Treatment-Resistant Depression in the 21st Century: A Scoping Review of Psychedelics and Neuromodulation in Transforming Care

Background: Treatment-resistant depression (TRD) affects a significant proportion of individuals with major depressive disorder and remains difficult to manage with conventional treatments. Psychedelic-assisted therapies and neuromodulation have emerged as innovative interventions targeting neurobiological mechanisms beyond traditional antidepressant approaches. Objectives: This scoping review mapped current evidence on psychedelic-assisted therapies and neuromodulation for TRD, identified research trends, and highlighted key knowledge gaps. Methods: Peer-reviewed studies published between 2010 and 2025 were identified from PubMed, PsycINFO, Web of Science, and Scopus. Eligible studies involved adults with TRD receiving psychedelic-assisted therapies (psilocybin, MDMA, ketamine) or neuromodulation interventions (transcranial magnetic stimulation, electroconvulsive therapy, deep brain stimulation). Findings were synthesized narratively with tabular and visual mapping. Results: Both intervention classes demonstrated rapid antidepressant effects, with psilocybin and ketamine showing fast symptom reduction and neuromodulation, exhibiting consistent efficacy in severe TRD. Evidence for long-term outcomes, comparative effectiveness, and personalized treatment strategies remains limited.