This grant application has been developed to test the hypothesis that insulin resistance and hyperglycemic trends parallel plasma cortisol levels in major depressive disorder (MDD). We will also test the more focused hypothesis that treatment of depressive symptoms ameliorates state of insulin resistance. We will approach these hypotheses by studying depressed Mexican-American women from a rigorously characterized cohort of patients who have been recruited into our NIGMS-funded project in pharmacogenomics of antidepressant treatment response (GM61394). This application builds on the enormous resource provided by that prospective study, which provides the opportunity to recruit and treat these individuals. That project is a carefully designed, prospective clinical phase IIA randomized longitudinal study, using two pharmacological agents (desipramine and fluoxetine) with demonstrated efficacy in the treatment of MDD in the Mexican-American population. Clinical status is assessed with clinical interview and ratings such as the Hamilton Ratings Scale for Depression, Beck Depression Inventory, and Hamilton Anxiety Rating Scale. These instruments have been extensively validated in Spanish. That project is a treatment study with single- and double-masking, with random assignment of treatment, and with outcomes assessed with clinical measures. All subjects will undergo comprehensive intake assessments, and will then have follow-up assessments. Treatment will be provided according to our approved protocol. We propose to conduct detailed endocrine, nutritional, and metabolic studies in normal-weight Mexican-American women, who are otherwise medically healthy and who will be extensively characterized for our pharmacogenomic study. This proposal will permit the ascertainment of degree of insulin resistance in MDD through the assessment of endocrine (HPA axis and leptin measurements), nutritional, body composition, and metabolic function (insulin sensitivity will be assessed by oral glucose tolerance test, glucose clamp and arginine stimulation test) before and after treatment. Treatment outcome data will be correlated with endocrine and metabolic endpoints. Several lines of evidence suggest diabetes mellitus is often associated with depression and that depression increases the risk of developing diabetes. This work will address this important area by the study of an population group who is markedly under represented in patient-oriented investigation. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hunter, Christine
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Yu, Chenglong; Baune, Bernhard T; Licinio, Julio et al. (2017) Whole-genome single nucleotide variant distribution on genomic regions and its relationship to major depression. Psychiatry Res 252:75-79
Wong, Ma-Li; Dong, Chuanhui; Flores, Deborah L et al. (2014) Clinical outcomes and genome-wide association for a brain methylation site in an antidepressant pharmacogenetics study in Mexican Americans. Am J Psychiatry 171:1297-309
Licinio, J; Negrao, A B; Wong, M-L (2014) Plasma leptin concentrations are highly correlated to emotional states throughout the day. Transl Psychiatry 4:e475
Berman, Steven M; Paz-Filho, Gilberto; Wong, Ma-Li et al. (2013) Effects of leptin deficiency and replacement on cerebellar response to food-related cues. Cerebellum 12:59-67
Wong, M-L; Dong, C; Andreev, V et al. (2012) Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factors. Mol Psychiatry 17:624-33
Ishibashi, K; Berman, S M; Paz-Filho, G et al. (2012) Dopamine D2/D3 receptor availability in genetically leptin-deficient patients after long-term leptin replacement. Mol Psychiatry 17:352-3
London, Edythe D; Berman, Steven M; Chakrapani, Shruthi et al. (2011) Short-term plasticity of gray matter associated with leptin deficiency and replacement. J Clin Endocrinol Metab 96:E1212-20
Paz-Filho, Gilberto; Mastronardi, Claudio; Delibasi, Tuncay et al. (2010) Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy. Arq Bras Endocrinol Metabol 54:690-7
Galgani, Jose E; Greenway, Frank L; Caglayan, Sinan et al. (2010) Leptin replacement prevents weight loss-induced metabolic adaptation in congenital leptin-deficient patients. J Clin Endocrinol Metab 95:851-5
Paz-Filho, Gilberto; Licinio, Julio; Wong, Ma-Li (2010) Pathophysiological basis of cardiovascular disease and depression: a chicken-and-egg dilemma. Rev Bras Psiquiatr 32:181-91

Showing the most recent 10 out of 43 publications