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

Journal article

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 experimental medicine 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 notably 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 has relevance considering previously identified beneficial impacts on cognitive performance with another 5-HT₄ receptor agonist, prucalopride.

Authors: de Cates, AN; Gillespie, AL; Scaife, J; Martens, MAG; Carson, J

• Publication status: Accepted
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Translational Psychiatry
• Acceptance date: 2026-05-22
• EISSN: 2158-3188
• Language: English