Role of impulsivity and reward in the anti-obesity actions of 5-HT2C receptor agonists

The selective 5-HT 2C receptor agonist lorcaserin entered clinical obesity trials with the prevalent view that satiety was a primary mechanism of action. Subsequent Phase II and III trials demonstrated efficacy in terms of weight loss, although the overall effect size (~3% placebo-corrected change) is considered modest. Lorcaserin has been approved by the FDA for the treatment of obesity with lifestyle modification, but since its introduction in 2013 its sales are in decline, probably due to its overall modest effect. However, in some individuals, lorcaserin has a much more clinically significant effect (i.e. >10% placebo-corrected change), although what common features, if any, define these high responders is presently unknown. In the present article we highlight the evidence that alternative mechanisms to satiety may contribute to the anti-obesity effect of lorcaserin, namely effects on constructs of primary and conditioned reward and impulsivity. This may better inform the clinical evaluation of lorcaserin (and any future 5-HT 2C receptor agonists) to subgroups of obese subjects characterized by overeating due to maladaptive impulsivity and reward mechanisms. One such population might be individuals diagnosed with binge eating disorder.