Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
Condition: Schizophrenia; Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Stayers; Switchers
Intervention type(s): Other; Other
Intervention description(s): Participants remain on their current antipsychotic.; Subjects are randomized to switch to aripiprazole from their current antipsychotic.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Schizophrenia; Obesity; Hyperglycemia; Dyslipidemia; Type 2 Diabetes Mellitus