Peripheral inflammatory biomarkers define biotypes of bipolar depression

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-alpha inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factor kappa B (p-NF kappa B), Fas-associated death domain (p-FADD), and I kappa B kinase (p-IKK alpha/beta) and TNF receptor-1 (TNFR1) comprised factor NEV1, whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted NEV2. Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r(2) = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-alpha signaling pathways, including NF-kappa B, IRS1, and MAPK.

Automated summary

This study identified three inflammatory biotypes among individuals with bipolar depression treated with the TNF-alpha inhibitor infliximab, and found associations between these biotypes and improvements in hedonic symptoms. The results suggest that modulation of multiple TNF-alpha signaling pathways may be necessary for the pro-hedonic effects of infliximab.