Pharmacology of second-generation antipsychotics: A validity of the serotonin-dopamine hypothesis

New atypical antipsychotic drugs such as risperidone, olanzapine and quetiapine, that have been modeled on the prototype agent clozapine and developed since the 1990's, are now referred to as second-generation antipsychotics (SGA). It has been proposed by Meltzer (1989) that the interaction between serotonin (5-HT) and dopamine (DA) systems may play a critical role in the mechanism of action for atypical antipsychotics because potent 5-HT_2A receptor antagonism together with relatively weak D₂ receptor antagonism could differentiate most atypical antipsychotics from typical antipsychotics. This serotonin-dopamine hypothesis has become a useful model for studying and developing new drugs to achieve a significant antipsychotic effect with lower incidence of extrapyramidal side effects compared to first-generation antipsychotics. In contrast, Kapur and Seeman (2001) argued the alternative "fast-off" theory that clozapine occupies D₂ receptors to a similar extent as typical antipsychotics do and then rapidly dissociates from D₂ receptors. This paper reviews the current issues on the serotonin-dopamine hypothesis and recent research on the role of 5-HT receptor subtypes in the mechanism of action for SGA. In particular, SGA-induced DA release in the prefrontal cortex, possibly through the functional activation of 5-HT_1A receptors by 5-HT_2A and D₂ receptor-mediated interaction, may be the basis for the cognitive effects of SGA.