The study investigates the antidepressant actions of ketamine metabolites, specifically (2S,6S,2R,6R)-hydroxynorketamine (HNK), and its enantiomer (2R,6R)-HNK, which are independent of NMDAR inhibition. Ketamine, a non-competitive NMDAR antagonist, has been shown to exert rapid and sustained antidepressant effects in depressed patients. The research demonstrates that the metabolism of ketamine to (2S,6S,2R,6R)-HNK is essential for its antidepressant effects, and that (2R,6R)-HNK exerts these effects in vivo. Notably, these actions are independent of NMDAR inhibition but involve early and sustained activation of AMPA receptors. The study also shows that (2R,6R)-HNK lacks the side effects associated with ketamine, such as sensory gating disruption and drug discrimination responses. These findings suggest a novel mechanism for ketamine's antidepressant properties and highlight the potential for developing next-generation, rapid-acting antidepressants based on (2R,6R)-HNK.The study investigates the antidepressant actions of ketamine metabolites, specifically (2S,6S,2R,6R)-hydroxynorketamine (HNK), and its enantiomer (2R,6R)-HNK, which are independent of NMDAR inhibition. Ketamine, a non-competitive NMDAR antagonist, has been shown to exert rapid and sustained antidepressant effects in depressed patients. The research demonstrates that the metabolism of ketamine to (2S,6S,2R,6R)-HNK is essential for its antidepressant effects, and that (2R,6R)-HNK exerts these effects in vivo. Notably, these actions are independent of NMDAR inhibition but involve early and sustained activation of AMPA receptors. The study also shows that (2R,6R)-HNK lacks the side effects associated with ketamine, such as sensory gating disruption and drug discrimination responses. These findings suggest a novel mechanism for ketamine's antidepressant properties and highlight the potential for developing next-generation, rapid-acting antidepressants based on (2R,6R)-HNK.