Validating 5HT4 agonism as a novel antidepressant mechanism (360G-Wellcome-216430_Z_19_Z)

Selective serotonin reuptake inhibitors (SSRIs) produce a generalised increase in brain serotonin levels, which leads to multiple side effects and several weeks’ delay for a clinical effect. Previous work indicates that medications activating only one type of serotonin (5-HT) receptor might be effective and rapidly-acting antidepressants. Therefore, I plan to examine the effects of drug treatments with specific activators of 5-HT4 receptors on a range of measures affected in depression, including how people see different facial expressions Firstly, I will examine the effect of 5-HT4 activators compared to SSRI and/or placebo on measures of emotional processing including a brain scan (fMRI), both in healthy volunteers and in un-medicated patients with depression. I will determine if, like clinically-effective antidepressants, 5-HT4 agonists produce positive biases in how people process emotions. I will also examine the effect of a 5-HT4 activator compared to placebo in healthy volunteers, examining both behavioural and brain responses to a reward/punishment task using fMRI. I will assess if this medication appears to reduce negative responses to anticipation of punishment. I will also assess for any early adverse effects. The key goal of this translational project is to confirm whether specific 5-HT receptor agents may have potential as antidepressants.