{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T09:08:51Z","timestamp":1771232931376,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T00:00:00Z","timestamp":1688342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alicia Koplowitz grant for Research in Neurosciences (Madrid, Spain)","award":["UGP14-01"],"award-info":[{"award-number":["UGP14-01"]}]},{"name":"Alicia Koplowitz grant for Research in Neurosciences (Madrid, Spain)","award":["UGP15-306"],"award-info":[{"award-number":["UGP15-306"]}]},{"name":"Alicia Koplowitz grant for Research in Neurosciences (Madrid, Spain)","award":["PMAFI-17\/21"],"award-info":[{"award-number":["PMAFI-17\/21"]}]},{"name":"Alicia Koplowitz grant for Research in Neurosciences (Madrid, Spain)","award":["PT13\/0001"],"award-info":[{"award-number":["PT13\/0001"]}]},{"name":"Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO, Valencia, Spain)","award":["UGP14-01"],"award-info":[{"award-number":["UGP14-01"]}]},{"name":"Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO, Valencia, Spain)","award":["UGP15-306"],"award-info":[{"award-number":["UGP15-306"]}]},{"name":"Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO, Valencia, Spain)","award":["PMAFI-17\/21"],"award-info":[{"award-number":["PMAFI-17\/21"]}]},{"name":"Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO, Valencia, Spain)","award":["PT13\/0001"],"award-info":[{"award-number":["PT13\/0001"]}]},{"name":"Universidad Cat\u00f3lica San Antonio de Murcia","award":["UGP14-01"],"award-info":[{"award-number":["UGP14-01"]}]},{"name":"Universidad Cat\u00f3lica San Antonio de Murcia","award":["UGP15-306"],"award-info":[{"award-number":["UGP15-306"]}]},{"name":"Universidad Cat\u00f3lica San Antonio de Murcia","award":["PMAFI-17\/21"],"award-info":[{"award-number":["PMAFI-17\/21"]}]},{"name":"Universidad Cat\u00f3lica San Antonio de Murcia","award":["PT13\/0001"],"award-info":[{"award-number":["PT13\/0001"]}]},{"name":"La Caixa Foundation (Barcelona, Spain)","award":["UGP14-01"],"award-info":[{"award-number":["UGP14-01"]}]},{"name":"La Caixa Foundation (Barcelona, Spain)","award":["UGP15-306"],"award-info":[{"award-number":["UGP15-306"]}]},{"name":"La Caixa Foundation (Barcelona, Spain)","award":["PMAFI-17\/21"],"award-info":[{"award-number":["PMAFI-17\/21"]}]},{"name":"La Caixa Foundation (Barcelona, Spain)","award":["PT13\/0001"],"award-info":[{"award-number":["PT13\/0001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The long-term use of psychopharmacology medications in autism spectrum disorder (ASD) hitherto remains controversial due to a lack of evidence about safety and tolerability. In this regard, genotyping the metabolizing enzyme cytochrome P450 (CYP) 2D6, especially its extreme phenotypes, could help to prevent drug-related adverse reactions or adverse events (AEs). There are several medications warranting CYP2D6 screening that are consumed by people with ASD, such as risperidone and aripiprazole to name a few. A naturalistic observational study was carried out in participants with ASD to analyze the influence of the CYP2D6 phenotype in drug tolerability using a local pharmacovigilance system created for this study. In this case, AEs were identified from participants\u2019 electronic health records (EHRs) and paper registries. Other variables were collected: socio-demographic information, comorbidities, and psychopharmacology prescriptions (polypharmacy defined as \u22654 simultaneous prescriptions) and doses. The genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number variations. All of these were used to determine theoretical phenotypes of the metabolic profiles: poor (PM); intermediate (IM); normal (NM); and ultra-rapid (UM). Sex differences were analyzed. A total of 71 participants (30 \u00b1 10 years old, 82% male, 45% CYP2D6 NM phenotype (32 participants)) with a median of 3 (IQR 2\u20134) comorbidities per person, mainly urinary incontinence (32%) and constipation (22%), were included. CYP2D6 UM showed the highest rate of polypharmacy, whilst, IM participants had the highest rates of neurological and psychiatric AEs, even worse if a CYP2D6 inhibitor drug was prescribed simultaneously. CYP2D6 pharmacogenomics and the monitoring of new antipsychotic prescriptions may make a difference in medication safety in adults with ASD. Particularly in those with psychopharmacology polymedication, it can help with AE avoidance and understanding.<\/jats:p>","DOI":"10.3390\/ph16070954","type":"journal-article","created":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T01:47:14Z","timestamp":1688435234000},"page":"954","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CYP2D6 Genotype and Pharmacovigilance Impact on Autism Spectrum Disorder: A Naturalistic Study with Extreme Phenotype Analysis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7345-448X","authenticated-orcid":false,"given":"Pura","family":"Ballester","sequence":"first","affiliation":[{"name":"Pharmacology Department, Pharmacy Degree, San Antonio Catholic University, 30107 Murcia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Espadas","sequence":"additional","affiliation":[{"name":"Bioengineering Institute, Pediatrics and Organic Chemistry Department, Miguel Hern\u00e1ndez University of Elche (UMH), 03202 Alicante, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susana","family":"Almenara","sequence":"additional","affiliation":[{"name":"Neuropharmacology on Pain Treatment and Neurodevelopmental Disorders, Dr. Balmis General University Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain"},{"name":"Clinical Pharmacology Unit, Alicante General University Hospital, 03010 Alicante, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4697-2783","authenticated-orcid":false,"given":"Jordi","family":"Barrachina","sequence":"additional","affiliation":[{"name":"Neuropharmacology