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

Quantitative Assessment and Comparison of Metabolic Changes in Non-psychotic Adults Taking the Antipsychotic Medications Fanapt (Iloperidone) or Zyprexa (Olanzapine) or Placebo

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 Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: olanzapine; Drug: iloperidone; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • New York State Psychiatric Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: olanzapine; 5mg BID olanzapine for up to 4 weeks	Drug: olanzapine; 5mg BID up to 4 weeks; Other Names: Zyprexa
EXPERIMENTAL: iloperidone; 6mg BID iloperidone up to 4 weeks	Drug: iloperidone; 6 mg BID up to 4 weeks; Other Names: Fanapt
PLACEBO_COMPARATOR: placebo; BID placebo up to 4 weeks	Drug: Placebo; BID up to 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Body Weight	Delineate a pathophysiological mechanism of antipsychotic induced weight gain	baseline and 6 week visit
Change in Adiposity	Total fat mass (excluding head) from baseline to Day 28	Baseline to Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Leptin	Leptin levels measured at Day 3 compared to baseline	change in baseline to Day 3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change Glucose in People Taking Olanzapine or Iloperidone	To quantify, prospectively, change in glucose from baseline to Day 28	Baseline to study termination (about 12 weeks)
Change in Insulin	Change in Insulin levels from baseline to Day 28	Baseline to Day 28
Insulin Resistance	Homeostatic model assessment for Insulin Resistance (HOMA-IR) is a method for assessing β-cell function and insulin resistance (IR) from basal (fasting) glucose and insulin.	Baseline to Day 28
Change in Food Intake	Total grams of food consumed	Baseline to Day 28
Change in Lipid Metabolism	Change in lipid metabolism as measured by cholesterol/HDL ratio	Baseline to Day 28

Collaborators and Investigators

• Sponsor: New York State Psychiatric Institute
• Collaborators: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Jeffrey Lieberman, MD, New York State Psychiatric Institute

Publications and helpful links

General Publications

• Ballon JS, Pajvani UB, Mayer LE, Freyberg Z, Freyberg R, Contreras I, Rosenbaum M, Leibel RL, Lieberman JA. Pathophysiology of drug induced weight and metabolic effects: findings from an RCT in healthy volunteers treated with olanzapine, iloperidone, or placebo. J Psychopharmacol. 2018 May;32(5):533-540. doi: 10.1177/0269881118754708. Epub 2018 Feb 15.

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (ACTUAL): August 1, 2014
• Study Completion (ACTUAL): September 1, 2014

Study Registration Dates

• First Submitted: August 8, 2013
• First Submitted That Met QC Criteria: August 8, 2013
• First Posted (ESTIMATE): August 12, 2013

Study Record Updates

• Last Update Posted (ACTUAL): March 20, 2017
• Last Update Submitted That Met QC Criteria: January 30, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Olanzapine; Iloperidone
• Other Study ID Numbers: 6525