Effects of Atypical Antipsychotic and Valproate Combination Therapy on Glucose and Lipid Metabolism in Schizophrenia

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.

Inclusion Criteria:

- Meets DSM-IV criteria for schizophrenia, any type, treated with atypical or high
potency typical neuroleptics for at least 3 months

- Aged 18 to 60 years

- Able to give informed consent

- No antipsychotic medication changes for 3 months, and no other medication changes for
2 weeks prior to Baseline Evaluations.

Exclusion Criteria:

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

- Involuntary legal status (as per Missouri law)

- The presence of any serious medical disorder that may (as confirmed by peer-reviewed
literature) confound the assessment of symptoms, relevant biologic measures or
diagnosis. The following conditions are currently identified:

- Type 1 diabetes mellitus or symptomatic type 2 diabetes mellitus

- Any intra-abdominal or intrathoracic surgery or limb amputation within the prior
6 months

- Any diagnosed cardiac condition causing documented hemodynamic compromise

- Any diagnosed respiratory condition causing documented or clinically recognized
hypoxia

- Pregnancy or high dose estrogens, fever, narcotic therapy, acute sedative
hypnotic withdrawal, corticosteroid or spironolactone therapy, dehydration,
epilepsy, endocrine disease, high-dose benzodiazepine therapy (> 25 mg/day of
diazepam), or any medical condition known to interfere with glucose utilization

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