Pharmacoepigenetics of Bipolar Disorder Treatment

1. Aged 18-65 with a Bipolar Spectrum Diagnosis (Bipolar I, II or NOS)
2. Currently treated with lithium or an antipsychotic as determined by a physician for at least 3 months at a stable dosage.
3. Non- obese with BMI \< 30
4. Able to communicate meaningfully with the investigator and legally competent to provide informed written consent.
5. Females must be non-lactating, have a pregnancy test and be on acceptable birth control

105 subjects will be studied in total from three groups:

1. One group will consist of 35 bipolar patients currently stable on an antipsychotics with impaired glucose tolerance (2-hour postprandial plasma glucose of 140-199mg/dL).
2. The second group will consist of 35 age, gender, and body composition matched bipolar patients currently stable on an antipsychotic with normal glucose tolerance (2-hour postprandial plasma glucose \<140mg/dL.
3. The third group will consist of 35 age, gender and body composition matched bipolar subjects stable on lithium with normal glucose tolerance.

Exclusion Criteria:

1. Currently diagnosed with diabetes (type I or II) or receiving treatment for diabetes. Any history of metabolic complications (weight gain, high cholesterol, high blood pressure) before taking an antipsychotic.
2. Active diagnosis of alcohol or substance abuse.
3. Primary relative diagnosed with type II diabetes.

4. Treated with any of the following medications: a) Systemic glucocorticoids (more than 2 weeks), antineoplastic agents, transplant medications, anti-retroviral medications within 6 months prior to screening.

   • Start or change of hormonal replacement therapy within 3 months prior to screening.

5. History or presence of any of the following conditions

   • Clinically significant heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on the EKG)
   • Peripheral vascular disease (history of claudication)
   • Clinically significant pulmonary disease.
   • Current uncontrolled hypertension (systolic BP>160 mmHg, diastolic BP>100 mmHg)
   • History or presence of malignancy other than basal cell or squamous cell skin cancer
   • Clinically significant hematologic disease

6. Any of the following abnormal laboratory values:

   • Hematocrit \< 35 vol%
   • Serum creatinine > 1.6 mg/dl
   • aspartate aminotransferase (AST), alanine aminotransferase (ALT) or Alkaline phosphatase > 2.5 times the upper limit of normal
   • Prothrombin time (PT), Partial thromboplastin time (PTT) outside the normal reference range
   • thyroid-stimulating hormone (TSH) outside the normal reference range
   • Triglycerides > 400 mg/dl
   • Platelet count \< 50,000
7. Blood donation within 2 months prior to screening
8. Engage in exercise with moderate to hard intensity for greater than 1 hour per day for 5 or more days per week.