(Scanned from the applicant?s description) Obesity, often the result of a person?s genetic predisposition, can lead to serious medical conditions, including non-insulin dependent diabetes, heart disease, stroke, high blood pressure, kidney failure, and depression. Clozapine is a highly prescribed anti-psychotic drug, but unfortunately, many patients become obese within several months after initiation of this drug therapy. Identification of the clozapine weight responsive genetic locus and subsequent gene identification will 1) further enhance our understanding of obesity, including genetic suscepibility and onset as well as the its underlying molecular basis, 2) allow psychiatric patients to be screened prior to clozapine treatment to avoid potential health risks brought on by obesity, 3) identify potential cross talk of neuronal and obesity-related metabolic pathways, and 4) help aid in the design of new anti-psychotic drugs that do not interfere with metabolic weight homeostasis. The potential correlation (positive or negative) between formation of the principal active metabolite of clozapine(N-desmethyl-clozapine) and the onset of obesity will be explored as a viable tool to screen psychiatric patients genetically predisposed to clozapine induced weight gain. The involvement of histamine (H1) receptors and the neuroleptic induced obesity phenotype has abeen eluded to but not formally addressed in the literature. The potential role of the H1 receptor will be examined directly by the proposed work.
