Metformin for early comorbid glucose dysregulation and schizophrenia spectrum disorders: a pilot double-blind randomized clinical trial

Sri Mahavir Agarwal, Roshni Panda, Kenya A Costa-Dookhan, Nicole E MacKenzie, Quinn Casuccio Treen, Fernando Caravaggio, Eyesha Hashim, General Leung, Anish Kirpalani, Kelly Matheson, Araba F Chintoh, Caroline K Kramer, Aristotle N Voineskos, Ariel Graff-Guerrero, Gary J Remington, Margaret K Hahn, Sri Mahavir Agarwal, Roshni Panda, Kenya A Costa-Dookhan, Nicole E MacKenzie, Quinn Casuccio Treen, Fernando Caravaggio, Eyesha Hashim, General Leung, Anish Kirpalani, Kelly Matheson, Araba F Chintoh, Caroline K Kramer, Aristotle N Voineskos, Ariel Graff-Guerrero, Gary J Remington, Margaret K Hahn

Abstract

Patients with schizophrenia have exceedingly high rates of metabolic comorbidity including type 2 diabetes and lose 15-20 years of life due to cardiovascular diseases, with early accrual of cardiometabolic disease. In this study, thirty overweight or obese (Body Mass Index (BMI) > 25) participants under 40 years old with schizophrenia spectrum disorders and early comorbid prediabetes or type 2 diabetes receiving antipsychotic medications were randomized, in a double-blind fashion, to metformin 1500 mg/day or placebo (2:1 ratio; n = 21 metformin and n = 9 placebo) for 4 months. The primary outcome measures were improvements in glucose homeostasis (HbA1c, fasting glucose) and insulin resistance (Matsuda index-derived from oral glucose tolerance tests and homeostatic model of insulin resistance (HOMA-IR)). Secondary outcome measures included changes in weight, MRI measures of fat mass and distribution, symptom severity, cognition, and hippocampal volume. Twenty-two patients (n = 14 metformin; n = 8 placebo) completed the trial. The metformin group had a significant decrease over time in the HOMA-IR (p = 0.043) and fasting blood glucose (p = 0.007) vs. placebo. There were no differences between treatment groups in the Matsuda index, HbA1c, which could suggest liver-specific effects of metformin. There were no between group differences in other secondary outcome measures, while weight loss in the metformin arm correlated significantly with decreases in subcutaneous, but not visceral or hepatic adipose tissue. Our results show that metformin improved dysglycemia and insulin sensitivity, independent of weight loss, in a young population with prediabetes/diabetes and psychosis spectrum illness, that is at extremely high risk of early cardiovascular mortality. Trial Registration: This protocol was registered with clinicaltrials.gov (NCT02167620).

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1. Flowchart of study participants.
Fig. 1. Flowchart of study participants.
All participants who were randomized and had received at least 1 dose of metformin or placebo were included in the analyses.
Fig. 2
Fig. 2
Change in insulin sensitivity (HOMA-IR) (A) and fasting glucose levels (B) with metformin compared to placebo at baseline, 8 weeks, and 16 weeks of treatment. Error bars represent ± 1 S.E.
Fig. 3
Fig. 3
Correlation between percentage change in weight and subcutaneous adipose tissue (SAT) volume with metformin treatment.

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