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What is the efficacy of tumor necrosis factor–antagonist infliximab in the treatment of bipolar depression?
This randomized clinical trial replicates a previous study indicating that infliximab is not significantly more efficacious compared with placebo for improving depressive symptoms in adults with a mood disorder.
Infliximab therapy is not efficacious at improving depressive symptoms in patients with bipolar depression.
To our knowledge, no study has previously evaluated whether individuals with bipolar depression enriched a priori on the basis of biochemical and/or phenotypic immuno-inflammatory activation would differentially respond to an anti-inflammatory agent for the treatment of depressive symptoms.
To assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions.
Design, Setting, and Participants
This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at 2 outpatient tertiary care sites in Canada and the United States. Eligible adults (aged 18-65 years) met DSM-5–defined criteria for bipolar I or bipolar II depression and exhibited pretreatment biochemical and/or phenotypic evidence of inflammatory activation. Participants were enrolled between October 1, 2015, and April 30, 2018. Data analysis was performed from May 1 through July 31, 2018, using modified intent-to-treat analysis.
Patients were randomized to receive 3 intravenous infusions of infliximab therapy or placebo at baseline and at weeks 2 and 6 of the 12-week study.
Main Outcomes and Measures
The primary efficacy outcome was baseline-to–end point (ie, week-12) change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. History of childhood maltreatment, as assessed by the Childhood Trauma Questionnaire, was used for exploratory analyses as 1 of several secondary outcomes.
A total of 60 participants were randomized to infliximab (n = 29 [48%]; mean [SD] age, 45.0 [11.7] years; 20 of 28 female [71%]) or to placebo (n = 31 [52%]; mean [SD] age, 46.8 [10.2] years; 26 of 30 female [87%]) across study sites. Overall baseline-to–end point change in MADRS total score was observed across treatment × time interaction (χ2 = 10.33; P = .04); reduction in symptom severity was not significant at week 12 (relative risk, 1.09; 95% CI, 0.80-1.50; df = 1; P = .60). As part of a secondary analysis, a significant treatment × time × childhood maltreatment interaction was observed in which infliximab-treated individuals with childhood history of physical abuse exhibited greater reductions in MADRS total score (χ2 = 12.20; P = .02) and higher response rates (≥50% reduction in MADRS total score) (χ2 = 4.05; P = .04).
Conclusions and Relevance
Infliximab did not significantly reduce depressive symptoms compared with placebo in adults with bipolar depression. Results from secondary analyses identified a subpopulation (ie, those reporting physical and/or sexual abuse) that exhibited a significant reduction in depressive symptoms with infliximab treatment compared with placebo.
ClinicalTrials.gov identifier: NCT02363738
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Accepted for Publication: January 23, 2019.
Corresponding Author: Roger S. McIntyre, MD, Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst St, Toronto, ON M5T 2S8, Canada (email@example.com).
Published Online: May 8, 2019. doi:10.1001/jamapsychiatry.2019.0779
Author Contributions: Dr McIntyre had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: McIntyre, Lee, Shekotikhina, Rosenblat, Brietzke, Soczynska, Suppes, Mansur.
Acquisition, analysis, or interpretation of data: McIntyre, Subramaniapillai, Lee, Pan, Carmona, Shekotikhina, Rosenblat, Brietzke, Cosgrove, Miller, Fischer, Kramer, Dunlap, Suppes, Mansur.
Drafting of the manuscript: McIntyre, Subramaniapillai, Lee, Pan, Shekotikhina, Soczynska, Miller, Fischer, Suppes, Mansur.
Critical revision of the manuscript for important intellectual content: McIntyre, Subramaniapillai, Lee, Pan, Carmona, Shekotikhina, Rosenblat, Brietzke, Soczynska, Cosgrove, Kramer, Dunlap, Suppes, Mansur.
Statistical analysis: McIntyre, Lee, Pan, Shekotikhina, Rosenblat, Brietzke, Mansur.
Obtained funding: McIntyre, Soczynska.
Administrative, technical, or material support: McIntyre, Subramaniapillai, Lee, Pan, Carmona, Shekotikhina, Rosenblat, Brietzke, Soczynska, Cosgrove, Miller, Fischer, Dunlap, Mansur.
Supervision: McIntyre, Subramaniapillai, Shekotikhina, Rosenblat, Cosgrove, Suppes.
Conflict of Interest Disclosures: Dr McIntyre reported receiving grants from Stanley Medical Research Institute during the conduct of the study; receiving grants from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/Chinese National Natural Research Foundation outside the submitted work; and receiving speaking/consultation fees from Lundbeck, Janssen, Shire, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, and Minerva outside the submitted work. Ms Subramaniapillai reported receiving grants from Stanley Medical Research Institute during the conduct of the study. Dr Brietzke reported receiving personal fees from Daiichi Sankyo and receiving grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, Sãn Paulo Research Foundation, Coordenação de Aperfeicoamento de Pessoal de Nível Superior (CAPES), and L’Oreal for Women in Science Award outside the submitted work. Dr Suppes reported receiving grants from Stanley Medical Research Institute during the conduct of the study and from the National Institute on Drug Abuse, the National Institutes of Health, National Institute of Mental Health, Palo Alto Health Sciences, Pathway Genomics, and VA Cooperative Studies Program; receiving personal and nonfinancial support from CMEology, Global Medical Education, and Sunovion Pharmaceuticals Inc; and receiving personal fees from Allergan Inc, Hogrefe Publishing, Jones and Bartlett, Medscape Education, and UpToDate. Dr Miller reported receiving grants from Stanley Medical Research Institute during the conduct of the study and from Merck & Co and Sunovion outside the submitted work. No other disclosures were reported.
Funding/Support: This study was supported by grant 13T-012 from the Stanley Medical Research Institute.
Role of the Funder/Sponsor: The Stanley Medical Research Institute had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.
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