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Strengths and weaknesses of pharmacogenetic studies of antipsychotic drugs: the potential value of the PEPs study

    Sergi Mas

    Department of Anatomic Pathology, Pharmacology & Microbiology, University of Barcelona, IDIBAPS, Casanova 143, E-08036, Barcelona, Spain

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Department of Psychiatry & Clinical Psychobiology, University of Barcelona, Barcelona, Spain

    ,
    Adrián LLerena

    Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain

    CICAB Clinical Research Center, Extremadura University Hospital Medical School, Badajoz, Spain

    ,
    Jerónimo Saíz

    Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain

    Department of Psychiatry, Hospital Ramón y Cajal, IRCYS, Universidad de Alcalá, Madrid, Spain

    ,
    Miquel Bernardo

    Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Department of Psychiatry & Clinical Psychobiology, University of Barcelona, Barcelona, Spain

    Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain

    Psychiatry Service, Hospital Clinic de Barcelona, Barcelona, Spain

    &
    Amalia Lafuente

    * Author for correspondence

    Department of Anatomic Pathology, Pharmacology & Microbiology, University of Barcelona, IDIBAPS, Casanova 143, E-08036, Barcelona, Spain.

    Published Online:https://doi.org/10.2217/pgs.12.159

    The successful application of pharmacogenetics in routine clinical practice is still a long way from becoming a reality. In order to favor the transfer of pharmacogenetic results to clinical practice, especially in psychiatry, these studies must be optimized. This article reviews the strengths and weaknesses that characterize pharmacogenetic studies in psychiatry and condition their implementation in clinical practice. We also include recommendations for improving the design of pharmacogenetic studies, which may convert their limitations into strengths and facilitate the implementation of their results into clinical practice. Finally, we discuss the potential value of naturalistic, prospective, multicenter and coordinated projects such as the ‘Phenotype–genotype and environmental interaction. Application of a predictive model in first psychotic episodes’ (known as the PEPs study, from the Spanish abbreviation) in pharmacogenetic studies.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    References