on Pain Treatment and Neurodevelopmental Disorders, Dr. Balmis General University Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Muriel","sequence":"additional","affiliation":[{"name":"Neuropharmacology on Pain Treatment and Neurodevelopmental Disorders, Dr. Balmis General University Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain"},{"name":"Clinical Pharmacology, Pediatrics and Organic Chemistry Department, Miguel Hern\u00e1ndez University of Elche (UMH), 03202 Alicante, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Ramos","sequence":"additional","affiliation":[{"name":"Bioengineering Institute, Pediatrics and Organic Chemistry Department, Miguel Hern\u00e1ndez University of Elche (UMH), 03202 Alicante, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Toral","sequence":"additional","affiliation":[{"name":"San Rafael Center\u2014San Francisco De Borja Foundation, Residential Facility, 03559 Alicante, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9sar","family":"Belda","sequence":"additional","affiliation":[{"name":"Infanta Leonor Center, Autism Parents Association Valencian Community Autism Association (APACV), 03010 Alicante, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2385-3749","authenticated-orcid":false,"given":"Ana M.","family":"Peir\u00f3","sequence":"additional","affiliation":[{"name":"Bioengineering Institute, Pediatrics and Organic Chemistry Department, Miguel Hern\u00e1ndez University of Elche (UMH), 03202 Alicante, Spain"},{"name":"Neuropharmacology on Pain Treatment and Neurodevelopmental Disorders, Dr. Balmis General University Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain"},{"name":"Clinical Pharmacology Unit, Alicante General University Hospital, 03010 Alicante, Spain"},{"name":"Clinical Pharmacology, Pediatrics and Organic Chemistry Department, Miguel Hern\u00e1ndez University of Elche (UMH), 03202 Alicante, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/acps.12644","article-title":"Use of psychotropic drugs in patients with autism spectrum disorders: A systematic review","volume":"135","author":"Jobski","year":"2017","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113321","DOI":"10.1016\/j.psychres.2020.113321","article-title":"Multimorbidity and psychotropic polypharmacy among participants with autism spectrum disorder with intellectual disability","volume":"292","author":"Espadas","year":"2020","journal-title":"Psychiatry Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1007\/s10803-010-0996-9","article-title":"The heavy burden of psychiatric comorbidity in youth with autism spectrum disorders: A large comparative study of a psychiatrically referred population","volume":"40","author":"Joshi","year":"2010","journal-title":"J. Autism Dev. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1517\/14656566.2016.1154536","article-title":"Psychopharmacological interventions in autism spectrum disorder","volume":"17","author":"Accordino","year":"2016","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1002\/aur.1848","article-title":"Psychiatric comorbidities and use of psychotropic medications in people with autism spectrum disorder in the United States","volume":"10","author":"Houghton","year":"2017","journal-title":"Autism Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s10803-016-2905-3","article-title":"The Relationship Between Adverse Childhood Events, Resiliency and Health Among Children with Autism","volume":"47","author":"Rigles","year":"2017","journal-title":"J. Autism Dev. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1080\/14740338.2016.1225721","article-title":"Therapeutic drug monitoring as a measure of proactive pharmacovigilance in child and adolescent psychiatry","volume":"15","author":"Gerlach","year":"2016","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/clpt.2013.254","article-title":"Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update","volume":"95","author":"Crews","year":"2014","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1007\/s10803-014-2170-2","article-title":"Psychiatric comorbidity and medication use in adults with autism spectrum disorder","volume":"44","author":"Buck","year":"2014","journal-title":"J. Autism Dev. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1345\/aph.1R333","article-title":"Pharmacogenetics of risperidone: A systematic review of the clinical effects of CYP2D6 polymorphisms","volume":"47","author":"Cartwright","year":"2013","journal-title":"Ann. Pharmacother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.dmpk.2016.01.005","article-title":"Detection of CYP2D6 polymorphism using Luminex xTAG technology in autism spectrum disorder: CYP2D6 activity score and its association with risperidone levels","volume":"31","author":"Vanwong","year":"2016","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1089\/cap.2014.0171","article-title":"Impact of CYP2D6 Polymorphism on Steady-State Plasma Levels of Risperidone and 9-Hydroxyrisperidone in Thai Children and Adolescents with Autism Spectrum Disorder","volume":"27","author":"Vanwong","year":"2017","journal-title":"J. Child Adolesc. Psychopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3389\/fpsyt.2018.00002","article-title":"Pharmacoresistant Severe Mental Health Disorders in Children and Adolescents: Functional Abnormalities of Cytochrome P450 2D6","volume":"9","author":"Dor","year":"2018","journal-title":"Front. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s40291-013-0028-5","article-title":"Applications of CYP450 testing in the clinical setting","volume":"17","author":"Samer","year":"2013","journal-title":"Mol. Diagn. