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.

难治性抑郁症（Treatment-resistant depression, TRD）是当前科研与临床实践中的重大挑战。各类临床指南均推荐不同的药物治疗方案。尽管传统上锂盐与第二代抗精神病药一直是药物抵抗患者的首选治疗药物，但近年来越来越多证据表明，艾司氯胺酮作为一种快速起效的抗抑郁药物具有良好疗效。尽管已有大量Meta分析证据，但针对这些药物的直接头对头比较研究仍较为匮乏。
本研究针对相关数据库开展系统综述，纳入针对成人难治性抑郁症患者，比较锂盐、喹硫平或（艾司）氯胺酮增效治疗的随机对照试验与自然主义头对头研究，并对相关Meta分析的结果进行了定性整合。
本研究共纳入4项研究，其中3项为比较锂盐与喹硫平的临床试验，1项为比较艾司氯胺酮与喹硫平的研究。综上：（1）上述三种药物均具有抗抑郁疗效；（2）艾司氯胺酮或在疗效上优于喹硫平，而喹硫平又可能优于锂盐。
本研究结果总体支持重新评估现有指南中的治疗方案流程。但由于三种药物分属完全不同的分子类别，具有各异的药代动力学与药效动力学特性，且在（1）不良反应与禁忌证、（2）治疗侧重点上均存在差异，因此将其纳入全面的临床诊疗情境中进行综合考量尤为重要。