Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole

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.

Inclusion Criteria:

- Patient meets DSM-IV criteria for Schizophrenia

- 18-60 years of age or older

- Able to give informed consent

- Treated with olanzapine, quetiapine, risperidone or ziprasidone for greater than or
equal to 3 months prior to enrollment

Exclusion Criteria:

- pregnant or breastfeeding women will be excluded

- Meets DSM-IV criteria for substance abuse or dependence within past 6 months

- involuntary legal status (as per Missouri law)

- any serious medical disorder that may confound assessment of symptoms

- subjects taking prescription medications except psychotropic meds

- meets DSM-IV criteria for Mental Retardation (mild or worse)

- Subjects taking tricyclic antidepressants or mood stabilizers