Side Effects of Antipsychotic Medications

Objectives: The use of atypical antipsychotics has been associated with increased weight
gain, the development of type-2 diabetes, and, in rare cases, diabetic ketoacidosis. It is
not clear if these changes are a direct function of antipsychotics on either insulin action
or insulin secretion, or simply related to their ability to induce weight gain in a
population at increased risk to develop hyperglycemia. The objective of this investigation
is to determine if treatment with the atypical antipsychotics olanzapine impairs the ability
of the pancreatic beta cell to increase its insulin secretory response to graded increases
in plasma glucose concentration in non-diabetic, insulin resistant individuals. In addition,
we will compare the range of insulin-mediated glucose uptake (IMGU) in olanzapine-treated
versus non-antipsychotic treated patients.

Research Plan and Methods: 120 subjects with psychiatric disorders will be enrolled; 60
patients on olanzapine and 60 patients with similar psychiatric diagnoses on a different
antipsychotic medication (ziprasidone, risperidone or aripiprazole). All subjects will have
a fasting plasma glucose concentration <126 mg/dL, and on no medication with a direct effect
on IMGU. Subjects will be admitted to the General Clinical Research Center (GCRC) at
Stanford Medical Center and evaluated by an insulin suppression test (IST) to determine
their IMGU. Subjects with a steady state plasma glucose (SSPG) concentration during the IST
that is >180 mg/dL will be defined as being insulin resistant. From this population of
subjects, 15 patients on olanzapine and 15 patients not on any antipsychotic, will return to
the GCRC to determine their glucose-stimulated insulin secretory dose-response curves
(GS-ISR). The GS-ISR at the same glucose concentration will be compared between the subjects
on olanzapine (n=15) and the not on an antipsychotic (n=15) by analysis of variance.
Analyses of the 120 subjects screened for insulin resistance will compare 1) the means and
distribution of the SSPG concentrations in olanzapine and non-olanzapine treated patients
with psychiatric diagnoses; and 2) the means of the two experimental groups with psychiatric
diagnoses to Dr. Reaven’s data base of volunteers without psychiatric disorders.

Inclusion Criteria:

- Participants 30-66 years of age

- Body mass index (BMI) >25 < 35 kg/m2.

- Fasting plasma glucose concentration < 126 mg/dL

- Stable on one of the following psychiatric medication: Olanzapine (Zyprexa®),
Ziprasidone (Geodon®), Aripiprazole (Abilify®), or Risperidone (Risperdal®)

- Stable on psychiatric medication for at least 3 months

Exclusion Criteria:

- Medications that directly affect insulin-mediated glucose disposal

- Intense suicidal impulses/intent

- Alcohol or substance abuse for 3 months.

- Major medical problems, i.e., clinically unstable medical disorder or condition;
cardiovascular, hepatic, renal, gastrointestinal, pulmonary, endocrine or other
systemic disease that would, in the investigator's clinical judgment interfere with
the endocrine measures obtained in this study.