Pharmacological augmentation in treatment-resistant depression: a neurobiologically informed, practical decision guide for treatment choice with lithium, quetiapine, or esketamine.

Abstract

The treatment of treatment-resistant depression (TRD) remains a clinical challenge. Pharmacologically, several augmentation options exist. The aim of this study was to present a mechanistically informed and clinically oriented decision-making framework for the established strategies of lithium, quetiapine, and esketamine. We conducted a narrative, non-systematic review, performing a targeted literature search on neurobiological mechanisms of action, clinical effects, and psychiatric, somatic, and practical decision-making factors. We considered international guidelines and supplemented them with clinical experience. Lithium, quetiapine, and esketamine differ substantially in pharmacological profile, monitoring requirements, and clinical application. Although their mechanisms of action vary, they appear to converge on pathways related to neuroplasticity. Their distinct clinical characteristics may guide treatment selection depending on psychiatric presentation, somatic comorbidity, and practical feasibility. All three agents represent augmentation strategies in TRD. A structured evaluation of clinical, somatic, and practical factors may support individualised treatment selection. However, validated predictive markers for differential response are currently lacking.