Acute Olanzapine and Lipid Response

Atypical antipsychotics are pharmaceutical drugs used to treat schizophrenia. Common side effects are weight gain, insulin resistance, and abnormal blood lipids. This increases the risk for type 2 diabetes and cardiovascular disease in patients taking these drugs. In particular, olanzapine is a highly effective therapy for schizophrenia but is commonly associated with metabolic disturbances. It has previously been shown that the negative effects on insulin sensitivity and glucose metabolism occur even after a single dose, independently of weight gain. These effects may be mediated by blocking the dopamine (D2) receptor. In this study the research team is investigating whether a single dose of olanzapine alters postprandial lipid metabolism after a high-fat drink. Olanzapine administered along with the high-fat drink will be compared to placebo or olanzapine plus bromocriptine (an activator of the D2 receptor).

Postprandial lipid and hormonal responses are being investigated in up to 15 individuals. Participants are their own control in a single-blind, placebo-controlled, crossover design. Participants are admitted after an overnight fast. Participants will consume a high-fat drink (50g of fat) along with either oral placebo, olanzapine (10mg) or olanzapine (10mg) plus bromocriptine (5mg). Study visits occur 2-4 weeks apart with the three treatments applied in random order. Blood samples will be taken at baseline and regular intervals after the treatments for up to 8 hours to measure glucose, insulin, triglycerides, fatty acids and other hormones/metabolites.

Eligibility Criteria:
Inclusion Criteria:

* Men and women, aged 18 to 60 years
* Body mass index (BMI) 20 to 40 kg/m2
* Hemoglobin in the normal range.
* Normal glucose tolerance in response to a 75 gram, 2-hr oral glucose tolerance test
* Women of reproductive age should be on contraception (oral contraceptive pill or intra-uterine device/coil) for at least 2 months prior to and after the study. Anyone with a positive urine pregnancy test (carried out at screening and the day before each kinetic study) will be excluded.

Exclusion Criteria:

* Any volunteer with evidence of prolonged corrected QT interval (\>470 ms in males and \>450ms in females)
* Any volunteer with morbid obesity (BMI\>40 or BMI\>30 with any obesity related medical complication such as diabetes, hypertension or coronary disease)
* Any history of a myocardial infarction or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on echocardiogram, unstable angina, or decompensated heart failure
* Study participant with a history of hepatic disease that has been active within the previous two years.
* Any current or previous history of biliary disease (including gall stones, biliary atresia and cholecystitis) or pancreatitis.
* Any current or previous history of endocrine disease, dyslipidemia or malignancy
* Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (Cr \> 1.5 mg/dL) genitourinary, hematological systems, or has severe uncontrolled treated or untreated hyper/ hypotension (sitting diastolic BP \> 100 or systolic \> 180 or systolic BP\<100) or proliferative retinopathy
* Use of immunosuppressive agents at any time during the study
* Allergy to any study medication
* Pregnancy (as ascertained by urinary human chorionic gonadotropin at screening and the day before each study visit) or breastfeeding
* Fasting blood glucose \> 6.0 mmol/l or known diabetes.
* Any laboratory values: aspartate aminotransferase \> 2x upper limit of normal (ULN); alanine transaminase \>2x ULN thyroid stimulating hormone \> 6 mU/l
* Current addiction to alcohol or substances of abuse as determined by the investigator or of any mental illness.
* Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation
* Taking any regular prescription or non-prescription medications at the time of the study. Occasional use of medications such as acetaminophen or Tylenol 1 or any use of natural health products may be permitted at the discretion of the investigator.
* Will not donate blood three months prior to and three months post study procedures
* Hemoglobin below the reference range (less than 130 g/l for males and 120 g/l for females) based on blood tests at screening and on the day before the kinetic study
* Hematocrit below the reference range (less than 0.38 for males and 0.37 for females) based on blood tests at screening and on the day before the kinetic study
* Soy allergy (component of high-fat drink)