Pro-cognitive effects of 5-HT4 receptor agonism in individuals with remitted depression

Background: Cognitive impairment is a common and persistent feature of depression, yet remains poorly understood and inadequately treated. Preclinical and human studies suggest that stimulating 5-HT4 receptors (5-HT4R) enhances neuroplasticity and rapidly improves learning and memory. This study is the first to examine the cognitive effects of 5-HT4R agonism in adults with a history of recurrent depression. We hypothesised that short term 5-HT4R agonist administration would produce a broad profile of pro-cognitive effects. Methods: 50 participants not currently depressed but with at least two previous episodes of depression (remitted depression) were randomised in a double-blind design to receive either prucalopride (2mg daily titrated from 1mg over 2 days) or placebo for 7-10 days. Participants completed self-report questionnaires and a cognitive task battery assessing declarative memory, working memory, emotional processing, and executive function before and after medication. Results: Compared to placebo, prucalopride significantly improved word recall on an auditory verbal learning task, and was associated with more faster response times on a complex working memory task without loss of accuracy. It also improved the accurate recognition of rapidly presented facial expressions. Prucalopride had minimal effects on emotionally-valenced cognitive tasks, consistent with previous findings. Cognitive improvements were independent of baseline mood symptoms or self-reported cognitive difficulties. Conclusions: Short-term 5-HT4R agonism improved performance on multiple objective cognitive measures in individuals with a history of depression. These findings replicate our previous results in healthy volunteers using prucalopride and support a role for 5-HT4Rs as a promising target for cognitive enhancement in mood disorders.