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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 preclinical literature demonstrating that both behavioral effects of dopamine receptor agonists and haloperidol-induced catalepsy could be modulated by serotonin 2 (5-HT2) receptor 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 receptor antagonist activity (Ansoms et al. 1977; Leysen et al. 1978).
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