Melatonin Metabolism Abnormality in Patients With Schizophrenia or Schizoaffective Disorder Treated With Olanzapine

Melatonin Metabolism Abnormality in Patients With Schizophrenia or Schizoaffective Disorder Treated With Olanzapine and Melatonin Dose Finding for the Correction of the Metabolic Abnormality

Atypical antipsychotic medications, such as olanzapine, cause metabolic side effects, including weight gain, extra fat around the middle of the body, high blood sugar, and high cholesterol. One of the mechanisms by which these medications may cause these effects is by reducing plasma melatonin. This study is a pilot project to evaluate 1) the effect of olanzapine on melatonin secretion levels and 2) the effect of melatonin on olanzapine-induced changes in melatonin secretion in patients with schizophrenia, schizoaffective, or bipolar disorder.

Study Overview

• Status: Completed
• Conditions: Obesity; Schizophrenia; Schizoaffective Disorder; Metabolic Syndrome; Bipolar Disorder
• Intervention / Treatment: Drug: olanzapine and melatonin

Detailed Description

To investigate the relationship between olanzapine, melatonin, and metabolic functioning, this pilot study is evaluating 20 patients with schizophrenia, schizoaffective disorder, or bipolar disorder over 15 weeks under three experimental conditions: 1) baseline (two weeks treatment with already established antipsychotic medication other than olanzapine or clozapine), 2) six weeks treatment with olanzapine only, and 3) six weeks treatment with olanzapine and melatonin. Half of the patients will receive 0.3 mg of oral melatonin and half will receive 3.0 mg of melatonin. Nocturnal melatonin production, as estimated by assay of urinary 6-sulfatoxymelatonin(aMT6s) adjusted for creatinine, will be measured weekly. In addition, weekly measurements of weight and other metabolic indices, including waist and hip measurements, fasting glucose, serum insulin, cholesterol, triglycerides, and leptin will be taken. It is anticipated that there will be an olanzapine-induced decrease in melatonin production. Furthermore, it is expected that the decrease in melatonin production associated with olanzapine treatment will be reversed by administration of melatonin with olanzapine.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Washington
    • Tacoma, Washington, United States, 98493
      • VA Puget Sound Health Care System

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age 18-65;
2. DSM-IV-TR diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder;
3. Patients who, in the clinical judgment of the investigator, may benefit from a switch to olanzapine;
4. Females must be of non-child bearing potential (i.e., surgically sterilized, or at least one year post-menopausal) or on an appropriate dose of oral/depot contraceptives or using barrier protection and not breast-feeding. Females must have a urine pregnancy test at screening;
5. Willingness and ability to take medications nightly at 10:00 p.m.; and
6. The subject or his/her legal representative must provide informed, written consent.

Exclusion Criteria:

1. Females who are pregnant or lactating;
2. Concurrent participation or participation within the prior 30 days in any study involving investigational medications;
3. Current (within the prior 30 days) diagnosis of substance abuse or dependence;
4. Use of olanzapine within the prior three months;
5. History of allergy or intolerable side-effects to olanzapine in the past;
6. History of significant head trauma, defined as head trauma resulting in loss of consciousness for more than five minutes and/or neurological or cognitive sequelae;
7. Evidence of any clinically relevant disease (e.g., renal or hepatic impairment, significant coronary artery disease, cerebrovascular disease, or cancer) or any clinical finding that in the opinion of the investigator could potentially be negatively affected by study participation or that could potentially affect study participation is criterion for exclusion from the study;
8. Use of fluvoxamine, nifedipine, or warfarin for 30 days prior to Baseline Visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IIA (0.3mg day melatonin); 0.3mg day melatonin	Drug: olanzapine and melatonin; In treatment phase I, all subjects will receive olanzapine, 10-25 mg/day. In treatment phase II, all subjects will receive olanzapine (10-25 mg/day) plus melatonin. Subjects will be randomized at a ratio of 1:1 to receive melatonin, 0.3 mg/day or 3.0 mg/day. Group IIA will receive 0.3mg day melatonin. Group IIB will receive 3.0 mg/day melatonin.; Other Names: Olanzapine (Zyprexa)
Experimental: IIB (3.0 mg/day melatonin); 3.0 mg/day melatonin	Drug: olanzapine and melatonin; In treatment phase I, all subjects will receive olanzapine, 10-25 mg/day. In treatment phase II, all subjects will receive olanzapine (10-25 mg/day) plus melatonin. Subjects will be randomized at a ratio of 1:1 to receive melatonin, 0.3 mg/day or 3.0 mg/day. Group IIA will receive 0.3mg day melatonin. Group IIB will receive 3.0 mg/day melatonin.; Other Names: Olanzapine (Zyprexa)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nocturnal Melatonin Production	Nocturnal melatonin production as estimated by assay of urinary 6-sulfatoxymelatonin (aMT6s) adjusted for creatinine	6 and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight	weight (measured in kilograms)	6 weeks & 12 weeks
Total Cholesterol	Total cholesterol on metabolic blood panel	6 weeks & 12 weeks

Collaborators and Investigators

• Sponsor: Seattle Institute for Biomedical and Clinical Research
• Collaborators: Eli Lilly and Company
• Investigators: Principal Investigator: Amanda E Wood, PhD, VA Puget Sound Health Care System; University of Washington

Publications and helpful links

General Publications

• Raskind MA, Burke BL, Crites NJ, Tapp AM, Rasmussen DD. Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats. Neuropsychopharmacology. 2007 Feb;32(2):284-8. doi: 10.1038/sj.npp.1301093. Epub 2006 May 10.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2007
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): December 1, 2024

Study Registration Dates

• First Submitted: August 3, 2007
• First Submitted That Met QC Criteria: August 6, 2007
• First Posted (Estimated): August 7, 2007

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 11, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: melatonin; obesity; schizophrenia; olanzapine; schizoaffective disorder; bipolar disorder; metabolic syndrome
• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Metabolic Diseases; Glucose Metabolism Disorders; Mood Disorders; Insulin Resistance; Hyperinsulinism; Congenital Abnormalities; Schizophrenia; Psychotic Disorders; Bipolar Disorder; Metabolic Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Central Nervous System Depressants; Neurotransmitter Agents; Membrane Transport Modulators; Tranquilizing Agents; Psychotropic Drugs; Antioxidants; Protective Agents; Neurotransmitter Uptake Inhibitors; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Antipsychotic Agents; Olanzapine; Melatonin
• Other Study ID Numbers: F1D-MC-X302