Psychedelic-informed Therapeutics and Functional Decoupling: Toward Experience-independent Rapid-acting Antidepressants

Abstract

Major depressive disorder remains a leading cause of global disability, and many patients show limited response to conventional antidepressants.Increasing evidence suggests that a substantial subgroup exhibits chronic low-grade inflammation, which may constrain synaptic plasticity and contribute to persistent depressive symptoms.In this review, we propose that depression can be conceptualized as a disorder of dysregulated inflammation-plasticity coupling, in which inflammatory signaling interferes with adaptive neural remodeling.Sterile neuroinflammation, triggered by non-infectious stressors such as psychosocial stress and metabolic dysfunction, disrupts glutamatergic transmission, reduces brain-derived neurotrophic factor signaling, and impairs synaptic plasticity.These processes may contribute to circuit rigidity, reduced neural flexibility, and treatment resistance.Psychoplastogens, including ketamine, serotonergic psychedelics, and emerging non-hallucinogenic analogues, offer a distinct therapeutic approach by rapidly enhancing synaptic plasticity.Rather than directly suppressing inflammation, these compounds may restore neural adaptability and functionally decouple plasticity-related processes from inflammatory constraints.A central contribution of this review is the integration of inflammation-plasticity coupling and relative functional decoupling as a translational framework for understanding rapid-acting antidepressant mechanisms.Within this framework, experience-independent psychoplastogens may represent a promising direction for future antidepressant development.However, such compounds should currently be regarded as an emerging drug-development strategy rather than an established therapeutic approach.Further research is needed to validate these mechanisms in humans and to optimize biomarker-guided, plasticity-focused treatment strategies for depression.