Assessment and Comparison of Metabolic Changes in Non-psychotic Adults Taking Iloperidone or Olanzapine or Placebo

Study hypotheses:

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

• Olanzapine will cause the greatest increase in calorie consumption from baseline on the multi-item meal compared with iloperidone or placebo.
• 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.
• 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.
• 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.

• Early signs of metabolic disturbance, including glucose intolerance (greater excursion on OGTT) and insulin resistance (higher plasma insulin) will precede any significant weight gain.
• 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.
• 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