The purpose of this pilot randomized clinical trial is to begin to delineate the pathophysiological changes associated with antipsychotic associated metabolic side effects. The study will be performed in 36 healthy people between the ages of 18 and 30, who have never taken an antipsychotic, will undergo baseline laboratory tests before being randomized to 5mg BID of olanzapine or 6mg BID of iloperidone or placebo to take for up to 4 weeks. The primary outcome measure will be a correlation of early changes in leptin with weight gain. We will also record changes in food intake, resting metabolic rate, oral glucose tolerance and fasting insulin and glucose levels, lipids and inflammation markers. Subjects will be followed closely to monitor for safety throughout the 4-week study and will be discontinued if there is a medically significant change in metabolic status or other antipsychotic side effects. Metabolic assessments will be performed again at the time of discontinuation or at the end of an 4-week period, and change from baseline in the two treatment groups will be compared.

Study hypotheses:

1. Early changes (baseline vs day 3) in leptin will correlate with later changes in weight (at study termination.)

   1. Olanzapine will cause the greatest increase in calorie consumption from baseline on the multi-item meal compared with iloperidone or placebo.
   2. Olanzapine subjects will report the greatest frequency/quantity of eating in food diaries, and report increased preference for calorically dense foods (ie, higher fat content) compared to iloperidone or placebo.
   3. Early markers of endocrine changes caused by olanzapine will be greater than those caused by iloperidone or placebo, and these early changes will correlate with weight gain.

2. Olanzapine will have greater effects on glucose homeostasis than iloperidone or placebo, and these effects will be separate from effects on body weight and composition.

   1. Early signs of metabolic disturbance, including glucose intolerance (greater excursion on OGTT) and insulin resistance (higher plasma insulin) will precede any significant weight gain.
   2. Early evidence of glucose intolerance and/or insulin resistance will predict greater metabolic derangements with further dosing of olanzapine, as evidenced by exacerbated glucose intolerance on OGTT or higher plasma glucose/insulin levels. These effects may not necessarily parallel weight gain.
   3. Olanzapine will be associated with greater markers of inflammation than iloperidone or placebo.

Inclusion Criteria:

• Male or female between the ages of 18-35 with no history of any Axis-I diagnosis
• Does not meet criteria for substance abuse or dependence in the past six months
• Female subjects will use barrier-method, non-hormonal contraception
• Capacity to understand all the relevant risks and potential benefits of the study (informed consent)
• Must be able to speak and read English

Exclusion Criteria:

• Current or past Axis I psychiatric diagnosis, including alcohol or substance abuse or dependence (except nicotine or caffeine), but not including minor Axis I disorders (e.g. simple phobia)
• Lifetime use of psychotropic medications, including antipsychotics, antidepressants, mood stabilizers, and anxiolytics
• Presence or history of medical or neurological illness that, in the judgment of the investigator, could influence the results of the study
• Diagnosis of diabetes, hemoglobin A1C > 6.5, hypertension, or dyslipidemias, or elevated random or fasting glucose, abnormal lipid levels, BP 130/85
• BMI 25 or < 19, history of BMI >35, and/or waist circumference >35 inches for females, 40 inches for males
• Subjects who are pregnant or breast-feeding or planning to become pregnant during the study
• Acute suicidality
• Meets criteria for a Diagnostic and Statistical Manual, Version 4 (DSM-IV) defined eating disorder
• Use of, or clinical indication for, one or more of the following medications: lithium, anti-epileptic medication, steroids (oral or inhaled), stimulants, serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants, thyroid supplementation, sibutramine, metformin, thiazolidinediones, beta-blockers, clonidine, niacin
• Subjects who have had >10% change in their body weight within the three months prior to enrollment
• HIV positive subjects
• Presence of mental retardation or pervasive developmental disorder
• History of recent (within 6 months) significant self-injurious behavior or violence
• Daily multivitamin or B-complex vitamin use
• A known history of dieting and difficulty with weight loss
• A strong family history of diabetes and/or heart disease
• History of congenital long QT syndrome or prolonged corrected QT interval (QTc) on screening EKG (>450ms)
• Concomitant use of any medication that inhibits 2D6 or 3A4 metabolism
• Low serum potassium or magnesium

4 weeks