Early effects of a novel 5-HT4 agonist (PF-04995274) and the SSRI citalopram on emotional cognition in unmedicated depression: the RESTAND study

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 (5-HT 4 R) 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-HT 4 R 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 5-HT4R agonists and investigation of pro-cognitive and mood effects. Clinicaltrials.gov registration number NCT03516604. Data set information Analysis scripts and selected data will be available on publication.