Association between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trial
<p><b>Background</b></p> 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 no...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cambridge University Press
2024
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| _version_ | 1824459119654862848 |
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| author | de Cates, AN Harmer, CJ Harrison, PJ Cowen, PJ Emmanuel, A Travis, S Murphy, SE Taquet, M |
| author_facet | de Cates, AN Harmer, CJ Harrison, PJ Cowen, PJ Emmanuel, A Travis, S Murphy, SE Taquet, M |
| author_sort | de Cates, AN |
| collection | OXFORD |
| description | <p><b>Background</b></p>
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.
<p><b>Aims</b></p>
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.
<p><b>Method</b></p>
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.
<p><b>Results</b></p>
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. |
| first_indexed | 2024-09-25T04:22:28Z |
| format | Journal article |
| id | oxford-uuid:ac85f7d4-5231-4bb3-ac53-3f87c96df39f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:36:43Z |
| publishDate | 2024 |
| publisher | Cambridge University Press |
| record_format | dspace |
| spelling | oxford-uuid:ac85f7d4-5231-4bb3-ac53-3f87c96df39f2025-02-05T10:18:38ZAssociation between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trialJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ac85f7d4-5231-4bb3-ac53-3f87c96df39fEnglishSymplectic ElementsCambridge University Press2024de Cates, ANHarmer, CJHarrison, PJCowen, PJEmmanuel, ATravis, SMurphy, SETaquet, M<p><b>Background</b></p> 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. <p><b>Aims</b></p> 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. <p><b>Method</b></p> 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. <p><b>Results</b></p> 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. |
| spellingShingle | de Cates, AN Harmer, CJ Harrison, PJ Cowen, PJ Emmanuel, A Travis, S Murphy, SE Taquet, M Association between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trial |
| title | Association between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trial |
| title_full | Association between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trial |
| title_fullStr | Association between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trial |
| title_full_unstemmed | Association between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trial |
| title_short | Association between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trial |
| title_sort | association between a selective 5 ht4 receptor agonist and incidence of major depressive disorder emulated target trial |
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