The NMDAR antagonist ketamine has rapid and sustained antidepressant effects; this has prompted a search for alternative NMDAR antagonists that have the same antidepressant properties but lack the undesirable side effects of ketamine. Todd Gould and colleagues now show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant activity, and that the (2R,6R)-HNK enantiomer exerts rapid and sustained antidepressant actions in mice. These effects are NMDAR-independent but require AMPAR activation. Importantly, (2R,6R)-HNK lacks the side effects associated with ketamine. These findings suggest new options for the development of novel rapid-acting antidepressants.
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