    • Conley RR, Buchanan RW. Evaluation of treatment-resistant schizophrenia. Schizophr. Bull.23,663–674 (1997).
    • Kahn RS, Fleischhacker WW, Boter H et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet371,1085–1097 (2008).
    • Almond S, Knapp M, Francois C, Toumi M, Brugha T. Relapse in schizophrenia: costs, clinical outcomes and quality of life. Br. J. Psychiatry184,346–351 (2004).
    • Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch. Gen. Psychiatry62,975–983 (2005).
    • Lencz T, Malhotra AK. Pharmacogenetics of antipsychotic-induced side effects. Dialogues Clin. Neurosci.11,405–415 (2009).
    • Zandi PP, Judy JT. The promise and reality of pharmacogenetics in psychiatry. Psychiatr. Clin. North Am.33,181–224 (2010).
    • Court MHA. A pharmacogenomics primer. J. Clin. Pharmacol.47,1087–1113 (2007).
    • Mas S, Lafuente A. Pharmacogenetics strategies: from candidate genes to whole-genome association analysis. Exploratory or confirmatory studies? Curr. Pharmacogenet. Personal. Med.7,59–69 (2009).
    • Prasad K, Breckenridge A. Pharmacogenomics: a new clinical or regulatory paradigm? European experiences of pharmacogenomics in drug regulation and regulatory initiatives. Drug Discov. Today16,867–872 (2011).
    • 10  Malhotra AK, Zhang JP, Lencz T. Pharmacogenetics in psychiatry: translating research into clinical practice. Mol. Psychiatry17,760–769 (2012).▪▪ Presents an overview of the weaknesses of pharmacogenetics and reviews recommendations to improve several methodological aspects of pharmacogenetic studies.
    • 11  Stroup TS, McEvoy JP, Swartz MS et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr. Bull.29,15–31 (2003).▪ Presents a description of CATIE trial design and protocol.
    • 12  Lieberman JA, Stroup TS, McEvoy JP et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med.353,1209–1223 (2005).
    • 13  Inada T, Koga M, Ishiguro H et al. Pathway-based association analysis of genome-wide screening data suggest that genes associated with the γ-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia. Pharmacogenet. Genomics18,317–323 (2008).
    • 14  Alkelai A, Greenbaum L, Rigbi A, Kanyas K, Lerer B. Genome-wide association study of antipsychotic-induced parkinsonism severity among schizophrenia patients. Psychopharmacology206,491–499 (2009).
    • 15  Aberg K, Adkins DE, Bukszár J et al. Genome-wide association study of movement-related adverse antipsychotic effects. Biol. Psychiatry67,279–282 (2010).
    • 16  Greenbaum L, Alkelai A, Rigbi A, Kohn Y, Lerer B. Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia. Mov. Disord.25,2809–2817 (2010).
    • 17  Adkins DE, Aberg K, McClay JL et al. Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Mol. Psychiatry16,321–332 (2011).
    • 18  McClay JL, Adkins DE, Aberg K et al. Genome-wide pharmacogenomic study of neurocognition as an indicator of antipsychotic treatment response in schizophrenia. Neuropsychopharmacology36,616–626 (2011).
    • 19  McClay JL, Adkins DE, Aberg K et al. Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics. Mol. Psychiatry16,76–85 (2011).
    • 20  Aberg K, Adkins DE, Liu Y et al. Genome-wide association study of antipsychotic-induced QTc interval prolongation. Pharmacogenomics J.12,165–172 (2012).
    • 21  Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat. Rev. Genet.11,415–425 (2010).
    • 22  Zhang JP, Malhotra AK. Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin. Drug Metab. Toxicol.7,9–37 (2011).
    • 23  Jovanović N, Božina N, Lovrić M, Medved V, Jakovljević M, Peleš AM. The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naive patients with first-episode schizophrenia treated with risperidone. Eur. J. Clin. Pharmacol.66,1109–1117 (2010).
    • 24  Lencz T, Robinson DG, Napolitano B et al.DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet. Genomics20,569–572 (2010).
    • 25  Kastelic M, Koprivsek J, Plesnicar BK et al.MDR1 gene polymorphisms and response to acute risperidone treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry34,387–392 (2010).
    • 26  Stingl Kirchheiner JC, Brockmöller J. Why, when, and how should pharmacogenetics be applied in clinical studies?: Current and future approaches to study designs. Clin. Pharmacol. Ther.89,198–209 (2011).▪▪ Presents an overview of study designs appropriate for pharmacogenetic research.
    • 27  Lavedan C, Licamele L, Volpi S et al. Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Mol. Psychiatry14,804–819 (2009).
    • 28  Volpi S, Heaton C, Mack K et al. Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia. Mol. Psychiatry14,1024–1031 (2009).
    • 29  Van der Baan FH, Klungel OH, Egberts ACG et al. Pharmacogenetics in randomized controlled trials: considerations for trial design. Pharmacogenomics12,1485–1492 (2011).▪▪ Comparative overview of different study design in clinical trials to be used in pharmacogenetics research.
