The overall objective of this proposal is to continue the study of hypothalamic-pituitary-adrenal (H-P-A) axis dysregulation in patients with major depressive disorder, endogenous subtype. We have two major goals: 1) To improve our understanding of the natural history and pathophysiologic processes that account for a higher frequency of H-P-A feedback dysregulation in depressed patients; and 2) to translate this understanding into improved laboratory correlates for medical decision-making with depressed patients. To accomplish these, this project will emphasize serial H-P-A measures during different phases of the affective life cycle, and will study H-P-A dysregulation from an expanded perspective using a battery of pre- and post-dexamethasone plasma cortisol, corticosterone, and B-endorphin/B-lipotropin-like-immunoreactivity. These measures are selected to reflect regulation at both adrenal and pituitary loci in the H-P-A axis. Plasma dexamethasone will be measured as a control variable. All qualifying drug-free patients hospitalized in a clinical research unit will be studied serially before, during, and after treatment during a 30-week follow-up. Non-depressed psychiatric patients and normal individuals will be studied as controls. The treatment design emphasizes blind placebo crossover points. Major hypotheses are: 1) a battery of H-P-A measures reflecting both pituitary and adrenal functions will serve as a more sensitive and specific laboratory correlate of depressive pathophysiology than single measures of adrenal output; 2) H-P-A changes are temporarily related to clinical changes and will monitor clinical progress; 3) pre-treatment H-P-A measures may predict response to somatic antidepressant treatment; 4) persistent H-P-A dysregulation despite treatment (""""""""failure to normalize"""""""") will identify patients with either a distinctive pathophysiology, incorrect diagnosis, or inadequate treatment, and will be an excellent predictgor of poor response to treatment and high risk of subsequent relapse; and 5) the resolution of H-P-A dysregulation during treatment will indicate when active antidepressant treatments can be discontinued safely. These hypotheses represent a logical extension of our studies on the dexamethasone suppression test (DST) during year 01-08 of this project. The placebo-controlled crossover design is perhaps the only strategy which will clarify current uncertainties about whether the DST or other H-P-A measures have clinical predictive value.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH040216-03
Application #
3378277
Study Section
(TDAB)
Project Start
1985-05-01
Project End
1988-11-30
Budget Start
1987-05-01
Budget End
1988-11-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Young, E A; Kotun, J; Haskett, R F et al. (1993) Dissociation between pituitary and adrenal suppression to dexamethasone in depression. Arch Gen Psychiatry 50:395-403
Akil, H; Haskett, R F; Young, E A et al. (1993) Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin. Biol Psychiatry 33:73-85
Meador-Woodruff, J H; Greden, J F; Grunhaus, L et al. (1990) Severity of depression and hypothalamic-pituitary-adrenal axis dysregulation: identification of contributing factors. Acta Psychiatr Scand 81:364-71
Pande, A C; Grunhaus, L J; Haskett, R F et al. (1990) Electroconvulsive therapy in delusional and non-delusional depressive disorder. J Affect Disord 19:215-9
Lee, M A; Flegel, P; Cameron, O G et al. (1988) Chronic caffeine consumption and the dexamethasone suppression test in depression. Psychiatry Res 24:61-5
Pande, A C; Krugler, T; Haskett, R F et al. (1988) Predictors of response to electroconvulsive therapy in major depressive disorder. Biol Psychiatry 24:91-3
Lee, M A; Flegel, P; Greden, J F et al. (1988) Anxiogenic effects of caffeine on panic and depressed patients. Am J Psychiatry 145:632-5
Grunhaus, L; Flegel, P; Haskett, R F et al. (1987) Serial dexamethasone suppression tests in simultaneous panic and depressive disorders. Biol Psychiatry 22:332-8
Tandon, R; Grunhaus, L; Greden, J F (1987) Imipramine and tinnitus. J Clin Psychiatry 48:109-11