| Samenvatting: | <p>Major depression is common, costly, and a global cause of significant morbidity. First-line antidepressant medication has a clinically problematic delay before therapeutic efficacy and is ineffective for a subset of those affected. In addition, many patients with depression, as well as other mental illnesses, find that cognitive impairment has a substantial impact on their quality of life and functioning. Cognitive impairment is poorly treated with medication such as antidepressants, and can persist after remission. Based on animal behavioural studies, as well as molecular and neurochemical evidence, 5-HT<sub>4</sub> receptor agonism has been suggested to have putative antidepressant effects and to improve cognition. However, there is relatively little evidence in humans demonstrating such effects.</p>
<p>The aim of this thesis is to investigate whether it is possible to translate the pre-clinical neurocognitive effects of 5-HT<sub>4</sub> agonism into humans. This would help to elucidate whether 5-HT<sub>4</sub> receptor agonism may have therapeutic potential within psychiatry as an antidepressant and / or a pro-cognitive treatment.</p>
<p>A series of experimental medicine fMRI studies were conducted using the 5-HT<sub>4</sub> receptor agonist, prucalopride, in healthy volunteers. Low dose prucalopride led to improved behavioural cognition on a memory encoding and implicit faces task, and increased neural activation in memory processing regions including the hippocampus. Resting-state fMRI provided further mechanistic support for prucalopride as a pro-cognitive agent. The latter findings were partially confirmed in a clinical population of unmedicated depressed patients treated with a novel 5-HT<sub>4</sub> agonist, PF-04995274. Here, 5-HT<sub>4</sub> agonism with PF-04995274 increased activation in another memory processing region and modulated activity within the hippocampus; however, the behavioural pro-cognitive behavioural effect seen with prucalopride was absent. Although there was no evidence of an antidepressant-like effect in experimental medicine studies, a pharmaco-epidemiological study suggested that one year of standard dose prucalopride for the treatment of gastrointestinal disorders was associated with reduced risk of depression.</p>
<p>Overall, this thesis identifies that 5-HT<sub>4</sub> receptor agonism has neurocognitive effects consistent with other pro-cognitive medications in healthy participants and depressed patients. Data using electronic health records indicates that it may also reduce incidence of future depressive episodes. Future studies should consider confirming the correct dose of individual agonists to ensure optimised central receptor binding in clinical populations, using larger sample sizes to allow for variability inherent in clinical populations, and / or to assess the effect of medication over a longer time period.</p>
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