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

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Psychiatry Pub Date : 2024-09-17 DOI:10.1038/s41380-024-02751-x
Michael T. Treadway, Sarah M. Etuk, Jessica A. Cooper, Shabnam Hossein, Evan Hahn, Samantha A. Betters, Shiyin Liu, Amanda R. Arulpragasam, Brittany A. M. DeVries, Nadia Irfan, Makiah R. Nuutinen, Evanthia C. Wommack, Bobbi J. Woolwine, Mandakh Bekhbat, Philip A. Kragel, Jennifer C. Felger, Ebrahim Haroon, Andrew H. Miller
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Abstract

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.

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TNF 拮抗剂治疗高度炎症性抑郁症患者的动机缺陷和相关皮质脑回路的随机机制验证试验
慢性低度炎症与重度抑郁症(MD)患者的动机缺陷有关。反过来,动机受损也与各种精神疾病的生活质量低下有关。因此,我们确定了抗炎药物英夫利昔单抗--一种强效肿瘤坏死因子(TNF)拮抗剂--对42名C反应蛋白为3毫克/升、病情稳定、未服药的重度抑郁症患者的行为和神经动机测量的影响。所有患者都接受了英夫利西单抗(5 毫克/千克)与安慰剂的双盲、安慰剂对照、单剂量随机临床试验。我们在基线和输注后两周评估了患者在努力决策任务中的行为表现、自我报告问卷以及事件相关功能磁共振成像中的神经反应。我们发现,与安慰剂相比,接受英夫利西单抗治疗的患者更愿意为获得奖励而付出努力。此外,努力选择的增加与可溶性 TNF 受体 2 型(sTNFR2)下降所反映的 TNF 信号的减少有关。基于努力的决策和sTNFR2的变化还与大脑区域网络中与任务相关的活动变化有关,包括背内侧前额叶皮层(dmPFC)、腹侧纹状体和普坦门,以及这些区域之间的功能连接。sTNFR2 的变化还介导了药物条件与行为和神经影像测量之间的关系。最后,自我报告的失乐症症状和努力折扣行为的变化与独立验证的全脑预测模型(又称 "神经特征")对金钱奖励敏感的更大反应相关。综上所述,这些数据支持使用抗炎治疗来改善高炎症抑郁症患者基于努力的决策和相关的大脑回路。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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