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Original Investigation
May 8, 2019

Efficacy of Adjunctive Infliximab vs Placebo in the Treatment of Adults With Bipolar I/II Depression: A Randomized Clinical Trial

Author Affiliations
  • 1Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
  • 2Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
  • 3Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
  • 4Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
  • 5Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada
  • 6Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil
  • 7Department of Psychiatry & Behavioral Sciences, Stanford University, School of Medicine, Palo Alto, California
JAMA Psychiatry. 2019;76(8):783-790. doi:10.1001/jamapsychiatry.2019.0779
Key Points

Question  What is the efficacy of tumor necrosis factor–antagonist infliximab in the treatment of bipolar depression?

Findings  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.

Meaning  Infliximab therapy is not efficacious at improving depressive symptoms in patients with bipolar depression.


Importance  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.

Objective  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.

Interventions  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.

Results  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.

Trial Registration  ClinicalTrials.gov identifier: NCT02363738