Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies

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Abstract
Multiple lines of evidence including recent imaging studies suggest that schizophrenia is associated with an imbalance of the dopaminergic system, entailing hyperstimulation of striatal dopamine (DA) D2receptors and understimulation of cortical DA D1receptors. This DA endophenotype presumably emerges from the background of a more general synaptic dysconnectivity, involving alterations inN-methyl-d-aspartate (NMDA) and glutamatergic (GLU) functions. Equally important is the fact that this DA dysregulation might further impair NMDA transmission. The first generation antipsychotic (FGA) drugs are characterized by high affinity to and generally high occupancy of D2receptors. The efficacy of FGAs is limited by a high incidence of extrapyramidal side-effects (EPS). Second generation antipsychotic (SGA) drugs display reduced EPS liability and modest but clinically significant enhanced therapeutic efficacy. Compared to FGAs, the improved therapeutic action of SGAs probably derives from a more moderate D2receptor blockade. We will review the effects of SGAs on other neurotransmitter systems and conclude by highlighting the importance of therapeutic strategies aimed at directly increasing prefrontal DA, D1receptor transmission or NMDA transmission to enhance the therapeutic effect of moderate D2receptor antagonism.