Hyperglycemia, Hyperlipidemia
Conditions
Keywords
healthy, sedentary, men, acute effects of antipsychotic, blood sugar, insulin sensitivity
Brief summary
Primary Aim: To test the acute effects of olanzapine or ziprasidone administration, in comparison to placebo, on insulin sensitivity in antipsychotic-naïve healthy young men, measured as whole-body dextrose infusion rates (mg/kg/min), hepatic glucose production (glucose rate of appearance \[Ra\]), primarily muscle glucose utilization (glucose rate of disappearance \[Rd\]), and adipose tissue related free fatty acid production (glycerol rate of appearance \[Ra\]). We hypothesize that olanzapine, but not ziprasidone, will result in acute decreases in insulin sensitivity. Secondary Aim: To test the acute effects of olanzapine or ziprasidone on insulin signaling pathways in antipsychotic naïve healthy young men. We hypothesize that olanzapine, but not ziprasidone, will result in acute alterations in insulin signaling.
Detailed description
See brief description
Interventions
DRUGOlanzapine
olanzapine/Zyprexa
DRUGZiprasidone
ziprasidone/Geodon
Sponsors
Washington University School of Medicine
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Males aged 18-45 years * BMI approximately ≥ 25 and \< 35 * insulin approximately ≥ 15 µU/ml or triglyceride approximately ≥ 130 mg/dl
Exclusion criteria
* Any DSM-IV Axis I diagnosis * prisoners * any serious medical disorder (i.e. metabolic diseases, type 1 or 2 diabetes mellitus, endocrine disease, coagulopathy, clinically significant anemia, acute infection) * taking prescription medications * non-sedentary lifestyle with \> 3 hours of exercise per week
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Whole Body Insulin Sensitivity | approximately 3 hours | To evaluate, using a within-subject placebo-controlled comparison, the acute effects of olanzapine or ziprasidone administration on insulin sensitivity in antipsychotic-naïve healthy young men, measured as whole-body dextrose infusion rates (mg/kg/min). |
| Hepatic Insulin Sensitivity | approximately 3 hours | To evaluate, using a within-subject placebo-controlled comparison, the acute effects of olanzapine or ziprasidone administration on insulin sensitivity in antipsychotic-naïve healthy young men, measured as hepatic glucose production (glucose rate of appearance \[Ra\]). |
| Peripheral Insulin Sensitivity | approximately 3 hours | To evaluate, using a within-subject placebo-controlled comparison, the acute effects of olanzapine or ziprasidone administration on insulin sensitivity in antipsychotic-naïve healthy young men, measured as primarily muscle glucose utilization (glucose rate of disappearance \[Rd\]). |
| Adipose Tissue Insulin Sensitivity | approximately 3 hours | To evaluate, using a within-subject placebo-controlled comparison, the acute effects of olanzapine or ziprasidone administration on insulin sensitivity in antipsychotic-naïve healthy young men, measured as free fatty acid release (glycerol rate of appearance \[Ra\]). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJohn W Newcomer, MD
Washington University School of Medicine and Florida Atlantic University
PRINCIPAL_INVESTIGATORGinger Nicol, MD
Washington University School of Medicine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Olanzapine (Drug First) Subjects from this group received an olanzapine injection at the first clamp followed by a saline injection at the second clamp. | 16 |
| Ziprasidone (Drug First) Subjects from this group received a ziprasidone injection at the first clamp followed by a saline injection at the second clamp. | 16 |
| Olanzapine (Placebo First) Subjects from this group received a saline injection at the first clamp followed by an olanzapine injection at the second clamp. | 8 |
| Ziprasidone (Placebo First) Subjects from this group received a saline injection at the first clamp followed by a ziprasidone injection at the second clamp. | 6 |
| Total | 46 |
Baseline characteristics
