We study the neurobiology of major depression. The fundamental central nervous system pathophysiological changes that underlie the core affective and cognitive symptoms of major depression also play a role in the fact that patients with major depression have twice the expected death rate at any age, independent of suicide. In addition, patients with major depression show a marked increase in the incidence of premature ischemic heart disease and osteoporosis. Our work consists of designing and performing studies to elucidate fundamental central nervous system mechanisms that contribute both to the affective and cognitive symptoms of major depression as well as their long-term medical consequences. As a corollary, our goal is to develop improved means for the diagnosis, treatment,, and prevention of the psychological and medical components of depressive disorders. Our clinical studies proceed predominantly in a group of 100 families studied longitudinally at the NIH for over twenty years. In 60 families the mother entered the study with a diagnosis of major depression and two children between the ages of 2 and 4. This population represents an ideal group for prospective studies in the years to come. In the past year, we have begun to elucidate the pathophysiology of the significant loss of bone mineral density we first described in patients with major depression via biospy of the anterior iliac crest. To date, we note decreased bone turnover and a marked decrease in the bone mineralization rate. We have also found that patients with major depression (matched closely with volunteers with respect to height, weight, and gender) show a significant decrement in lean body mass that correlates with bone mineral density. We have also found that patients with melancholic depression show profound, around-the-clock increases in CSF NE levels, that NE and the hypercortisolism mutually reinforce one another, and that these defects are closely related to defects in specific components of the central CRH system. We have developed and deployed a non-peptide CRH type 1 receptor antagonist. Utilizing this compound, we have demonstrated that CRHplays a tonic role in the behavioral, autonomic, metabolic, and endocrine responses to stress in rhesus macaques. These studies are premonitory to introducing this compound for study in human subjects.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U.S. National Institute of Mental Health
United States
Zip Code
Gold, P W (2015) The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry 20:32-47
Kling, Mitchel A; Coleman, Victoria H; Schulkin, Jay (2009) Glucocorticoid inhibition in the treatment of depression: can we think outside the endocrine hypothalamus? Depress Anxiety 26:641-9
Eskandari, Farideh; Martinez, Pedro E; Torvik, Sara et al. (2007) Low bone mass in premenopausal women with depression. Arch Intern Med 167:2329-36
Kino, Tomoshige; Boos, Terrence L; Sulima, Agnieszka et al. (2007) 3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit: potential clinical implications. J Allergy Clin Immunol 120:437-44
Kling, Mitchel A; Alesci, Salvatore; Csako, Gyorgy et al. (2007) Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A. Biol Psychiatry 62:309-13
Wersinger, S R; Caldwell, H K; Martinez, L et al. (2007) Vasopressin 1a receptor knockout mice have a subtle olfactory deficit but normal aggression. Genes Brain Behav 6:540-51
Ilias, Ioannis; Alesci, Salvatore; Gold, Philip W et al. (2006) Depression and osteoporosis in men: association or casual link? Hormones (Athens) 5:9-16
Alesci, S; Manoli, I; Michopoulos, V J et al. (2006) Development of a human mitochondria-focused cDNA microarray (hMitChip) and validation in skeletal muscle cells: implications for pharmaco- and mitogenomics. Pharmacogenomics J 6:333-42
Meyer, Stephanie E; Carlson, Gabrielle A; Wiggs, Edythe A et al. (2006) A prospective high-risk study of the association among maternal negativity, apparent frontal lobe dysfunction, and the development of bipolar disorder. Dev Psychopathol 18:573-89
Ronsaville, Donna S; Municchi, Giovanna; Laney, Carolyn et al. (2006) Maternal and environmental factors influence the hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone infusion in offspring of mothers with or without mood disorders. Dev Psychopathol 18:173-94

Showing the most recent 10 out of 72 publications