Physical Therapy for Treatment-Resistant Depression A Comprehensive Review of Efficacy, Safety, and Evidence Grading

Major depressive disorder (MDD) is a common psychiatric illness that is primarily treated with antidepressant medications in clinical practice. Depression that responds poorly to antidepressant therapy is referred to as treatment-resistant depression (TRD). However, the definition and pathogenesis of TRD are unclear, which may contribute to delayed diagnosis and management for some patients, ultimately affecting their prognosis. Although antidepressant drug therapy remains the first-line treatment for MDD, a growing body of evidence suggests that physical therapies may offer advantages over pharmacological treatments in improving depressive symptoms in selected patients. This review summarizes and comparatively analyzes recommendations from major international guidelines, including CANMAT, RANZCP, WFSBP, APA, and NICE, regarding the definition of TRD and physical treatment strategies. Widely used physical therapies for TRD are evaluated with respect to efficacy, safety and tolerability, clinical positioning, target populations, and regulatory status. Current evidence supports ECT and rTMS as the principal established treatment options for TRD. VNS may be considered for highly refractory TRD characterized by chronicity, recurrent episodes, and failure of multiple treatments, although it is generally positioned as a later-line intervention. Acupuncture and Neurofeedback may serve as adjunctive interventions with limited supporting evidence. Emerging techniques, including tACS, DBS, MST, EpCS, and FUS, lack sufficient high-quality evidence and standardized treatment protocols and should currently be conducted primarily in specialized centers or research settings. In addition, this review also highlights novel physical approaches and combination strategies with potential therapeutic value for TRD, provides scientific evidence and treatment references for clinical practice.