Abstract:
Treatment-resistant depression (TRD) represents a major public health challenge, affecting nearly one-third of
patients with depressive disorders. Persistent neurobiological dysregulation of serotonergic, dopaminergic,
glutamatergic, and GABAergic systems, combined with altered neuroplasticity and network connectivity,
underlies its chronic and recurrent nature. A narrative synthesis of recent findings (2018–2025) on
neurotransmitter modulation and neurocircuit reconfiguration was conducted, integrating data from fMRI,
PET, and electrophysiological studies, alongside clinical experience in TRD management. The review
highlights pharmacological, neuromodulatory, and integrative approaches that restore functional connectivity
within cortico-limbic and default mode networks. Novel antidepressant strategies target glutamatergic
transmission via NMDA antagonists (ketamine, esketamine), promoting synaptogenesis through BDNF
activation and AMPA receptor modulation. Dopaminergic enhancement (e.g., aripiprazole, bupropion)
rebalances reward circuitry and improves motivation. GABAergic agents (brexanolone, zuranolone) regulate
cortical inhibition and stress response.
Non-pharmacological interventions—rTMS, tDCS, vagus nerve stimulation, and neurofeedback—facilitate
circuit-level reorganization, improving functional integration between the prefrontal cortex, hippocampus, and
amygdala. Nutraceuticals (omega-3 PUFAs, L-tryptophan, magnesium) and microbiome-targeted therapies
further support monoaminergic balance and neuroimmune modulation. Treatment-resistant depression
involves multidimensional dysregulation across neurochemical and connectivity domains. Combining
neurotransmitter modulation with network-targeted interventions represents a paradigm shift toward
precision psychiatry. Integrated pharmacological, neuromodulatory, and lifestyle-based strategies hold promise
for restoring resilience and sustained remission in TRD.
