Effect of Short Term Atypical Antipsychotic Administration Compared to Placebo on Hepatic Insulin Extraction
Condition: Normal Non-fluency
Study type: Interventional
Phase: Phase 1

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.
    

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.
    

Intervention name(s): Olanzapine
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Zyprexa
Intervention MeSH terms: Olanzapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: Metabolic Disorders