Serotonin-4 receptor agonism improves memory and attention in participants with previous depression

Introduction: Cognitive impairment is common in depression, but poorly understood and treated [1], and 40% of individuals will continue to experience subjective cognitive deficits after other symptoms of depression have resolved. Stimulating serotonin-4 receptors (5-HT4R) rapidly improves learning and memory in rodent and human models [2], consistent with their role in hippocampal neuroplasticity [3]. Therefore, we aimed to explore the effects of 5-HT4R agonism on cognition in a novel study with euthymic individuals who had previously experienced depression. We hypothesised that in participants with previous depression, 5-HT4R agonism would show a broad profile of pro-cognitive effects. Methods: 49 healthy participants with at least two previous episodes of depression were randomised to receive 7-10 days of the highly selective 5-HT4R agonist prucalopride (2mg titrated from 1mg over 2 days; 24 participants) or placebo (25 participants) in a double-blind design. A battery of behavioural cognitive tasks was conducted at the end of the study, measuring declarative memory, working memory, emotional processing and executive function. Self-report questionnaires measured mood and affect, subjective cognitive deficit, anxiety and side effects. Primary pre-specified analyses were repeated-measures analysis of variance (ANOVA), or covariance (ANCOVA) where baseline data was available, to assess group differences in behavioural performance (RStudio (4.3.3)). Models included baseline mood, subjective cognition, education and native language as sensitivity analyses. The protocol was pre-registered with clinicaltrials.gov (NCT05220228). Results: Prucalopride was well tolerated compared to placebo administration, with no significant time*group differences in reports of total side effects [F(1,47)=0.12, p=0.73, np2