Novel perspectives for glutamatergic strategies, psychedelics and antipsychotic augmentation in Treatment Resistant Depression: A narrative review

Introduction: Treatment-Resistant Depression (TRD) affects approximately 30-50% of patients with Major Depressive Disorder (MDD) who fail to respond to at least two adequate antidepressant trials. This condition presents substantial clinical and functional challenges, and no universally accepted treatment algorithm currently exists. Emerging therapeutic strategies, particularly glutamatergic modulators and psychedelics, have shown promising results in managing TRD. Methods: We conducted a narrative review using PubMed and Scopus with the query “(treatment resistant depression OR TRD) AND (glutamatergic OR glutamate OR psychedelic OR psilocybin OR antipsychotic augmentation) NOT (review OR animal OR mouse).” After applying inclusion/exclusion criteria, 60 articles were selected. Results: The most frequently studied treatments (43 studies) are glutamatergic agents, particularly intravenous ketamine and intranasal esketamine, which have consistently demonstrated rapid and clinically meaningful reductions in depressive symptoms. Augmentation with atypical antipsychotics also showed effectiveness for partial responders. Psychedelic-assisted therapies yielded sustained antidepressant benefits and modulated biomarkers such as BDNF and inflammatory markers. Discussion and Conclusion: The findings support a potential paradigm shift away from traditional monoaminergic-based treatments toward more personalized, mechanism-driven strategies for managing TRD. Ketamine and esketamine offer rapid-onset relief suitable for acute high-risk cases, while augmentation strategies remain valuable for partial responders. Psychedelic interventions, although still experimental, hold promise as adjunctive options. Furthermore, biomarkers and early response predictors may help guide individualized treatment decisions.