Ketamine, a non-competitive NMDAR antagonist, rapidly and sustainably alleviates depressive symptoms. This study reveals that its antidepressant effects are mediated by its metabolite, (2R,6R)-hydroxynorketamine (HNK), which acts through AMPA receptor activation, independent of NMDAR inhibition. (2R,6R)-HNK exhibits antidepressant effects in vivo, including behavioral, electroencephalographic, and electrophysiological changes, and lacks the side effects of ketamine. It induces long-term synaptic potentiation via AMPA receptor activation, contributing to its sustained antidepressant effects. Unlike ketamine, (2R,6R)-HNK does not produce dissociative effects or sensory gating deficits. These findings suggest that (2R,6R)-HNK could be a promising candidate for next-generation rapid-acting antidepressants with fewer side effects. The study also highlights the importance of metabolite activity in ketamine's antidepressant mechanism, offering new insights into the development of more effective and safer antidepressants.Ketamine, a non-competitive NMDAR antagonist, rapidly and sustainably alleviates depressive symptoms. This study reveals that its antidepressant effects are mediated by its metabolite, (2R,6R)-hydroxynorketamine (HNK), which acts through AMPA receptor activation, independent of NMDAR inhibition. (2R,6R)-HNK exhibits antidepressant effects in vivo, including behavioral, electroencephalographic, and electrophysiological changes, and lacks the side effects of ketamine. It induces long-term synaptic potentiation via AMPA receptor activation, contributing to its sustained antidepressant effects. Unlike ketamine, (2R,6R)-HNK does not produce dissociative effects or sensory gating deficits. These findings suggest that (2R,6R)-HNK could be a promising candidate for next-generation rapid-acting antidepressants with fewer side effects. The study also highlights the importance of metabolite activity in ketamine's antidepressant mechanism, offering new insights into the development of more effective and safer antidepressants.