Background: Selective serotonin reuptake inhibitors (SSRIs) are limited by inadequate response in a significant minority of patients, slow onset, minimal cognitive benefit, and side effects. Preclinical studies suggest selective serotonin 4 receptor (5HT4R) agonists may produce faster antidepressant effects via distinct mechanisms, however there has been no experimental research in clinical populations to date. Aims: To test whether the novel 5HT4R partial agonist PF-04995274 produces early behavioural and neural changes in emotional cognition similar to SSRIs in patients with unmedicated major depressive disorder (MDD). Method: In a double-blind, placebo-controlled trial, 90 participants with MDD were randomised to 7 days of PF-04995274 (15 mg), citalopram (20 mg), or placebo. Emotional processing was assessed using a behavioural facial expression recognition task and fMRI of implicit emotional face processing (days 6-9). Observer- and self-reported symptoms of depression were also measured at baseline and study end. Results: As anticipated, citalopram reduced accuracy and reaction time for negative faces, with corresponding fMRI changes (reduced left amygdala activation to emotional faces and valence-specific shifts in cortical regions). In contrast, PF-04995274 produced no change in behavioural negative bias or amygdala activity but increased medial-frontal cortex activation across valences. While this was not a clinical trial, both active treatments reduced observer-rated depression severity relative to placebo; PF-04995274 also reduced self-reported depression, state anxiety, and negative affect. No major adverse events occurred. Conclusions: PF-04995274 was not associated with the typical antidepressant profile of negative bias reductions seen with citalopram but was associated with distinct medial-frontal activation during an emotional faces task and displayed preliminary evidence of early clinical improvement, suggesting a potential alternative mechanism for antidepressant effects. Findings support further clinical trials of 5HT4R agonists and investigation of pro-cognitive and mood effects.

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. ALG has received consultancy fees from Zogenix and Johnson & Johnson Pharmaceuticals. BRG has received consultancy fees from Tiefenbatcher Pharmaceuticals via Lindus Health CRO.

NCT03516604

This study was funded by the Medical Research Council (MRC): MR/S035591/1 and Pfizer under the MRC asset sharing scheme. This study has been delivered through the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre (BRC) including the Oxford Health cognitive health Clinical Research Facility, and the Oxford Centre for Human Brain Activity (OHBA) part of the Wellcome Centre for Integrative Neuroimaging. The views expressed are those of the author(s) and not necessarily those of the MRC, the NIHR or the Department of Health and Social Care. 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 and MAGM also are supported by the NIHR Oxford Health Biomedical Research Centre.

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The South-Central NHS Research Ethics Committee (18/SC/0076) gave ethical approval for this work.

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All behavioural data produced in the present study will be made available online by the end of 2025 and are available upon reasonable request to the authors.