Clinical trial NCT00816907: The Use of Metformin in the Treatment of Antipsychotic-Induced Weight Gain in Schizophrenia (The METS Study)
Official title: Metformin in the Treatment of Antipsychotic-Induced Weight Gain in Schizophrenia (METS) - Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia
Keywords: Schizoaffective Disorder
Lead sponsor: National Institute of Mental Health (NIMH)
Sponsor class: NIH
First posted: 2009-01-05
Enrollment: 146
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will test the usefulness of the medication metformin in treating people with schizophrenia or schizoaffective disorder who are overweight and also taking antipsychotic medications.

Detailed description: Schizophrenia is a chronic mental disorder that is characterized, in part, by psychotic symptoms. Psychotic symptoms include hallucinations and delusions, in which a person has abnormal experiences or beliefs, and are commonly treated with antipsychotic medications. Unfortunately, a side effect of many antipsychotics is unwanted weight gain, which can lead to physical illness. Use of the drug metformin has resulted in weight loss among diabetics. Metformin has also been shown to cause weight loss in preliminary studies of people taking atypical antipsychotics-a newer, second generation of antipsychotic medications. Metformin is currently approved by the Food and Drug Administration to treat only people with diabetes. This study will test the usefulness of prescribing metformin as a second medication to treat people with schizophrenia or schizoaffective disorder who are overweight and taking antipsychotics. The study will also provide important feasibility information for future larger studies.

Participation in this study will last 16 weeks. After undergoing baseline assessments, participants will be randomly assigned to receive either metformin or placebo, both of which will be taken twice daily for the duration of the study. All participants will also receive behavioral therapy that will teach them about reducing their weight through diet and exercise. Participants will undergo assessments at 11 study visits: the first 2 will include screening and baseline testing, the next 2 visits will take place after the first and second weeks of receiving treatment, and the last 7 visits will take place every 2 weeks until the end of the study. Assessments will include measurements of body weight, waist-to-hip ratio, and vital signs; clinical interviews about medication adherence, side effects, and alcohol use; and monthly blood tests to assess levels of lipids, glucose, insulin, and hemoglobin A1c.

Eligibility criteria: Inclusion Criteria:

* Outpatients with a diagnosis of schizophrenia or schizoaffective disorder, as defined by DSM-IV-TR criteria and confirmed by the Structured Clinical Interview for DSM-IV (SCID)
* Duration of illness greater than 1 year, as defined by having initiated antipsychotic treatment at least 1 year prior to study entry
* Adequate decisional capacity to make a choice about participating in this research study
* Body mass index (BMI) at or greater than 27
* Currently being treated with one or a combination of two antipsychotic medications (typical or atypical) and on that drug regimen for at least 2 months prior to study entry, with stable dosages for at least 1 month
* If taking antidepressants, mood stabilizers, or anxiolytics, the dose must be stable for at least 1 month prior to study entry
* Willing to use an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study. Acceptable methods include oral, injectable, or implanted contraceptives; intrauterine devices or barrier methods such as condoms; and diaphragms and spermicides.

Exclusion Criteria:

* Inpatient status
* Clinical Global Impression Severity (CGI-S) score greater than 6
* Currently being treated with more than two antipsychotic medications
* Fasting glucose greater than 125
* Diagnosis of diabetes mellitus or treatment with insulin or oral hypoglycemics
* Previous or current treatment with metformin
* Diagnosis of congestive heart failure
* Renal impairment, as defined by a serum creatinine level greater than 1.5 in males or greater than 1.4 in females, or creatinine estimated glomerular filtration rate (GFR) outside of normal limits
* Hepatic disease, as defined by aspartate transaminase (AST), alanine transaminase (ALT), or c-glutamyl transferase (CGT) greater than 1.5 times upper limit of normal (ULN), or total bilirubin greater than 1.2 times ULN
* Metabolic acidosis, as defined by serum carbon dioxide less than the lower limit of normal
* Known hypersensitivity to metformin
* Pregnant or breastfeeding
* Recent (in the past 30 days) or scheduled radiological studies involving iodinated contrast material
* Alcohol abuse or dependence within the past month, as determined by the SCID
* Other serious and unstable medical condition in the judgment of the investigator
* Diagnosis of mental retardation, delirium, or dementia, as defined by DSM-IV-TR
* Failed to discontinue 4 weeks prior to study entry any medication used for weight loss
* Concurrent treatment with certain drugs that are known to increase metformin blood levels should be discussed with the Project Medical Officer.

Primary outcomes:
measure: Mean Difference in Body Weight Change Between Participants Assigned to Metformin and Participants Assigned to Placebo
timeFrame: Measured at the last study visit
Secondary outcomes:
measure: Change in Total Cholesterol From Baseline to 16 Weeks
timeFrame: 16 weeks
measure: Change in HDL Cholesterol From Baseline to 16 Weeks
timeFrame: 16 weeks
measure: Change in LDL Cholesterol From Baseline to 16 Weeks
timeFrame: 16 weeks
measure: Change in Triglycerides From Baseline to 16 Weeks
timeFrame: 16 weeks
measure: Change in Fasting Glucose From Baseline to 16 Weeks
timeFrame: 16 weeks
measure: Change in Fasting Insulin From Baseline to 16 Weeks
timeFrame: 16 weeks
measure: Change in Hemoglobin A1c From Baseline to 16 Weeks
timeFrame: 16 weeks
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Boca Raton
country: United States
facility: Mental Health Advocates
state: Florida
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Wichita
country: United States
facility: Clinical Research Institute
state: Kansas
city: Glen Burnie
country: United States
facility: Clinical Insights
state: Maryland
city: Boston
country: United States
facility: Freedom Trail Clinic
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota School of Medicine
state: Minnesota
city: Albuquerque
country: United States
facility: New Mexico VA Healthcare System
state: New Mexico
city: New York
country: United States
facility: Research Foundation for Mental Hygiene
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Schizophrenia Research
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
Study officials:
affiliation: Columbia University
name: L. Fredrik Jarskog, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: Jeffrey A. Lieberman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: T. Scott Stroup, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang B, Ogburn EL, Rosenblum M. Analysis of covariance in randomized trials: More precision and valid confidence intervals, without model assumptions. Biometrics. 2019 Dec;75(4):1391-1400. doi: 10.1111/biom.13062. Epub 2019 Jun 3.
citation: Jarskog LF, Hamer RM, Catellier DJ, Stewart DD, Lavange L, Ray N, Golden LH, Lieberman JA, Stroup TS; METS Investigators. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder. Am J Psychiatry. 2013 Sep;170(9):1032-40. doi: 10.1176/appi.ajp.2013.12010127.
citation: Khan AY, Macaluso M, McHale RJ, Dahmen MM, Girrens K, Ali F. The adjunctive use of metformin to treat or prevent atypical antipsychotic-induced weight gain: a review. J Psychiatr Pract. 2010 Sep;16(5):289-96. doi: 10.1097/01.pra.0000388624.91039.a3.