    • 30  Curtin F, Schulz P. Assessing benefit:risk ratio of a drug-randomized and naturalistic evidence. Dialogues Clin. Neurosci.13,183–190 (2011).▪▪ Presents an overview of different strategies in therapeutic intervention.
    • 31  de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics47,75–85 (2006).
    • 32  Kirchheiner J, Brøsen K, Dahl ML et al.CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr. Scand.104,173–192 (2001).
    • 33  Lafuente A, Bernardo M, Mas S et al. Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics. Schizophr. Res.90,115–122 (2007).
    • 34  Crescenti A, Mas S, Gassó P, Parellada E, Bernardo M, Lafuente A. CYP2D6*3, *4, *5 and *6 polymorphisms and antipsychotic-induced extrapyramidal side-effects in patients receiving antipsychotic therapy. Clin. Exp. Pharmacol. Physiol.35,807–811 (2008).
    • 35  Lafuente A, Bernardo M, Mas S et al. Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders. Psychiatry Res.161,131–141 (2008).
    • 36  Gassó P, Mas S, Bernardo M, Alvarez S, Parellada E, Lafuente A. A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharmacogenomics J.9,404–410 (2009).
    • 37  Gassó P, Mas S, Crescenti A et al. Lack of association between antipsychotic-induced extrapyramidal symptoms and polymorphisms in dopamine metabolism and transport genes. Psychiatry Res.175,173–175 (2010).
    • 38  Gassó P, Mas S, Oliveira C et al. Searching for functional SNPs or rare variants in exonic regions of DRD3 in risperidone-treated patients. Eur. Neuropsychopharmacol.21,294–299 (2010).
    • 39  Liou YJ, Bai YM, Lin E et al. Gene–gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics. Pharmacogenomics J.12,54–61 (2012).
    • 40  Wang YC, Bai YM, Chen JY, Lin CC, Lai IC, Liou YJ. Genetic association between TNF-α-308 G>A polymorphism and longitudinal weight change during clozapine treatment. Hum. Psychopharmacol.25,303–309 (2010).
    • 41  Houston JP, Fijal B, Heinloth AN, Adams DH. Genetic associations of prolactin increase in olanzapine/fluoxetine combination-treated patients. Psychiatry Res.175,171–172 (2010).
    • 42  Kang CY, Xu XF, Shi ZY, Yang JZ, Liu H, Xu HH. Interaction of catechol-O-methyltransferase (COMT) Val108/158 Met genotype and risperidone treatment in Chinese Han patients with schizophrenia. Psychiatry Res.176,94–95 (2010).
    • 43  Sicard MN, Zai CC, Tiwari AK et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics11,1561–1571 (2010).
    • 44  Kuzman MR, Medved V, Bozina N, Grubišin J, Jovanovic N, Sertic J. Association study of MDR1 and 5-HT2C genetic polymorphisms and antipsychotic-induced metabolic disturbances in female patients with schizophrenia. Pharmacogenomics J.11,35–44 (2011).
    • 45  Liu H, Wang C, Chen PH et al. Association of the manganese superoxide dismutase gene Ala-9Val polymorphism with clinical phenotypes and tardive dyskinesia in schizophrenic patients. Prog. Neuropsychopharmacol. Biol. Psychiatry34,692–696 (2010).
    • 46  Al Hadithy AF, Wilffert B, Bruggeman R et al. Lack of association between antipsychotic-induced Parkinsonism or its subsymptoms and rs4606 SNP of RGS2 gene in African–Caribbeans and the possible role of the medication: the Curacao extrapyramidal syndromes study X. Hum. Psychopharmacol.24,123–128 (2009).
    • 47  Zhang JP, Lencz T, Malhotra AK. D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am. J. Psychiatry167,763–772 (2010).
    • 48  Xu M, Li S, Xing Q et al. Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study. Eur. J. Hum. Genet.18,707–712 (2010).
    • 49  Gupta M, Bhatnagar P, Grover S et al. Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment. Pharmacogenomics10(3),385–397 (2009).
    • 50  Sumiyoshi T, Tsunoda M, Higuchi Y et al. Serotonin-1A receptor gene polymorphism and the ability of antipsychotic drugs to improve attention in schizophrenia. Adv. Ther.27,307–313 (2010).
    • 51  Kohlrausch FB, Salatino-Oliveira A, Gama CS, Lobato MI, Belmonte-de-Abreu P, Hutz MH. Influence of serotonin transporter gene polymorphisms on clozapine response in Brazilian schizophrenics. J. Psychiatr. Res.44,1158–1162 (2010).
    • 52  Julius RJ, Novitsky MA Jr, Dubin WR. Medication adherence: a review of the literature and implications for clinical practice. J. Psychiatr. Pract.15,34–44 (2009).▪ Overview of current state-of-the-art adherence monitoring for clinical practice.
    • 53  Hiemke C, Baumann P, Bergemann N et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry44,195–235 (2011).
    • 54  Lohoff FW, Ferraro TN. Pharmacogenetic considerations in the treatment of psychiatric disorders. Expert Opin. Pharmacother.11,423–439 (2010).