Core Insights - The World Health Organization reports approximately 332 million people suffer from depression globally, with about one-third experiencing treatment-resistant depression. In China, around 95 million people are affected by depression. Current treatments face challenges such as significant side effects and a lack of understanding of underlying mechanisms [1][2]. Research Breakthrough - A research team from Beijing Brain Science and Brain-Inspired Research Institute has identified a common mechanism driving the rapid antidepressant effects of both ketamine and electroconvulsive therapy (ECT), specifically through the adenosine signaling pathway in the medial prefrontal cortex (mPFC) [1][3][4]. - This discovery provides a new biological target for depression treatment and has led to the development of candidate drugs with fewer side effects and a non-drug therapy called intermittent hypoxia (aIH), which is currently in clinical validation [1][3][7]. Research Journey - The research journey spanned twelve years, with significant progress made after an unexpected finding in 2019. The team utilized gene-encoded fluorescent probes to observe adenosine signaling in live animal brains, confirming that both ketamine and ECT lead to a rapid increase in adenosine levels in the mPFC [2][3][5][6]. - Initial challenges included inconsistent results in early experiments and the failure of traditional drug development approaches based on ketamine's known targets [4][5]. Drug Development - The team has designed over 30 new ketamine derivatives, with "dechloroketamine" (DCK) showing promising results in inducing adenosine release at lower doses compared to traditional ketamine, while also exhibiting fewer side effects [7][8]. - The development of these new molecules is expected to take 3 to 5 years to complete all necessary clinical trials before market introduction [8]. Non-Drug Therapy - The team is also exploring a non-drug therapy, intermittent hypoxia, which aims to induce adenosine production through controlled low-oxygen breathing. This method has entered clinical trials with the potential for home use [9][10][11]. - If proven effective, this therapy could provide a non-invasive, convenient, and low-cost treatment option for depression patients [11].

Core Insights - The research published in the journal "Nature" confirms that the adenosine signaling pathway is a common core mechanism for the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT), providing a clear target for developing safer and more effective depression treatments [1][2] Group 1: Research Findings - Approximately one-third of treatment-resistant depression patients do not respond well to traditional medications, highlighting the need for effective interventions like ketamine and ECT, which have known efficacy but also significant side effects [1] - The research team utilized genetically encoded adenosine probes and fiber photometry to monitor adenosine levels in the brains of mice, discovering that both ketamine and ECT rapidly and persistently elevated adenosine levels in key brain regions associated with emotional regulation [1][2] - The study identified that the adenosine A1 and A2A receptors are essential for the antidepressant effects, as their knockout or blockade resulted in the complete loss of the antidepressant effects of both therapies [1] Group 2: Mechanism Exploration - Ketamine was found to directly inhibit the mitochondrial tricarboxylic acid cycle, regulating cellular energy metabolism and increasing intracellular adenosine reserves, which are released extracellularly, independent of the traditional NMDA receptor inhibition mechanism [2] - A ketamine derivative, deketamine, was developed, showing stronger antidepressant efficacy and weaker side effects related to motor hyperactivity [2] - The proposed "intermittent hypoxia intervention" can safely induce adenosine release in the brain, achieving rapid antidepressant effects in depression model mice [2] Group 3: Collaborative Efforts and Future Directions - The research was led by the laboratory of Luo Minmin, in collaboration with the Changchun Institute of Applied Chemistry and Peking University, addressing a long-standing mystery in the field of antidepressant mechanisms [2] - This study paves the way for transitioning rapid antidepressant therapies from empirical use to precision medicine, laying a solid foundation for the development of small molecule new drugs and non-drug intervention techniques [2] - Clinical trials for related non-drug therapies have already commenced, with expected phased results by 2026 [2]