Jeffrey R Bishop, Chuan Zhou, Andrea Gaedigk, Beth Krone, Rick Kittles, Edwin H Cook, Jeffrey H Newcorn, Mark A Stein
{"title":"哌醋甲酯与阿托莫西汀交叉研究中多巴胺转运体和 CYP2D6 基因与注意缺陷/多动障碍治疗反应的关系。","authors":"Jeffrey R Bishop, Chuan Zhou, Andrea Gaedigk, Beth Krone, Rick Kittles, Edwin H Cook, Jeffrey H Newcorn, Mark A Stein","doi":"10.1089/cap.2024.0069","DOIUrl":null,"url":null,"abstract":"<p><p><b><i>Background:</i></b> Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-<i>SLC6A3</i> also commonly known as <i>DAT1</i>) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 <i>CYP2D6</i>) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. <b><i>Methods:</i></b> Genetic variations in <i>DAT1</i> and <i>CYP2D6</i> were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. <b><i>Results:</i></b> Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: <i>p</i> = 0.058, Methylphenidate [MPH]: <i>p</i> = 0.044). There was also a trend for the <i>DAT1</i> 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (<i>p</i> = 0.029). Participants with <i>DAT1</i> 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. <b><i>Conclusions:</i></b> Most children with ADHD who were CYP2D6 normal metabolizers or had <i>DAT1</i> 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of <i>CYP2D6</i> and <i>DAT1</i> with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential <i>DAT1</i> association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the <i>DAT1</i> in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.</p>","PeriodicalId":15277,"journal":{"name":"Journal of child and adolescent psychopharmacology","volume":null,"pages":null},"PeriodicalIF":1.5000,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dopamine Transporter and <i>CYP2D6</i> Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study.\",\"authors\":\"Jeffrey R Bishop, Chuan Zhou, Andrea Gaedigk, Beth Krone, Rick Kittles, Edwin H Cook, Jeffrey H Newcorn, Mark A Stein\",\"doi\":\"10.1089/cap.2024.0069\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b><i>Background:</i></b> Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-<i>SLC6A3</i> also commonly known as <i>DAT1</i>) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 <i>CYP2D6</i>) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. <b><i>Methods:</i></b> Genetic variations in <i>DAT1</i> and <i>CYP2D6</i> were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. <b><i>Results:</i></b> Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: <i>p</i> = 0.058, Methylphenidate [MPH]: <i>p</i> = 0.044). There was also a trend for the <i>DAT1</i> 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (<i>p</i> = 0.029). Participants with <i>DAT1</i> 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. <b><i>Conclusions:</i></b> Most children with ADHD who were CYP2D6 normal metabolizers or had <i>DAT1</i> 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of <i>CYP2D6</i> and <i>DAT1</i> with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential <i>DAT1</i> association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the <i>DAT1</i> in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.</p>\",\"PeriodicalId\":15277,\"journal\":{\"name\":\"Journal of child and adolescent psychopharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.5000,\"publicationDate\":\"2024-10-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of child and adolescent psychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1089/cap.2024.0069\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PEDIATRICS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of child and adolescent psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1089/cap.2024.0069","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PEDIATRICS","Score":null,"Total":0}
Dopamine Transporter and CYP2D6 Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study.
Background: Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-SLC6A3 also commonly known as DAT1) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 CYP2D6) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Methods: Genetic variations in DAT1 and CYP2D6 were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Results: Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: p = 0.058, Methylphenidate [MPH]: p = 0.044). There was also a trend for the DAT1 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (p = 0.029). Participants with DAT1 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Conclusions: Most children with ADHD who were CYP2D6 normal metabolizers or had DAT1 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of CYP2D6 and DAT1 with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential DAT1 association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the DAT1 in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.
期刊介绍:
Journal of Child and Adolescent Psychopharmacology (JCAP) is the premier peer-reviewed journal covering the clinical aspects of treating this patient population with psychotropic medications including side effects and interactions, standard doses, and research on new and existing medications. The Journal includes information on related areas of medical sciences such as advances in developmental pharmacokinetics, developmental neuroscience, metabolism, nutrition, molecular genetics, and more.
Journal of Child and Adolescent Psychopharmacology coverage includes:
New drugs and treatment strategies including the use of psycho-stimulants, selective serotonin reuptake inhibitors, mood stabilizers, and atypical antipsychotics
New developments in the diagnosis and treatment of ADHD, anxiety disorders, schizophrenia, autism spectrum disorders, bipolar disorder, eating disorders, along with other disorders
Reports of common and rare Treatment Emergent Adverse Events (TEAEs) including: hyperprolactinemia, galactorrhea, weight gain/loss, metabolic syndrome, dyslipidemia, switching phenomena, sudden death, and the potential increase of suicide. Outcomes research.