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.
Level 2 - randomized trial
Individual randomized controlled trial
PubMed 35120288 · doi:10.4088/JCP.21m14022
What was done
A 26-week, 2-site, quadruple-masked, randomized, placebo-controlled parallel-group trial evaluating metformin (titrated up to 2,000 mg/day) versus placebo in 45 patients with DSM-5 bipolar I or II disorder, insulin resistance (IR), and treatment-resistant bipolar depression. The primary outcome was the change in Montgomery-Asberg Depression Rating Scale (MADRS) scores at 14 weeks compared between participants whose insulin resistance resolved (converters) versus those whose IR persisted (non-converters). Secondary outcomes included changes in Global Assessment of Functioning (GAF), Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP) up to 26 weeks.
What was found
Reversal of insulin resistance at 14 weeks or later occurred in 11 patients: 10 of 20 (50%) in the metformin arm versus 1 of 25 (4%) in the placebo arm (P = .0009). Patients who converted out of insulin resistance experienced statistically significant improvements compared to non-converters starting at week 6 and sustained to week 26 on MADRS (P values ranged from .031 to .008; Cohen d > 1 at weeks 14 and 26) and GAF (P values ranged from .045 to .008; Cohen d > 1 at weeks 14 and 26). HAM-A (P = .022 at week 14; P = .019 at week 26) and CGI-BP (P = .046 at week 26) change scores also favored converters, with large effect sizes at week 26. Transient gastrointestinal side effects were reported in both treatment conditions.
Why it matters
This trial suggests that targeting metabolic dysfunction and reversing insulin resistance with metformin may offer a therapeutic strategy for patients with treatment-resistant bipolar depression.
Limits
The sample size was small (n = 45), resulting in only 11 total metabolic converters (10 in the metformin group, 1 in the placebo group). The primary endpoint was evaluated by metabolic conversion status rather than a standard intention-to-treat comparison between randomized arms, and long-term durability beyond 26 weeks was not assessed.
Cited by
- supports A study showed that metformin adjunctively improved outcomes in patients with treatment-resistant bipolar depression.