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No. 1 (2026)

GENERAL THERAPY QUESTIONS AND REVIEWS

The Role of the Gut Microbiome in the Development of Treatment-Resistant Depression (A Narrative Review)

https://doi.org/10.48612/psyph/hn3u-2946-tx22

Published 2026-03-30

  • M.Yu. Popov

M.Yu. Popov
V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology

Abstract

Treatment-resistant depression (TRD) constitutes a major clinical and public health challenge. This narrative review aims to synthesize and critically evaluate the current evidence on the role of the gut microbiome in the development and persistence of TRD. The review reveals a specific, resistance-associated microbial signature distinct from and superimposed on general depressive dysbiosis. This signature is characterized by reduced alpha-diversity, shifts in predominance of certain bacterial taxa, and impaired microbial metabolism of neuroactive molecules. Evidence from fecal microbiota transplantation studies confirms a causal role for gut dysbiosis, demonstrating that antidepressant resistance can be transferred. Key pathophysiological mechanisms include dysbiosis-induced neuroinflammation, metabolic and neurotransmitter dysregulation, and impaired neuroplasticity. We propose the concept of “microbiome rigidity” as a core mechanism, wherein the inability of the microbial community to undergo adaptive restructuring compromises the treatment response. The review also provides a critical appraisal of microbiome-targeted strategies designed to overcome this rigidity, including targeted probiotics, dietary interventions, antimicrobial drugs, fecal microbiota transplantation, and innovative biotechnological approaches. Finally, we outline the main limitations of current research and promising directions for future investigations. Collectively, the evidence supports targeting the gut microbiome as a novel, pathogenetically-grounded approach to the management of TRD.

Keywords

treatment-resistant depression, gut microbiome, gut-brain axis, neuroinflammation, neuroplasticity, microbiome modulation

PDF (Русский)

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