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

Published online by Cambridge University Press:  16 April 2020

Anissa Abi-Dargham  and
Marc Laruelle
Anissa Abi-Dargham*
Affiliation:
Departments of Psychiatry and Radiology, New York State Psychiatric Institute, Unit 31, Columbia University College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA
Marc Laruelle
Affiliation:
Departments of Psychiatry and Radiology, New York State Psychiatric Institute, Unit 31, Columbia University College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA
*
*Corresponding author. Tel.: +1 212 543 5066; fax: +1 212 568 6171. E-mail address: [email protected] (A. Abi-Dargham).
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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) D2 receptors and understimulation of cortical DA D1 receptors. This DA endophenotype presumably emerges from the background of a more general synaptic dysconnectivity, involving alterations in N-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 D2 receptors. 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 D2 receptor 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, D1 receptor transmission or NMDA transmission to enhance the therapeutic effect of moderate D2 receptor antagonism.

Keywords

Antipsychotic drugsDopamineGlutamateSchizophreniaPETSPECT
Type
Original article
Information
European Psychiatry , Volume 20 , Issue 1 , January 2005 , pp. 15 - 27
Copyright
Copyright © Elsevier SAS 2005

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