Effect of Atypical Antipsychotic Drugs Olanzapine and Amisulpride on Glucose Metabolism

Effects of the Serotonin 2A Receptor on Insulin Sensitivity and Secretion: a Double-blind Controlled Comparison of Olanzapine vs. Amisulpride:

Patients suffering from schizophrenia have a high risk to become obese and develop diabetes. Risk of obesity is particularly high with some newer schizophrenia drugs, such as clozapine or olanzapine. These drugs are called atypical drugs and exert their action in part by occupying receptors for serotonin, particularly the 5HT2A receptor subtype. This receptor may also interfere with glucose metabolism and insulin action. The purpose of this study is to compare an atypical antipsychotic drugs, olanzapine, which acts by occupying the 5HT2A receptor, to another antipsychotic drug, amisulpride, which mainly acts through the dopamine pathway. Healthy volunteers are recruited and asked to take a single dose of each drug and of placebo on separate days. Then, a combined glucose clamp study will be performed in order to test the effects of these drugs on insulin sensitivity and insulin secretion.

Study Overview

• Status: Completed
• Conditions: Diabetes; Schizophrenia; Insulin Resistance
• Intervention / Treatment: Procedure: Glucose clamp technique; Drug: Amisulpride; Drug: Olanzapine; Drug: Placebo

Detailed Description

10 male healthy volunteers are recruited. After informed consent, they are admitted to the study ward at 10:00 p.m. prior to the study day and kept fasting until the next morning. At 8:00 a.m. they receive their study medication (olanzapine, amisulpride or placebo). Subsequently, measurements of insulin sensitivity and insulin secretion are performed by euglycemic hyperinsulinemic clamp technique followed by hyperglycemic clamp.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Mannheim, Germany, 68159
    • Central Institute of Mental Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• healthy male volunteers
• written informed consent

Exclusion Criteria:

• BMI > 30 kg/m²
• Diabetes mellitus
• Hypertension
• Treatment with drugs interfering with lipid or glucose metabolism (e.g. statins, oral antidiabetic drugs, glucocorticoids)
• History of seizures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Amisulpride; Single dose of amisulpride 200 mg p.o. given at 8:00 a.m.	Procedure: Glucose clamp technique; euglycemic hyperinsulinemic clamp with target blood glucose of 90 mg/dl (5 mmol/l), followed by hyperglycemic clamp, target blood glucose of 180 mg/dl (10 mmol/l) for measurement of insulin sensitivity and insulin secretion; Drug: Amisulpride; Single dose of amisulpride 200 mg p.o. given at 8:00 a.m.
Experimental: Olanzapine; Single dose of olanzapine 10 mg p.o. given at 8:00 a.m.	Procedure: Glucose clamp technique; euglycemic hyperinsulinemic clamp with target blood glucose of 90 mg/dl (5 mmol/l), followed by hyperglycemic clamp, target blood glucose of 180 mg/dl (10 mmol/l) for measurement of insulin sensitivity and insulin secretion; Drug: Olanzapine; Single dose of olanzapine 10 mg p.o. given at 8:00 a.m.
Placebo Comparator: Placebo; Placebo capsules are given at 8:00 a.m. Procedures are performed as described above.	Procedure: Glucose clamp technique; euglycemic hyperinsulinemic clamp with target blood glucose of 90 mg/dl (5 mmol/l), followed by hyperglycemic clamp, target blood glucose of 180 mg/dl (10 mmol/l) for measurement of insulin sensitivity and insulin secretion; Drug: Placebo; Placebo capsules are given at 8:00 a.m.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin sensitivity	m-value during euglycemic glucose clamp (glucose infusion rate divided by time and body weight)	90 thru 120 min after application of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pancratic c-peptide secretion	C-peptide measured 4 times during hyperglycemic clamp period at time 0 min (prior to glucose bolus), 5 min, 10 min and 60 min after glucose bolus	120 thru 180 minutes after administration of study drug

Collaborators and Investigators

• Sponsor: Central Institute of Mental Health, Mannheim
• Collaborators: Sanofi
• Investigators: Principal Investigator: Daniel Kopf, M.D., Central Institute of Mental Health, Mannheim

Study record dates

Study Major Dates

• Study Start: May 1, 2004
• Primary Completion (Actual): October 1, 2006
• Study Completion (Actual): October 1, 2006

Study Registration Dates

• First Submitted: July 9, 2010
• First Submitted That Met QC Criteria: July 12, 2010
• First Posted (Estimate): July 13, 2010

Study Record Updates

• Last Update Posted (Estimate): August 3, 2010
• Last Update Submitted That Met QC Criteria: August 2, 2010
• Last Verified: August 1, 2010

More Information

Terms related to this study

• Keywords: diabetes; schizophrenia; olanzapine; insulin resistance; insulin secretion; hyperglycemic clamp; glucose; atypical antipsychotic drugs; amisulpride; euglycemic hyperinsulinemic clamp
• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Schizophrenia Spectrum and Other Psychotic Disorders; Hyperinsulinism; Schizophrenia; Insulin Resistance; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agents; Dopamine Antagonists; Antidepressive Agents, Second-Generation; Olanzapine; Amisulpride
• Other Study ID Numbers: DeuOlanAmi

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No