Core Viewpoint - The article discusses a significant breakthrough in understanding the treatment mechanisms of resistant depression, revealing a common neurobiological mechanism behind ketamine and electroconvulsive therapy (ECT) that could lead to safer and more effective treatments [3][5]. Group 1: Research Findings - A recent study published in Nature identified that both ketamine and ECT treatments for resistant depression significantly increase adenosine levels in key brain areas [4][5]. - The research indicates that adenosine signaling is the core pathway driving the rapid antidepressant effects of both therapies, challenging the traditional focus on NMDA receptor inhibition [5][6]. - Approximately one-third of depression patients are classified as having resistant depression, which does not respond well to conventional treatments [5][6]. Group 2: Implications for Treatment - The study's findings suggest that understanding the adenosine pathway could help decouple the efficacy of treatments from their side effects, which include potential addiction and cognitive impairments [5][6]. - The research team has developed a new ketamine derivative that shows superior antidepressant effects at lower doses with reduced side effects, indicating strong clinical translation potential [7]. - A novel non-drug therapy called acute intermittent hypoxia (aIH) has been identified, which effectively activates the brain's adenosine signaling and demonstrates promising antidepressant effects [8]. Group 3: Future Directions - The research team is collaborating with clinical teams to advance clinical trials for the aIH therapy, aiming to explore its potential as a core component of combined treatment strategies [8]. - The ongoing development of drug screening platforms based on the adenosine pathway is expected to deepen the understanding and application of new therapeutic options for resistant depression [8].

Core Insights - The research reveals a common neurobiological mechanism behind the antidepressant effects of ketamine and electroconvulsive therapy (ECT) for treatment-resistant depression, highlighting the role of adenosine signaling [1][2][3] Group 1: Treatment Landscape - Depression affects nearly 100 million people in China, with about one-third of patients being treatment-resistant [1][2] - Ketamine and ECT are currently the two main effective treatments for treatment-resistant depression, but both have significant side effects [2][3] - The study aims to decouple the efficacy of these treatments from their adverse effects by understanding their underlying mechanisms [2][4] Group 2: Research Findings - The research team utilized genetically encoded fluorescent probes to demonstrate that both ketamine and ECT lead to a significant and sustained increase in adenosine levels in key brain regions [2][3] - The study found that the activation of the adenosine pathway by ketamine occurs through the regulation of cellular energy metabolism, rather than the previously believed NMDA receptor pathway [3][4] - Evidence shows that blocking adenosine signaling negates the antidepressant effects of both treatments, while directly activating this pathway produces clear antidepressant effects [2][3] Group 3: Development of New Therapies - The research team has successfully designed a new ketamine derivative that achieves superior antidepressant effects at lower doses with reduced side effects, indicating strong clinical translation potential [4] - A novel non-drug therapy called acute intermittent hypoxia (aIH) has been developed, which effectively activates the brain's adenosine signaling and shows promise as a safe, non-invasive treatment option [5] - The team is collaborating with clinical teams to advance clinical trials for the aIH therapy, aiming to enhance treatment durability and reduce tolerance issues [5]