Efficacy of Adjunctive Infliximab vs Placebo in the Treatment of Adults With Bipolar I/II Depression

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 (χ 2 = 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 (χ 2 = 12.20; P = .02) and higher response rates (Ն50% reduction in MADRS total score) (χ 2 = 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.

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression

“…The clinical study was a 12-week randomized, double-blind, placebo-controlled, parallel-group, fixed-dose trial evaluating the efficacy, safety, and tolerability of adjunctive infliximab for the treatment of individuals with bipolar I/II depression meeting inflammatory criteria [15]. The study was approved by the Institutional Ethics Board at the University Health Network, Toronto, ON, Canada, as well as Stanford University, Palo Alto, California.…”

“…Results have been mixed. For example, whereas anti-cytokine treatments have shown antidepressant activity in chronic inflammatory conditions [13], two recent clinical trials failed to demonstrate this effect in the intent-to-treat cohorts with treatment-resistant major depressive disorder and BD [14,15].…”

“…Nonetheless, both studies identified subpopulations, in secondary analyses, who were more likely to respond to the TNF-α antagonist infliximab, based on biochemical (e.g., elevated plasma CRP) or phenotypic criteria (e.g., exposure to early childhood adversity) [14,15]. It remains unclear, however, if these responders represent actual "inflammatory biotypes", within or across mood disorders, which may be more responsive to anti-inflammatory interventions.…”

“…Supporting this idea, a follow-up analysis of the study of Raison et al [14], which identified elevated CRP at baseline as a predictor of favorable response to infliximab, documented that changes in the expression of genes related to innate immune signaling and nuclear factor-kappa B (NF-κB) in peripheral blood mononuclear cells (PBMCs) was associated with antidepressant response [16]. In our recently completed randomized, double-blind, placebo controlled, clinical trial evaluating infliximab for the treatment of bipolar depression, we identified early life trauma (i.e., childhood physical abuse) as a predictor of response [15]. Replicated evidence indicates that early childhood adversity is associated with elevated peripheral immuno-inflammatory activity in adulthood [17,18].…”

“…Our primary hypothesis was that NEVs of infliximab-treated compared to placebo-treated participants would display changes in levels of TNFR/NF-κB signaling effectors, in association with antidepressant response. Based on the results of this controlled clinical trial of infliximab in bipolar depression [15], it is also an a priori hypothesis that a history of childhood abuse would moderate infliximab's effects on TNFR/NF-κB pathway biomarkers. A secondary, exploratory hypothesis was that changes in TNFR/NF-κB pathway biomarkers would be associated with changes in global cortical thickness.…”