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 - A Chinese research team has identified a common mechanism driving the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT), focusing on the adenosine signaling pathway in the medial prefrontal cortex [2][5][12]. Group 1: Research Findings - The study published in the journal Nature confirms that both ketamine and ECT induce a significant and sustained increase in adenosine levels in the brain, which is crucial for their antidepressant effects [2][5]. - The research utilized gene-encoded fluorescent probes to observe adenosine signaling in live animal brains, marking a significant advancement in understanding the biological mechanisms behind these therapies [5][12]. - The team conducted experiments that demonstrated blocking adenosine signaling negated the antidepressant effects of both treatments, while activating this pathway produced similar effects in animal models [5][12]. Group 2: Development of New Treatments - The research has led to the design of new candidate drugs with fewer side effects, as well as a non-drug therapy called intermittent hypoxia (aIH), which is currently in clinical validation [2][12][15]. - The new drug candidates, including "dechloroketamine" (DCK), have shown promising results in animal tests, achieving significant adenosine release at lower doses compared to traditional ketamine [12][13]. - The aIH therapy aims to safely induce adenosine production through controlled low-oxygen breathing, with the potential for home use if clinical trials prove effective [14][15]. Group 3: Historical Context and Challenges - The research journey spanned over twelve years, with initial challenges in linking the immediate effects of ketamine on neural activity to its delayed antidepressant outcomes [6][7]. - A pivotal moment occurred in 2019 when the team successfully observed adenosine signaling dynamics in response to ketamine, leading to a renewed focus on this pathway [8][11]. - The team faced setbacks with traditional drug development approaches, prompting a shift towards exploring the anti-inflammatory properties of ketamine as a potential breakthrough [6][7].

Core Insights - A Chinese research team has identified a common biological mechanism driving the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT), focusing on the adenosine signaling pathway in the medial prefrontal cortex [3][6][12] - This discovery opens new avenues for antidepressant treatments, leading to the development of candidate drugs with fewer side effects and a non-drug therapy called intermittent hypoxia, which is currently in clinical validation [3][13][19] Group 1: Research Findings - The study published in the journal Nature confirms that both ketamine and ECT induce a significant and sustained increase in adenosine levels in the brain, which is crucial for their antidepressant effects [3][6][12] - The research utilized gene-encoded fluorescent probes to observe adenosine signaling in live animal brains, marking a significant advancement in understanding the mechanisms behind these therapies [6][10] Group 2: Development of New Therapies - The research team is designing new drug candidates that effectively activate the adenosine pathway while minimizing side effects, with over 30 new derivatives of ketamine already synthesized and tested [13][14] - The promising candidate, "dechloroketamine" (DCK), showed comparable adenosine release effects at lower doses than traditional ketamine, indicating a potential for reduced side effects [14] Group 3: Non-Drug Therapy Approach - The team is also developing a non-drug therapy, intermittent hypoxia, which aims to safely induce adenosine production through controlled low-oxygen breathing [15][18] - Clinical trials for this therapy are set to begin, with expectations that it could provide a low-cost, non-invasive treatment option for patients with treatment-resistant depression [19]