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<0.01]. Prucalopride significantly improved the immediate recall of words on an auditory verbal learning task compared with placebo [F(1,226)=8.12, p=0.005, np2=0.176]. Furthermore, prucalopride improved the accurate recognition of rapidly presented facial expressions [F(1,270)=9.99, p<0.002, np2=0.024], but with no interaction between group and emotion [F(5,270)=0.44, p=0.82, np2<0.01]. The prucalopride group were significantly quicker at completing a complex working memory task across all levels of the task (0- to 3-back) [F(1,179)=8.56, p=0.004, np2=0.03] with a trend for both overall increased accuracy, and greater accuracy at quicker reaction times reflected by the relationship between d’ and group [t(-1.68, 45.53), p=0.099]. In contrast to performance on the working memory task, speed of completion was significantly reduced during other tasks with prucalopride compared to the placebo group; signal detection analyses suggested prucalopride participants were potentially more cautious regarding decision-making in particular tasks. There was limited impact of prucalopride in terms of emotionally-valenced performance across emotional processing tasks. Executive functioning tasks appeared unaffected by 5-HT₄R agonism. Performance across tasks was unchanged when we accounted for baseline subjective cognitive difficulties or mood symptom scores.

Conclusion: In participants with previous depression, 5-HT₄R agonism improved performance on multiple cognitive tasks, measuring learning, memory and attention. This is a replication of our previous findings in healthy volunteers without prior mental illness using prucalopride [4,5], and is consistent with preclinical evidence establishing an important role for 5-HT₄R agonism in human learning and memory.