Effects on hippocampal activity following 5-HT4 receptor agonism in unmedicated patients with depression: the RESTAND study

Cognitive impairment is a common but under-treated feature of Major Depressive Disorder (MDD). Preclinical and early human studies suggest that 5-HT4 receptor (5-HT4R) agonists rapidly improve learning and memory, consistent with this receptor’s role in hippocampal neuroplasticity. However, their effects in clinically depressed patients, remain unexplored. In this double-blind, randomised study, 52 right-handed, unmedicated individuals with MDD received 6-9 days of the 5-HT4R agonist PF-04995274 (15mg, once daily) or placebo. Participants subsequently underwent fMRI scanning during a memory encoding task and completed behavioural measures of auditory verbal learning and spatial working memory. Compared to placebo, PF-04995274 significantly increased activity in the hippocampus (ROI analysis) in response to novel versus familiar images, particularly in the left hemisphere. Whole brain analysis also revealed greater activation in the left inferior parietal lobule, a key region for memory processing. In contrast with previous studies using the 5-HT4R agonist prucalopride, PF-04995274 had limited effects on behavioural measures of memory. The results demonstrate that short term 5-HT4R agonism enhances hippocampal and parietal activity during memory encoding in patients with depression. This replicates and extends previous findings in healthy volunteers using prucalopride, and is consistent with preclinical evidence establishing a key role for 5-HT4Rs in hippocampal-dependent learning and memory. This translational evidence supports a role for 5-HT4R activation in modulating memory-related brain circuits in MDD and highlights its therapeutic potential for treating cognitive symptoms of depression. ### Competing Interest Statement This study was funded by the Medical Research Council (MRC): MR/S035591/1 and Pfizer under the MRC asset sharing scheme. CJH has received consultancy fees from P1vital Ltd., Jannsen Pharmaceuticals, UCB, Compass Pathways, and Lundbeck. She is a co-director of TnC Psychiatry and Neuroscience. SEM has received consultancy fees from Zogenix, Sumitomo Dainippon Pharma, P1vital Ltd. and Johnson & Johnson Pharmaceuticals. CJH and SEM recently held grant income from Zogenix, UCB Pharma and Janssen Pharmaceuticals and ADM. CJH, SEM and PJC recently held grant income from a collaborative research project with Pfizer. Other authors have no conflicts of interest to declare. ### Clinical Trial NCT03516604 ### Funding Statement ANdeC is funded by an NIHR Clinical Lectureship and also receives funding and support from the NIHR Mental Health Translational Research Collaboration (MH-TRC) Mental Health Mission and the NIHR Oxford Health Biomedical Research Centre. She has previously received funding from the Guarantors of Brain and a Wellcome Trust Clinical Doctoral Research Fellowship (216430/Z/19/Z). ALG, MAGM and WH also are supported by the NIHR Oxford Health Biomedical Research Centre. BG is also supported by the NIHR Mental Health Translational Research Collaboration (MH-TRC) Mental Health Mission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the South Central Research Ethics Committee (18/SC/0076) and pre-registered with [clinicaltrials.gov][1] ([NCT03516604][2]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. Code is available at OSF. [1]: http://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03516604&atom=%2Fmedrxiv%2Fearly%2F2025%2F09%2F03%2F2025.08.29.25333049.atom