A decade before clozapine was approved for marketing in the United States, Janssen Pharmaceuticals established a program to examine the potential role of serotonergic agents in schizophrenia. Early interest in serotonergic agents stemmed from a preclinical literature demonstrating that both behavioral effects of dopamine agonists and haloperidol-induced catalepsy could be modulated by serotonin₂ (5-HT₂) antagonists; in addition, the early butyrophenone derivative pipamperone, which was observed to reduce agitation and improve social activity in patients with severe depression, was found to possess primarily 5-HT₂ antagonist activity (Ansoms et al. 1977; Leysen et al. 1978).