Hypothalamus-Pituitary-Adrenal System Regulation and Suicidal Behavior in Depression Andrea Pfennig, Heike E. Kunzel, Nikola Kern, Marcus Ising, Matthias Majer, Brigitte Fuchs, Gertrud Ernst, Florian Holsboer, and Elisabeth B. Binder Background: One of the most demanding tasks in psychiatry is to protect patients from suicidal attempts. Preventive strategies could be improved by increasing our knowledge on the pathophysiologic disturbances underlying this behavior. More than 70 – 80% of suicides occur in the context of depressive disorders, in which dysregulation of the hypothalamus–pituitary–adrenal (HPA) axis is one of the most prominent neurobiological findings. So far data on the involvement of the HPA axis in the pathophysiology of suicidal behavior in depressed patients are controversial. Methods: In this retrospective study, we administered the combined dexamethasone-suppression/CRH stimulation (Dex/CRH) test to 310 patients with a depressive syndrome characterized at admission for acute and past suicidal behavior within the first 10 days after hospitalization. Results: Suicidal behavior in depressed patients, including past and recent suicide attempts as well as suicidal ideation, was associated with a lower adrenocorticotropin and cortisol response in the combined Dex/CRH test, with lowest hormone levels observed in patients with a recent suicide attempt. Discussion: The findings suggest that suicidal behavior may alter HPA axis regulation in depressed patients. Large-scale prospective studies assessing neuroendocrine changes may help to develop predictors for an early identification of patients at risk for committing suicide. Key Words: Depressive syndrome, Dex/CRH test, HPA axis, neu- roendocrinology, suicide attempt, suicidal ideation D epression is one of the most common psychiatric disorders with lifetime prevalences reaching up to 20% (Kessler et al 1994; Wittchen et al 1998). The most dramatic consequence of depression, the risk of suicide, however, remains difficult to influence with pharmaceutical interventions. Close to 10% of pa- tients with a depressive disorder commit suicide, and 16% report having attempted suicide during their lifetime (Brown et al 2000; Chen and Dilsaver 1996; Kessler et al 1999; Mann et al 1999) making suicide the second leading cause of death in Western societies among people under age 40 (World Health Organization 2001). The pathophysiology of suicidal behavior is still poorly understood, hampering early detection and prevention of suicidal behavior. Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is one of the most robust neurobiological findings in affective disorder (Holsboer 1999, 2000). Postmortem studies reveal an increased number of corticotropin-releasing hormone (CRH) mRNA expressing neurons in the hypothalamus and a reduced CRH receptor binding capacity in the frontal cortex of depressed patients (Nemeroff et al 1988; Raadsheer et al 1994, 1995). Increased CRH concentrations in cerebrospinal fluid (CSF) are also reported for patients with a history of depression (Heuser et al 1998; Nemeroff et al 1984; Risch et al 1992). These observations are complemented by neuroendocrine findings demonstrating altered feedback regulation of the HPA axis via the glucocorticoid and mineralocorticoid receptors (GR), which is reflected by a basal hypercortisolemia at baseline (Halbreich et al 1985) and elevated cortisol secretion following dexamethasone administration (Stokes et al 1984) as well as an increased corticotropin and cortisol release in the combined dexamethasone suppression/CRH stimulation (Dex/CRH) test (Heuser et al 1994; Modell et al 1997; von Bardeleben and Holsboer 1991). Thus far, the Dex/CRH test appears to be the most sensitive tool to detect depression-related changes in the HPA axis (Heuser et al 1994). It is difficult to interpret the impact of a dysregulation of the stress hormone system on suicidality without having to consider depres- sion as a confounder. The postmortem studies cited here revealing fewer CRH receptor binding sites in the frontal cortex (Nemeroff et al 1988) and an increased number of hypothalamic CRH secreting neurons (Raadsheer et al 1995) were conducted in depressed patients who died from suicide. An unambiguous attribution of these changes to depression or suicide is thus impossible. Inconsis- tent data have also been reported for CRH CSF levels in relation to suicide. Whereas Arato et al (1989) reported increased CRH CSF concentration in suicide victims, Westrin et al (1999) observed lower CSF and plasma levels of this peptide in patients following a suicide attempt than in healthy control subjects. Neuroendocrine evaluations of the HPA axis in depressed patients with and without history of suicide attempts may clarify some of the controversial data. So far, however, only conflicting results in studies with relatively small sample sizes have been reported. Coryell and Schlesser (2001) observed that of eight patients who committed suicide in a follow-up period of 15 years, seven were dexamethasone suppression test (DST) nonsuppressors during the index hospitalization. A regression analysis suggested an increased likelihood of future suicide and serious suicide attempts in nonsuppressors. This finding could not be replicated by Black et al (2002), and a meta-analysis by Lester (1992) found no consistent association of the DST and recent suicide attempts. A study from the Max-Planck Institute of Psychiatry administering the Dex/CRH test reported a nonsignificantly reduced HPA axis hyperactivity in depressed suicide attempters (n = 8) compared with depressed patients without suicide attempts (n = 7; Brunner et al 2002). In this retrospective study, we investigated the HPA system regulation using the Dex/CRH test in a large sample (n = 310) of currently depressed inpatients with and without acute suicidal behavior at admission and history of suicide attempts. The analysis focused on the impact of acute suicidality and history of suicide attempts on the degree of HPA axis dysregulation. From the Max-Planck Institute of Psychiatry, Munich, Germany. Address reprint requests to Dr. Andrea Pfennig, Department of Psychiatry and Psychotherapy, Charité–University Medicine Berlin, Campus Mitte, Schumannstr. 20/21, 10117 Berlin; E-mail: andrea.pfennig@charite.de. Received June 21, 2004; revised October 6, 2004; accepted November 9, 2004. BIOL PSYCHIATRY 2005;57:336 –342 0006-3223/05/$30.00 doi:10.1016/j.biopsych.2004.11.017 © 2005 Society of Biological Psychiatry