Therapeutic Shifts and Scientific Influence in Treatment-Resistant Depression Research: A Data-Driven Perspective.

Background: Treatment-resistant depression (TRD) remains a major psychiatric challenge, with therapeutic paradigms evolving over the last 50 years. However, research on TRD is fragmented across molecular mechanisms, clinical interventions, and epidemiological trends, highlighting the need for a comprehensive synthesis to guide future studies and enhance clinical outcomes. Methods: We conducted a large-scale bibliometric analysis of 16,198 TRD-related publications from PubMed, Web of Science, and Scopus (1974-2025). Using CiteSpace, VOSviewer, and Bibliometrix, we quantified publication trends, collaborative networks, and thematic shifts. Special attention was paid to influential researchers and institutions, as well as examining the shifting research focus from traditional invasive therapies, including deep brain stimulation, to emerging pharmacological advancements such as ketamine-based treatments. Results: We identified leading countries, institutions, and key contributors on TRD research. Thematic clusters revealed sustained focus on neurobiological mechanisms (glutamate dysfunction, inflammation) and clinical efficacy. A pivotal shift from invasive techniques (dominant before 2000) to ketamine-based therapies was observed, with ketamine-related publications surging after 2010. High-impact journals such as Biological Psychiatry and American Journal of Psychiatry anchored 3 intellectual clusters: molecular neuropharmacology, pathophysiology, and clinical psychiatry. Despite progress, gaps persist in understanding ketamine's systemic effects and noncanonical NMDA receptor roles. Conclusions: This bibliometric study traces TRD research evolution from the 1970s onward, revealing key shifts from invasive interventions to novel pharmacotherapies such as ketamine, a transformative advance highlighting a mechanism-driven approach. By analyzing influential contributors, collaborations, and emerging trends, our work synthesizes decades of fragmented knowledge, providing clinicians and researchers with a cohesive road map for future TRD investigations.