Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention.
Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention.
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DOI：
10.1126/stke.2252004re5
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发表时间：
2004-03-16
期刊：
影响因子：
--
通讯作者：
Manji, Husseini K
中科院分区：
文献类型：
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作者：
Charney, Dennis S;Manji, Husseini K
重度抑郁症是一种常见的、严重的、慢性的、经常危及生命的疾病。越来越多的人认识到，严重抑郁症远非一种纯粹的心理表现，而是一种对多个器官系统产生有害影响的系统性疾病。压力性生活事件与抑郁症有很大的因果关系，现在有令人信服的证据表明，即使是早期生活压力也构成了随后患抑郁症的主要风险因素。新出现的证据表明，遗传学、早期生活压力和持续压力的结合可能最终决定个体对压力的反应和对精神疾病（如抑郁症）的脆弱性。遗传因素和生活压力不仅可能导致神经化学变化，而且可能导致抑郁症中观察到的细胞可塑性和弹性受损。最近的临床前和临床研究表明，参与调节细胞可塑性和弹性的信号通路是抗抑郁药作用的长期靶点。能够逆转抑郁症中假设的细胞弹性损伤、脑体积减少和细胞死亡或萎缩的药物有可能成为新的抗抑郁药物治疗类别。新的细胞靶点包括靶向神经营养途径、糖皮质激素信号传导、磷酸二酯酶活性和代谢能通量的药物。因此，未来开发的治疗方法更直接地靶向调节细胞可塑性的关键CNS（中枢神经系统）信号通路中的分子，有望成为新型的，改善的长期治疗重度抑郁症的方法。
Major depression is a common, severe, chronic, and often life-threatening illness. There is a growing appreciation that, far from being a disease with purely psychological manifestations, major depression is a systemic disease with deleterious effects on multiple organ systems. Stressful life events have a substantial causal association with depression, and there is now compelling evidence that even early life stress constitutes a major risk factor for the subsequent development of depression. The emerging evidence suggests that the combination of genetics, early life stress, and ongoing stress may ultimately determine individual responsiveness to stress and the vulnerability to psychiatric disorders, such as depression. It is likely that genetic factors and life stress contribute not only to neurochemical alterations, but also to the impairments of cellular plasticity and resilience observed in depression. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell plasticity and resilience are long-term targets for the actions of antidepressant agents. Agents capable of reversing the hypothesized impairments of cellular resilience, reductions in brain volume, and cell death or atrophy in depression have the potential of becoming new therapeutic classes of antidepressant drugs. Novel cellular targets include agents targeting neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and glutamatergic throughput. The future development of treatments that more directly target molecules in critical CNS (central nervous system) signaling pathways that regulate cellular plasticity thus hold promise as novel, improved long-term treatments for major depression.