Leo Sher, M.D.

Our research paper, “Age effects on cortisol levels in depressed patients with and without comorbid post-traumatic stress disorder, and healthy volunteers” was published 15 years ago in the October 2004 issue of the Journal of Affective Disorders (1). We examined the effect of age on the hypothalamic-pituitary-adrenal (HPA) system in depressed patients with or without comorbid posttraumatic stress disorder (PTSD).

Thirty-one depressed patients without PTSD, 12 depressed patients with PTSD, and 23 healthy volunteers were enrolled in the study. All study participants were medication free for a minimum of 14 days (6 weeks in the case of fluoxetine and 1 month in the case of oral antipsychotics) prior to the study. Participants had studies on 2 consecutive days after fasting from midnight and throughout the test. They received placebo on the first day and fenfluramine on the second day in a single blind design. Cortisol levels were drawn 15 minutes and immediately before placebo or fenfluramine administration to ascertain baseline levels. An oral dose of approximately 0.8 mg/kg of DL-fenfluramine (or identical pill containing placebo) was administered at 9 am. Cortisol, fenfluramine and norfenfluramine levels were drawn hourly for 5 hours thereafter.

We observed that cortisol levels increase with age in depressed patients without PTSD but not in depressed patients with PTSD or in healthy volunteers. Our finding is consistent with the view that glucocorticoid feedback through both corticosteroid receptors types is less responsive over succeeding episodes of major depression. This effect is apparently aggravated by increasing age. This is not a simple aging effect because it is absent in healthy volunteers. Also, it appears that the HPA changes associated with PTSD may ‘‘neutralize’’ the HPA alterations associated with aging and depression.

We also found that number of previous major depressive episodes was a predictor of the cortisol response to fenfluramine administration in depressed patients without PTSD. This finding is in agreement with the hypothesis that stress during recurrent depressive episodes results in cumulative hippocampal injury, and consequently, impairment of this HPA axis feedback pathway.

Reference:

1. Sher L, Oquendo MA, Galfalvy HC, Cooper TB, Mann JJ. Age effects on cortisol levels in depressed patients with and without comorbid post-traumatic stress disorder, and healthy volunteers. J Affect Disord. 2004 Oct 1;82(1):53-9.