TY - JOUR
T1 - Peripheral inflammatory biomarkers define biotypes of bipolar depression
AU - Lee, Yena
AU - Mansur, Rodrigo B
AU - Brietzke, Elisa
AU - Kapogiannis, Dimitrios
AU - Delgado-Peraza, Francheska
AU - Boutilier, Justin J
AU - Chan, Timothy C Y
AU - Carmona, Nicole E
AU - Rosenblat, Joshua D
AU - Lee, JungGoo
AU - Maletic, Vladimir
AU - Vinberg, Maj
AU - Suppes, Trisha
AU - Goldstein, Benjamin I
AU - Ravindran, Arun V
AU - Taylor, Valerie H
AU - Chawla, Sahil
AU - Nogueras-Ortiz, Carlos
AU - Cosgrove, Victoria E
AU - Kramer, Nicole E
AU - Ho, Roger
AU - Raison, Charles A
AU - McIntyre, Roger S
N1 - © 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.
PY - 2021/7
Y1 - 2021/7
N2 - We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α 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 factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) 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 (r2 = 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-α signaling pathways, including NF-κB, IRS1, and MAPK.
AB - We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α 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 factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) 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 (r2 = 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-α signaling pathways, including NF-κB, IRS1, and MAPK.
KW - Biomarkers
KW - Bipolar Disorder/drug therapy
KW - Humans
KW - Infliximab/therapeutic use
KW - Insulin Receptor Substrate Proteins
KW - MAP Kinase Signaling System
KW - NF-kappa B
KW - Tumor Necrosis Factor-alpha
UR - http://www.scopus.com/inward/record.url?scp=85102052185&partnerID=8YFLogxK
U2 - 10.1038/s41380-021-01051-y
DO - 10.1038/s41380-021-01051-y
M3 - Journal article
C2 - 33658605
VL - 26
SP - 3395
EP - 3406
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 7
ER -