Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects
Antipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. However, about one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play...
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doaj-98227a227d5f4a4bb103ef79df71ba092020-11-25T02:09:38ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402019-01-01910.3389/fpsyt.2018.00702410399Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New ProspectsAntonio Rampino0Antonio Rampino1Aleksandra Marakhovskaia2Tiago Soares-Silva3Silvia Torretta4Federica Veneziani5Jean Martin Beaulieu6Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari, ItalyAzienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, ItalyDepartment of Pharmacology and Toxicology, University of Toronto, Toronto, ON, CanadaDepartment of Pharmacology and Toxicology, University of Toronto, Toronto, ON, CanadaDepartment of Basic Medical Science, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari, ItalyDepartment of Basic Medical Science, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari, ItalyDepartment of Pharmacology and Toxicology, University of Toronto, Toronto, ON, CanadaAntipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. However, about one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play a role in schizophrenia pathophysiology. Most of these schizophrenia risk variants are not related to dopamine or antipsychotic drugs mechanism of action. Genetic factors have also been implicated in defining response to antipsychotic medication. In contrast to disease risk, variation of genes coding for molecular targets of antipsychotics have been associated with treatment response. Among genes implicated, those involved in dopamine signaling mediated by D2-class dopamine receptor, including DRD2 itself and its molecular effectors, have been implicated as key genetic predictors of response to treatments. Studies have also reported that genetic variation in genes coding for proteins that cross-talk with DRD2 at the molecular level, such as AKT1, GSK3B, Beta-catenin, and PPP2R2B are associated with response to antipsychotics. In this review we discuss the relative contribution to antipsychotic drug responsiveness of candidate genes and GWAS identified genes encoding proteins involved in dopamine responses. We also suggest that in addition of these older players, a deeper investigation of new GWAS identified schizophrenia risk genes such as FXR1 can provide new prospects that are not clearly engaged in dopamine function while being targeted by dopamine-associated signaling molecules. Overall, further examination of genes proximally or distally related to signaling mechanisms engaged by medications and associated with disease risk and/or treatment responsiveness may uncover an interface between genes involved in disease causation with those affecting disease remediation. Such a nexus would provide realistic targets for therapy and further the development of genetically personalized approaches for schizophrenia.https://www.frontiersin.org/article/10.3389/fpsyt.2018.00702/fulldopaminerisk factorsantipsychotic agentsgenetic variantsschizophrenia therapy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Antonio Rampino Antonio Rampino Aleksandra Marakhovskaia Tiago Soares-Silva Silvia Torretta Federica Veneziani Jean Martin Beaulieu |
spellingShingle |
Antonio Rampino Antonio Rampino Aleksandra Marakhovskaia Tiago Soares-Silva Silvia Torretta Federica Veneziani Jean Martin Beaulieu Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects Frontiers in Psychiatry dopamine risk factors antipsychotic agents genetic variants schizophrenia therapy |
author_facet |
Antonio Rampino Antonio Rampino Aleksandra Marakhovskaia Tiago Soares-Silva Silvia Torretta Federica Veneziani Jean Martin Beaulieu |
author_sort |
Antonio Rampino |
title |
Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects |
title_short |
Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects |
title_full |
Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects |
title_fullStr |
Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects |
title_full_unstemmed |
Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects |
title_sort |
antipsychotic drug responsiveness and dopamine receptor signaling; old players and new prospects |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Psychiatry |
issn |
1664-0640 |
publishDate |
2019-01-01 |
description |
Antipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. However, about one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play a role in schizophrenia pathophysiology. Most of these schizophrenia risk variants are not related to dopamine or antipsychotic drugs mechanism of action. Genetic factors have also been implicated in defining response to antipsychotic medication. In contrast to disease risk, variation of genes coding for molecular targets of antipsychotics have been associated with treatment response. Among genes implicated, those involved in dopamine signaling mediated by D2-class dopamine receptor, including DRD2 itself and its molecular effectors, have been implicated as key genetic predictors of response to treatments. Studies have also reported that genetic variation in genes coding for proteins that cross-talk with DRD2 at the molecular level, such as AKT1, GSK3B, Beta-catenin, and PPP2R2B are associated with response to antipsychotics. In this review we discuss the relative contribution to antipsychotic drug responsiveness of candidate genes and GWAS identified genes encoding proteins involved in dopamine responses. We also suggest that in addition of these older players, a deeper investigation of new GWAS identified schizophrenia risk genes such as FXR1 can provide new prospects that are not clearly engaged in dopamine function while being targeted by dopamine-associated signaling molecules. Overall, further examination of genes proximally or distally related to signaling mechanisms engaged by medications and associated with disease risk and/or treatment responsiveness may uncover an interface between genes involved in disease causation with those affecting disease remediation. Such a nexus would provide realistic targets for therapy and further the development of genetically personalized approaches for schizophrenia. |
topic |
dopamine risk factors antipsychotic agents genetic variants schizophrenia therapy |
url |
https://www.frontiersin.org/article/10.3389/fpsyt.2018.00702/full |
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