Cleare Anthony J, Kerr-Gaffney Jess, Goldsmith Kimberley, Zenasni Zohra, Yaziji Nahel, Jin Huajie, Colasanti Alessandro, Geddes John R, Kessler David, McAllister-Williams R Hamish, Young Allan H, Barrera Alvaro, Marwood Lindsey, Taylor Rachael W, Tee Helena
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Lancet Psychiatry. 2025 Apr;12(4):276-288. doi: 10.1016/S2215-0366(25)00028-8.
Lithium and quetiapine are first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. We aimed to assess whether quetiapine augmentation therapy is more clinically effective and cost-effective than lithium for patients with treatment-resistant depression over 12 months.
We did this pragmatic, open-label, parallel-group, randomised controlled superiority trial at six National Health Service trusts in England. Eligible participants were adults (aged ≥18 years) with a current episode of major depressive disorder meeting DSM-5 criteria, with a score of 14 or higher on the 17-item Hamilton Depression Rating Scale at screening who had responded inadequately to two or more therapeutic antidepressant trials. Exclusion criteria included having a diagnosis of bipolar disorder or current psychosis. Participants were randomly assigned (1:1) to the decision to prescribe lithium or quetiapine, stratified by site, depression severity, and treatment resistance, using block randomisation with randomly varying block sizes. After randomisation, pre-prescribing safety checks were undertaken as per standard care before proceeding to trial medication initiation. The coprimary outcomes were depressive symptom severity over 12 months, measured weekly using the Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation. Economic analyses compared the cost-effectiveness of the two treatments from both an NHS and personal social services perspective, and a societal perspective. Primary analyses were done in the intention-to-treat population, which included all randomly assigned participants. People with lived experience were involved in the trial. The trial is completed and registered with the International Standard Randomised Controlled Trial registry, ISRCTN16387615.
Between Dec 5, 2016, and July 26, 2021, 212 participants (97 [46%] male gender and 115 [54%] female gender) were randomly assigned to the decision to prescribe quetiapine (n=107) or lithium (n=105). The mean age of participants was 42·4 years (SD 14·0 years) and 188 (89%) of 212 participants were White, seven (3%) were of mixed ethnicity, nine (4%) participants were Asian, four (2%) were Black, three (1%) were of Other ethnicity, and ethnicity was not recorded for one (1%) participant. Participants in the quetiapine group had a significantly lower overall burden of depressive symptom severity than participants in the lithium group (area under the between-group differences curve -68·36 [95% CI -129·95 to -6·76; p=0·0296). Time to discontinuation did not significantly differ between the two groups. Quetiapine was more cost-effective than lithium. 32 serious adverse events were recorded in 18 participants, one of which was deemed possibly related to the trial medication in a female participant in the lithium group. The most common serious adverse event was overdose, occurring in three (3%) of 107 participants in the quetiapine group (seven events) and three (3%) of 105 participants in the lithium group (five events).
Results of the trial suggest that quetiapine is more clinically effective than lithium as a first-line augmentation option for reducing symptoms of depression in the long-term management of treatment-resistant depression, and is probably more cost-effective than lithium.
National Institute for Health and Care Research Health Technology Assessment programme.
锂盐和喹硫平是难治性抑郁症的一线增效治疗选择；然而，很少有研究对它们进行直接比较，且没有超过8周的研究。我们旨在评估在12个月的时间里，对于难治性抑郁症患者，喹硫平增效治疗在临床疗效和成本效益方面是否优于锂盐。
我们在英国的6个国民医疗服务体系信托机构开展了这项实用、开放标签、平行组、随机对照优效性试验。符合条件的参与者为年龄≥18岁的成年人，目前患有符合《精神疾病诊断与统计手册》第5版标准的重度抑郁症发作，筛查时17项汉密尔顿抑郁量表评分≥14分，且对两种或更多种抗抑郁治疗试验反应不佳。排除标准包括患有双相情感障碍或目前患有精神病。参与者按1:1随机分配接受开具锂盐或喹硫平的决定，按地点、抑郁严重程度和治疗抵抗情况分层，采用随机分组块大小随机变化的区组随机化方法。随机分组后，在开始试验用药前按照标准护理进行处方前安全检查。共同主要结局为12个月内的抑郁症状严重程度，每周使用抑郁症状快速清单进行测量，以及全因治疗停药时间。经济分析从国民医疗服务体系和个人社会服务角度以及社会角度比较了两种治疗的成本效益。主要分析在意向性治疗人群中进行，该人群包括所有随机分配的参与者。有实际生活经验的人参与了该试验。该试验已完成并在国际标准随机对照试验注册库ISRCTN16387615注册。
在2016年12月5日至2021年7月26日期间，212名参与者（97名[46%]男性和115名[54%]女性）被随机分配接受开具喹硫平（n = 107）或锂盐（n = 105）的决定。参与者的平均年龄为42.4岁（标准差14.0岁），212名参与者中有188名（89%）为白人，7名（3%）为混合种族，9名（4%）参与者为亚洲人，4名（2%）为黑人，3名（1%）为其他种族，1名（1%）参与者未记录种族信息。喹硫平组参与者的抑郁症状严重程度总体负担显著低于锂盐组（组间差异曲线下面积为 -68.36 [95%置信区间 -129.95至 -6.76；p = 0.0296]）。两组的停药时间无显著差异。喹硫平比锂盐更具成本效益。18名参与者记录了32起严重不良事件，其中1起被认为可能与锂盐组一名女性参与者的试验用药有关。最常见的严重不良事件是过量用药，喹硫平组107名参与者中有3名（3%）发生（7起事件），锂盐组105名参与者中有3名（3%）发生（5起事件）。
试验结果表明，作为难治性抑郁症长期管理中减轻抑郁症状的一线增效选择，喹硫平在临床疗效上优于锂盐，且可能在成本效益上也优于锂盐。
国家卫生与保健研究所卫生技术评估项目。
