People with depression often receive treatment with antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). SSRIs produce activation of all types of serotonin receptors and some of these receptors are thought to mediate side-effects rather than the therapeutic effect of SSRIs. Also activation of certain other serotonin receptors may delay the onset of therapeutic action of the SSRI treatment. Animal experimental studies have suggested that the 5-HT4 serotonin receptor may be important in mediating the antidepressant effects of SSRIs and targeting this receptor directly may work more quickly than conventional SSRI treatment. Carrying out large-scale clinical trials of new agents in depressed patients is costly and time consuming and therefore one would only want to pursue this approach when there was supporting evidence from experimental medicine studies in humans that 5-HT4 receptor drugs may well be useful in depression. We have developed models of emotional processing (psychological tests that measure how people respond to emotional stimuli) that can detect potential antidepressant effects of novel compounds after only a few days of treatment. We therefore plan to use these models to see whether a new drug that selectively activates 5-HT4 receptors can produce antidepressant-like changes in emotional processing after just one week of treatment. We will carry out these studies in two separate groups of depressed patients: first, those who are not taking any antidepressant medication and second, people who have not experienced a good response to their current treatment. Both these clinical situations are where advances in drug treatment are badly needed. Positive results from one or both of these studies will lead on to formal clinical trials of a 5-HT4 receptor agonist drug in depressed patients.