Mechanisms of the Metabolic Side Effects of Atypical Antipsychotics
Open Access
- Author:
- Albaugh, Vance Lee
- Graduate Program:
- Physiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 28, 2009
- Committee Members:
- Christopher J Lynch, Dissertation Advisor/Co-Advisor
Christopher J Lynch, Committee Chair/Co-Chair
Charles H Lang, Committee Member
Robert Nickerson Cooney, Committee Member
Yuguang Shi, Ph D, Committee Member
Andras Hajnal, Committee Member - Keywords:
- metabolic syndrome
hyperphagia
obesity
insulin resistance
diabetes
clozapine
olanzapine
antipsychotic drugs
respiratory exchange ratio
hyperinsulinemic-euglycemic clamp
glucose tolerance - Abstract:
- Second generation ‘atypical’ antipsychotics are a popular and effective treatment for schizophrenia and other psychiatric illnesses. These drugs revolutionized the treatment of psychotic disorders because they lacked the debilitating movement side effects, sedation and hypotension that plagued first generation compounds. However, post-marketing studies revealed unexpected side effects of these atypical drugs, including obesity and diabetes. The aim of this project was to develop a rodent model of these metabolic effects in order to identify potential mechanisms involved in the diabetes and obesity observed clinically. Animal models of the obesity and insulin resistance side effects were developed that showed similarities to the clinical situation, including hyperphagia, weight gain, increased adiposity and insulin resistance. Sexually dimorphic effects were observed in rats; for example, whereas females became obese, males accumulated adiposity without increased body weight gain. In female rats, the mechanism underlying this hyperphagia appears to be an acute lowering of the circulating concentration of several satiety factors, including glucose, insulin and leptin. Chronic olanzapine did not alter food intake or body weight in male rats, although they exhibited increased adiposity and insulin resistance. Several factors likely contribute to the increased fat mass. First, male rats provided olanzapine displayed decreased physical activity but maintained food intake. Thus, food intake did not decline to compensate for the level of activity. This relative hyperphagia was associated with lowering of plasma leptin. Other metabolic changes in these animals that favor increased adiposity include increased nutrient partitioning to fat and decreased fat mobilization in response to fasting or isoproterenol. Insulin resistance occurred acutely in male rats, suggesting that it was a direct drug effect and not secondary to adiposity. It was also tissue-specific, only affecting the heart and skeletal muscles and not fat, which exhibited either unaffected or improved insulin sensitivity. A recent retrospective study of patients revealed a major new side effect of atypical antipsychotics, increased risk of sudden cardiac death due to a ventricular arrhythmia that is frequently associated with metabolic disorders. Plasma free fatty acids, the heart’s preferred fuel, were lowered by olanzapine in our model. Acute studies revealed that this was due not only to impaired in vivo lipolysis, but also to a robust shift in the use of lipid fuels. This shift was confirmed by alterations in plasma nutrients after food deprivation, rapid and robust declines in respiratory exchange ratio, improved triglyceride tolerance without changes in hepatic secretion, and elevated FFA uptake (~2-fold or greater) into most tissues. Notably, the heart appeared to be more severely insulin resistant than other tissues and olanzapine did not stimulate uptake of FFAs as it did in other tissues. Furthermore, olanzapine increased heart rate without changing blood pressure or stroke volume. These results suggest that olanzapine may elevate cardiac risk by simultaneously causing cardiac insulin resistance, repartitioning of fatty fuels and tachycardia, while decreasing availability of free fatty acids from lipolysis. The olanzapine-induced metabolic inflexibility may explain its glucose sparing and glucose intolerance effects.