Résumé
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.
| Langue d'origine | English |
|---|---|
| Numéro d'article | 21m14022 |
| Journal | Journal of Clinical Psychiatry |
| Volume | 83 |
| Numéro de publication | 2 |
| DOI | |
| Statut de publication | Published - mars 2022 |
Note bibliographique
Funding Information:The investigative team would like to thank Ms Julie Garnham, RN, BN, who played a critical role at study commencement as research program coordinator (Halifax site) in preparing the submission of the study protocol to Health Canada and to the Nova Scotia Health Authority (NSHA) Research Ethics Board (REB), in aiding in procuring study drug and placebo, in facilitating investigative pharmacy and laboratory services, and in coordinating and participating in the start-up visit at the Pittsburgh site. We thank Drs Patricia Pearce, MD; Külli Põder, MD; and Sreenivasa Bhaskara, MBBS, and other psychiatrists and clinical staff at Nova Scotia Health’s Mental Health Outpatient clinics for referring patients under their care to the TRIO-BD study and we thank the research assistants and students for contributing to scheduling participant follow-up and data collection (Halifax). We thank the late Ms Patricia Schlicht, RN, MA, who played a pivotal role as the research program coordinator (Pittsburgh site), and Drs Mohammad Ismael, MD; Jatinder Babbar, MD; Marcia DeLeo, CRNP; and Holly Swartz, MD, and other clinical staff and doctors at the Bellefield Clinic and CRS Oxford Clinic for referring patients under their care to the TRIO-BD study (Pittsburgh). We gratefully thank Ms Joan Spinogatti, AAS, for coordinating all Institutional Review Board processes and US Food and Drug Administration (FDA) communications and facilitating Pittsburgh/ Halifax and Data and Safety Monitoring Board (DSMB) meetings and coordination among the authors prior to manuscript submission. We thank Dr Jaspreet Brar, MBBS, MPH, PhD, for completing study procedures of the last couple of subjects upon Ms Schlicht’s passing. We would also like to thank the pharmacy staff of Ford’s Pharmacy for undertaking all investigative pharmacy services associated with the study medications. We are grateful for oversight provided by the DSMB and would like to thank Drs Samuel Gershon, MD (chair); Paul Grof, MD; and Thomas Ransom, MD, as well as the study monitors (Darlene Baxendale, BScN [Halifax], and Joan Rea, RN, BSN [Pittsburgh]). We also thank Dr Carl Jarvis, MD, and Dr Paige Forrest, MD, for their medical oversight in Halifax and Pittsburgh, respectively.
Publisher Copyright:
© Copyright 2022 Physicians Postgraduate Press, Inc.
ASJC Scopus Subject Areas
- Psychiatry and Mental health
PubMed: MeSH publication types
- Journal Article
- Multicenter Study
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
ODD de l’ONU
Cette action contribue à la réalisation des objectifs de développement durable suivants
