Healthy
Conditions
Brief summary
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.
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.
Interventions
DRUGolanzapine
5mg BID up to 4 weeks
DRUGiloperidone
6 mg BID up to 4 weeks
DRUGPlacebo
BID up to 4 weeks
Sponsors
Novartis Pharmaceuticals
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Adiposity | Baseline to Day 28 | Total fat mass (excluding head) from baseline to Day 28 |
| Change in Body Weight | baseline and 6 week visit | Delineate a pathophysiological mechanism of antipsychotic induced weight gain |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Leptin | change in baseline to Day 3 | Leptin levels measured at Day 3 compared to baseline |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin | Baseline to Day 28 | Change in Insulin levels from baseline to Day 28 |
| Change in Food Intake | Baseline to Day 28 | Total grams of food consumed |
| Insulin Resistance | Baseline to Day 28 | 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. |
| Change in Lipid Metabolism | Baseline to Day 28 | Change in lipid metabolism as measured by cholesterol/HDL ratio |
| Change Glucose in People Taking Olanzapine or Iloperidone | Baseline to study termination (about 12 weeks) | To quantify, prospectively, change in glucose from baseline to Day 28 |
Countries
United States
Participant flow
Pre-assignment details
There were a total of 69 consents in the study, 31 of which were randomized (started study medication). 24 subjects completed the study. The baseline characteristics reported were for the 24 subjects who completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Olanzapine 5mg BID olanzapine for up to 4 weeks
olanzapine: 5mg BID up to 4 weeks | 7 |
| Iloperidone 6mg BID iloperidone up to 4 weeks
iloperidone: 6 mg BID up to 4 weeks | 7 |
| Placebo BID placebo up to 4 weeks
Placebo: BID up to 4 weeks | 10 |
| Total | 24 |
Baseline characteristics
| Characteristic | Total | Iloperidone | Placebo | Olanzapine |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 7 Participants | 10 Participants | 7 Participants |
| Education (years) | 15 years | 13.6 years | 14.9 years | 16.4 years |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 5 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 1 Participants | 4 Participants | 1 Participants |
| Region of Enrollment United States | 24 participants | 7 participants | 10 participants | 7 participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 18 Participants | 4 Participants | 9 Participants | 5 Participants |
| Starting BMI | 23.0 kg/m^2 STANDARD_DEVIATION 0.5 | 23.6 kg/m^2 STANDARD_DEVIATION 0.6 | 22.7 kg/m^2 STANDARD_DEVIATION 0.5 | 22.7 kg/m^2 STANDARD_DEVIATION 0.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 7 | 6 / 7 | 2 / 10 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 0 / 10 |
Outcome results
Primary
Change in Adiposity
Total fat mass (excluding head) from baseline to Day 28
Time frame: Baseline to Day 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Change in Adiposity | Baseline | 11942 grams | Standard Deviation 3635 |
| Olanzapine | Change in Adiposity | Day 28 | 13312 grams | Standard Deviation 4246 |
| Iloperidone | Change in Adiposity | Baseline | 14741 grams | Standard Deviation 7349 |
| Iloperidone | Change in Adiposity | Day 28 | 16366 grams | Standard Deviation 6857 |
| Placebo | Change in Adiposity | Baseline | 11690 grams | Standard Deviation 5469 |
| Placebo | Change in Adiposity | Day 28 | 12081 grams | Standard Deviation 4649 |
Primary
Change in Body Weight
Delineate a pathophysiological mechanism of antipsychotic induced weight gain
Time frame: baseline and 6 week visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Change in Body Weight | 3.2 kg | Standard Deviation 1 |
| Iloperidone | Change in Body Weight | 0.8 kg | Standard Deviation 0.7 |
| Placebo | Change in Body Weight | 0.4 kg | Standard Deviation 0.5 |
Secondary
Change in Leptin
Leptin levels measured at Day 3 compared to baseline
Time frame: change in baseline to Day 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Change in Leptin | 2.47 ng/dL | Standard Deviation 1.17 |
