Gene Markers: Antipsychotic-Induced Metabolic Syndrome

Ruano, Gualberto

Abstract

This Phase I SBIR Program will develop genetic diagnostic products to improve the safety of atypical antipsychotics (e.g. olanzapine) for treating psychiatric disorders, including schizophrenia. Atypical antipsychotics are prescribed as long-term treatments for an increasing number of indications even to adolescent's patients. In up to 50% of patients, these highly effective drugs induce metabolic syndrome. Genomas and the Institute of Living (IOL) at Hartford bring together the power of genomics and expert psychiatric care to discover genetic markers of susceptibility to drug-induced metabolic syndrome for clinical management of psychiatric disorders. These novel and highly predictive markers are termed """"""""physiotypes"""""""" and result from combinations of various contributory genes and baseline characteristics. From patients being first treated with olanzapine as part of best medical practices at IOL, 250 will be asked to participate in this study and requested to consent for genetic analysis. Patients will be followed for 6 months. Clinical assessment, including weight, waist size, lipids, fasting blood glucose and blood pressure will be ascertained at baseline, and 2 and 6 months after initiation of olanzapine treatment. Genomas will haplotype 200 genes in each patient with highly multiplexed genotyping assays. Candidate genes are drawn from CNS, metabolic, cell biological, and genetic studies and represent antipsychotic pharmacology (dopamine, serotonin, histamine), appetite control (leptin, neuropeptide Y), energy regulation (uncoupling proteins), endocrinology (insulin) and cholesterol homeostasis (apolipoproteins). Based on review of medical records, the study has been powered to detect common haplotypes of even modest individual predictive power (odds ratio of 1.7). When combined into physiotypes, the markers have specificity and sensitivity of 80% or more. Genomas will construct physiotypes of drug-induced metabolic syndrome and apply statistical validation techniques to the discoveries. The physiotype generates new knowledge about antipsychotic pharmacology and pathophysiology of metabolic syndrome and becomes intellectual property for development of multigene diagnostic products. The physiotype will have utility for personalized therapy, drug monitoring, and medical prophylaxis. This novel approach utilizing multple physiological pathways, haplotyping, covariate analysis and standardized clinical practice will result in personalized """"""""double-preventive"""""""" diagnostics of natural and drug-induced disease. ? ?