Cortisol metabolic predictors of response to psychotherapy for symptoms of PTSD in survivors of the World Trade Center attacks on September 11, 2001

Background: A proportion of subjects with symptoms of posttraumatic stress disorder (PTSD) are unresponsive to specialized psychotherapy, but a biological basis for this has not been described. To observe whether differences in cortisol or its metabolites predict or correlate with response to therapy for PTSD symptoms, cortisol and its metabolites were measured from urine samples at pre-treatment, at the conclusion of psychotherapy, and at 3-month follow-up. Methods: 28 survivors of the World Trade Center attacks on September 11, 2001 seeking psychological treatment for PTSD symptoms received four sessions of either exposure therapy or supportive counseling, followed by up to 10 sessions of prolonged exposure in a specialized PTSD treatment program at a private hospital serving the New York City metropolitan area. 24-h mean integrated cortisol excretion was assessed by radioimmunoassay (RIA); urinary free cortisol and metabolites cortisone, 5 alpha-tetrahydrocortisol (5 alpha-THF), 5 beta-tetrahydrocortisol, and tetrahydrocortisone were assessed by gas chromatography-mass spectrometry (GC-MS); and indices of enzyme activity for 5 alpha- and 5 beta-reductase and for the 11 beta-hydroxysteroid dehydrogenases were derived from the metabolite and glucocorticoid measures. Results: 5 alpha-Reductase activity was significantly tower at pre-treatment among non-responders, whereas there were no significant pre-treatment differences between responders and non-responders in any other hormone or metabolite level. In repeated measures analyses across the three time points, 5 alpha-reductase activity, as well as 5 alpha-THF and total glucocorticoids, significantly differed between responders and non-responders. For urinary cortisol measured by RIA, there was a significant group x time interaction indicating that, although not different at pre-treatment, urinary cortisol levels declined over time in the non-responder group, such that by follow-up, towered cortisol significantly distinguished non-responders from responders. Indices of 5 alpha-reductase activity, including 5 alpha-THF and total glucocorticoids, were significantly negatively correlated with avoidance symptom severity at pre-treatment. At follow-up, indices of 5 alpha-reductase activity were significantly negatively correlated with severity of all three PTSD symptom clusters and with total PTSD severity scores. Conclusion: Lower 5 alpha-reductase activity is associated with avoidance severity and predicts non-responsiveness to psychological treatment for PTSD symptomatology. Relatively diminished 5 alpha-reductase activity may mark a state of primary vulnerability, perhaps via attenuated peripheral catabolism of cortisol resulting in the suppression of hypothalamic-pituitary-ad renal axis responsiveness. Lower cortisol levels appear later in the progression to chronic, treatment-resistant PTSD. Published by Elsevier Ltd.