| Iloperidone | Change in Leptin | 1.76 ng/dL | Standard Deviation 0.8 |
| Placebo | Change in Leptin | 1.16 ng/dL | Standard Deviation 1.15 |
Other Pre-specified
Change Glucose in People Taking Olanzapine or Iloperidone
To quantify, prospectively, change in glucose from baseline to Day 28
Time frame: Baseline to study termination (about 12 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Change Glucose in People Taking Olanzapine or Iloperidone | Day 28 | 11276.43 mg/dL | Standard Deviation 1231.773 |
| Olanzapine | Change Glucose in People Taking Olanzapine or Iloperidone | Baseline | 11500.71 mg/dL | Standard Deviation 2721.448 |
| Iloperidone | Change Glucose in People Taking Olanzapine or Iloperidone | Day 28 | 13975 mg/dL | Standard Deviation 3813.754 |
| Iloperidone | Change Glucose in People Taking Olanzapine or Iloperidone | Baseline | 14430 mg/dL | Standard Deviation 2148.776 |
| Placebo | Change Glucose in People Taking Olanzapine or Iloperidone | Baseline | 10925.5 mg/dL | Standard Deviation 1134.236 |
| Placebo | Change Glucose in People Taking Olanzapine or Iloperidone | Day 28 | 12179.5 mg/dL | Standard Deviation 1252.944 |
Other Pre-specified
Change in Food Intake
Total grams of food consumed
Time frame: Baseline to Day 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Change in Food Intake | Day 28 | 1198.4071 grams | Standard Deviation 303.15123 |
| Olanzapine | Change in Food Intake | Baseline | 1101.7715 grams | Standard Deviation 288.60787 |
| Iloperidone | Change in Food Intake | Day 28 | 1154.1286 grams | Standard Deviation 686.19597 |
| Iloperidone | Change in Food Intake | Baseline | 1196.6557 grams | Standard Deviation 527.22574 |
| Placebo | Change in Food Intake | Baseline | 1567.526 grams | Standard Deviation 608.53519 |
| Placebo | Change in Food Intake | Day 28 | 1458.108 grams | Standard Deviation 731.06392 |
Other Pre-specified
Change in Insulin
Change in Insulin levels from baseline to Day 28
Time frame: Baseline to Day 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Change in Insulin | Baseline | 9.7749 mlU/L | Standard Deviation 3.42727 |
| Olanzapine | Change in Insulin | Day 28 | 12.0862 mlU/L | Standard Deviation 7.39234 |
| Iloperidone | Change in Insulin | Baseline | 9.9316 mlU/L | Standard Deviation 2.29266 |
| Iloperidone | Change in Insulin | Day 28 | 10.873 mlU/L | Standard Deviation 5.9051 |
| Placebo | Change in Insulin | Baseline | 10.9619 mlU/L | Standard Deviation 2.66812 |
| Placebo | Change in Insulin | Day 28 | 10.785 mlU/L | Standard Deviation 2.62637 |
Other Pre-specified
Change in Lipid Metabolism
Change in lipid metabolism as measured by cholesterol/HDL ratio
Time frame: Baseline to Day 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Change in Lipid Metabolism | Day 28 | 3.14 ratio | Standard Deviation 1.069 |
| Olanzapine | Change in Lipid Metabolism | Baseline | 2.71 ratio | Standard Deviation 0.756 |
| Iloperidone | Change in Lipid Metabolism | Baseline | 2.57 ratio | Standard Deviation 0.787 |
| Iloperidone | Change in Lipid Metabolism | Day 28 | 2.57 ratio | Standard Deviation 0.787 |
| Placebo | Change in Lipid Metabolism | Baseline | 2.7 ratio | Standard Deviation 0.483 |
| Placebo | Change in Lipid Metabolism | Day 28 | 2.5 ratio | Standard Deviation 0.527 |
Other Pre-specified
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.
Time frame: Baseline to Day 28
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine | Insulin Resistance | Baseline | 2.0477 HOMA-IR score | Standard Deviation 0.70188 |
| Olanzapine | Insulin Resistance | Day 28 | 2.6147 HOMA-IR score | Standard Deviation 1.78901 |
| Iloperidone | Insulin Resistance | Baseline | 2.0661 HOMA-IR score | Standard Deviation 0.56517 |
| Iloperidone | Insulin Resistance | Day 28 | 2.4733 HOMA-IR score | Standard Deviation 1.60855 |
| Placebo | Insulin Resistance | Baseline | 2.2988 HOMA-IR score | Standard Deviation 0.52346 |
| Placebo | Insulin Resistance | Day 28 | 2.3362 HOMA-IR score | Standard Deviation 0.68093 |