Treating Insulin Resistance With Metformin as a Strategy to Improve Clinical Outcomes in Treatment-Resistant Bipolar Depression (the TRIO-BD Study)

Abstract

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.

Reversal of insulin resistance is associated with repair of blood–brain barrier dysfunction and remission in a patient with treatment‐resistant bipolar depression

“…This is consistent with the overall primary results of our TRIO-BD clinical trial, which demonstrates that treating IR improves depression and anxiety and overall functioning in TRBD, with large effect sizes. 1 Further, metformin appears to have repaired the patient's extensive BBB leakage. This suggests, for the first time, that BBB leakage is dynamic and likely an underlying mechanism of neuroprogression in BD, mediated by sensitivity to insulin.…”

“…The patient was deemed to have treatment-resistant bipolar depression (TRBD) and was invited to participate in our randomized quadruple-masked placebo-controlled clinical trial of reversing IR with metformin to improve outcome in BD (the TRIO-BD study). 1 Upon recruitment to the TRIO-BD study (prior to taking study drug), the patient's HOMA-IR was 2.08, Montgomery Asberg Depression Rating Scale (MADRS) was 32 (indicative of severe depression), Hamilton Anxiety (HAM-A) score was 25 (indicative of severe anxiety), and Global Assessment of Functioning (GAF) score was 50 (indicative of serious impairment in functioning, Figure 1, time 0 weeks). He completed the 26-week trial while still on study drug (now known to have been placebo) with no improvement: HOMA-IR of 1.97 and MADRS of 33, HAM-A 29 and GAF 50 (Figure 1, time 26 weeks).…”

“…Subsequently, he was started on metformin 500mg with breakfast and supper for 1 week, then 1000 mg with breakfast and supper. After 14 weeks of treatment, he had repeat laboratory tests, mood rating scales -as per the TRIO-BD protocol, 1…”

“…In the M&M Program, the patient failed trials with lithium (at therapeutic blood levels) + quetiapine, lithium monotherapy for a minimum of 6 months as well as in combination with lamotrigine at maximum doses for at least 2 months and later the addition of 15 sessions of cognitive behavioral therapy (CBT). The patient was deemed to have treatment‐resistant bipolar depression (TRBD) and was invited to participate in our randomized quadruple‐masked placebo‐controlled clinical trial of reversing IR with metformin to improve outcome in BD (the TRIO‐BD study) 1 …”

The Function of Metformin in Aging-Related Musculoskeletal Disorders

“…Research has revealed that metformin has potential side effects. Some individuals experience transient gastrointestinal adverse reactions after taking metformin, including abdominal discomfort, diarrhea, nausea, vomiting, bloating, and dyspepsia ( Wang and Hoyte, 2019 ; Calkin et al, 2022 ). In addition, metformin may increase lactate levels in mice and humans ( Huang et al, 2017 ; Soukas et al, 2019 ), but these appear to be clinically insignificant and rare.…”