Efficacy of Adjunctive Infliximab vs Placebo in the Treatment of Adults With Bipolar I/II 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) metDSM-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