Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents.
OBJECTIVE
To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism.


METHODS
Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance.


RESULTS
Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting approximately 24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted.


CONCLUSIONS
A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Vance L
VL
Albaugh
Cathy R
CR
Henry
Nicholas T
NT
Bello
Andras
A
Hajnal
Susan L
SL
Lynch
Beth
B
Halle
Christopher J
CJ
Lynch
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology*; D004195:Disease Models, Animal; D002149:Energy Intake / Q000187:drug effects*; D005260:Female; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000139:chemically induced* / Q000378:metabolism; D000077152:Olanzapine; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors
D014150:Antipsychotic Agents; D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D011954:Receptors, Dopamine; D001569:Benzodiazepines; D003024:Clozapine; D000077152:Olanzapine