Neurobiological correlates of treatment-resistant depression: implications for pharmacotherapy
Neuropsychiatria i Neuropsychologia January 1, 2026 Joanna Kot, Ewa Ferensztajn-Rochowiak, Oryna Kaliuzhna et al.
Treatment-resistant depression (TRD) affects about 30% of patients with major depressive disorder and involves complex neurobiological mechanisms beyond the traditional monoamine hypothesis. Research indicates roles for glutamatergic dysfunction, GABA system dysfunction, impaired neuroplasticity, dysregulation of the hypothalamic-pituitary-adrenal axis, and neuroinflammatory processes. The kynurenine pathway and NLRP3 inflammasome are highlighted as mechanisms linking chronic stress, neuroinflammation, and treatment resistance. Impaired neuroplasticity related to BDNF is also key, with chronic stress reducing BDNF synthesis. Emerging therapeutic strategies include ketamine and psilocybin due to their effects on the glutamatergic system and neuroplasticity. The paper presents current concepts of TRD's neurobiological background and their therapeutic implications.