The Progress and Pitfalls of Pharmacogenetics-Based Precision Medicine in Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis

The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsycho...

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Published in:	Journal of personalized medicine Vol. 13; no. 3; p. 471
Main Authors:	Teng, Yuxin, Sandhu, Amrit, Liemburg, Edith J., Naderi, Elnaz, Alizadeh, Behrooz Z.
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 04.03.2023 MDPI
Subjects:	Antipsychotic drugs Antipsychotics Brain-derived neurotrophic factor Clinical outcomes Clozapine Complications and side effects CYP2D6 protein Cytochrome P450 Decision making Development and progression Dopamine D1 receptors Dopamine D2 receptors Dopamine D3 receptors Dopamine receptors Drb1 protein Drug therapy Genetic aspects Information sources Mental disorders Meta-analysis Metabolic syndrome Metabolism Movement disorders Neutropenia Patient compliance Pharmacogenetics Pharmacokinetics Phenotypes Plasma levels Precision medicine Prolactin Psychiatry Psychotropic drugs Schizophrenia SNAP-25 protein Systematic Review Tardive dyskinesia Netherlands drug response weigh-gain personalized psychiatry antipsychotics pharmacokinetics CYP adverse events schizophrenia pharmacogenetics tardive dyskinesia
ISSN:	2075-4426, 2075-4426
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Abstract	The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010–2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice.
AbstractList	The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010-2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice. The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010-2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of , and 3 of . We observed weak unadjusted nominal significant ( < 0.05) additive effects of PGx variants of , , , , , , and (10 variants) on antipsychotic response; , , , , , , , , , and (14 variants) on weight gain; (one variant) on metabolic syndrome; (one variant) on prolactin levels; and (two variants) on TD; HLA-DRB1 (one variant) on CLA; (four phenotypes) and (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice. The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010-2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice.The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010-2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice.
Audience	Academic
Author	Alizadeh, Behrooz Z. Teng, Yuxin Naderi, Elnaz Sandhu, Amrit Liemburg, Edith J.
AuthorAffiliation	2 Department of Psychiatry, Rob Giel Research Center, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands 3 Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA 1 Department of Epidemiology, University Medical Centre Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
AuthorAffiliation_xml	– name: 2 Department of Psychiatry, Rob Giel Research Center, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands – name: 1 Department of Epidemiology, University Medical Centre Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands – name: 3 Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
Author_xml	– sequence: 1 givenname: Yuxin orcidid: 0009-0003-6552-354X surname: Teng fullname: Teng, Yuxin – sequence: 2 givenname: Amrit surname: Sandhu fullname: Sandhu, Amrit – sequence: 3 givenname: Edith J. surname: Liemburg fullname: Liemburg, Edith J. – sequence: 4 givenname: Elnaz orcidid: 0000-0003-1671-7471 surname: Naderi fullname: Naderi, Elnaz – sequence: 5 givenname: Behrooz Z. orcidid: 0000-0002-1415-8007 surname: Alizadeh fullname: Alizadeh, Behrooz Z.
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Snippet	The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report...
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SubjectTerms	Antipsychotic drugs Antipsychotics Brain-derived neurotrophic factor Clinical outcomes Clozapine Complications and side effects CYP2D6 protein Cytochrome P450 Decision making Development and progression Dopamine D1 receptors Dopamine D2 receptors Dopamine D3 receptors Dopamine receptors Drb1 protein Drug therapy Genetic aspects Information sources Mental disorders Meta-analysis Metabolic syndrome Metabolism Movement disorders Neutropenia Patient compliance Pharmacogenetics Pharmacokinetics Phenotypes Plasma levels Precision medicine Prolactin Psychiatry Psychotropic drugs Schizophrenia SNAP-25 protein Systematic Review Tardive dyskinesia
Title	The Progress and Pitfalls of Pharmacogenetics-Based Precision Medicine in Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis
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