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Role of Dopamine D2 Receptors for Antipsychotic Activity

  • Nathalie Ginovart
  • Shitij KapurEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 212)

Abstract

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 D2 and non-D2 receptor blockade in the treatment of schizophrenia and highlights a preponderant role of D2 receptors in the mechanism of antipsychotic action. Neuroimaging studies have defined a narrow, but optimal, therapeutic window of 65–78 % D2 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 D2 blockade are unclear and current theories on clozapine’s mechanisms of action are discussed, including transiency of its D2 receptor blocking effects or preferential blockade of limbic D2 receptors. Evidence is also highlighted to consider the use of extended antipsychotic dosing to achieve transiency of D2 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.

Keywords

Schizophrenia Antipsychotic drugs Dopamine receptor D2 blockade PET imaging 

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© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Psychiatry, Unité de NeuroimagerieUniversity of Geneva, Hôpital Belle IdéeGenevaSwitzerland
  2. 2.Department of Psychological MedicineInstitute of Psychiatry, King’s College LondonLondonUK

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