Resolving a paradox: antidepressants, neuroinflammation, and neurodegeneration

R. Rajkumar
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Abstract

Depression is a known risk factor for dementia. Antidepressants are the most commonly used treatment for this condition, and are effective in at least half to two-thirds of cases. Extensive evidence from in vitro and animal models suggests that antidepressants have anti-inflammatory and neuroprotective properties. These effects have been shown to reduce the oxidative damage, amyloid aggregation, and expression of pro-inflammatory genes associated with animal models of neurodegenerative disorders. However, longitudinal research in humans has shown that antidepressants do not protect against dementia, and may even be associated with a risk of cognitive deterioration over time in older adults. The contrast between two sets of findings represents a paradox of significant clinical and public health significance, particularly when treating depression in late life. This review paper attempts to resolve this paradox by critically reviewing the medium- and long-term effects of antidepressants on peripheral immune-inflammatory responses, infection risk, gut microbiota, and neuroendocrine responses to stress, and how these effects may influence the risk of neurodegeneration. Briefly stated, it is possible that the peripheral actions of antidepressant medications may antagonize their beneficial effects against neuroinflammation. The implications of these findings are then explored with a particular focus on the development and testing of multimodal neuroprotective and anti-inflammatory treatments that could reduce the risk of Alzheimer’s and related dementias in patients suffering from depression.
解决悖论:抗抑郁药、神经炎症和神经退行性变
抑郁症是痴呆症的一个已知风险因素。抗抑郁药是最常用的治疗方法,对至少一半到三分之二的病例有效。来自体外和动物模型的大量证据表明,抗抑郁药具有抗炎和保护神经的作用。这些作用已被证明可以减少氧化损伤、淀粉样蛋白聚集以及与神经退行性疾病动物模型相关的促炎基因的表达。然而,对人类的纵向研究表明,抗抑郁药并不能预防痴呆症,甚至可能与老年人认知能力随时间推移而退化的风险有关。两组研究结果之间的反差是一个具有重大临床和公共卫生意义的悖论,尤其是在治疗晚年抑郁症时。本综述论文试图通过批判性地回顾抗抑郁药对外周免疫炎症反应、感染风险、肠道微生物群和神经内分泌对压力反应的中长期影响,以及这些影响可能如何影响神经变性的风险,来解决这一悖论。简而言之,抗抑郁药物的外周作用可能会拮抗其对神经炎症的有益作用。研究人员随后探讨了这些发现的意义,并特别关注开发和测试多模式神经保护和抗炎疗法,以降低抑郁症患者罹患阿尔茨海默氏症和相关痴呆症的风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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