Role of dopamine D(2) receptors for antipsychotic activity

This review summarizes the current state of knowledge regarding the proposed mechanisms by which antipsychotic agents reduce the symptoms of schizophrenia while giving rise to adverse side effects. The first part summarizes the contribution of neuroimaging studies to our understanding of the neurochemical substrates of schizophrenia, putting emphasis on direct evidence suggestive of a presynaptic rather than a postsynaptic dysregulation of dopaminergic neurotransmission in this disorder. The second part addresses the role of D(2) and non-D(2) receptor blockade in the treatment of schizophrenia and highlights a preponderant role of D(2) receptors in the mechanism of antipsychotic action. Neuroimaging studies have defined a narrow, but optimal, therapeutic window of 65-78 % D(2) receptor blockade within which most antipsychotics achieve optimal clinical efficacy with minimal side effects. Some antipsychotics though do not conform to that therapeutic window, notably clozapine. The reasons for its unexcelled clinical efficacy despite subthreshold levels of D(2) blockade are unclear and current theories on clozapine's mechanisms of action are discussed, including transiency of its D(2) receptor blocking effects or preferential blockade of limbic D(2) receptors. Evidence is also highlighted to consider the use of extended antipsychotic dosing to achieve transiency of D(2) blockade as a way to optimize functional outcomes in patients. We also present some critical clinical considerations regarding the mechanisms linking dopamine disturbance to the expression of psychosis and its blockade to the progressive resolution of psychosis, keeping in perspective the speed and onset of antipsychotic action. Finally, we discuss potential novel therapeutic strategies for schizophrenia.