Treatment-resistant depression (TRD) affects about 30% of patients with major depressive disorder and remains a major clinical challenge. The limited effectiveness of classical antidepressants suggests that the pathophysiology of TRD is complex and extends beyond the traditional monoamine hypothesis. The aim of this paper was to present current concepts of the neurobiological background of TRD and their therapeutic implications.

Research findings indicate an important role of glutamatergic dysfunction and excitotoxicity, GABA system dysfunction, impaired neuroplasticity, dysregulation of the hypothalamic–pituitary–adrenal axis, and neuroinflammatory processes. Increasing evidence also highlights the role of the kynurenine pathway and the NLRP3 inflammasome as mechanisms linking chronic stress, neuroinflammation, and treatment resistance. Neuroinflammation is associated with poorer prognosis, higher treatment resistance, and elevated mortality risk in depression. Impaired neuroplasticity related to BDNF also appears to play a key role. Chronic stress may reduce BDNF synthesis, leading to impaired neuronal plasticity and depressive symptoms.

Among emerging therapeutic strategies, ketamine and psilocybin are of particular interest because of their effects on the glutamatergic system and neuroplasticity. Neuroimaging studies suggest the involvement of frontal brain regions and reduced connectivity within the default mode network in TRD. Genetic studies have not identified single variants with major clinical significance, but increasing attention is focused on epigenetic mechanisms and pharmacogenomics. Other promising approaches include substances affecting cellular energy metabolism.

Treatment-resistant depression is a multifactorial disorder involving complex neurotrophic, inflammatory, metabolic, neuroendocrine, and genetic mechanisms. A better understanding of these processes may support the development of more personalized and effective treatments.