Association between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trial

Abstract

Background: The serotonin 4 receptor (5-HT₄R) is a promising target for the treatment of depression. Highly selective 5-HT₄R agonists, such as prucalopride, have antidepressant-like and procognitive effects in preclinical models, but their clinical effects are not yet established.

Aims: To determine whether prucalopride (a 5-HT₄R 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.

Method: 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.

Results: 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; P = 0.038; n = 8572 in each matched cohort) and lubiprostone (hazard ratio 0.79, 95% CI 0.69-0.91; P < 0.001; n = 8281). Significantly lower risks of all mood disorders and psychosis were also observed. Results were similar across robustness analyses.

Conclusions: These findings support preclinical data and suggest a role for 5-HT₄R 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.

Keywords: Electronic health records; antidepressants; big data; depressive disorders; survival analysis.

Fig. 1

Locations of 5-HT₄Rs in the brain and actions of prucalopride. (a) Brain regions where 5-HT₄Rs are particularly highly expressed (see Beliveau et al). Darker shading indicates regions of highest expression (i.e. basal ganglia); lighter shading indicates relatively lower expression (i.e. neocortex). (b) Action of prucalopride at a serotonin synapse as a highly selective agonist at transmembrane G-protein-coupled 5-HT₄Rs. 5-HT₄R, serotonin 4 receptor; 5-HTP, 5-hydroxytryptophan; cAMP, cyclic adenosine monophosphate.

Fig. 2

Kaplan–Meier curves showing the cumulative incidence of depression diagnosis over 12 months in those receiving (a) prucalopride versus linaclotide and (b) prucalopride versus lubiprostone. The shaded areas around curves represent 95% CI.

Fig. 3

Interrupted time-series analysis comparing (a) the incidence of depression and (b) any negative control outcomes, before and after prucalopride prescription, shown as a proportion of people who had a healthcare encounter during each month.