Examining the Effects of Antipsychotic Medications on Insulin Sensitivity

• Sponsor: Veterans Medical Research Foundation (Other)
• Overall Status: Completed
• CT.gov ID: NCT00895921
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 19
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

This study will examine the effects of two different antipsychotic medications on control of blood sugar in people who are at risk of diabetes but mentally healthy.

Condition or Disease	Intervention/Treatment	Phase
Diabetes	Drug: Olanzapine; Drug: Aripiprazole	Phase 4

Detailed Description

Antipsychotic medications are those that treat the most severe psychiatric symptoms, such as hallucinations, paranoid thoughts, and delusions. Research shows that some of these medications may put people at a higher risk of metabolic derangements, such as insulin resistance. Certain antipsychotics, like clozapine and olanzapine, are associated with a higher risk of metabolic side effects than others, like aripiprazole and ziprasidone. Because people with schizophrenia may experience adverse side effects from switching antipsychotic medications and because it is difficult to find people with schizophrenia who do not have experience taking antipsychotics, this study will use people without psychiatric disorders who are at risk for diabetes in place of people with schizophrenia. The study will compare the effects of single doses of two antipsychotic medications, olanzapine and aripiprazole, on insulin action in this population. In addition to determining metabolic effects of these medications, this study will also seek to demonstrate the feasibility of using mentally healthy people at risk of diabetes as a substitute for people with schizophrenia in studying these effects.

Participation in this study will last 4 weeks. Participants will first complete a screening visit that will include the following: an oral glucose tolerance test (OGTT), which involves a blood draw, consumption of a sugar drink, and then a second blood draw; a review of medical and psychiatric history, including use of medicines and psychiatric medications; and measurement of participants' height and weight. The second visit, scheduled 2 weeks after screening, will include a tracer-clamp study to test how participants' bodies handle sugar. The tracer-clamp study will be conducted over the course of one night and morning and will require participants to stay at the study location overnight. At 3 AM, participants will receive an intravenous line (IV) with a sugar solution. Just before 8 AM, they will receive a second IV in the opposite arm that will draw blood and monitor blood sugar levels.

At 8 AM, participants will begin receiving insulin in the first IV; blood samples will be drawn and blood sugar levels will be monitored during this time to ensure they remain within a healthy range. At 11 AM, participants will receive an injection of an antipsychotic medication into their arm muscles. The antipsychotic, which will be randomly assigned, will be either olanzapine or aripiprazole. Participants will be monitored for 3 hours after receiving the injection of antipsychotic medication; during this time, more blood samples will be drawn, blood sugar levels will be monitored to ensure they are within a healthy range, and secondary medications will be available to counteract certain side effects of the antipsychotics. After 2 more weeks, participants will undergo a third study visit in which they repeat the OGTT.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Acute Impact of Antipsychotics on Insulin Sensitivity: A Novel Human Model
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Aripiprazole Participants will receive an injection of aripiprazole during the tracer-clamp study.	Drug: Aripiprazole; Single intramuscular 9.75-mg dose; Other Names: Abilify
Active Comparator: Olanzapine Participants will receive an injection of olanzapine during the tracer-clamp study.	Drug: Olanzapine; Single intramuscular 10-mg dose; Other Names: Zyprexa

Outcome Measures

Primary Outcome Measures

1. Change in Glucose Disposition [Measured over 6 hours]

   Ratio of post-antipsychotic/pre-antipsychotic glucose disposition as measured using the hyperglycemic clamp technique. This method allows one to measure either how well an individual metabolizes glucose or how sensitive an individual is to insulin.

Secondary Outcome Measures

1. Change in Percent of Insulin Suppression of Endogenous Glucose Production [Measured over 6 hours]

   Ratio of Post-Antipsychotic/Pre-Antipsychotic Percent of Insulin Suppression of Endogenous Glucose Production

2. Akathisia [6 hours]

   Number of subjects reporting mild or greater complaints of akathisia after antipsychotic administration

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 65 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Prediabetic, defined as 2-hour post-load serum glucose between 140 and 199 mg/dl on a 75-gram standard oral glucose tolerance test (OGTT) within the past 90 days

• Family history of type 2 diabetes mellitus

• Body mass index (BMI) between 25 and 35 kg/m2

• English speaker

• Nonsmoker

Exclusion Criteria:

• History of Axis I mood, anxiety, or psychotic disorder, confirmed by Structured Clinical Interview for DSM-IV

• Use of psychotropic drugs

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA San Diego Healthcare System	San Diego	California	United States	92161

Sponsors and Collaborators

• Veterans Medical Research Foundation
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Jonathan M. Meyer, MD, UCSD and Veterans Affairs San Diego

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jonathan M. Meyer, MD, Research Scientist, Veterans Medical Research Foundation
• ClinicalTrials.gov Identifier: NCT00895921
• Other Study ID Numbers: R21MH082805; R21MH082805; DATR A5-ETSE; 071224
• First Posted: May 8, 2009
• Last Update Posted: Aug 11, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Jonathan M. Meyer, MD, Research Scientist, Veterans Medical Research Foundation: Insulin Resistance; Antipsychotic Medications
• Additional relevant MeSH terms: Insulin Resistance; Olanzapine; Aripiprazole

