ThecombinedDEX-CRHtestintreatmentcourseandlong-term outcome of major depression Martin Hatzinger*, Ulrich M. Hemmeter, Kathrin Baumann, Serge Brand, Edith Holsboer-Trachsler Psychiatric University Hospital, Depression Research Unit, Wilhelm Kleinstr. 27, CH-4025 Basel, Switzerland Received 20 November 2001; received in revised form 1 January 2002; accepted 16 April 2002 Abstract Neuroendocrinestudiesstronglysuggestthatthehypothalamic–pituitary–adrenocortical(HPA)systemplaysacrucialroleinthe developmentandcourseofdepression.TheinteractionbetweenthediseaseprocessandHPAsystemfunctioninlong-termcourse, however, is unclear. Since improvement of HPA system deterioration has been demonstrated to be associated with treatment response, the question has arisen whether the course of therapy response as reflected by, for example, early improvement or response(after1or2weeksoftherapy)isalsobasedonHPAsystemdysfunctionandwhetherthecourseofHPAregulationduring treatment is only a state marker or has additional predictive implications for long-term outcome. In order to elucidate these ques- tions a long-term study was carried out to investigate whether HPA system disturbance is associated (1) with the course of treat- ment response, predominantly early treatment response, during acute depression and (2) with the long-term course of depression, i.e. number of episodes. Twenty patients with affective disorders who participated in earlier controlled antidepressant treatment studiesover6weekswereenrolledinanexploratoryfollow-upstudy.UsingthecombinedDEX/CRHtestitwasdemonstratedthat (1)earlyimprovement,earlytreatmentresponseandbeneficialtreatmentoutcomeafter6weekswereassociatedwithalowerHPA systemactivityandthat(2)inlong-termcourseofdepressiontheHPAsystemdeteriorationincreasesinparallelwiththenumberof previous episodes. These findings suggest that HPA system alterations are closely related to treatment response and long-term outcome of depression. # 2002ElsevierScienceLtd.Allrightsreserved. Keywords: Depression;HPAsystem;DEX/CRHtest;Treatmentresponse;Long-termcourse 1. Introduction In the search for pathophysiological mechanisms responsible for the initiation and the course of depres- sion as well as for the prediction of treatment response the hypothalamic–pituitary–adrenocortical (HPA) sys- tem has received considerable attention in recent years. A large amount of clinical and preclinical studies sup- port the evidence of HPA system dysregulation in depression (for review: Holsboer, 2000): In the depres- sivestatecortisolsecretionisincreased(Halbreichetal., 1985; Pfohl et al., 1985; Deuschle et al., 1997b) and many patients with severe depression display an insuffi- cient suppression of cortisol secretion after admini- stration of the synthetic glucocorticoid dexamethasone (DEX) suggesting feedback resistance (Carroll et al., 1981). In recent years the combined DEX/corticotropin releasing hormone (CRH) test has proved to pick up peripherally measurable HPA axis changes with greater sensitivitythandootherneuroendocrinetests(Heuseret al., 1994a). Serial monitoring of HPA activity and severity of depressive symptoms during treatment with antidepressants revealed that excessive HPA activity as reflectedbytheDEX/CRHtestgraduallydecreasesand thatthiseffectprecedesresolutionofdepressivepsycho- pathology (Holsboer and Barden, 1996). In contrast, patients who are less responsive to psychotherapy dur- ing depression (Thase et al., 1996) and/or do not respond to antidepressant treatment continue to have HPA dysregulation (Holsboer et al., 1987; Holsboer- Trachsler et al., 1991, 1994; Heuser et al., 1996) which suggests that normalization of stress hormone regu- lationiscloselyassociatedwithclinicalrecovery.Inthis context it is of interest that most of our knowledge 0022-3956/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII:S0022-3956(02)00021-3 Journal of Psychiatric Research 36 (2002) 287–297 www.elsevier.com/locate/jpsychires * Correspondingauthor.Tel.:+41-61-325-53-81;fax:+41-61-325- 55-13. E-mail address: martin.hatzinger@pukbasel.ch (M. Hatzinger).