PMID- 35120288 OWN - NLM STAT- MEDLINE DCOM- 20220307 LR - 20220307 IS - 1555-2101 (Electronic) IS - 0160-6689 (Linking) VI - 83 IP - 2 DP - 2022 Feb 1 TI - Treating Insulin Resistance With Metformin as a Strategy to Improve Clinical Outcomes in Treatment-Resistant Bipolar Depression (the TRIO-BD Study): A Randomized, Quadruple-Masked, Placebo-Controlled Clinical Trial. LID - 21m14022 [pii] LID - 10.4088/JCP.21m14022 [doi] AB - Objective: Therapeutic options are limited for treatment-resistant bipolar depression (TRBD). Insulin resistance (IR) confers increased risk for TRBD. We investigated metformin, an insulin sensitizer, to reverse IR and improve clinical outcomes in TRBD. Methods: Using a random-assignment (1:1), intent-to-treat, 2-site, quadruple-masked, parallel-group (metformin to 2,000 mg/d or placebo) clinical trial design, patients with DSM-5 bipolar disorder (BD) type I or II and IR received study medication for 26 weeks (February 2016 to October 2019). The primary outcome was the change in depression rating scores (Montgomery-Asberg Depression Rating Scale [MADRS]) at 14 weeks between those who no longer met IR criteria (converters) and those who still did (non-converters). Additional outcomes included scores on the Global Assessment of Functioning (GAF); the Clinical Global Impressions Scale, Bipolar Disorders version (CGI-BP); and the Hamilton Anxiety Rating Scale (HAM-A) and maintenance of improved outcomes up to 26 weeks. Results: Forty-five BD patients were randomized to metformin (n = 20) or placebo (n = 25), and at 14 weeks or later, 11 subjects no longer met IR criteria (n = 10 with metformin, n = 1 with placebo; P = .0009). These converters experienced significant improvements in MADRS (P values ranged from .031 to .008) and GAF (P values ranged from .045 to .008) scores compared to non-converters beginning at week 6, sustained to week 26. HAM-A (P = .022 at week 14 and .019 at week 26) and CGI-BP change scores (P = .046 at 26 weeks) significantly favored converters over non-converters. Effect sizes were large for the MADRS and GAF (Cohen d > 1 at 14 and 26 weeks) and large for the HAM-A and CGI-BP at 26 weeks. Transient gastrointestinal side effects occurred under both treatment conditions. Conclusions: Pending replication, this early study suggests that reversal of IR by metformin offers a path out of TRBD. Further characterization of metformin converters with TRBD will prove informative. Trial Registration: ClinicalTrials.gov identifier: NCT02519543. CI - (c) Copyright 2022 Physicians Postgraduate Press, Inc. FAU - Calkin, Cynthia V AU - Calkin CV AD - Faculty of Medicine, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. AD - Mood and Metabolism Program, QE II Health Sciences Centre, Nova Scotia Health, Halifax, Nova Scotia, Canada. AD - Faculty of Medicine, Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada. AD - Corresponding author: Cynthia V. Calkin, MD, CCFP, FRCPC, Departments of Psychiatry and Medical Neuroscience, Director, Mood and Metabolism Program, QE II Health Sciences Centre, Room 4108, Abbie J. Lane Bldg, Halifax, NS B3H 2E2 CANADA (Cindy.Calkin@nshealth.ca). FAU - Chengappa, K N Roy AU - Chengappa KNR AD - Western Psychiatric Hospital, University of Pittsburgh Medical Centre, Pittsburgh, Pennsylvania. FAU - Cairns, Kathleen AU - Cairns K AD - Mood and Metabolism Program, QE II Health Sciences Centre, Nova Scotia Health, Halifax, Nova Scotia, Canada. FAU - Cookey, Jacob AU - Cookey J AD - Faculty of Medicine, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. FAU - Gannon, Jessica AU - Gannon J AD - Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. AD - Western Psychiatric Hospital, University of Pittsburgh Medical Centre, Pittsburgh, Pennsylvania. FAU - Alda, Martin AU - Alda M AD - Faculty of Medicine, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. AD - Mood Disorders Program, QE II Health Sciences Center, Nova Scotia Health, Halifax, Nova Scotia, Canada. FAU - O'Donovan, Claire AU - O'Donovan C AD - Faculty of Medicine, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. AD - Mood Disorders Program, QE II Health Sciences Center, Nova Scotia Health, Halifax, Nova Scotia, Canada. FAU - Reardon, Claire AU - Reardon C AD - Mood and Metabolism Program, QE II Health Sciences Centre, Nova Scotia Health, Halifax, Nova Scotia, Canada. FAU - Sanches, Marcos AU - Sanches M AD - The Centre for Mental Health and Addiction, Toronto, Ontario, Canada. FAU - Ruzickova, Martina AU - Ruzickova M AD - Faculty of Medicine, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada. AD - Mood and Metabolism Program, QE II Health Sciences Centre, Nova Scotia Health, Halifax, Nova Scotia, Canada. LA - eng SI - ClinicalTrials.gov/NCT02519543 PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20220201 PL - United States TA - J Clin Psychiatry JT - The Journal of clinical psychiatry JID - 7801243 RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) SB - IM MH - Adult MH - Bipolar Disorder/*drug therapy/metabolism MH - Depressive Disorder, Treatment-Resistant/*drug therapy/metabolism MH - Female MH - Humans MH - Hypoglycemic Agents/*therapeutic use MH - *Insulin Resistance MH - Male MH - Metformin/*therapeutic use MH - Middle Aged MH - Psychiatric Status Rating Scales MH - Treatment Outcome EDAT- 2022/02/05 06:00 MHDA- 2022/03/08 06:00 CRDT- 2022/02/04 17:12 PHST- 2022/02/04 17:12 [entrez] PHST- 2022/02/05 06:00 [pubmed] PHST- 2022/03/08 06:00 [medline] AID - 21m14022 [pii] AID - 10.4088/JCP.21m14022 [doi] PST - epublish SO - J Clin Psychiatry. 2022 Feb 1;83(2):21m14022. doi: 10.4088/JCP.21m14022.