Study Results

Participant Flow

Arm/Group Title	Aripiprazole	Olanzapine
Arm/Group Description	Participants will receive an injection of aripiprazole during the trace-clamp study. Aripiprazole: Single intramuscular 9.75-mg dose	Participants will receive an injection of olanzapine during the trace-clamp study. Olanzapine: Single intramuscular 10-mg dose
Period Title: Overall Study
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Aripiprazole	Olanzapine	Total
Arm/Group Description	Participants will receive an injection of aripiprazole during the tracer-clamp study. Aripiprazole: Single intramuscular 9.75-mg dose	Participants will receive an injection of olanzapine during the tracer-clamp study. Olanzapine: Single intramuscular 10-mg dose	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.9 (5.57)	54.4 (5.97)	51.17 (5.77)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	15 100%	15 100%	30 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 13.3%	3 20%	5 16.7%
Not Hispanic or Latino	13 86.7%	12 80%	25 83.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 26.7%	3 20%	7 23.3%
White	11 73.3%	12 80%	23 76.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	15 100%	15 100%	30 100%
Glucose Disposition (mg/kg/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/kg/min]	3.88 (1.99)	3.31 (1.35)	3.60 (1.67)
Insulin Suppression of Endogenous Glucose Production (EGP) (% suppression of EGP) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% suppression of EGP]	84.28 (20.30)	86.52 (22.34)	85.40 (21.32)

Outcome Measures

1. Primary Outcome

Title	Change in Glucose Disposition
Description	Ratio of post-antipsychotic/pre-antipsychotic glucose disposition as measured using the hyperglycemic clamp technique. This method allows one to measure either how well an individual metabolizes glucose or how sensitive an individual is to insulin.
Time Frame	Measured over 6 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aripiprazole	Olanzapine
Arm/Group Description	Participants will receive an injection of aripiprazole during the tracer-clamp study. Aripiprazole: Single intramuscular 9.75-mg dose	Participants will receive an injection of olanzapine during the tracer-clamp study. Olanzapine: Single intramuscular 10-mg dose
Measure Participants	15	15
Mean (Standard Deviation) [ratio of post/pre values]	1.18 (.324)	1.42 (.300)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.042
	Comments	The a priori threshold for statistical significance is <0.05.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	.242
	Confidence Interval	(2-Sided) 95%; .00943 to .47605
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .1139
	Estimation Comments

2. Secondary Outcome

Title	Change in Percent of Insulin Suppression of Endogenous Glucose Production
Description	Ratio of Post-Antipsychotic/Pre-Antipsychotic Percent of Insulin Suppression of Endogenous Glucose Production
Time Frame	Measured over 6 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aripiprazole	Olanzapine
Arm/Group Description	Participants will receive an injection of aripiprazole during the tracer-clamp study. Aripiprazole: Single intramuscular 9.75-mg dose	Participants will receive an injection of olanzapine during the tracer-clamp study. Olanzapine: Single intramuscular 10-mg dose
Measure Participants	15	15
Mean (Standard Deviation) [ratio of post/pre values]	1.0594 (.519)	1.312 (.642)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Olanzapine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.269
	Comments	The a priori threshold for statistical significance was < 0.05.
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	.253
	Confidence Interval	(2-Sided) 95%; -0.208 to 0.714
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.224
	Estimation Comments

3. Secondary Outcome

Title	Akathisia
Description	Number of subjects reporting mild or greater complaints of akathisia after antipsychotic administration
Time Frame	6 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aripiprazole	Olanzapine
Arm/Group Description	Participants will receive an injection of aripiprazole during the tracer-clamp study. Aripiprazole: Single intramuscular 9.75-mg dose	Participants will receive an injection of olanzapine during the tracer-clamp study. Olanzapine: Single intramuscular 10-mg dose
Measure Participants	15	15
Number [participants]	1 6.7%	7 46.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aripiprazole, Olanzapine
	Comments	Comparison of akathisia rates between the two arms.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	Chi-squared, Corrected
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.400
	Confidence Interval	(2-Sided) 95%; .095 to .705
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.149
	Estimation Comments

Adverse Events

Time Frame	1 day
Arm/Group Title	Aripiprazole		Olanzapine
Arm/Group Description	Participants will receive an injection of aripiprazole during the tracer-clamp study. Aripiprazole: Single intramuscular 9.75-mg dose		Participants will receive an injection of olanzapine during the tracer-clamp study. Olanzapine: Single intramuscular 10-mg dose
All Cause Mortality
	Aripiprazole		Olanzapine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Aripiprazole		Olanzapine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Aripiprazole		Olanzapine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		7/15 (46.7%)
Psychiatric disorders
Akathisia	1/15 (6.7%)	1	7/15 (46.7%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.