Hare Brendan D, Ghosal Sriparna, Duman Ronald S
Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
Chronic Stress (Thousand Oaks). 2017 Feb;1. doi: 10.1177/2470547017697317. Epub 2017 Apr 10.
Stress-associated disorders, including depression and anxiety, impact nearly 20% of individuals in the United States. The social, health, and economic burden imposed by stress-associated disorders requires in depth research efforts to identify suitable treatment strategies. Traditional medications (e.g., selective serotonin reuptake inhibitors, monoamine oxidase inhibitors) have significant limitations, notably a time lag for therapeutic response that is compounded by low rates of efficacy. Excitement over ketamine, a rapid acting antidepressant effective in treatment resistant patients, is tempered by transient dissociative and psychotomimetic effects, as well as abuse potential. Rodent stress models are commonly used to produce behavioral abnormalities that resemble those observed in stress-associated disorders. Stress models also produce molecular and cellular morphological changes in stress sensitive brain regions, including the prefrontal cortex and hippocampus that resemble alterations observed in depression. Rapid acting antidepressants such as ketamine can rescue stress-associated morphological and behavioral changes in rodent models. Here, we review the literature supporting a role for rapid acting antidepressants in opposing the effects of stress, and summarize research efforts seeking to elucidate the molecular, cellular, and circuit level targets of these agents.
包括抑郁症和焦虑症在内的应激相关障碍影响着美国近20%的人口。应激相关障碍所带来的社会、健康和经济负担需要深入的研究工作来确定合适的治疗策略。传统药物（如选择性5-羟色胺再摄取抑制剂、单胺氧化酶抑制剂）有显著局限性，尤其是治疗反应存在时间延迟，且疗效欠佳加剧了这一问题。氯胺酮作为一种对难治性患者有效的速效抗抑郁药，其兴奋感因短暂的解离和拟精神病作用以及滥用可能性而有所缓和。啮齿动物应激模型通常用于产生类似于应激相关障碍中所观察到的行为异常。应激模型还会在应激敏感脑区产生分子和细胞形态学变化，包括前额叶皮层和海马体，这些变化类似于在抑郁症中观察到的改变。像氯胺酮这样的速效抗抑郁药可以挽救啮齿动物模型中与应激相关的形态学和行为变化。在此，我们综述支持速效抗抑郁药在对抗应激影响中作用的文献，并总结旨在阐明这些药物分子、细胞和回路水平靶点的研究工作。
