(2R,6R)-Hydroxynorketamine, A Metabolite of Ketamine: The Antidepressant Actions and the Mechanisms

Current antidepressant medications acting on monoaminergic systems take long time (weeks to months) to induce beneficial effects at low rates (about 30%). Accumulating evidences demonstrate that ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, produces rapid and long-lasting antidepressant effects in patients with major depressive disorder as well as treatment-resistant depression. A metabolite of ketamine, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], produces rapid and sustained antidepressant-like effects in animal models without ketamine-like side effects, which have recently gained much attention. Notably, (2R,6R)-HNK does not block the NMDA receptor, the primary target of ketamine. However, the molecular signaling mechanisms of antidepressant-like effects of (2R,6R)-HNK remain unknown.