Metformin in Co-morbid Diabetes or Prediabetes and Serious Mental Illness

Schizophrenia is associated with a lifespan shortened by 20 years, due to cardiovascular disease (CVD), with antipsychotic (AP) medications understood to contribute to this risk through associated metabolic side-effects. Metformin, a medication used to treat prediabetes, and diabetes in the general population, holds promise with regard to reduction of AP-related metabolic problems, but has not been directly tested in early episode patients beyond weight loss, nor specifically in patients with diabetes or prediabetes and psychosis. We propose to replicate findings that metformin can reduce weight gain, and dysglycemia uniquely focusing on an early episode population diagnosed with prediabetes or diabetes. To help determine long-term risk/benefit of adjunctive metformin, we propose to look at changes in abdominal and liver fat, two well-established risk factors for CVD. Given links between dysglycemia, obesity with hippocampal volume loss and cognitive dysfunction, we will explore if improvements in metabolic indices are associated in changes in cognition and brain structure.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Schizophrenia
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

Detailed Description

This is a 16 week, double-blind, randomized pilot study, which proposes to recruit 24 patients with schizophrenia, or schizoaffective disorders (DSM 5), who are overweight or obese (BMI >25) and have prediabetes or type 2 diabetes. Randomization occurs on a 2:1 basis, with 16 patients randomised to metformin, and 8 to placebo. Metfomin/placebo is dispensed monthly. The baseline and /or screening visit includes a physical exam (including anthropometric measures), medical history, fasting blood work (glucose, insulin, HbA1c, lipids, electrolytes, thyroid, liver/kidney function), in addition to a urine drug screen. Women of child-bearing age are given a pregnancy test. Patients who meet inclusion criteria and consent to the study have an oral glucose tolerance test (OGTT), and a baseline abdominal and brain MRI (to respectively assess visceral adiposity, a key risk factor for CV disease, and hippocampal volumes). Anthropometric measures and pill counts are repeated bi-weekly. At week 8, fasting insulin/glucose, HbA1C, and liver function tests are measured. End of study measures (week 16), include the same panel of bloodwork conducted at baseline, as well as a repeat OGTT, and an abdominal and brain MRI. Rountine psychopathology scales, including BPRS, CGI, and CDS will be measured at baseline, and week 16. The Brief Assessment of Cognition in Schizophrenia (BACS) will also be completed at baseline, and study end.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Center for Addiction and Mental Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients within 5 years of diagnosis of schizophrenia, schizoaffective disorder , or bipolar disorder(DSM V), or those younger than 40 years old, regardless of duration of illness
• Co-morbid diagnosis of prediabetes or diabetes (Canadian or American Diabetes Association criteria)

Exclusion Criteria:

• Patients with co-morbid axis, other than nicotine dependence, or cannabis abuse
• Patients with liver, or renal dysfunction,
• Patients with a positive drug urine screen (other than cannabis or nicotine)
• Females with a positive pregnancy test will be excluded.
• Prior trial with metformin, and reported lack of tolerability
• Patients with an A1C > 9.5%, or symptomatic hyperglycemia with metabolic decompensation

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Metformin; Metformin/ placebo will be dispensed on a biweekly basis, and pill counts conducted at each visit.	Drug: Metformin; Metformin will be dispensed on a biweekly basis, and pill counts conducted at each visit.
Placebo Comparator: Placebo; Metformin/ placebo will be dispensed on a biweekly basis, and pill counts conducted at each visit.	Drug: Placebo; Placebo will be dispensed on a biweekly basis, and pill counts conducted at each visit.; Other Names: Sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in HbA1C derived from Oral glucose tolerance test (Matsuda, index of insulin sensitivity; area under glucose curve; insulin secretion sensitivity index-2 (ISSI-2))	HbA1c value assessment	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Decreases in visceral adiposity	Visceral adiposity assessment via MRI	3 years
Decreases in hepatic adiposity	Hepatic adiposity assessment via MRI	3 years
Greater than 5% decrease in body weight	Body weight assessment	3 years
Improvements in cognition	Cognition assessment	3 years
Improvements in hippocampal volume	Cognition assessment	3 years

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Investigators: Principal Investigator: Margaret Hahn, Center for Addiction and Mental Health

Publications and helpful links

General Publications

• Agarwal SM, Panda R, Costa-Dookhan KA, MacKenzie NE, Treen QC, Caravaggio F, Hashim E, Leung G, Kirpalani A, Matheson K, Chintoh AF, Kramer CK, Voineskos AN, Graff-Guerrero A, Remington GJ, Hahn MK. Metformin for early comorbid glucose dysregulation and schizophrenia spectrum disorders: a pilot double-blind randomized clinical trial. Transl Psychiatry. 2021 Apr 14;11(1):219. doi: 10.1038/s41398-021-01338-2.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: June 17, 2014
• First Submitted That Met QC Criteria: June 17, 2014
• First Posted (Estimate): June 19, 2014

Study Record Updates

• Last Update Posted (Actual): July 30, 2018
• Last Update Submitted That Met QC Criteria: July 27, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Schizophrenia Spectrum and Other Psychotic Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 2; Schizophrenia; Mental Disorders; Prediabetic State; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 007/2014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No