Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects, but the role of NMDA receptor activation in these effects is unclear. In male mice, ketamine showed an inverted U-shaped dose-response in antidepressant-sensitive tests, indicating that excessive NMDA receptor inhibition can prevent its antidepressant actions. Pretreatment with other NMDA receptor antagonists blocked ketamine's behavioral effects, upregulation of AMPA receptor subunits, and metaplasticity. The antidepressant-like actions of other rapid-acting compounds were also blocked by NMDA receptor inhibition. Ketamine acted synergistically with an NMDA receptor positive allosteric modulator. The authors conclude that rapid-acting antidepressants share a common downstream NMDA receptor activation-dependent effector mechanism, and promoting NMDA receptor signaling may be an effective antidepressant strategy.
The discovery that low doses of ketamine and esketamine can rapidly and persistently relieve depression in treatment-resistant patients has shifted thinking about how quickly depression can be treated. Impaired excitatory synapses in mood-regulating brain circuits likely contribute to depression. Metaplasticity—the process of priming neurons to alter their future capacity for plasticity—may be harnessed by drugs called metaplastogens to reverse depression's underlying pathophysiology. This review argues that diverse rapid-acting antidepressants, including ketamine mimetics and psychedelics, converge on common downstream molecular mediators to strengthen synapses and produce lasting effects. Targeting metaplastic mechanisms could reduce dosing frequency and side effects by eliminating the need for continuous drug presence.