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

Abstract

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.

Conflict of interest statement

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.

Figures

Figure 1.. Flow Diagram

Figure 2.. Depressive Symptom Severity Observed in Both Treatment Groups With vs Without History of Physical Abuse

Modified intent-to-treat generalized estimating equation analysis of 58 participants with bipolar disorder who were administered 3 infusions of infliximab (n = 28) or placebo (n = 30) at baseline and at weeks 2 and 6 of a 12-week trial. Error bars indicate 95% CIs; LS, least squares; and MADRS, Montgomery-Asberg Depression Rating Scale.

Figure 3.. Treatment Outcomes at Week 12 Among Individuals With vs Without Clinically Significant History of Physical Abuse

Percentage of infliximab-randomized (n = 28) and placebo-randomized (n = 30) individuals meeting criteria for treatment response (≥50% decrease in the MADRS total score) or remission (MADRS total score ≤12) at week 12. Error bars indicate standard error of mean; MADRS, Montgomery-Asberg Depression Rating Scale.