Lower Cortisol Levels in Depressed Patients with Comorbid Post-Traumatic Stress Disorder

Neuropsychopharmacology (2003) 28, 591–598 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org Lower Cortisol Levels in Depressed Patients with Comorbid Post-Traumatic Stress Disorder MA Oquendo*,1, G Echavarria1, HC Galfalvy1, MF Grunebaum1, A Burke1, A Barrera1, TB Cooper1, KM Malone1 and J John Mann1 1 Department of Neuroscience, New York State Psychiatric Institute, Columbia University, New York, NY, USA Post-traumatic stress disorder (PTSD) is often comorbid with major depressive episodes (MDEs) and both conditions carry a higher rate of suicidal behavior. Hypothalamic–pituitary–adrenal (HPA) axis and serotonin abnormalities are associated with both conditions and suicidal behavior, but their inter-relation is not known. We determined cortisol response to placebo or fenfluramine in MDE, MDE and PTSD (MDE+PTSD), and healthy volunteers (HVs) and examined the relation of cortisol responses to suicidal behavior. A total of 58 medication-free patients with MDE (13 had MDE+PTSD) and 24 HVs were studied. They received placebo on the first day and fenfluramine on the second day. Cortisol levels were drawn before challenge and for 5 h thereafter. The MDE+PTSD group had the lowest plasma cortisol, the MDE group had the highest, and HVs had intermediate levels. There were no group differences in cortisol response to fenfluramine. Suicidal behavior, sex, and childhood history of abuse were not predictors of baseline or postchallenge plasma cortisol. Cortisol levels increased with age. This study finds elevated cortisol levels in MDE and is the first report of lower cortisol levels in MDE+PTSD. The findings underscore the impact of comorbidity of PTSD with MDE and highlight the importance of considering comorbidity in psychobiology. Neuropsychopharmacology (2003) 28, 591–598. doi:10.1038/sj.npp.1300050 Keywords: post-traumatic stress disorder; major depression; cortisol; suicidal behavior; childhood abuse; fenfluramine; serotonin INTRODUCTION Post-traumatic stress disorder (PTSD) develops in 15–25% of those exposed to trauma (Davidson, 1995; Maes et al, 2000). It is associated with significant morbidity and mortality, and increases the risk for suicidal behavior as much as 14-fold (Davidson et al, 1991). PTSD is often comorbid with major depressive episodes (MDEs), with a significant overlap in the symptoms required for diagnosis based on DSM IV criteria. Major depression, PTSD and suicidal acts often are present in the same individual, and are all associated with Hypothalamic–pituitary–adrenal (HPA) axis dysfunction. Since MDE and suicide are associated with HPA overactivity and PTSD is associated with HPA underactivity (Carroll, 1982; Yehuda, 2001), HPA axis function in comorbid MDE and PTSD, and its interaction with history of suicidal acts, is of interest. *Correspondence: Dr MA Oquendo, Department of Neuroscience, New York State Psychiatric Institute, Columbia University, 1051 Riverside Drive Unit 42, New York, NY 10032, USA, Tel: +1 212 543 5835, Fax: +1 212 543 6017, E-mail: Received 2 May 2002; revised 31 July 2002; accepted 2 August 2002 Online publication: 19 August 2002 at http://www.acnp.org/citations/ Npp081902370 Studies of PTSD have found low levels of 24 h urinary cortisol (Yehuda et al, 1990; Mason et al, 1986), low plasma cortisol (Yehuda et al, 1995; Kanter et al, 2001), and hypersuppression of cortisol in dexamethasone suppression tests (DSTs) (Reist et al, 1995; Stein et al, 1997). In contrast, elevated cortisol levels have been reported in MDE (Westrin et al, 1999), and about half of the in-patients with MDE fail to suppress cortisol secretion after dexamethasone (Brown et al, 1987; Duval et al, 2001; Yehuda et al, 1996; Halbreich et al, 1989). Most (Coryell and Schlesser, 2001; Meltzer et al, 1984; Norman et al, 1990; Oei et al, 1990; Inder et al, 1997; Roy, 1992), but not all, (Cleare et al, 1996; Duval et al, 2001; Westrin et al, 1999) studies of HPA axis in suicidal behavior suggest that there is elevation of cortisol or dexamethasone resistance in future suicide completers. Some of these discrepancies may be related to the spectrum of suicidal behavior that is assessed, such that suicidal ideation or the presence of attempts in a subject’s history may have less of an effect on cortisol secretion than the violence of the attempt (Roy, 1992) or ultimate suicide completion (Coryell and Schlesser, 2001). The HPA axis has a close bidirectional relation with the serotonergic system (Meijer and De Kloet, 1998). For example, agonism of the 5HT1A receptor with ipsapirone results in secretion of adrenocorticotropin hormone (ACTH) and cortisol, as occurs with fenfluramine, a less selective agent (Lesch et al, 1990). On the other hand, Lower cortisol levels in depressed patients MA Oquendo et al 592 hippocampal 5HT1A binding is observed to be elevated in rats in response to cortisol surges in the context of acute stress (Magarinos and McEwen, 1995) and decreased in response to chronic stress (Watanabe et al, 1993). Changes in 5HT2A binding in rat cortex as a consequence of stress have been described as well (Brown et al, 1999). Despite the frequent co-occurrence of PTSD and MDE, we could find only one study of the HPA axis when these conditions are comorbid (Halbreich et al, 1989). That study found a normal DST response and plasma cortisol in MDE and PTSD, in contrast with evidence of higher plasma cortisol in those with MDE alone. A computer-assisted literature search did not uncover any studies of the biology of MDE, PTSD, and suicidal behavior. It is possible that the variability in rates of suicidal behavior in different depressed populations contributes to the inconsistency of findings regarding cortisol levels in studies of MDE. Similarly, the rate of PTSD in depressed populations is likely to differ from study to study also contributing to the inconsistency of findings, especially in depression. Therefore, in order to examine the relation of PTSD, MDE, and suicidal behavior to HPA axis response and to evaluate the relation of serotonergic function to HPA function, we measured cortisol levels over a period of 5 h and following a placebo, and a fenfluramine challenge. Serotonin causes release of ACTH from the anterior pituitary. We compared patients with MDE, MDE and PTSD (MDE+PTSD), and healthy volunteers (HVs). We also examined the relation of plasma cortisol to reported childhood abuse and to suicidal behavior in the patient groups. We hypothesized that those with MDE+PTSD would have lower levels of cortisol compared with MDE alone and HVs. For exploratory analyses, we evaluated the relations of suicidal behavior, childhood abuse, melancholia, psychosis, and severity of depression to cortisol levels on placebo and fenfluramine. METHODS Subjects A total of 58 patients with MDE were diagnosed based on the Structured Clinical Interview for DSM-III-R; Patient version (SCID-P) (American Psychiatr (...truncated)