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"Effect of Atypical Antipsychotics on the Enteric Nervous System: Implications for Weight Gain"

by
Caroline B. Palavicino-Maggio
Pharmacology & Physiology Program
B.S., 2002, Rider University, New Jersey

Thesis Advisors

Eldo Kuzhikandathil, Ph.D.
Associate Professor
Department of Pharmacology and Physiology

Ronaldo P. Ferraris, Ph.D.
Professor
Department of Pharmacology and Physiology

Victoria Arango, Ph.D.
Professor, Columbia University
Associate Director MIND at NYSPI

Monday, May 13, 2013
10:30 A.M., MSB H690


Abstract

Abstract
Antipsychotics induce significant weight gain, which increases the risk of chronic health problems such as diabetes, metabolic syndrome and cardiovascular disease. Antipsychotic-induced weight gain contributes to medication non-compliance, which can result in psychotic relapse. Additionally, the mortality risk of patients suffering from mental disorders is much higher than the general population and 60% of these deaths are due to the chronic health problems associated with obesity. It is important to determine the mechanisms by which antipsychotics induce weight gain. In this dissertation, I explored the hypothesis that antipsychotics induce weight gain by altering fructose absorption and metabolism in the intestine. The following observations were made: (1) target receptors for antipsychotics including dopamine, serotonin and histamine are expressed in the intestine; (2) chronic clozapine treatment increases intestinal fructose uptake in C57BL/6 wild type mice; (3) C57BL/6 wild type mice show significant weight gain following chronic clozapine treatment; however, GLUT5 fructose- specific facilitated transporter GLUT5 null mice of the same genetic background fail to show any clozapine-induced weight gain under the same experimental paradigm. Taken together, the results indicate a novel action of antipsychotics in gut. Specifically, these findings suggest that the intestinal GLUT5 fructose transporter is involved in clozapine-induced weight gain through the histamine 1 receptor (H1R) expressed in the mucosa. This novel finding may lead to new therapeutic approaches such as diet restrictions or the development of new adjuvant medications that can minimize antipsychotic-induced weight gain and associated co-morbidities. This will help to improve the quality of life of those suffering from neuropsychiatric disorders who rely on these medications.


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