Targeting metaplasticity mechanisms to promote sustained antidepressant actions.
Molecular psychiatry April 1, 2024 Kyle A. Brown, Todd D. Gould 45 citations
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.