Modulation of neurotransmitters and reconfiguration of brain circuits in treatment-resistant depression

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.