Antipsychotic drug-induced weight gain: development of an animal model

Cope, Mark B.; Nagy, Tim R.; Fernández, José R.; Geary, Nori; Casey, Dympna; Allison, David B.

doi:10.1038/sj.ijo.0802928

Cited by 101 publications

(89 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chronic risperidone treatment lead to increases in both body weight gain and food intake in female rats (Baptista et al, 2002b andPouzet et al, 2003). A similar effect on body weight gain was observed in risperidone-treated female mice but without any accompanying increase in food intake (Cope et al, 2005). In contrast to the commonly observed body weight gain in female rodents, haloperidol or risperidone did not induce body weight gain in male rats (Baptista et al, 2002b andPouzet et al, 2003).…”

Section: Introductionmentioning

confidence: 84%

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

et al. 2006

View full text Add to dashboard Cite

Antipsychotic drugs have been used effectively for the treatment of schizophrenia symptoms, but they are often associated with metabolic side effects such as weight gain and endocrine disruptions. To investigate the possible mechanisms of antipsychotic-induced metabolic effects, we studied the impact of chronic administration of a typical antipsychotic drug (haloperidol) and an atypical antipsychotic (risperidone) to male rats on food intake, body weight, adiposity, and the circulating concentrations of hormones and metabolites that can influence energy homeostasis. Chronic (28 days) haloperidol administration had no effect on food intake, weight gain or adiposity in male rats, whereas risperidone treatment resulted in a transient reduction in food intake and significantly reduced body weight gain compared to vehicle-treated control rats. Whereas neither antipsychotic had any effect on serum lipid profiles, glucose tolerance or the circulating concentrations of hormones controlled by the hypothalamo-pituitary-thyroid (free T4), -adrenal (corticosterone), -somatotropic (IGF-1), orgonadotropic axes (testosterone), haloperidol increased circulating insulin levels and risperidone increased serum glucagon levels. This finding suggests that haloperidol or risperidone induce distinct metabolic effects. Since metabolic disorders such as obesity and type 2 diabetes mellitus represent serious health issues, understanding antipsychotic-induced endocrine and metabolic effects may ultimately allow better control of these side effects.

show abstract

Section: Introductionmentioning

confidence: 84%

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Antipsychotic drugassociated weight gain in a male rodent model has been shown by Minet-Ringuet et al (2006); however, clozapine has not been found to induce weight gain or metabolic abnormalities in female rats, but was found to increase adiposity (Cooper et al, 2007). Although antipsychotic drugassociated weight gain in rodent models is in dispute in regard to sex, drug administration, diet, dose, and antipsychotic agents used, the use of OLZ in female rats has consistently been demonstrated to reproduce the weight gain, increased adiposity, and metabolic disturbances seen in patients (Albaugh et al, 2006;Arjona et al, 2004;Coccurello et al, 2006;Cooper et al, 2005;Cope et al, 2005;Goudie et al, 2002;Raskind et al, 2007). With a similar rodent model, we have shown that ZNS both inhibits and reverses SGA-associated hyperphagia, weight gain, and increased feed efficiency.…”

Section: Discussionmentioning

confidence: 99%

“…SGAs such as olanzapine (OLZ) have been found to cause rapid and pronounced hyperphagia in both rodents Cope et al, 2005) and humans (Brixner et al, 2006;Goudie et al, 2005). One hypothetical pathway for this dramatic increase in food consumption may be the activation of orexin neurons in the lateral hypothalamus (LH), and in turn, the release of neuropeptides known to be critical in body weight regulation (Fadel et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats

Wallingford

Sinnayah

Bymaster

et al. 2008

Neuropsychopharmacol

View full text Add to dashboard Cite

Olanzapine (OLZ), one of the second-generation atypical antipsychotics (SGAs), has shown relative advantages in patient adherence and outcomes. However, OLZ has also been associated with a higher incidence of weight gain than most other SGAs. Excessive weight gain may in turn contribute to long-term health concerns for some individuals. Zonisamide (ZNS), a medication approved in the United States as an adjunct in the management of epilepsy, has a diverse pharmacological profile, including sodium channel blockade, monoamine enhancement, and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents. We hypothesized that this profile might be beneficial when co-administered with OLZ. To test this hypothesis, we evaluated the effects of OLZ on body weight, as well as the pathways known to regulate feeding behavior and arousal in the Sprague-Dawley rat. As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ-associated development of hyperphagia, weight gain and elevated blood glucose in the rat was also found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs. Future studies of this combination in patients through appropriately designed human clinical studies are encouraged.

show abstract

“…Observational preclinical (Thornton-Jones et al, 2002;Ota et al, 2002;Hartfield et al, 2003a;Arjona et al, 2004;Cope et al, 2005) and clinical data suggest that one of the ways SGAs can lead to changes in the patterns of food intake is by increasing appetite (Figure 5b; Bromel et al, 1998;Briffa and Meehan, 1998;Eder et al, 2001;Basson et al, 2001;Kinon et al, 2005) and subsequent consumption of the previously preferred diet (Gothelf et al, 2002;Kane et al, 2004).…”

Section: Effects Of Sgas On Food Intakementioning

confidence: 99%

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

133

142

View full text Add to dashboard Cite

Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies. INTRODUCTIONObesity has reached pandemic proportions and it is rapidly surpassing smoking as a number one killer in the industrialized world (Sturm, 2002;Skidmore and Yarnell, 2004). Its annual cost to the American society is staggering, and is estimated to be around $117 billion owing to related illnesses and loss of productivity (National Institute of Diabetes and Digestive and Kidney Diseases, 2005).In schizophrenia, obesity is twice as prevalent as in the general public, afflicting over half this patient population (Allison et al, 1999a;Dixon et al, 2000; American Diabetes Association, 2004;Marder et al, 2004;Wirshing, 2004). Besides negative psychosocial impacts (distorted selfesteem and societal stigmatization) and medications noncompliance, schizophrenics appear to be particularly susceptible to the detrimental medical sequelae of obesity such as the 'Metabolic Syndrome', which is a cluster of cardiovascular risk factors, including abdominal adiposity, insulin resistance, impaired, glucose tolerance, dyslipidemia, and hypertension (McKee et al, 1986;Mukherjee et al, 1996;Brown et al, 2000;Haupt and Newcomer, 2002;Ryan and Thakore, 2002;Ryan et al, 2003;Holt et al, 2004;Kohen, 2004;Marder et al, 2004;Lieberman et al, 2005).Excessive body weight gain (BWG) could be attributed to a constellation of endocrine, molecular, genetic, demographic, and lifestyle-related factors. Provided that a common tra...

show abstract

Antipsychotic drug-induced weight gain: development of an animal model

Cited by 101 publications

References 32 publications

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Contact Info

Product

Resources

About