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1002\/jcph.530","article-title":"CYP2D6 predicted metabolizer status and safety in adult patients with attention-deficit hyperactivity disorder participating in a large placebo-controlled atomoxetine maintenance of response clinical trial","volume":"55","author":"Fijal","year":"2015","journal-title":"J. Clin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1111\/j.1526-4637.2009.00641.x","article-title":"The impact of CYP2D6 genetic polymorphisms on postoperative morphine consumption","volume":"10","author":"Candiotti","year":"2009","journal-title":"Pain Med."},{"key":"ref_17","first-page":"71","article-title":"Sex Differences in Associations Between CYP2D6 Phenotypes and Response to Opioid Analgesics","volume":"13","author":"Lopes","year":"2020","journal-title":"Pharm. Pers. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1097\/01.jcp.0000145341.30547.f0","article-title":"Impact of the CYP2D6 ultrarapid metabolizer genotype on mirtazapine pharmacokinetics and adverse events in healthy volunteers","volume":"24","author":"Kirchheiner","year":"2004","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0074-7742(08)00001-9","article-title":"Gender differences in pharmacological response","volume":"83","author":"Anderson","year":"2008","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3109\/15563650.2015.1049355","article-title":"CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants","volume":"53","author":"Haufroid","year":"2015","journal-title":"Clin. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"983","DOI":"10.2165\/00003088-200443140-00003","article-title":"Genetic predictors of the clinical response to opioid analgesics: Clinical utility and future perspectives","volume":"43","author":"Skarke","year":"2004","journal-title":"Clin. Pharmacokinet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"29","DOI":"10.2133\/dmpk.DMPK-13-RV-032","article-title":"Influence of Cytochrome P450, Family 2, Subfamily D, Polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics","volume":"29","author":"Zahari","year":"2014","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1177\/1362361316665222","article-title":"Comorbidity prevalence, healthcare utilization, and expenditures of Medicaid enrolled adults with autism spectrum disorders","volume":"21","author":"Vohra","year":"2017","journal-title":"Autism Int. J. Res. Pract."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.chc.2005.08.007","article-title":"Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents","volume":"15","author":"Correll","year":"2006","journal-title":"Child Adolesc. Psychiatr. Clin. N. Am."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1001\/jama.2009.1549","article-title":"Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents","volume":"302","author":"Correll","year":"2009","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e8505","DOI":"10.1097\/MD.0000000000008505","article-title":"Multiple adverse drug reactions and genetic polymorphism testing: A case report with negative result","volume":"96","author":"Arellano","year":"2017","journal-title":"Medicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1111\/bcpt.12960","article-title":"Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers","volume":"122","author":"Belmonte","year":"2018","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/pds.4422","article-title":"Discontinuation and dose adjustment of metoprolol after metoprolol-paroxetine\/fluoxetine co-prescription in Dutch elderly","volume":"27","author":"Bahar","year":"2018","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_29","first-page":"621","article-title":"Aripiprazole for autism spectrum disorders (ASD)","volume":"6","author":"Ching","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1172\/JCI32483","article-title":"Antipsychotics in the treatment of autism","volume":"118","author":"Posey","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_31","first-page":"131","article-title":"CYP2D6 polymorphisms and their influence on risperidone treatment","volume":"9","author":"Puangpetch","year":"2016","journal-title":"Pharm. Pers. Med."},{"key":"ref_32","first-page":"2377","article-title":"A method of assessing the sensitivity of the Cochran-Mantel-Haenszel test to an unobserved confounder","volume":"366","author":"Yu","year":"2008","journal-title":"Philos. Trans. Ser. A Math. Phys. Eng. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/cts.12692","article-title":"Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmaco-genetics Implementation Consortium and Dutch Pharmacogenetics Working Group","volume":"13","author":"Caudle","year":"2020","journal-title":"Clin. Transl. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/gim.2016.80","article-title":"Prediction of CYP2D6 phenotype from genotype across world populations","volume":"19","author":"Gaedigk","year":"2017","journal-title":"Genet. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1517\/17425255.2014.964204","article-title":"Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations","volume":"10","author":"LLerena","year":"2014","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_36","first-page":"485","article-title":"High frequency of CYP2D6 ultrarapid metabolizers in Spain: Controversy about their misclassification in worldwide population studies","volume":"16","author":"Naranjo","year":"2016","journal-title":"Pharm. J."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/7\/954\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:05:00Z","timestamp":1760126700000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/7\/954"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,3]]},"references-count":36,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["ph16070954"],"URL":"https:\/\/doi.org\/10.3390\/ph16070954","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,3]]}}}