Beyond first-line antidepressants: lithium, quetiapine, or esketamine? Integrating meta-analyses and preliminary head-to-head evidence

Treatment-resistant depression (TRD) poses a major challenge in research and clinical practice. Various guidelines recommend different pharmacological approaches. While lithium and second-generation antipsychotics have traditionally been the drugs of choice in cases of medication resistance, recent years have seen increasing evidence for the efficacy of esketamine as a fast-acting agent against depression. Although there is a large body of meta-analytical evidence, direct comparisons between the agents are scarce. A systematic review of databases was conducted for randomised and naturalistic head-to-head studies comparing augmentation with lithium, quetiapine, or (es)ketamine in adults with TRD was included. Findings from relevant meta-analyses were integrated qualitatively. We found four studies, comprising three trials comparing lithium and quetiapine and one comparing esketamine and quetiapine. In summary, (1) all three agents are effective, (2) there may be a descriptive superiority of esketamine over quetiapine and of quetiapine over lithium. The results generally argue for a re-evaluation of existing treatment algorithms in guidelines. However, since all three are fundamentally different molecules with different pharmacokinetic and pharmacodynamic properties and differ in (1) side effects and contraindications as well as (2) profile focus, embedding them in a comprehensive clinical context is important.