Effect of Short Term Atypical Antipsychotic Administration Compared to Placebo on Hepatic Insulin Extraction

May 14, 2015 updated by: Michael Rickels

The Effect of Short Term Atypical Antipsychotic Administration Compared to Placebo on Hepatic Insulin Extraction and Muscarinic Mediation of B-Cell Function: A Small Mechanistic, Single-Site Study

Within the past 20 years, there has been a striking increase in the incidence of obesity 1;2, type 2 diabetes mellitus (T2DM) 3-5, and cardiovascular diseases (CVD) in the schizophrenic population 6-8 . Large NIH-funded trials indicate that the prevalence of metabolic syndrome is twice to three times greater in schizophrenic patients on a specific class of drug termed the "atypical antipsychotics" (AAPs), of which olanzapine is an example, as compared to matched controls 8. Identification of the pathophysiological mechanisms contributing to metabolic disease in schizophrenic patients on AAPs has been hampered by the inability to differentiate underlying disease from treatment-emergent complications. In addition, despite falling within the same drug class, different AAPs exhibit differential associations with metabolic disease. Olanzapine is one of the AAPs associated with the greatest weight gain and degree of metabolic impairments.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The increased incidence of T2DM and CVD with the AAPs has been assumed a consequence of weight gain. However, accumulating evidence of weight-independent effects derived from in vitro and rodent studies suggests a direct effect of some AAPs on the pancreatic B-cell and the liver. We have recently completed the first of two studies supported by an NIH grant which provides evidence for a direct effect of olanzapine on metabolism, independent of weight gain or psychiatric disease. Findings from the first study indicate that short-term administration (9-days) of olanzapine compared to aripiprazole, another AAP as well as placebo dramatically increases post-prandial insulin levels in healthy control subjects independent of weight gain; providing evidence of tissue specific effects of the drug in humans. We also found that the increase in insulin was not accompanied by an increase in plasma C-peptide concentrations suggesting that olanzapine may decrease hepatic insulin extraction. Decreases in hepatic insulin extraction can be mediated through muscarinic blockade and in fact, data from our laboratory demonstrates that atropine (the muscarinic antagonist) inhibits hepatic insulin extraction in humans. Blockade of muscarinic receptors is consistent with the receptor binding profile of olanzapine which shows a higher receptor antagonism for muscarinic receptors compared to other AAPs. In addition, we also found significant increases in glucagon-like peptide 1 (GLP-1) and decreases in insulin sensitivity following olanzapine administration compared to aripiprazole and placebo. The proposed study follows up on these findings with a study designed to investigate the mechanisms contributing to the olanzapine-induced post-prandial hyperinsulinemia and GLP-1. The overall hypothesis of this study is that olanzapine blocks peripheral muscarinic receptors, leading to a compensatory increase in vagal efferent activation which contributes to an increase in insulin secretion.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
15

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 40 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Men and women ages 18-40
  2. BMI 19-24.5kg/m2
  3. Systolic BP <130mm Hg
  4. Diastolic BP <85mm Hg
  5. Subjects capable of giving informed consent, with no past or present psychiatric history
  6. Only women on oral contraceptives with constant dosing regimens or Depo-Provera for >3 months, to ensure uniform hormonal delivery throughout the study duration
  7. No medications except as above noted
  8. Weight stable
  9. Minimal exercise regime that includes walking, running or biking

Exclusion Criteria:

  1. History of heart disease, colitis, autonomic neuropathy, hepatic or renal disease
  2. DSM-IV diagnosis of past or present psychiatric history, including clinically significant depression
  3. Drug/Alcohol dependence, homelessness, or inability to give informed consent
  4. History of asthma, congenital obstructive bladder, peptic ulcer, vasomotor instability, epilepsy, Parkinsonism, elevated thyroid hormone levels
  5. Diagnosis of diabetes
  6. BMI>25 kg/m2
  7. Prescription medication (excluding the contraceptive methods described above)
  8. Hemoglobin <11
  9. Abnormal laboratory tests which are clinically significant per the investigator
  10. Females pregnant or lactating
  11. Females: not taking hormonal contraceptives; taking hormonal contraceptives of varying dosage throughout the month
  12. Currently on a weight loss diet
  13. Moderate to significant exercise regime that includes swimming, weight lifting or other form of exercise not reproducible within CTRC.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Olanzapine
Olanzapine administration
Drug: Olanzapine
Olanzapine is approved for the treatment of schizophrenia and mania associated with bipolar disorder. Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-4methyl-1 piperazinyl-10H-thienol (2,3-b)[1,5]benzodiazepine. The molecular formula is C17H20N4S which corresponds to a molecular weight of 312.44.Olanzpine is a yellow crystalline solid which is practically insoluble in water. Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors:5HT2A2C, 5HT6, dopamine 2-4, histamine H1, and adrenergic α-1. In addition olanzapine is an antagonist with moderate affinity for muscarinic M1-5 and 5HT3. The mechanism of action of olanzapine is unknown although it may be mediated through a combination of dopamine and serotonergic type 2 receptors.
Other Names:
  • Zyprexa
Placebo Comparator: Placebo
Placebo administration
Drug: Olanzapine
Olanzapine is approved for the treatment of schizophrenia and mania associated with bipolar disorder. Olanzapine is a psychotropic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-4methyl-1 piperazinyl-10H-thienol (2,3-b)[1,5]benzodiazepine. The molecular formula is C17H20N4S which corresponds to a molecular weight of 312.44.Olanzpine is a yellow crystalline solid which is practically insoluble in water. Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors:5HT2A2C, 5HT6, dopamine 2-4, histamine H1, and adrenergic α-1. In addition olanzapine is an antagonist with moderate affinity for muscarinic M1-5 and 5HT3. The mechanism of action of olanzapine is unknown although it may be mediated through a combination of dopamine and serotonergic type 2 receptors.
Other Names:
  • Zyprexa

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Determine the vagal contribution to the olanzapine-induced increase in circulating insulin levels.
Time Frame: 12 days
12 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Determine if olanzapine increases meal-related/satiety peptides
Time Frame: 12 days
12 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Michael Rickels

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of Pennsylvania

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 1, 2012

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2014

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2014

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 25, 2012

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 14, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 19, 2015

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 19, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 14, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 815905

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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