin. A trend for CSF CRH to increase with aging was found only in controls (r = 0.3; P < 0.09); patients did not show a significant association here. Finally, CSF neuropeptide concentration at baseline did not differ between the group of depressed patients and healthy controls. Our study corroborates the evolving concept that antidepressants effect various components of the HPA system with the net result of a reduction in its activity. In addition, we found CSF CRH and CSF somatostatin concentrations to be better reflections of age than of depression and, finally, that during aging and during depression the HPA system changes in similar directions. Depression and Anxiety 8:71–79, 1998. © 1998 Wiley‐Liss, Inc.