Exploring Biological Risk Factors in Treatment-Resistant Depression

Treatment-resistant depression (TRD) affects 20–30% of patients with major depressive disorder and presents a significant clinical challenge due to its biological diversity. This review highlights standard mechanisms that contribute to treatment resistance beyond traditional monoaminergic models. Evidence supports serotonergic dysregulation, including 5-HT1A autoreceptor dysfunction and “serotonin flooding” as well as dopaminergic deficits linked to anhedonia and an imbalance between glutamate and GABA that impair synaptic plasticity. Changes in neurotrophic signaling, such as reduced BDNF and VEGF activity, complicate recovery by limiting neural repair and regeneration. Chronic inflammation and oxidative stress contribute to neuronal dysfunction, while HPA axis dysregulation may exacerbate depressive symptoms and resistance to antidepressants. Emerging evidence suggests that obesity and gut microbiota imbalance reduce the production of short-chain fatty acids by bacteria and increase intestinal permeability, thereby influencing neuroinflammatory and neurochemical processes in TRD. Neuroimaging studies reveal hyperconnectivity within the default mode network and impaired reward circuits, both of which are associated with persistent symptoms and a poor treatment response. By combining evidence on inflammation, oxidative stress, neuroendocrine disturbances, microbiome changes, and brain connectivity issues, this review develops a comprehensive framework for understanding TRD. It emphasizes the importance of biomarker-based subtyping to guide personalized future treatments.