Soczynska Joanna K, Kennedy Sidney H, Goldstein Benjamin I, Lachowski Angela, Woldeyohannes Hanna O, McIntyre Roger S
Institute of Medical Sciences, University of Toronto, Canada.
Neurotoxicology. 2009 Jul;30(4):497-521. doi: 10.1016/j.neuro.2009.03.004. Epub 2009 Mar 24.
Bipolar disorder (BD) is associated with high rates of morbidity, comorbidity, disability, economic and human capital costs as well as premature mortality. Although, the past decade has witnessed substantial progress in the treatment of BD, high rates of non-recovery, inter-episodic symptomatology, and episode recurrence remain an ongoing deficiency. Conventional treatments for BD are capable of alleviating 'surface-based' symptomatology yet no agent is disease-modifying. Translational research initiatives provide evidence that mood disorder symptomatology is subserved by disturbances in interacting immuno-inflammatory, metabolic, and neuroendocrine networks. Numerous studies document elevated pro-inflammatory circulating cytokines [e.g. interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha)], in individuals with BD as compared to healthy volunteers. Elevated peripheral levels of TNF-alpha and its receptors (i.e. TNF-R1 and TNF-R2) are a frequent findings across depressive and manic states and may persist into euthymia. As such, TNF-alpha may constitute a trait marker of BD. Other markers of inflammation including acute phase reactants (e.g. C-reactive protein) and vascular adhesion molecules (e.g. intercellular adhesion molecule-1) are also altered in BD. Herein, we review supporting evidence for the hypothesis that disturbances in inflammatory homeostasis, as marked by elevated TNF-alpha levels, are salient to the pathophysiology of BD and provide a platform for novel drug discovery. In this review, we propose that TNF-alpha modulation is a target for disease-modifying treatment of BD. To support this hypothesis, we review evidence from clinical trials evaluating the efficacy of TNF-alpha antagonists (i.e. adalimumab, etanercept, and infliximab) on depressive symptoms and mental health-associated quality of life measures.
双相情感障碍（BD）与高发病率、共病率、残疾率、经济和人力资本成本以及过早死亡率相关。尽管在过去十年中，BD的治疗取得了显著进展，但未康复率、发作间期症状以及发作复发率居高不下仍是一个持续存在的问题。BD的传统治疗方法能够缓解“表面”症状，但尚无药物能够改变疾病进程。转化研究表明，情绪障碍症状是由免疫炎症、代谢和神经内分泌网络相互作用紊乱所导致的。大量研究表明，与健康志愿者相比，BD患者循环中促炎细胞因子[如白细胞介素-1（IL-1）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）]水平升高。TNF-α及其受体（即TNF-R1和TNF-R2）外周水平升高在抑郁和躁狂状态中均常见，且可能持续至心境正常期。因此，TNF-α可能是BD的一个特质标记物。BD患者中其他炎症标志物，包括急性期反应物（如C反应蛋白）和血管黏附分子（如细胞间黏附分子-1）也发生了改变。在此，我们综述了相关证据，支持以下假说：以TNF-α水平升高为标志的炎症稳态紊乱在BD的病理生理学中起重要作用，并为新药研发提供了一个平台。在本综述中，我们提出TNF-α调节是BD疾病修饰治疗的一个靶点。为支持这一假说，我们综述了评估TNF-α拮抗剂（即阿达木单抗、依那西普和英夫利昔单抗）对抑郁症状和心理健康相关生活质量指标疗效的临床试验证据。
