One of the most important critical decision to be taken when designing a randomized controlled trial (RCT) in clinical psychopharmacology is the choice of the comparator. This choice is crucial because it affects many issues related to both internal and external validity. The aim of a RCT may be to establish efficacy in absolute terms, against an inert treatment (usually a placebo), or to establish efficacy with respect to another treatment (also known as comparator), a trial may be designed to demonstrate that the new drug is superior to the control intervention or, by contrast, that the new drug is similar to the control intervention in terms of, say, symptoms' reduction. Three kinds of RCTs may be designed: Superiority trials, Equivalence studies, Non-inferiority studies.