| Characteristic | Total | Olanzapine (Drug First) | Ziprasidone (Drug First) | Olanzapine (Placebo First) | Ziprasidone (Placebo First) |
|---|---|---|---|---|---|
| Age, Continuous | 33.1 years STANDARD_DEVIATION 8.6 | 34.5 years STANDARD_DEVIATION 9.1 | 32.9 years STANDARD_DEVIATION 9 | 37.0 years STANDARD_DEVIATION 5.6 | 29.7 years STANDARD_DEVIATION 8.7 |
| Body Mass Index (BMI) | 30.69 kg/m^2 STANDARD_DEVIATION 2.44 | 29.60 kg/m^2 STANDARD_DEVIATION 2.13 | 30.86 kg/m^2 STANDARD_DEVIATION 2.82 | 33.18 kg/m^2 STANDARD_DEVIATION 1.56 | 30.84 kg/m^2 STANDARD_DEVIATION 1.45 |
| DEXA Total Fat | 27.1 kilograms STANDARD_DEVIATION 6.9 | 25.8 kilograms STANDARD_DEVIATION 7.3 | 27.4 kilograms STANDARD_DEVIATION 8.3 | 32.2 kilograms STANDARD_DEVIATION 5.9 | 27.8 kilograms STANDARD_DEVIATION 5.5 |
| Diastolic Blood Pressure | 78 mmHg STANDARD_DEVIATION 9 | 80 mmHg STANDARD_DEVIATION 8 | 74 mmHg STANDARD_DEVIATION 11 | 81 mmHg STANDARD_DEVIATION 13 | 71 mmHg STANDARD_DEVIATION 10 |
| Fasting Cholesterol | 179.8 mg/dL STANDARD_DEVIATION 36.6 | 193.6 mg/dL STANDARD_DEVIATION 40.3 | 171.9 mg/dL STANDARD_DEVIATION 37.7 | 171.6 mg/dL STANDARD_DEVIATION 32.1 | 175.3 mg/dL STANDARD_DEVIATION 24.2 |
| Fasting HDL Cholesterol | 39.2 mg/dL STANDARD_DEVIATION 13.3 | 42.3 mg/dL STANDARD_DEVIATION 17.1 | 38.9 mg/dL STANDARD_DEVIATION 9.6 | 43.4 mg/dL STANDARD_DEVIATION 11.1 | 29.2 mg/dL STANDARD_DEVIATION 6.5 |
| Fasting Insulin | 16.2 uIU/mL STANDARD_DEVIATION 9.3 | 16.3 uIU/mL STANDARD_DEVIATION 10.8 | 13.4 uIU/mL STANDARD_DEVIATION 5.1 | 21.1 uIU/mL STANDARD_DEVIATION 7.6 | 17.0 uIU/mL STANDARD_DEVIATION 10.4 |
| Fasting LDL Cholesterol | 111.6 mg/dL STANDARD_DEVIATION 30.4 | 117.9 mg/dL STANDARD_DEVIATION 33.5 | 105.2 mg/dL STANDARD_DEVIATION 26.3 | 104.2 mg/dL STANDARD_DEVIATION 38.5 | 116.3 mg/dL STANDARD_DEVIATION 27.2 |
| Fasting Triglycerides | 140.3 mg/dL STANDARD_DEVIATION 57.9 | 152.8 mg/dL STANDARD_DEVIATION 52.4 | 125.9 mg/dL STANDARD_DEVIATION 58.7 | 128.6 mg/dL STANDARD_DEVIATION 79.3 | 171.0 mg/dL STANDARD_DEVIATION 55.2 |
| Heart Rate | 67 beats per minute STANDARD_DEVIATION 11 | 67 beats per minute STANDARD_DEVIATION 12 | 71 beats per minute STANDARD_DEVIATION 11 | 57 beats per minute STANDARD_DEVIATION 5 | 66 beats per minute STANDARD_DEVIATION 7 |
| Race/Ethnicity, Customized African American | 18 participants | 7 participants | 5 participants | 4 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Caucasian | 17 participants | 5 participants | 7 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Native American | 2 participants | 1 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 46 Participants | 16 Participants | 16 Participants | 8 Participants | 6 Participants |
| Sex/Gender, Customized Female | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Sex/Gender, Customized Male | 37 participants | 14 participants | 12 participants | 5 participants | 6 participants |
| Systolic Blood Pressure | 130 mmHg STANDARD_DEVIATION 10 | 130 mmHg STANDARD_DEVIATION 9 | 127 mmHg STANDARD_DEVIATION 9 | 135 mmHg STANDARD_DEVIATION 14 | 130 mmHg STANDARD_DEVIATION 10 |
| Waist Circumference | 104.9 centimeters STANDARD_DEVIATION 9.7 | 102.0 centimeters STANDARD_DEVIATION 8.3 | 104.3 centimeters STANDARD_DEVIATION 10.7 | 111.4 centimeters STANDARD_DEVIATION 4.2 | 106.2 centimeters STANDARD_DEVIATION 8.7 |
| Weight | 98.0 kilograms STANDARD_DEVIATION 11.4 | 94.6 kilograms STANDARD_DEVIATION 10.9 | 96.7 kilograms STANDARD_DEVIATION 10.7 | 113.1 kilograms STANDARD_DEVIATION 9.4 | 96.2 kilograms STANDARD_DEVIATION 6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| other Total, other adverse events | 12 / — | 12 / — | 63 / — | 82 / — | 72 / — | 88 / — | 12 / — | 10 / — |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 5 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Adipose Tissue Insulin Sensitivity
To evaluate, using a within-subject placebo-controlled comparison, the acute effects of olanzapine or ziprasidone administration on insulin sensitivity in antipsychotic-naïve healthy young men, measured as free fatty acid release (glycerol rate of appearance \[Ra\]).
