HORMONE RHYTHMS--METABOLIC SIGNIFICANCE IN DEPRESSION

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This is a five-year revised renewal application to continue our studies of HPA axis hyperactivity in major depression. Our hypothesis, bases on our and others'data, is that this is a central nervous system (CNS)-driven HPA hyperactivity, with normal adaptive physiology of the axis itself (no qualitative dysregulation or defects), as reflected in a reduced ACTH response to CRH administration (corticotroph downregulation) and perhaps adrenal hyperresponsivity to ACTH administration and hypertrophy as well. To elucidate this, we are undertaking investigations of the HPA axis in major depressives and individually matched controls. ACTH(1-24) stimulation is being used to assess the sensitivity of the adrenal gland, ovine CRH (oCRH) stimulation is being used to assess corticotroph downregulation, and magnetic resonance (MR) imaging of the adrenal glands is being used for size determination. Hormone measures include plasma ACTH(1-39),ACTH(1-24). cortisol, and OCRH. Bioactive ACTH will be determined as well. Adolescent major depressives in different pubertal stages also are being studied to ascertain the contribution of development from early puberty through adulthood to HPA axis activity an responsivity depressive illness. We hypothesize that HPA axis hyperactivity in depression is state- dependent, and that following treatment, the hormone measures will return to normal in a consistent manner. Thus, all patients are being tracked through their treatment and are being studied a second time when are in remission and off medication for at least one month. The studies proposed herein should add to the evidence that HPA axis hyperactivity is a coordinated physiologic phenomenon resulting from increased CNS stimulation of CRH production. This will give even more impetus to the study of CNS neurotransmitter regulation of HPA axis activity in major depression, stress states, and other condiitons leading to increased HPA axis activity.