Faculty of Medicine, Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
Mood and Metabolism Program, QE II Health Sciences Centre, Nova Scotia Health, Halifax, Nova Scotia, Canada.
J Clin Psychiatry. 2022 Feb 1;83(2):21m14022. doi: 10.4088/JCP.21m14022.
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. 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 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. 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; = .0009). These converters experienced significant improvements in MADRS ( values ranged from .031 to .008) and GAF ( values ranged from .045 to .008) scores compared to non-converters beginning at week 6, sustained to week 26. HAM-A ( = .022 at week 14 and .019 at week 26) and CGI-BP change scores ( = .046 at 26 weeks) significantly favored converters over non-converters. Effect sizes were large for the MADRS and GAF (Cohen > 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. 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. ClinicalTrials.gov identifier: NCT02519543.
治疗抵抗性双相情感障碍（TRBD）的选择有限。胰岛素抵抗（IR）会增加 TRBD 的风险。我们研究了二甲双胍，一种胰岛素增敏剂，以逆转 IR 并改善 TRBD 的临床结果。
使用随机分组（1:1）、意向治疗、2 个地点、四重盲、平行组（二甲双胍 2000mg/d 或安慰剂）临床试验设计，患有 1 型或 2 型双相情感障碍（BD）和 IR 的患者接受研究药物治疗 26 周（2016 年 2 月至 2019 年 10 月）。主要结局是在 14 周时，不再符合 IR 标准的患者（转化者）和仍符合 IR 标准的患者（非转化者）之间抑郁评分（蒙哥马利-阿斯伯格抑郁评定量表[MADRS]）的变化。其他结局包括总体功能评估（GAF）评分；临床总体印象量表，双相障碍版（CGI-BP）；和汉密尔顿焦虑量表（HAM-A）以及在 26 周内保持改善的结果。45 名 BD 患者被随机分配至二甲双胍（n=20）或安慰剂（n=25），在 14 周或之后，11 名患者不再符合 IR 标准（n=10 名接受二甲双胍，n=1 名接受安慰剂； = .0009）。这些转化者在 MADRS（ 值范围从 .031 到.008）和 GAF（ 值范围从 .045 到.008）评分上的改善明显优于非转化者，从第 6 周开始，持续到第 26 周。HAM-A（第 14 周为 .022，第 26 周为 .019）和 CGI-BP 变化评分（第 26 周为 .046）在 26 周时明显有利于转化者。MADRS 和 GAF 的效应大小较大（14 周和 26 周时 Cohen >1），HAM-A 和 CGI-BP 在 26 周时的效应大小较大。两种治疗条件下均出现短暂的胃肠道副作用。
在等待复制的情况下，这项早期研究表明，二甲双胍逆转 IR 为 TRBD 提供了一条出路。对 TRBD 的二甲双胍转化者进行进一步特征描述将提供有价值的信息。
临床试验.gov 标识符：NCT02519543。
