Early effects of a novel 5-HT 4 R agonist (PF-04995274) and the SSRI citalopram on emotional cognition in unmedicated depression: RESTAND study

Journal article

Background: Selective serotonin reuptake inhibitors (SSRIs) are limited by inadequate response in a significant proportion of patients, slow onset, minimal cognitive benefit and side-effects. Preclinical studies suggest selective serotonin 4 receptor (5-HT4R) 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 5-HT4R 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 functional magnetic resonance imaging (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 relative accuracy and increased relative reaction time to identify negative faces, with corresponding changes in neural activity (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 demonstrated an early treatment response with reduced observer-rated depression severity relative to placebo; PF-04995274 also reduced self-reported depression, state anxiety and negative affect. Conclusions: PF-04995274 did not show the typical antidepressant profile of negative bias reductions observed with citalopram. Instead, it was associated with distinct increased medial-frontal activation during an emotional faces task, coupled with preliminary evidence of early clinical improvement, suggesting a potential alternative pathway for antidepressant effects. Findings support further clinical trials of 5-HT4R agonists and investigation of pro-cognitive and mood effects. Clinical trials registration number: NCT03516604.

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

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cambridge University Press
• Journal: The British Journal of Psychiatry
• Pages: 1-10
• Publication date: 2026-05-28
• Acceptance date: 2026-04-16
• DOI: 10.1192/bjp.2026.10664
• EISSN: 1472-1465
• ISSN: 0007-1250
• Language: English
• Keywords: cognitive neuroscience; neuroimaging; antidepressants; Depressive disorders; psychopharmacology