Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole

Overview

This proposal aims to use well-validated methodologies such as dual energy x-ray absorptiometry (DEXA), frequently sampled oral glucose tolerance tests (fsOGTTs), and hyperinsulinemic euglycemic clamps to characterize the metabolic effects of 12 weeks of aripiprazole treatment following chronic pretreatment with olanzapine, quetiapine, risperidone or ziprasidone. We hypothesize that switching to aripiprazole treatment will induce improvements in total body adiposity, inflammation (e.g., high sensitivity C-reactive protein \[hsCRP\]), glucose metabolism (e.g., insulin sensitivity) and lipid metabolism (e.g., fasting plasma triglyceride), in comparison to chronic pretreatment with olanzapine, risperidone and quetiapine.

Schizophrenia is associated with increased rates of obesity, hyperglycemia, dyslipidemia and type 2 diabetes mellitus (T2DM), causing increased morbidity and mortality due to acute (e.g., diabetic ketoacidosis) and long-term (e.g., vascular disease) complications.1-5As a result, cardiovascular (CV) mortality remains one of the leading causes of excess mortality in patients with psychotic disorders.6,7 T2DM is characterized by disturbances in insulin secretion and insulin action at skeletal muscle (i.e., decreased glucose disposal), liver (i.e., increased glucose production) and adipose tissue (i.e., increased lipolysis), leading to disturbances in glucose and lipid metabolism. The metabolic syndrome of insulin resistance, hyperinsulinemia, dyslipidemia and abdominal adiposity usually includes a procoagulant state and endothelial dysfunction, and is strongly associated with increased CV morbidity and mortality. Hyperglycemia was first noted in patients with schizophrenia prior to the introduction of antipsychotic medications, but glucoregulatory defects, dyslipidemia and increased adiposity are all additionally associated with both older and newer antipsychotic treatments.1 In most patients, these metabolic derangements are primarily related to increases in adiposity, although treatment effects independent of adiposity may also play a role in up to 25% of cases of new onset T2DM during antipsychotic treatment.8,9 Increased adiposity, especially visceral abdominal adiposity, is associated with insulin resistance, elevated plasma lipids, and increases in inflammatory markers. All of these conditions contribute to elevated mortality and all can be directly measured in patients treated with different medications. Direct measures of adiposity, insulin action and secretion, plasma lipid levels and inflammation are available and have been well validated as predictors of CV disease and T2DM complications. Unfortunately, to date, studies using large population-based samples of patients taking antipsychotic medications have only used insensitive measures, like random glucose, or surrogate measures such as prescription of an oral hypoglycemic agent, to estimate the prevalence of T2DM during antipsychotic treatment. No data are available concerning insulin sensitivity and secretion, plasma lipids or inflammatory markers from large population-based samples of individuals treated with antipsychotic medications. Reviewed below, limited data are available from smaller analytic studies using sensitive measures. Despite convergent evidence for the contribution of adiposity to the metabolic derangements associated with antipsychotic treatment, investigators have only begun to use direct measures of adiposity to characterize the weight gain associated with antipsychotic treatment. This proposal aims to use well-validated methodologies such as dual energy x-ray absorptiometry (DEXA), frequently sampled oral glucose tolerance tests (fsOGTTs), and hyperinsulinemic euglycemic clamps to characterize the metabolic effects of 12 weeks of aripiprazole treatment following chronic pretreatment with olanzapine, quetiapine, risperidone or ziprasidone. We hypothesize that switching to aripiprazole treatment will induce improvements in total body adiposity, inflammation (e.g., high sensitivity C-reactive protein \[hsCRP\]), glucose metabolism (e.g., insulin sensitivity) and lipid metabolism (e.g., fasting plasma triglyceride), in comparison to chronic pretreatment with olanzapine, risperidone and quetiapine. Aim 1: To characterize the glucoregulatory effects of 12 weeks of aripiprazole treatment. This study hypothesizes that switching to aripiprazole treatment will be associated with statistically significant improvements in glucose metabolism (e.g., insulin sensitivity) in comparison to chronic pretreatment with olanzapine. Given the planned sample size and study duration, we hypothesize that aripiprazole treatment will be associated with numerical, but not statistically significant, improvements in comparison to pretreatment with risperidone or quetiapine. We hypothesize that aripiprazole treatment will be associated with no significant change in comparison to pretreatment with ziprasidone. These hypotheses will be evaluated by measuring insulin sensitivity and other indices via fsOGTTs and hyperinsulinemic euglycemic clamps. Aim 2: To evaluate medication-related measures of abdominal fat, total body fat and total fat-free mass. This study hypothesizes that switching to aripiprazole treatment will be associated with reductions in adipose tissue mass in comparison to olanzapine. We hypothesize that aripiprazole treatment will be associated with numerical, but not statistically significant, reductions in comparison to pretreatment with risperidone or quetiapine. We hypothesize that aripiprazole treatment will be associated with no change in comparison to pretreatment with ziprasidone. These hypotheses will be evaluated by measuring body composition using dual energy x-ray absorptiometry (DEXA) and anthropomorphic measurements to provide estimates of total body fat, abdominal fat and fat-free mass.