Time frame: approximately 3 hours
Population: The analysis was per protocol and involved subjects who completed both a clamp that involved an injection of either olanzapine or ziprasidone, and a clamp that involved a placebo injection. Nine subjects did not complete a second clamp as they were lost to follow-up. This resulted in the analysis of 37 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine (Drug/Placebo)-Drug | Adipose Tissue Insulin Sensitivity | 43.3 % change from basal to insulin phase | Standard Deviation 13.2 |
| Olanzapine (Drug/Placebo)-Placebo | Adipose Tissue Insulin Sensitivity | 45.2 % change from basal to insulin phase | Standard Deviation 15.8 |
| Olanzapine (Placebo/Drug)-Placebo | Adipose Tissue Insulin Sensitivity | 52.8 % change from basal to insulin phase | Standard Deviation 13.8 |
| Olanzapine (Placebo/Drug)-Drug | Adipose Tissue Insulin Sensitivity | 53.1 % change from basal to insulin phase | Standard Deviation 14.4 |
| Ziprasidone (Placebo/Drug)-Placebo | Adipose Tissue Insulin Sensitivity | 39.5 % change from basal to insulin phase | Standard Deviation 14.6 |
| Ziprasidone (Placebo/Drug)-Drug | Adipose Tissue Insulin Sensitivity | 37.6 % change from basal to insulin phase | Standard Deviation 8.9 |
| Ziprasidone (Drug/Placebo)-Drug | Adipose Tissue Insulin Sensitivity | 47.8 % change from basal to insulin phase | Standard Deviation 11.7 |
| Ziprasidone (Drug/Placebo)-Placebo | Adipose Tissue Insulin Sensitivity | 44.4 % change from basal to insulin phase | Standard Deviation 12.1 |
Comparison: The null hypothesis is that olanzapine and ziprasidone would result in acute decreases in insulin sensitivity compared to placebo at adipose tissue, which was measured by evaluating the rate of appearance of labeled glycerol. The alternative hypothesis is that olanzapine, but not ziprasidone, would result in acute decreases in insulin sensitivity compared to placebo at adipose tissue.p-value: 0.57ANCOVA
Primary
Hepatic Insulin Sensitivity
To evaluate, using a within-subject placebo-controlled comparison, the acute effects of olanzapine or ziprasidone administration on insulin sensitivity in antipsychotic-naïve healthy young men, measured as hepatic glucose production (glucose rate of appearance \[Ra\]).
Time frame: approximately 3 hours
Population: The analysis was per protocol and involved subjects who completed both a clamp that involved an injection of either olanzapine or ziprasidone, and a clamp that involved a placebo injection. Nine subjects did not complete a second clamp as they were lost to follow-up. This resulted in the analysis of 37 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine (Drug/Placebo)-Drug | Hepatic Insulin Sensitivity | 81.0 % change from basal to insulin phase | Standard Deviation 9.4 |
| Olanzapine (Drug/Placebo)-Placebo | Hepatic Insulin Sensitivity | 79.1 % change from basal to insulin phase | Standard Deviation 6.1 |
| Olanzapine (Placebo/Drug)-Placebo | Hepatic Insulin Sensitivity | 73.1 % change from basal to insulin phase | Standard Deviation 16.2 |
| Olanzapine (Placebo/Drug)-Drug | Hepatic Insulin Sensitivity | 78.5 % change from basal to insulin phase | Standard Deviation 8.1 |
| Ziprasidone (Placebo/Drug)-Placebo | Hepatic Insulin Sensitivity | 84.0 % change from basal to insulin phase | Standard Deviation 13.5 |
| Ziprasidone (Placebo/Drug)-Drug | Hepatic Insulin Sensitivity | 80.7 % change from basal to insulin phase | Standard Deviation 8.5 |
| Ziprasidone (Drug/Placebo)-Drug | Hepatic Insulin Sensitivity | 82.1 % change from basal to insulin phase | Standard Deviation 8.6 |
| Ziprasidone (Drug/Placebo)-Placebo | Hepatic Insulin Sensitivity | 83.4 % change from basal to insulin phase | Standard Deviation 6.8 |
Primary
Peripheral Insulin Sensitivity
To evaluate, using a within-subject placebo-controlled comparison, the acute effects of olanzapine or ziprasidone administration on insulin sensitivity in antipsychotic-naïve healthy young men, measured as primarily muscle glucose utilization (glucose rate of disappearance \[Rd\]).
