Atypical antipsychotic drug actions: unitary or multiple mechanisms for ‘atypicality’?

Abstract

Over the past decade or so, atypical antipsychotic drugs have revolutionized the pharmacologic treatment of schizophrenia and related disorders. All currently approved atypical antipsychotic drugs, which are available in the US, are characterized by relatively weak affinities for D2-family dopamine receptors and relatively high affinities for 5-HT2A-serotonin receptors, when compared with typical antipsychotic drugs. The potent interaction with 5-HT2A receptors, with a relative sparing of D2-family dopamine receptors, is likely responsible for the salutary effects of atypical antipsychotic drugs on mood and cognition in comparison with typical antipsychotic drugs. Another class of atypical antipsychotic drugs, available in Europe, is characterized by potent and relatively selective interactions with D2- and D3-dopamine receptors. These drugs, as a class, have weak affinity for 5-HT2A-serotonin receptors and exert their ‘atypical actions’ presumably via combined D2/D3-dopamine receptor blockade. A new class of atypical antipsychotic drugs, exemplified by aripiprazole, is characterized by partial agonist actions at a variety of dopaminergic and serotonergic receptors. We also highlight the various neuronal circuits involved in atypical antipsychotic drug actions. In addition to these actions, several atypical antipsychotic drugs are characterized by a ‘fast dissociation’ rate from D2-dopamine receptors and/or relatively high affinities for α2-adrenergic receptors. It is clear that multiple molecular targets can be targeted to yield drugs with appreciable ‘atypical’ actions in humans. It is also evident that no unitary pharmacologic mechanism can account for the multiplicity of actions of atypical antipsychotic drugs. Instead, we suggest that elucidating the actions of atypical antipsychotic drugs requires a combined understanding of the circuitry of neocortical and subcortical regions which will provide a framework on which to posit the actions of atypical antipsychotic drugs.