Effects of Atypical Antipsychotic and Valproate Combination Therapy on Glucose and Lipid Metabolism in Schizophrenia
Condition: Insulin Resistance; Body Composition
MeSH terms: Insulin Resistance; Schizophrenia
Study type: Interventional

Summary: 
      This project aims to a) evaluate the effects of haloperidol, olanzapine, and risperidone in
      combination with valproate on insulin secretion and insulin actions, b) evaluate medication
      effects on abdominal fat, total body fat and total fat-free mass, and c) evaluate treatment
      effects on glucose tolerance, lipid profiles, and plasma levels of leptin, adiponectin,
      ghrelin and C-reactive protein. Hypotheses will be evaluated by measuring 1) insulin action
      and secretion using frequently sampled intravenous glucose tolerance tests, 2) body
      composition using dual energy x-ray absorptiometry, magnetic resonance scans, and
      anthropomorphic measurements, and 3) changes in hormone levels and lipid profiles. The aims
      will be addressed in non-diabetic schizophrenia patients chronically treated with
      haloperidol, olanzapine or risperidone who will have valproate added to their treatment.
      Relevant data is critically needed to target basic research, identify long-term
      cardiovascular risks, and plan therapeutic interventions.
    

Detailed description: 
      Schizophrenia is associated with increased rates of obesity, hyperglycemia, dyslipidemia and
      type 2 diabetes mellitus, causing increased morbidity and mortality due to acute (e.g.,
      diabetic ketoacidosis) and long-term (e.g., vascular disease) complications. The association
      of type 2 diabetes and hyperglycemia with schizophrenia was first noted prior to the
      introduction of antipsychotic medications. However, additional glucoregulatory abnormalities,
      dyslipidemia, and increased adiposity have all been associated with antipsychotics.
      Risperidone and olanzapine are the most prescribed antipsychotics for schizophrenia in the
      U.S. In addition, schizophrenia patients in clinical practice are commonly treated with
      multi-class polypharmacy, with 35% of atypical antipsychotic prescriptions accompanied by
      co-prescription of valproate. This combination continues to increase in popularity, despite
      reports that the addition of valproate may further disturb glucose and lipid metabolism and
      weight regulation. While sensitive and validated measures of glucose and lipid metabolism and
      weight regulation are available, very few studies have addressed the metabolic consequences
      of this common type of polypharmacy.

      This project aims to a) evaluate the effects of haloperidol, olanzapine, and risperidone in
      combination with valproate on insulin secretion and insulin actions, b) evaluate medication
      effects on abdominal fat, total body fat and total fat-free mass, and c) evaluate treatment
      effects on glucose tolerance, lipid profiles, and plasma levels of leptin, adiponectin,
      ghrelin and C-reactive protein. Hypotheses will be evaluated by measuring 1) insulin action
      and secretion using frequently sampled intravenous glucose tolerance tests, 2) body
      composition using dual energy x-ray absorptiometry, magnetic resonance scans, and
      anthropomorphic measurements, and 3) changes in hormone levels and lipid profiles. The aims
      will be addressed in non-diabetic schizophrenia patients chronically treated with
      haloperidol, olanzapine or risperidone who will have valproate added to their treatment.
      Relevant data is critically needed to target basic research, identify long-term
      cardiovascular risks, and plan therapeutic interventions.
    

Intervention name(s): Depakote (valproate)
Intervention type(s): Drug
Intervention description(s): 500 mg -2000 mg QD based on individual tolerance and VPA levels
Intervention MeSH terms: Valproic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment