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.

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.

"There's no one-size-fits-all solution. What matters is choosing the right strategy based on individual conditions, under professional guidance," said Xie Zhijuan, associate chief physician at the medical psychology department of Peking University People's Hospital.

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.

"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.

The study also provides a new path for non-pharmacological treatments.

"We discovered that a brief, controlled period of breathing low-oxygen air can activate the brain's adenosine signaling, and animal studies have demonstrated that this physical intervention is both safe and effective, producing a powerful antidepressant effect," Luo said.

The team has developed a prototype of a therapeutic device based on the breathing technique and begun efficacy validation in collaboration with Beijing Anding Hospital affiliated with Capital Medical University. Initial research shows that the physical intervention therapy is safe and inexpensive.

Having obtained US Food and Drug Administration approval for stroke rehabilitation, the therapy now aims to complete clinical validation for depression and be introduced into the Chinese market within the next two to three years.