TRANSLATING 5-HT4R AGONISM INTO MENTAL ILLNESS: POTENTIAL CLINICAL APPLICATIONS FOR MOOD DISORDER AND COGNITIVE IMPAIRMENT

Abstract Background Depression is common and costly. First-line antidepressants are ineffective for many and have little impact against cognitive deficits. Stimulating 5-HT4 receptors (5-HT4R) rapidly improves learning and has antidepressant-like effects in rodents 1,2. The highly-selective 5-HT4R agonist, prucalopride (licensed for constipation), had a facilitatory effect on behavioural learning/memory in healthy humans after a single 3 and 6 days' treatment 4,5. Neurally, it also increased hippocampal activity 4 and reduced activation within the default mode network 5, findings supported at a network level by resting state analyses 6. Aims & Objectives Here, we present results from 2 further translational studies, examining 5-HT4R agonists in the context of mental illness. In study 1, we hypothesised that 5-HT4R agonism in participants with un-medicated depression would also increase hippocampal activation during a memory encoding task. In study 2, using a live electronic health record database, we investigated whether a prescription of prucalopride for constipation compared to alternative anti-constipation agents would reduce the future risk of depression. Method For study 1, 57 right-handed un-medicated depressed patients were randomised to a 5-HT4R agonist PF-04995274 (15mg) or placebo in a double-blind design. 53 participants received a 3T scan and fMRI memory task eliciting hippocampal activation 7 on day 6-9. Emotionally-neutral “familiar” pictures were viewed before the scan, and again in the scanner with similar “novel” images. Imaging data were analysed with FSL and corrected for multiple comparisons/sex/perfusion/grey matter. Study 2 was an emulated target trial using anonymised routinely collected data from TriNetX Analytics. We included adults without prior mental illness who received either a prescription of prucalopride (primary cohort) or linaclotide/lubiprostone (comparator cohorts). Cohorts were matched for 118 covariates capturing sociodemographics, comorbidities, and concurrent medications. The primary outcome was a first diagnosis of depressive disorder (ICD-10 F32) within two years of prescription date. Results 5-HT4 versus placebo participants had significantly lower HAM-D scores after study 1 [HAM-D 17: F(1,56)=7.6; p<0.01]. In hippocampal analyses, while processing scenes, the 5-HT4 group had significantly increased activity to novel compared to familiar images, particularly in the left hemisphere [condition*hemisphere*group: F(1,49)=3.56, p=0.04, ηρ2=0.08); novel vs familiar (i) prucalopride L (p=0.035) &R hemisphere (p=0.050); (ii) placebo L (p=0.789) &R hemisphere (p=0.053)]. In study 2, treatment with prucalopride was associated with reduced incidence of depression compared to both lubiprostone [HR 0.84, 95% CI 0.73-0.96, p=0.01, n=7101) and linaclotide (HR 0.85, 95% CI 0.75-0.97, p=0.016, n=6460]. Secondary analyses indicated robustness and specificity of the results. Discussion & Conclusion In participants with un-medicated depression, the 5-HT4R agonist PF-04995274 increased hippocampal activation during a memory task; a replication of previous results in healthy volunteers using another 5-HT4R agonist. The pharmaco-epidemiological findings also suggest 5-HT4R agonists may be novel agents in the prevention of depression. Results from both studies are consistent with preclinical evidence establishing a key role for 5-HT4Rs in mood disorders and cognitive deficits. References 1) Lucas G, Rymar VV, Du J, et al. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 2007; 55(5): 712-25. 2) Murphy SE, de Cates AN, Gillespie AL, et al. Translating the promise of 5HT4 receptor agonists for the treatment of depression. Psychol Med 2021; 51(7): 1111-20. 3) Murphy S, Wright L, Browning M, Cowen P, Harmer C. A role for 5-HT4 receptors in human learning and memory. Psychol Med 2020; 50(16): 2722-30. 4)de Cates AN, Wright LC, Martens MAG, et al. Deja-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task. Trans Psychiatry 2021; 11: 497. 5) de Cates AN, Martens MAG, Wright LC, et al. The effect of the 5-HT4 agonist, prucalopride, on an fMRI faces task in the healthy human brain. Frontiers in Psychiatry 2022; 13(859123). 6) de Cates AN, Martens MAG, Wright LC, et al. 5-HT4 receptor agonist effects on functional connectivity in the human brain; Implications for pro-cognitive action. Biol Psychiatry Cogn Neurosci Neuroimaging 2023. 7) Filippini N, MacIntosh BJ, Hough MG, et al. Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A 2009; 106(17): 7209-14.