Ketamine: Leading us into the future for development of antidepressants.
Ketamine: Leading us into the future for development of antidepressants.
复制标题
DOI：
10.1016/j.bbr.2020.112532
复制
发表时间：
2020-04-06
影响因子：
2.7
通讯作者：
Frazer A
中科院分区：
文献类型：
--
作者：
Carreno FR;Lodge DJ;Frazer A
许多随机双盲临床试验一致表明，对难治性抑郁症患者单次静脉注射亚麻醉剂量氯胺酮可在两小时内迅速改善抑郁症状，效果长达七天。尽管氯胺酮的效果非常有希望，但长期以来一直与滥用的可能性有关，因为它会导致精神副作用，如幻觉、错误信念以及严重的判断和其他认知过程障碍。因此，在过去的二十年里，已经开展了临床前研究，目的是了解氯胺酮的作用机制和参与氯胺酮抗抑郁作用的大脑回路，本文对这两个方面进行了讨论。此外，由于海马体是氯胺酮有益的抗抑郁作用的关键靶点，我们和其他人已经开始检查药物对行为和神经化学的影响，这些药物由于其受体靶点的优先位置而选择性地作用于海马体。这类药物是α受体的负变构调节剂和正变构调节剂。在氯胺酮的经验教训如何指向针对GABA能系统的新型药物的框架内讨论了这些化合物，这些药物可以概括氯胺酮的抗抑郁作用，而不会产生不良影响。
Numerous randomized double-blind clinical trials have consistently shown that that a single intravenous administration of a subanesthetic dose of ketamine to treatment-resistant depressed patients significantly improved depressive symptomatology rapidly, within two hours, with the effect lasting up to seven days. Despite its very promising effects, ketamine has long been associated with potential for abuse as it can cause psychotropic side effects, such as hallucinations, false beliefs, and severe impairments in judgment and other cognitive processes. Consequently, within the last two decades preclinical research has been carried out aimed at understanding its mechanisms of action and the brain circuits involved in ketamine’s antidepressant effects, both of which are discussed in this review. Furthermore, with the hippocampus being a key target for ketamine’s beneficial antidepressant effects, we and others have begun to examine behavioral and neurochemical effects of drugs that act selectively on the hippocampus due to the preferential location of their receptor targets. Such drugs are negative allosteric modulators (NAMs) and positive allosteric modulator (PAM) of the α5-GABAA receptor. Such compounds are discussed within the framework of how lessons learned with ketamine point to novel classes of drugs, targeting the GABAergic system, that can recapitulate the antidepressant effects of ketamine without its adverse effects.
登录
查看更多内容
影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
影响因子：
3.7
作者：
Ali, Afia B.;Thomson, Alex M.
通讯作者：
Thomson, Alex M.
影响因子：
7.6
作者：
Fischell, Jonathan;Van Dyke, Adam M.;Thompson, Scott M.
通讯作者：
Thompson, Scott M.
影响因子：
4.8
作者：
Carreno, Flavia R.;Collins, Gregory T.;Lodge, Daniel J.
通讯作者：
Lodge, Daniel J.
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH