Toward an understanding of antipsychotic drug induced weight gain - use of a rodent model
2017-01-16T23:39:35Z (GMT) by
Antipsychotic drug therapy is a fundamental tool in the treatment of schizophrenia and other psychoses. Recent years have seen the development of new antipsychotic compounds with an improved acute adverse effect profile; however these are often associated with weight gain and increased risk of metabolic disturbances. Olanzapine, despite its considerable adverse impact on weight gain and associated pathologies, has been recognized as the most efficacious antipsychotic drug in the treatment of schizophrenia. This thesis aims to further elucidate the mechanisms responsible for antipsychotic drug induced changes in body weight and glucose metabolism. The first part of this thesis involves the establishment of an animal model of olanzapine induced weight gain in order to examine the contribution of shifts in energy expenditure, particularly those involving centrally mediated changes in thermogenesis, to the body weight gain associated with the administration of olanzapine to rats. These studies identify a significant contribution from reduced brown adipose tissue thermogenesis and physical activity in combination with a transient elevation in food intake. Given the establishment of an effective model for olanzapine induced weight gain, the second series of experiments involves co-administration of olanzapine with zonisamide, an anti-epileptic drug previously shown to possess weight loss properties. These studies aim to use the rodent model to further assess the impact of olanzapine on other indices of weight gain, including whole body energy expenditure and lipid metabolism, and more importantly, determine the efficacy of zonisamide in preventing these metabolic disturbances. This part of the study shows that olanzapine induced weight gain is associated with a reduction in fat oxidation and physical activity and an increase in food intake. Moreover, olanzapine induces an accumulation of visceral and subcutaneous adipose tissue depots, in addition to a reduction in lipolytic capacity. Zonisamide completely ameliorates each of these olanzapine-induced metabolic changes. The final part of the thesis aims to examine the critical elements that underpin shifts in glucose metabolism mediated by antipsychotic drugs, specifically addressing the question as to whether these changes are directly or indirectly associated with olanzapine treatment. Acute olanzapine administration causes rapid hyperglycemia (2 hours post injection), in addition to a dramatic reduction in glucose tolerance and insulin sensitivity. Chronic administration of olanzapine is associated with significant hyperinsulinemia in response to a glucose challenge, in addition to a significant reduction in insulin sensitivity. The profound effects of olanzapine on glucose metabolism do not involve proinflammatory signaling in muscle or liver. These findings indicate that olanzapine can cause acute and chronic derangements in glucose metabolism consistent with a direct action of the drug. Overall the data presented here provide insights into the mechanisms that underpin the metabolic changes that substantially limit the potential of antipsychotic drugs in the treatment of schizophrenia and other disorders. Just as importantly they help to highlight new directions in this field including the use of companion therapies to reduce the impact of antipsychotic drugs on weight gain and the nature of the acute and direct effects of antipsychotic drugs on diabetic status independent of weight gain.