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

BackgroundCognitive 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. Methods50 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. ResultsCompared to placebo, prucalopride significantly improved word recall on an auditory verbal learning task, and was associated with 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. ConclusionsShort-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.