A narrative review presents a decision-making framework for three pharmacological augmentation strategies for treatment-resistant depression: lithium, quetiapine, and esketamine. The agents differ in pharmacological profile, monitoring requirements, and clinical application, though their mechanisms appear to converge on neuroplasticity pathways. Treatment selection may be guided by psychiatric presentation, somatic comorbidity, and practical feasibility. Validated predictive markers for differential response are currently lacking.
For treatment-resistant depression, lithium, quetiapine, and esketamine are all effective augmentation options. A systematic review of head-to-head studies found only four trials: three comparing lithium and quetiapine, and one comparing esketamine and quetiapine. The evidence suggests a descriptive superiority of esketamine over quetiapine and of quetiapine over lithium. However, because the three drugs have fundamentally different properties, side effects, and contraindications, the choice should be made in a comprehensive clinical context. The findings argue for re-evaluating existing treatment algorithms in guidelines.