Chinese researchers reveal shared antidepressant mechanism of ketamine and ECT

The world's leading multidisciplinary science journal Nature has published a major breakthrough by Chinese scientists in the field of depression treatment research.

For the first time, researchers have uncovered the shared mechanism behind two fast-acting and powerful antidepressant therapies – ketamine and electroconvulsive therapy (ECT) – identifying the adenosine signaling pathway as their common target.

The discovery not only unveils the long-elusive mechanisms underlying rapid-acting antidepressants, but also provides a clear roadmap for developing safer and more effective new treatments.

The study was led by Professor Luo Minmin's laboratory at the Chinese Institute for Brain Research, Beijing, in collaboration with Professor Wang Xiaohui's team at the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, which was responsible for new drug synthesis, and Professor Li Yulong's team at Peking University, which provided molecular probe tools, among others. 

According to the researchers, ketamine and ECT are currently among the most effective interventions for treatment-resistant depression. Both can produce rapid and robust therapeutic effects within hours, yet their underlying mechanisms have remained unclear.

Moreover, their potential side effects – such as hallucinations and cognitive impairment – have limited their wider clinical use. Understanding the mechanisms of these existing treatments and developing improved strategies has therefore become a key priority in depression research.

Facing this long-standing challenge, Luo's team achieved a major breakthrough through multidisciplinary collaboration. Using cutting-edge genetically encoded fluorescent probe technology, they were the first to visualize in real time that how both ketamine and ECT trigger a rapid and sustained increase of adenosine levels in key emotion-regulating regions of the brain, revealing the adenosine signaling pathway as the shared core mechanism underlying both therapies.

To further confirm the central regulatory role of this pathway, the team conducted genetic and pharmacological experiments demonstrating that blocking adenosine signaling in the brain abolished the antidepressant effects of both treatments. Conversely, direct activation of the pathway reproduced a robust antidepressant response.

"Ketamine and ECT are like turning the same faucet from two different directions," Luo explained.

"The former suppresses cellular energy production, while the latter drastically increases neuronal energy consumption. Both ultimately disrupt the brain's energy balance, prompting a massive release of adenosine from cells that rapidly alleviates depressive symptoms – while remaining distinct from the targets responsible for hallucinations and other side effects," he added.

This discovery provides a clear roadmap for developing a new generation of drugs that retain therapeutic benefits while minimizing risks. Based on this mechanism, the team successfully designed and synthesized a novel ketamine derivative with greater potency and fewer side effects.

Animal studies show that the new compound achieves superior antidepressant efficacy at lower doses and exhibits significantly reduced adverse effects, demonstrating strong potential for clinical translation.

The study also offers new directions for non-pharmacological therapies. Using an acute intermittent hypoxia (aIH) protocol – which exposes subjects to short, controlled bouts of low-oxygen air, the researchers found that this approach effectively activates the adenosine signaling pathway and produces antidepressant effects, opening a promising avenue for developing non-invasive, drug-free physiological treatments.

This research marks a major step in transforming rapid-acting antidepressant treatments from empirical practice to mechanism-based precision medicine. It unifies the biological principles underlying pharmacological, electrical, and physiological interventions, solving a scientific puzzle that has persisted for decades.

Luo said that patents have already been filed for the related small-molecule drugs and hypoxia-based treatment devices. The team has completed prototype development of the device and has launched clinical validation trials in collaboration with Beijing Anding Hospital, affiliated with the Capital Medical University.

Moving forward, the team will make every effort to accelerate the translation of both the new drug and the treatment device, with the goal of providing a milestone innovation in depression treatment at the earliest opportunity.