Therapeutic Shifts and Scientific Influence in Treatment-Resistant Depression Research: A Data-Driven Perspective
Yunsheng Liu, Zengwei Kou
Abstract
Background Treatment-resistant depression (TRD) remains a major psychiatric challenge, with therapeutic paradigms evolving over 50 years. Yet, 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. Method 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 TRP research. Thematic clusters revealed sustained focus on neurobiological mechanisms (glutamate dysfunction, inflammation) and clinical efficacy. A pivotal shift from invasive techniques (dominant pre-2000) to ketamine-based therapies was observed, with ketamine-related publications surging post-2010. High-impact journals like Biological Psychiatry and American Journal of Psychiatry anchored three intellectual clusters: molecular neuropharmacology, pathophysiology, and clinical psychiatry. Despite progress, gaps persist in understanding ketamine’s systemic effects and non-canonical NMDA receptor roles. Conclusion This bibliometric study traces TRD research evolution from the 1970s onward, revealing key shifts from invasive interventions to novel pharmacotherapies like ketamine-a transformative advance highlighting 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 roadmap for future treatment-resistant depression investigations.