Serotonergic anti-obesity agents: past experience and future prospects

The role of serotonin (5-hydroxytryptamine) in appetite control is long established. Serotonergic manipulations reduce food intake in rodents in a manner consistent with satiety. In humans, drugs such as fenfluramine, dexfenfluramine and sibutramine all reduce energy intake, suppress hunger and enhance satiety. Effects on eating behaviour and subjective sensations of appetite are associated with the weight loss-inducing effects of these treatments. Currently, no appetite-suppressing drugs are approved specifically for the treatment of obesity. However, a new generation of serotonergic drugs have progressed through clinical development. The serotonin 5-HT(2C)-receptor selective agonist lorcaserin, a drug specifically developed to target satiety without producing the side effect profiles of its predecessors, has been shown to significantly reduce energy intake and body weight. The weight loss produced by lorcaserin appears modest, and behavioural effects, particularly its supposed satiety-enhancing effects, have yet to be characterized. The monoaminergic re-uptake inhibitor tesofensine has also been shown to produce impressive weight loss in smaller-scale clinical studies. It remains unclear if this drug produces any effects on appetite mediated by serotonin, or whether weight loss is produced largely through enhanced energy expenditure. Evidence indicates that tesofensine strengthens satiety, but behavioural specificity and psychological side effects remain an issue. The serotonergic system remains a viable target for anti-obesity treatment. In this review, we examine the limited behavioural data available on these two new CNS-acting appetite suppressants.