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.
Psychedelics can activate serotonin receptors located inside cells, a site that serotonin itself cannot reach. This intracellular action may explain why psychedelics produce profound and lasting changes in brain function and behavior, distinct from the effects of the body's own serotonin.
Ketamine's rapid antidepressant effects in depressed patients may depend on a specific metabolite, (2R,6R)-hydroxynorketamine ((6)-HNK). In male BALB/cJ mice with high anxiety, blocking liver enzymes that break down ketamine (using fluconazole) raised ketamine and norketamine levels in blood and brain but sharply reduced (6)-HNK levels. This blockade prevented ketamine's sustained antidepressant-like effects 24 hours later in behavioral tests and stopped the increase in cortical GABA levels. Giving a single dose of (2R,6R)-HNK alone restored the antidepressant-like activity. The findings indicate that (6)-HNK is essential for ketamine's lasting antidepressant effects and suggest that drug interactions affecting ketamine metabolism could matter in patients.