Department of Psychiatry, Warneford Hospital, University of Oxford, UK; and Institute for Mental Health, University of Birmingham, UK.
Department of Psychiatry, Warneford Hospital, University of Oxford, UK; Warneford Hospital, Oxford Health NHS Foundation Trust, Oxford, UK; and Oxford Centre for Human Brain Activity and Oxford Centre for Functional MRI of the Brain, Wellcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, UK.
Br J Psychiatry. 2024 Sep;225(3):371-378. doi: 10.1192/bjp.2024.97.
The serotonin 4 receptor (5-HTR) is a promising target for the treatment of depression. Highly selective 5-HTR agonists, such as prucalopride, have antidepressant-like and procognitive effects in preclinical models, but their clinical effects are not yet established.
To determine whether prucalopride (a 5-HTR agonist and licensed treatment for constipation) is associated with reduced incidence of depression in individuals with no past history of mental illness, compared with anti-constipation agents with no effect on the central nervous system.
Using anonymised routinely collected data from a large-scale USA electronic health records network, we conducted an emulated target trial comparing depression incidence over 1 year in individuals without prior diagnoses of major mental illness, who initiated treatment with prucalopride versus two alternative anti-constipation agents that act by different mechanisms (linaclotide and lubiprostone). Cohorts were matched for 121 covariates capturing sociodemographic factors, and historical and/or concurrent comorbidities and medications. The primary outcome was a first diagnosis of major depressive disorder (ICD-10 code F32) within 1 year of the index date. Robustness of the results to changes in model and population specification was tested. Secondary outcomes included a first diagnosis of six other neuropsychiatric disorders.
Treatment with prucalopride was associated with significantly lower incidence of depression in the following year compared with linaclotide (hazard ratio 0.87, 95% CI 0.76-0.99; = 0.038; = 8572 in each matched cohort) and lubiprostone (hazard ratio 0.79, 95% CI 0.69-0.91; < 0.001; = 8281). Significantly lower risks of all mood disorders and psychosis were also observed. Results were similar across robustness analyses.
These findings support preclinical data and suggest a role for 5-HTR agonists as novel agents in the prevention of major depression. These findings should stimulate randomised controlled trials to confirm if these agents can serve as a novel class of antidepressant within a clinical setting.
5-羟色胺 4 受体（5-HTR）是治疗抑郁症的有前途的靶点。高度选择性的 5-HTR 激动剂，如普卡必利，在临床前模型中具有抗抑郁和认知促进作用，但它们的临床效果尚未确定。
确定与没有中枢神经系统作用的抗便秘药物相比，普卡必利（一种 5-HTR 激动剂，用于治疗便秘）是否与没有精神疾病既往史的个体中抑郁症发病率降低相关。
使用来自美国大型电子健康记录网络的匿名常规收集数据，我们进行了一项模拟目标试验，比较了在没有先前诊断为主要精神疾病的个体中，在一年内使用普卡必利与两种不同作用机制的替代抗便秘药物（利那洛肽和鲁比前列酮）治疗的情况下，抑郁症的发病率。队列根据 121 个协变量进行匹配，这些协变量包括社会人口统计学因素以及历史和/或并发合并症和药物。主要结局是在索引日期后的 1 年内首次诊断为重度抑郁症（ICD-10 编码 F32）。还测试了模型和人群规范变化对结果的稳健性。次要结局包括其他六种神经精神疾病的首次诊断。
与利那洛肽（风险比 0.87，95%CI 0.76-0.99；P=0.038；每个匹配队列中为 8572 例）和鲁比前列酮（风险比 0.79，95%CI 0.69-0.91；P<0.001；P=8281）相比，普卡必利治疗与下一年抑郁症的发生率显著降低相关。还观察到所有心境障碍和精神病的风险显著降低。稳健性分析结果相似。
这些发现支持临床前数据，并表明 5-HTR 激动剂作为新型抗抑郁药的作用。这些发现应该会刺激随机对照试验，以确认这些药物是否可以在临床环境中作为新型抗抑郁药。
