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]

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]

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]

Core Insights - Depression is a significant challenge in clinical psychiatry, as highlighted by the Beijing Brain Science and Brain-like Research Institute's recent findings [1] - The study published in Nature identifies adenosine signaling as a key pathway for the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT) [1] - The research proposes an "intermittent hypoxia intervention" (aIH) to safely and controllably induce adenosine release in the brain, leading to significant antidepressant effects [1] Summary by Categories Research Findings - The study confirms that adenosine signaling is a common mechanism underlying the rapid antidepressant actions of both ketamine and ECT [1] - This discovery enhances the understanding of rapid antidepressant mechanisms and provides a solid theoretical basis for developing new generation antidepressant strategies with fewer side effects [1] Implications for Treatment - The findings suggest potential for developing small molecule drugs and non-drug interventions targeting adenosine signaling [1] - The research opens avenues for safer and more effective treatment options for depression, addressing a critical need in mental health care [1]

Core Insights - Chinese scientists have made a significant breakthrough in depression treatment research by revealing the common mechanism behind ketamine and electroconvulsive therapy (ECT), which is the adenosine signaling pathway [1][2][3] - This discovery provides a clear path for developing safer and more effective new treatment options for depression [1][3] Research Collaboration - The research was led by the Beijing Brain Science and Brain-like Research Institute, in collaboration with the Changchun Institute of Applied Chemistry and Peking University [1][2] - The project leader, Luo Minmin, has over 30 years of experience in neuroscience and has made several original contributions in various fields [1][2] Depression Statistics - Depression is one of the most common mental disorders globally, with the World Health Organization estimating over 300 million patients annually [1] - Approximately one-third of patients do not respond well to traditional medications, known as treatment-resistant depression [1] Mechanism of Action - The study utilized advanced gene-encoded fluorescent probe technology to observe that both ketamine and ECT cause a rapid and sustained increase in adenosine levels in key brain areas related to emotional regulation [2][3] - Blocking the brain's reception of adenosine signals negated the antidepressant effects of both therapies, while directly activating this pathway produced clear antidepressant effects [2][3] Drug Development - The research has led to the design and synthesis of more efficient ketamine derivatives that show superior antidepressant effects at lower doses with significantly reduced side effects [2][3] - The study provides a roadmap for developing next-generation drugs that retain the benefits of existing therapies while minimizing adverse effects [2][3] Non-Pharmacological Approaches - The research also opens new avenues for non-drug treatments, such as using acute intermittent hypoxia to activate the adenosine signaling pathway and produce antidepressant effects [3] - This shift from empirical use to mechanism-based precision medicine could revolutionize the treatment of depression [3] Future Directions - The team has applied for patents on related small molecule drugs and hypoxia treatment devices, and has initiated efficacy validation in collaboration with Beijing Anding Hospital [5] - The next steps involve advancing the translation of new drugs and treatment devices to provide groundbreaking solutions for depression treatment [5]

Core Viewpoint - The research published by the Beijing Brain Science and Brain-like Research Institute highlights the significant role of adenosine signaling in the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT), proposing a new intermittent hypoxia intervention to safely induce adenosine release in the brain for effective depression treatment [1] Group 1: Research Findings - The study identifies adenosine as a key signaling molecule that mediates the rapid antidepressant actions of ketamine and ECT [1] - The research confirms that the adenosine signaling pathway is a common mechanism underlying the rapid antidepressant effects of both treatments [1] - The findings provide a solid theoretical basis and clear targets for developing new generation antidepressant strategies that are based on adenosine signaling modulation, potentially leading to smaller side effects [1] Group 2: Implications for Treatment - The proposed intermittent hypoxia intervention (aIH) aims to safely and controllably induce adenosine release in the brain, achieving significant antidepressant effects [1] - This research deepens the understanding of the mechanisms behind rapid antidepressant effects, which could lead to innovative treatment options [1] - The study opens avenues for the development of small molecule drugs and non-drug interventions targeting adenosine signaling for depression treatment [1]