The new atypical antipsychotic drugs have proven to be very effective in the treatment of psychoses, however, one very alarming side effect of these drugs is excessive weight gain. In humans it has been shown that average weight gains of 4 to 4.5 kg can occur during a 10-week treatment period to nearly a 12 kg increase after one year of treatment. This increase in body weight is associated with an increase in impaired glucose tolerance and hypertension and therefore is likely to increase mortality rates. The mechanisms involved in the drug-induced weight gain are currently unknown. We have developed a mouse model in which we can induce weight gain with three of the currently available and commonly prescribed antipsychotic drugs (olanzapine, quetiapine, and risperidone). Weight gain in our model is reproducible and occurs within four weeks using twice-daily oral treatment. We hypothesize that olanzapine and quetiapine produce weight gain via increased food intake and risperidone produces weight gain by decreasing energy expenditure. We further hypothesize that these drug-induced changes in food intake and energy expenditure are due to differential changes in hypothalamic gene expression patterns relating to alternative mechanisms of regulating energy balance. Lastly, alterations either in food intake, body weight, and/or body composition, or the direct action of the drugs will produce decreases in insulin sensitivity in vivo. With the proposed studies, we will determine the mechanisms of drug-induced weight gain associated with these drugs. Once known, attempts could be made to avoid the deleterious side effects, or at least allow one to more accurately consider benefits versus risks dependent upon the presence of other confounding variables (family history of obesity, diabetes, and hypertension).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068261-02
Application #
6894031
Study Section
Nutrition Study Section (NTN)
Program Officer
Yanovski, Susan Z
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$261,820
Indirect Cost
Name
University of Alabama Birmingham
Department
Nutrition
Type
Schools of Allied Health Profes
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Li, Xingsheng; Johnson, Maria S; Smith Jr, Daniel L et al. (2013) Effects of risperidone on energy balance in female C57BL/6J mice. Obesity (Silver Spring) 21:1850-7
Cope, Mark B; Li, Xingsheng; Jumbo-Lucioni, Patricia et al. (2009) Risperidone alters food intake, core body temperature, and locomotor activity in mice. Physiol Behav 96:457-63
Cope, M B; Jumbo-Lucioni, P; Walton, R G et al. (2007) No effect of dietary fat on short-term weight gain in mice treated with atypical antipsychotic drugs. Int J Obes (Lond) 31:1014-22
Cope, M B; Nagy, T R; Fernandez, J R et al. (2005) Antipsychotic drug-induced weight gain: development of an animal model. Int J Obes (Lond) 29:607-14