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

Normal Non-fluency Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02447835
• Other study ID #: 815905
• Status: Completed
• Phase: Phase 1
• First received: October 25, 2012
• Last updated: May 14, 2015
• Start date: August 2012
• Est. completion date: December 2014

Study information

• Verified date: May 2015
• Source: Monell Chemical Senses Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 40 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Normal Non-fluency

Intervention

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 a-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.

Locations

Country	Name	City	State
United States	University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Michael Rickels	University of Pennsylvania

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Determine the vagal contribution to the olanzapine-induced increase in circulating insulin levels.		12 days	No
Secondary	Determine if olanzapine increases meal-related/satiety peptides		12 days	No