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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Normal Non-fluency

Intervention / Treatment
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* Drug: Olanzapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ages 18-40 BMI 19-24.5kg/m2 Systolic BP <130mm Hg Diastolic BP <85mm Hg Subjects capable of giving informed consent, with no past or present psychiatric history Only women on oral contraceptives with constant dosing regimens or Depo-Provera for >3 months, to ensure uniform hormonal delivery throughout the study duration No medications except as above noted Weight stable Minimal exercise regime that includes walking, running or biking Exclusion Criteria: History of heart disease, colitis, autonomic neuropathy, hepatic or renal disease DSM-IV diagnosis of past or present psychiatric history, including clinically significant depression Drug/Alcohol dependence, homelessness, or inability to give informed consent History of asthma, congenital obstructive bladder, peptic ulcer, vasomotor instability, epilepsy, Parkinsonism, elevated thyroid hormone levels Diagnosis of diabetes BMI>25 kg/m2 Prescription medication (excluding the contraceptive methods described above) Hemoglobin <11 Abnormal laboratory tests which are clinically significant per the investigator Females pregnant or lactating Females: not taking hormonal contraceptives; taking hormonal contraceptives of varying dosage throughout the month Currently on a weight loss diet Moderate to significant exercise regime that includes swimming, weight lifting or other form of exercise not reproducible within CTRC.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Olanzapine<br>Olanzapine administration | Drug: Olanzapine<br>* 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.<br>* Other names: Zyprexa;|
| Placebo Comparator: Placebo<br>Placebo administration | Drug: Olanzapine<br>* 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.<br>* Other names: Zyprexa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the vagal contribution to the olanzapine-induced increase in circulating insulin levels. |  | 12 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine if olanzapine increases meal-related/satiety peptides |  | 12 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolic Disorders