Serotonergic agents and the irritable bowel syndrome: what goes wrong?

It is now nine years since the first large randomised controlled trials showed the benefit of a 5HT(3) antagonist in irritable bowel syndrome (IBS) with diarrhoea (IBS-D) and a 5HT(4) partial agonist in IBS with constipation (IBS-C). Although both of these drugs have now been withdrawn because of rare complications (ischaemic colitis and thrombotic episodes respectively), their clinical effectiveness has stimulated substantial advances in our understanding of the physiological role of serotonin and its disturbance in IBS. 5HT-containing enteroendocrine cells are most numerous in the duodenum and colon and are responsive to a range of stimuli including tastants, mechanic force and short chain fatty acids. Several studies have described an excess of 5HT in IBS-D and abnormally low 5HT availability in IBS-C. Serotonin transporter (SERT) is only weakly expressed in the colon and whether this is further reduced in IBS is unclear with conflicting reports. SERT promoter polymorphisms are inconsistently related to IBS subtypes but appear to partly predict response to both 5HT(3) antagonists and 5HT(4) agonists. Stressors release serotonin and 5HT(3) antagonists have been shown to inhibit the associated acceleration of colonic transit. Newer 5HT(3) antagonists and 5HT(4) agonists are under development. Their undoubted effectiveness in subgroups of IBS should stimulate further work to define biomarkers of both responsiveness and of risk of developing adverse events to improve the risk benefit balance for these potentially useful therapies.