抑郁症是全球主要的精神疾病之一，影响着数亿人的生活。北京时间11月6日，我国科研团队在国际顶级学术期刊《自然》上发表研究成果，首次揭示氯胺酮和电休克疗法这两种快速强效抗抑郁疗法背后的共同作用机制——腺苷信号通路，为开发新一代基于腺苷信号调控且副作用更小的抗抑郁疗法提供了坚实的理论依据和明确的靶点。

Research led by Chinese scientists has for the first time revealed the common mechanism behind two fast-acting and potent antidepressant therapies, paving the way for developing the next generation of safe and effective treatments.

The team, led by Luo Minmin, director of the Chinese Institute for Brain Research, Beijing, together with collaborators from the Changchun Institute of Applied Chemistry of the Chinese Academy of Sciences and Peking University, published the findings in the international academic journal Nature on Thursday.

据介绍，氯胺酮和电休克疗法是目前针对难治性抑郁症患者较为有效的干预手段，这两种疗法能在数小时内带来快速且强劲的疗效，但其作用机制尚未明确，且伴随着致幻、认知损伤等副作用风险，限制了其广泛应用。探索现有抑郁症疗法背后的原理机制，进而开发出更优的治疗策略，成为了抑郁症研究领域的重中之重。

Globally, about 5.7 percent of adults suffer from depression, according to World Health Organization estimates. Currently, ketamine and electroconvulsive therapy, or ECT, are among the most effective interventions, capable of producing robust therapeutic effects within hours, making them vital for acute suicidal depression.

However, ketamine administration is strictly limited to regulated medical settings due to potential risks.

Ketamine and ECT therapies face a common clinical dilemma: despite being used for decades to save lives, the fundamental mechanism of how they work has remained a mystery. This long-standing uncertainty has hindered clinicians' ability to fully harness their efficacy and manage serious side effects such as dissociation, addiction and cognitive impairment, ultimately limiting broader application.

面对这一长期困扰医学界的难题，北京脑科学与类脑研究所罗敏敏团队联合国内多个顶尖实验室，利用前沿的基因编码荧光探针技术，首次在活体大脑中发现，在氯胺酮和电休克治疗过程中，都会引起情绪调控关键脑区腺苷水平的急剧、持续飙升，揭示了这两种疗法背后共同的核心通路——腺苷信号通路。

研究团队进一步通过遗传学与药物试验发现，当“关闭”大脑感知腺苷信号的接收器时，两种疗法的抗抑郁效果便完全消失，而激活该通路则能产生明确的抗抑郁效果。

罗敏敏说，这项研究成功将疗效与副作用“解绑”，为开发新一代药物提供了清晰的路线图。此外，该研究还为非药物治疗带来了新的思路。研究证实，一种被称为“急性间歇性低氧”的安全物理干预手段，同样能有效激活大脑腺苷信号，产生强大的抗抑郁效果。为后续开发完全非侵入、无药物依赖的生理疗法奠定了坚实基础。

"Considering the above condition, uncovering the core mechanisms of existing antidepressant therapies to develop better treatment strategies has thus become a top priority in depression research," Luo said.

Using a novel technique that acts like a fluorescent tag on cells, the team visually observed, for the first time in the living brain, that both ketamine and ECT induce a sharp and sustained surge in adenosine levels in key brain regions responsible for mood regulation. This revealed a common initiating signal behind two seemingly disparate treatments.

The research further found that ketamine activates the adenosine pathway primarily by modulating cellular energy metabolism, rather than through another previously hypothesized bio-mechanism closely linked to side effects such as dissociation.

Based on this finding, the team successfully designed and synthesized novel ketamine derivatives. In animal experiments, one compound achieved antidepressant effects comparable to or better than ketamine at lower doses and significantly reduced side effects, showing great potential for clinical translation.

该研究由北京脑科学与类脑研究所的罗敏敏实验室牵头，联合中国科学院长春应用化学研究所王晓辉团队、北京大学李毓龙团队等多个实验室协同完成。研究得到了中国医学科学院创新工程及医学创新基金、中国脑计划、国家自然科学基金以及新基石研究员项目等的大力支持。

记者：王松松

来源：中国日报 新华社