Cynthia V Calkin, K N Roy Chengappa, Kathleen Cairns, Jacob Cookey, Jessica Gannon, Martin Alda, Claire O'Donovan, Claire Reardon, Marcos Sanches, Martina Růzicková
{"title":"二甲双胍治疗胰岛素抵抗作为改善治疗难治性双相抑郁症临床结果的策略(the TRIO-BD研究):一项随机、四盲、安慰剂对照的临床试验。","authors":"Cynthia V Calkin, K N Roy Chengappa, Kathleen Cairns, Jacob Cookey, Jessica Gannon, Martin Alda, Claire O'Donovan, Claire Reardon, Marcos Sanches, Martina Růzicková","doi":"10.4088/JCP.21m14022","DOIUrl":null,"url":null,"abstract":"<p><p><b><i>Objective:</i></b> 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.</p><p><p><b><i>Methods:</i></b> 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 <i>DSM-5</i> 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.</p><p><p><b><i>Results:</i></b> 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; <i>P</i> = .0009). These converters experienced significant improvements in MADRS (<i>P</i> values ranged from .031 to .008) and GAF (<i>P</i> values ranged from .045 to .008) scores compared to non-converters beginning at week 6, sustained to week 26. HAM-A (<i>P</i> = .022 at week 14 and .019 at week 26) and CGI-BP change scores (<i>P</i> = .046 at 26 weeks) significantly favored converters over non-converters. Effect sizes were large for the MADRS and GAF (Cohen <i>d</i> > 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.</p><p><p><b><i>Conclusions:</i></b> 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.</p><p><p><b><i>Trial Registration:</i></b> ClinicalTrials.gov identifier: NCT02519543.</p>","PeriodicalId":516853,"journal":{"name":"The Journal of Clinical Psychiatry","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2022-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"22","resultStr":"{\"title\":\"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.\",\"authors\":\"Cynthia V Calkin, K N Roy Chengappa, Kathleen Cairns, Jacob Cookey, Jessica Gannon, Martin Alda, Claire O'Donovan, Claire Reardon, Marcos Sanches, Martina Růzicková\",\"doi\":\"10.4088/JCP.21m14022\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b><i>Objective:</i></b> 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.</p><p><p><b><i>Methods:</i></b> 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 <i>DSM-5</i> 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.</p><p><p><b><i>Results:</i></b> 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; <i>P</i> = .0009). These converters experienced significant improvements in MADRS (<i>P</i> values ranged from .031 to .008) and GAF (<i>P</i> values ranged from .045 to .008) scores compared to non-converters beginning at week 6, sustained to week 26. HAM-A (<i>P</i> = .022 at week 14 and .019 at week 26) and CGI-BP change scores (<i>P</i> = .046 at 26 weeks) significantly favored converters over non-converters. Effect sizes were large for the MADRS and GAF (Cohen <i>d</i> > 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.</p><p><p><b><i>Conclusions:</i></b> 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.</p><p><p><b><i>Trial Registration:</i></b> ClinicalTrials.gov identifier: NCT02519543.</p>\",\"PeriodicalId\":516853,\"journal\":{\"name\":\"The Journal of Clinical Psychiatry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"22\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Clinical Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.4088/JCP.21m14022\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Clinical Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4088/JCP.21m14022","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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.
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.
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