R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects.
R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects.
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DOI：
10.1038/tp.2015.136
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发表时间：
2015-09-01
影响因子：
6.8
通讯作者：
Hashimoto K
中科院分区：
文献类型：
--
作者：
Yang C;Shirayama Y;Zhang JC;Ren Q;Yao W;Ma M;Dong C;Hashimoto K
虽然快速起效和持续的抗抑郁药racketamine对难治性抑郁症患者的疗效是一个偶然的发现，但由于拟精神病副作用和滥用倾向，氯胺酮的临床使用有限。采用行为学和副作用评价试验对氯胺酮的两种立体异构体进行比较。为了阐明其潜在的治疗机制，我们研究了这些立体异构体对脑源性神经营养因子（BDNF）-TrkB信号传导和选定脑区域的突触发生的影响。在抑郁症的社交失败压力和习得性无助模型中，R-氯胺酮显示出比S-氯胺酮（艾司氯胺酮）更大的效力和更持久的抗抑郁作用。此外，与S-氯胺酮相比，R-氯胺酮对抑郁小鼠前额叶皮层（PFC）、CA 3和海马齿状回（DG）中树突棘密度、BDNF-TrkB信号传导和突触发生的降低具有更强的有益作用。然而，无论是立体异构体影响抑郁症小鼠的脑桥核的这些变化。在副作用的行为测试中，S-氯胺酮而不是R-氯胺酮会导致行为异常，如过度运动、前脉冲抑制缺陷和奖励效应。此外，单次给予S-氯胺酮（而非R-氯胺酮）导致内侧PFC和DG的边缘前区域中的小白蛋白（PV）阳性细胞减少。这些发现表明，与S-氯胺酮不同，R-氯胺酮可以引起持续的抗抑郁作用，由PFC、DG和CA 3中增加的BDNF-TrkB信号传导和突触发生介导。相对于S-氯胺酮，R-氯胺酮似乎是一种有效、持久和安全的抗抑郁药，因为R-氯胺酮似乎没有拟精神病副作用和滥用倾向。
Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
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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.
DOI：
10.4088/jcp.09m05327blu
发表时间：
2010-12
期刊：
The Journal of clinical psychiatry
影响因子：
--
作者：
DiazGranados N;Ibrahim LA;Brutsche NE;Ameli R;Henter ID;Luckenbaugh DA;Machado-Vieira R;Zarate CA Jr
通讯作者：
Zarate CA Jr
影响因子：
5
作者：
Ebert, B;Mikkelsen, S;Borgbjerg, FM
通讯作者：
Borgbjerg, FM
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
5.6
作者：
Hashimoto K
通讯作者：
Hashimoto K