Journal Article

A randomized proof-of-mechanism trial of TNF antagonism for motivational deficits and related corticostriatal circuitry in depressed patients with high inflammation

Felger, Jennifer C., Betters, Samantha A., Liu, Shiyin, DeVries, Brittany A. M., Etuk, Sarah M., Hahn, Evan, Arulpragasam, Amanda R., Cooper, Jessica A., Hossein, Shabnam, Kragel, Philip A., Miller, Andrew H., Haroon, Ebrahim, Treadway, Michael T., Nuutinen, Makiah R., Irfan, Nadia, Woolwine, Bobbi J., Wommack, Evanthia C., Bekhbat, Mandakh

2025

Overview

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab–a potent tumor necrosis factor (TNF) antagonist–on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein >3 mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5 mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dorsomedial prefrontal cortex (dmPFC), ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka “neural signature”) sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/21 / 59/57 / 631/378 / 692/699/476/1414 / Adult / Anti-inflammatory agents / Behavioral Sciences / Biological Psychology / Brain - drug effects / C-reactive protein / Clinical trials / Corpus Striatum - drug effects / Decision making / Decision Making - drug effects / Depression - drug therapy / Depressive Disorder, Major - drug therapy / Depressive Disorder, Major - metabolism / Depressive Disorder, Major - physiopathology / Double-Blind Method / Female / Functional magnetic resonance imaging / Hedonic response / Humans / Inflammation / Inflammation - drug therapy / Inflammation - metabolism / Infliximab / Infliximab - pharmacology / Infliximab - therapeutic use / Magnetic resonance imaging / Magnetic Resonance Imaging - methods / Male / Medicine / Medicine & Public Health / Mental disorders / Mental task performance / Middle Aged / Monoclonal antibodies / Motivation - drug effects / Neostriatum / Neural networks / Neuroimaging / Neurosciences / Patients / Pharmacotherapy / Placebos / Prediction models / Prefrontal Cortex / Psychiatry / Putamen / Quality of life / Receptors, Tumor Necrosis Factor, Type II - metabolism / Reward / Tumor necrosis factor receptors / Tumor Necrosis Factor-alpha - antagonists & inhibitors / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-TNF / Tumor necrosis factor-α