MICA: 5-HT4 receptor activation as a novel mechanism of antidepressant action

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.

The study will explore the potential antidepressant effect of PF-04995274, a novel 5-HT4 receptor partial agonist originally developed by Pfizer for dementia and cognitive impairment. We will use an experimental medicine model, sensitive to the early effects of antidepessant drug treatment, in depressed patients. This battery of tasks measures different aspects of emotional processing (perception, memory, attention and physiological reactivity) and is affected early in treatment by a range of antidepressant drug treatments. The study will recruit two groups of depressed patients, those currently unmedicated and those who have failed to respond to current SSRI treatment. In study one, unmedicated patients will be randomised to PF-04995274, citalopram (as a positive control) or placebo. In study two, patients not responding to current therapy will be randomised to either the addition of PF-04995274 or placebo while they continue their current treatment. The treatment period in both studies will be seven days. Study design will be parallel group, double-blind, placebo-controlled and with emotional processing measured before and after the seven day treatment period. It is hypothesised that PF-04995274 will show antidepressant-like effects in these models, expressed as an increase in perception and memory for positive vs negative stimuli. A positive screen in these models would provide support for assessment of 5HT4 agonists in the treatment of depression.

Depression is the leading cause of disability worldwide, and is a major contributor to the overall global burden of disease. Current treatments are limited in terms of efficacy, time to onset and unwanted side effects.

The aim of the current research project is to assess a role for a specific serotonin receptor (the 5-HT4 receptor) in antidepressant drug action based on exciting evidence from preclinical approaches. If this research is successful it could lead to the first use of a selective 5-HT receptor subtype ligand to treat clinical depression both as a first line treatment and in treatment resistant depression. Patients with depression (particularly that which does not respond to current approaches) and their families will therefore benefit by a new form of drug treatment becoming available.

In addition to patients, the research will be of value to clinicians, particularly those treating depression, because it will increase awareness of the availability of new approaches.

The work will also be of importance to the field of psychiatry in general, emphasising the link that it is possible to continue to improve antidepressant drug treatments and that basic research and 'drug repurposing' are important in this effort.

Other beneficiaries could be the Pharmaceutical Industry who will benefit from the ability to have new targets to treat depression and associated disorders.