The article discusses the role of metaplasticity in the development of rapid-acting antidepressants. Metaplasticity refers to the process of regulating future plasticity by priming neurons with stimulation that alters later neuronal plasticity responses. The study highlights that the mechanisms of rapid-acting antidepressants, such as ketamine and its stereoisomer esketamine, converge on consistent downstream molecular mediators that facilitate the expression and maintenance of increased synaptic strength and persistent antidepressant effects. These mechanisms involve metaplastic effects that enhance excitatory neurotransmission and alter synaptic plasticity capacity. The article reviews evidence that the initiating mechanisms of pharmacologically diverse rapid-acting antidepressants converge on consistent downstream molecular mediators that facilitate the expression/maintenance of increased synaptic strength and resultant persisting antidepressant effects. The study concludes that the convergence of these therapeutic mechanisms provides the opportunity for metaplasticity processes to be harnessed as a druggable plasticity mechanism by next-generation therapeutics. The article also discusses the synaptic mechanisms of plasticity, including short-term and long-term synaptic plasticity, and the role of NMDAR in these processes. It highlights the importance of metaplasticity in the context of depression and the potential for targeting metaplastic mechanisms to improve depression symptoms. The study also discusses the pharmacological direct and indirect NMDAR activators and the converging druggable metaplasticity mechanisms of ketamine mimetics. The article concludes that the field of psychiatry is primed for investigations aimed at leveraging metaplastic mechanisms to enhance antidepressant efficacy and design novel therapeutics.The article discusses the role of metaplasticity in the development of rapid-acting antidepressants. Metaplasticity refers to the process of regulating future plasticity by priming neurons with stimulation that alters later neuronal plasticity responses. The study highlights that the mechanisms of rapid-acting antidepressants, such as ketamine and its stereoisomer esketamine, converge on consistent downstream molecular mediators that facilitate the expression and maintenance of increased synaptic strength and persistent antidepressant effects. These mechanisms involve metaplastic effects that enhance excitatory neurotransmission and alter synaptic plasticity capacity. The article reviews evidence that the initiating mechanisms of pharmacologically diverse rapid-acting antidepressants converge on consistent downstream molecular mediators that facilitate the expression/maintenance of increased synaptic strength and resultant persisting antidepressant effects. The study concludes that the convergence of these therapeutic mechanisms provides the opportunity for metaplasticity processes to be harnessed as a druggable plasticity mechanism by next-generation therapeutics. The article also discusses the synaptic mechanisms of plasticity, including short-term and long-term synaptic plasticity, and the role of NMDAR in these processes. It highlights the importance of metaplasticity in the context of depression and the potential for targeting metaplastic mechanisms to improve depression symptoms. The study also discusses the pharmacological direct and indirect NMDAR activators and the converging druggable metaplasticity mechanisms of ketamine mimetics. The article concludes that the field of psychiatry is primed for investigations aimed at leveraging metaplastic mechanisms to enhance antidepressant efficacy and design novel therapeutics.