Time frame: approximately 3 hours
Population: The analysis was per protocol and involved subjects who completed both a clamp that involved an injection of either olanzapine or ziprasidone, and a clamp that involved a placebo injection. Nine subjects did not complete a second clamp as they were lost to follow-up. This resulted in the analysis of 37 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine (Drug/Placebo)-Drug | Peripheral Insulin Sensitivity | 152.2 % change from basal to insulin phase | Standard Deviation 88 |
| Olanzapine (Drug/Placebo)-Placebo | Peripheral Insulin Sensitivity | 183.5 % change from basal to insulin phase | Standard Deviation 130.7 |
| Olanzapine (Placebo/Drug)-Placebo | Peripheral Insulin Sensitivity | 157.0 % change from basal to insulin phase | Standard Deviation 72.2 |
| Olanzapine (Placebo/Drug)-Drug | Peripheral Insulin Sensitivity | 83.7 % change from basal to insulin phase | Standard Deviation 60.5 |
| Ziprasidone (Placebo/Drug)-Placebo | Peripheral Insulin Sensitivity | 208.2 % change from basal to insulin phase | Standard Deviation 96 |
| Ziprasidone (Placebo/Drug)-Drug | Peripheral Insulin Sensitivity | 161.0 % change from basal to insulin phase | Standard Deviation 85 |
| Ziprasidone (Drug/Placebo)-Drug | Peripheral Insulin Sensitivity | 135.6 % change from basal to insulin phase | Standard Deviation 128.4 |
| Ziprasidone (Drug/Placebo)-Placebo | Peripheral Insulin Sensitivity | 185.3 % change from basal to insulin phase | Standard Deviation 136.5 |
Primary
Whole Body Insulin Sensitivity
To evaluate, using a within-subject placebo-controlled comparison, the acute effects of olanzapine or ziprasidone administration on insulin sensitivity in antipsychotic-naïve healthy young men, measured as whole-body dextrose infusion rates (mg/kg/min).
Time frame: approximately 3 hours
Population: The analysis was per protocol and involved subjects who completed both a clamp that involved an injection of either olanzapine or ziprasidone, and a clamp that involved a placebo injection. Nine subjects did not complete a second clamp as they were lost to follow-up. This resulted in the analysis of 37 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine (Drug/Placebo)-Drug | Whole Body Insulin Sensitivity | 4.9 mg/kg/min | Standard Deviation 2.2 |
| Olanzapine (Drug/Placebo)-Placebo | Whole Body Insulin Sensitivity | 5.4 mg/kg/min | Standard Deviation 2.6 |
| Olanzapine (Placebo/Drug)-Placebo | Whole Body Insulin Sensitivity | 4.1 mg/kg/min | Standard Deviation 1.2 |
| Olanzapine (Placebo/Drug)-Drug | Whole Body Insulin Sensitivity | 2.9 mg/kg/min | Standard Deviation 1 |
| Ziprasidone (Placebo/Drug)-Placebo | Whole Body Insulin Sensitivity | 5.8 mg/kg/min | Standard Deviation 2.2 |
| Ziprasidone (Placebo/Drug)-Drug | Whole Body Insulin Sensitivity | 4.7 mg/kg/min | Standard Deviation 1.8 |
| Ziprasidone (Drug/Placebo)-Drug | Whole Body Insulin Sensitivity | 4.5 mg/kg/min | Standard Deviation 3.1 |
| Ziprasidone (Drug/Placebo)-Placebo | Whole Body Insulin Sensitivity | 5.3 mg/kg/min | Standard Deviation 3.3 |
Comparison: The hypothesis being tested is whether there is a significant effect of one or both antipsychotics on whole body insulin sensitivity. Sample size was calculated using power calculations to detect significant effects of treatment on insulin sensitivity. Drug assignment is a 2-level fixed factor (olanzapine vs ziprasidone) as is order (drug first vs placebo first). Baseline of the dependent variable as well as baseline DEXA total fat were entered into the model as covariates.p-value: 0.001ANCOVA