Chinese scientists uncover key mechanism behind rapid antidepressant therapies

The prestigious journal Nature has published a groundbreaking study by Chinese scientists who, for the first time, uncovered a shared mechanism behind two rapid and powerful antidepressant treatments — ketamine and electroconvulsive therapy. The research identified the adenosine signaling pathway as the key driver of their effects, shedding light on a long-standing mystery in depression therapy and paving the way for safer and more effective treatment options.

The article titled "Adenosine signaling drives antidepressant actions of ketamine and ECT" was published by Nature on Wednesday local time. The authors include researchers from the Beijing Institute for Brain Research, the State Key Laboratory of Membrane Biology of Peking University, and Laboratory of Chemical Biology of the Changchun Institute of Applied Chemistry in Chinese Academy of Sciences.

According to Luo Minmin, one of the authors of the article, depression is one of the most common mental disorders worldwide. About one-third of patients show poor response to conventional medications — a condition known medically as treatment-resistant depression (TRD). For these patients, ketamine and electroconvulsive therapy are currently the fastest-acting treatments, capable of alleviating symptoms within hours, according to people.cn.

However, both are accompanied by side effects such as hallucinations, addiction, and cognitive impairment, which are difficult to manage effectively. The lack of clarity surrounding their underlying mechanisms has long hindered their broader clinical application, said the report. 

"Therefore, uncovering the core mechanisms behind existing depression therapies and developing improved treatment strategies have become top priorities in depression research," Luo was cited by people.cn. 

Confronted with this long-standing challenge in the medical field, Luo's laboratory, in collaboration with other research teams, has achieved a major breakthrough. Using cutting-edge genetically encoded fluorescent probe technology, the team was able to "see" in real time, for the first time, how both ketamine and electroconvulsive therapy (ECT) trigger a rapid and sustained surge of adenosine levels in key brain regions that regulate mood. This discovery reveals the shared initiating signal underlying these two seemingly distinct therapeutic approaches.

"Ketamine and electroconvulsive therapy are like turning on the same 'faucet' from different directions," explained Luo. "The former works by suppressing cellular energy production, while the latter increases neuronal energy consumption. Though their approaches differ, both disrupt the brain's energy balance, prompting a massive release of adenosine from within cells, which rapidly alleviates depressive symptoms. Importantly, this process is distinct from the pathways that cause hallucinations and other side effects."

Based on this mechanism, the team successfully designed and synthesized a more efficient ketamine derivative. Animal studies show that the new compound achieves stronger antidepressant effects than ketamine at lower doses, with significantly reduced side effects — demonstrating clear potential for clinical translation, according to the people.cn report. 

The study marks a major advance, shifting rapid-acting antidepressant therapies from empirical use to mechanism-based precision medicine. It resolves a decades-old scientific puzzle and identifies clear targets and pathways for developing safer, more effective treatments — bringing new hope to patients with treatment-resistant depression, according to the report. 

Luo revealed that related small-molecule drugs and hypoxia-based therapeutic devices have already been filed for patents. Their next goal is to accelerate the translation of both the new drug and the treatment device into clinical application — aiming to deliver a milestone innovation in depression therapy as soon as possible.

(Global Times)