The article discusses the potential of targeting metaplasticity mechanisms to enhance the sustained antidepressant effects of treatments for major depressive disorder (MDD). Metaplasticity is the process by which neurons alter their responsiveness to future stimuli, and it plays a crucial role in regulating synaptic plasticity. The authors review evidence that rapid-acting antidepressants, such as ketamine and its metabolites, converge on consistent molecular mediators that enhance excitatory neurotransmission and improve synaptic plasticity. These mechanisms, which include NMDA receptor activation, metabotropic glutamate receptor antagonism, and AMPA receptor potentiation, may lead to sustained antidepressant effects by modifying the threshold for synaptic plasticity induction. The article highlights the advantages of targeting metaplasticity, such as reduced dosing frequency and fewer adverse effects. It also explores the potential of developing novel therapeutics, known as metaplastogens, that directly engage metaplastic mechanisms. The review concludes by emphasizing the need for further research to understand the temporal progression and mechanisms of metaplasticity, particularly in the context of antidepressant treatments.The article discusses the potential of targeting metaplasticity mechanisms to enhance the sustained antidepressant effects of treatments for major depressive disorder (MDD). Metaplasticity is the process by which neurons alter their responsiveness to future stimuli, and it plays a crucial role in regulating synaptic plasticity. The authors review evidence that rapid-acting antidepressants, such as ketamine and its metabolites, converge on consistent molecular mediators that enhance excitatory neurotransmission and improve synaptic plasticity. These mechanisms, which include NMDA receptor activation, metabotropic glutamate receptor antagonism, and AMPA receptor potentiation, may lead to sustained antidepressant effects by modifying the threshold for synaptic plasticity induction. The article highlights the advantages of targeting metaplasticity, such as reduced dosing frequency and fewer adverse effects. It also explores the potential of developing novel therapeutics, known as metaplastogens, that directly engage metaplastic mechanisms. The review concludes by emphasizing the need for further research to understand the temporal progression and mechanisms of metaplasticity, particularly in the context of antidepressant treatments.