Severity of depression and hypothalamic-pituitary-adrenal dysregulation zyx : identification of contributing factors Meador-Woodruff JH, Greden JF, Grunhaus L, Haskett RF. Severity of depression and hypothalamic-pituitary-adrenal axis dysregulation: identifi- cation of contributing factors. Acta Psychiatr Scand 1990: 81: zyxwvut 364-371. Severity of depression, as reflected by total scores on depression rating scales, has been established as one of several major sources of variance associated with hypothalamic-pituitary-adrenal axis dysregulation in patients with major depressivedisorder. To determinewhich of the symptoms comprising clinically defined severity of illness contribute most to this re- lationship, we studied the associations between postdexamethasone plasma cortisol levels and components of the Hamilton Rating Scale for Depression (HRSD) in 114 patients with major depressive disorder. At pretreatment baseline, severity of depression was modestly but significantly correlated with postdexamethasone plasma cortisol; a large part of this relationship was associated with the anxiety components of the zyxwv HRSD. When relationships between postdexamethasone plasma cortisol and severity measures were studied longitudinally during treatment, this con- tribution of the anxiety items persisted. The anxiety associated with depres- sion appears to be a major clinical factor associated with the hypothalamic- pituitary-adrenal axis dysregulation in major depressive disorder. I Dy sregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in many individuals with major depressive disorder (1-5). This disturbance has most often been studied by the dexamethasone sup- pression test (DST), although other challenge paradigms, such as corticotropin-releasing hormone (CRH) infusions, have been employed (6-8). The DST was originally conceived as a possible biologi- cal correlate specific to endogenous depression (1). As various investigative groups have accumulated neuroendocrine data on large groups of patients, however, it has become apparent that this dysregu- lation is complex and has many determinants, and the DST may better serve as a paradigm to study pathophysiology rather than as a diagnostic test. Multiple clinical factors influence postdexa- methasone plasma cortisol levels. These include severity of depressive episode (9-19), age (20-23), history of recent weight loss (24,25), the presence of delusions (26-29), and recent use or withdrawal of psychotropic medication (30-33). Severity of de- pressive symptoms, as reflected by rating scale scores, is positively correlated with plasma post- dexamethasone cortisol levels (9-14), as well as with axis J. H. Meador-Woodruff J. F. Gredenla2, L. Grunhaus’, R. F. Haskett’ ’ Clinical Studies Unit, University of Michigan Depression Program, Mental Health Research Institute, Department of Psychiatry, University of Michigan Medical Center, Ann Arbor, Michigan, USA Key words: dexamethasone suppression test; cortisol; depression; anxiety James H. Meador-Woodruff, M.D., Department of Psychiatry, Mental Health Research Institute, University of Michigan Medical Center, 205 Washtenaw Place, Ann Arbor, MI 48109, USA Accepted for publication November 25, 1989 circulating levels of pituitary hormones associated with the HPA axis (11). This severity relationship appears to account for approximately 20% of the total variance associated with the DST (9-14). The rating scales that are used for these types of investi- gations (most often the 17-item Hamilton Rating Scale for Depression (HRSD) (34)), however, are composed of many symptoms. We undertook this study to determine which of the items that comprise clinically defined severity of depressive illness account for the relationship between postdexa- methasone plasma cortisol levels and severity of de- pression. Material and methods Subjects A total of 114 patients of the Clinical Studies Unit (CSU) of the University of Michigan Depression Program of the Department of Psychiatry at the University of Michigan Medical Center were studied. Patients admitted to CSU undergo an extensive diagnostic evaluation, including 2 or more unstructured clinical interviews by psychiatrists, a 364