Personalizing atomoxetine dosing in children with ADHD: what can we learn from current supporting evidence

Fu, Di; Guo, Hongli; Hu, Yahui; Fang, Weirong; Liu, Qianqi; Xu, Jing; Wu, Dandan; Chen, Feng

doi:10.1007/s00228-022-03449-1

Cited by 5 publications

(6 citation statements)

References 157 publications

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“…Atomoxetine is mainly metabolized by a highly polymorphic enzyme, Cytochrome P450 2D6, and this may account in large part for the marked heterogeneity observed in the pediatric response to atomoxetine treatment [35,38]. Poor metabolizers face an increased risk of adverse effects, whereas ultra-rapid metabolizers may experience reduced efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…For this reason, it is important that the dose be slowly titrated to determine each individual's target dose that balances these outcomes. Prospective studies evaluating methods of atomoxetine dose optimization (e.g., pharmacogenetic testing and pharmacokinetic modelling) in pediatric patients with a range of metabolizer profiles would be invaluable in determining the most effective and tolerated dosing range [38].…”

Section: Discussionmentioning

confidence: 99%

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Atomoxetine Treatment of Attention Deficit/Hyperactivity Disorder Symptoms in 3–6-Year-Old Children with Autism Spectrum Disorder: A Retrospective Cohort Study

Alsayouf,

Alsarhan,

Khreisat

et al. 2024

Children

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Atomoxetine is indicated for the management of attention deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6 to 18 years. Few studies have assessed the safety and tolerability of atomoxetine in younger patients. This retrospective cohort study included 133 children aged 3–6 years who were diagnosed with ADHD comorbid with autism spectrum disorder (ASD). The primary endpoint was the evaluation of the safety profile of atomoxetine. In total, 50 patients (37.6%) experienced adverse events (AEs), which led to treatment discontinuation in 23 patients (17.3%). The most common AEs were gastrointestinal (24.1%), aggression or hostility (12.8%), and increased hyperactivity (9.0%). In the 23 patients who discontinued treatment, all the AEs resolved after treatment ceased. Among the 110 patients who completed at least 6 months’ treatment, atomoxetine titrated to a dose of 1.2–1.8 mg/kg/day appeared to be well tolerated and effective. The Clinical Global Impression—Improvement score improved to 1 (“very much improved”) and 2 (“much improved”) in 62.4% and 20.3% of children, respectively, at their last visit. Overall, atomoxetine appeared to be well tolerated in younger children with comorbid ADHD and ASD. Nevertheless, close patient monitoring remains essential, and the study limitations necessitate caution in generalizing these findings to broader populations. Long-term prospective studies are required.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Atomoxetine Treatment of Attention Deficit/Hyperactivity Disorder Symptoms in 3–6-Year-Old Children with Autism Spectrum Disorder: A Retrospective Cohort Study

Alsayouf,

Alsarhan,

Khreisat

et al. 2024

Children

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“…We aimed to review the published literature that assessed the comparative clinical effectiveness and costeffectiveness of pharmacogenomic tests for guiding the treatment of psychiatric disorders compared with treatment as usual (i�e�, no pharmacogenomic testing to guide medication selection)� Additionally, we sought studies that have evaluated patients' perspectives and experiences related to pharmacogenomic testing� Because the clinical evidence about the use of pharmacogenomic testing varies by patient population, the findings are presented by psychiatric disorder. When available, the emerging evidence summarized in published health technology assessments (HTAs) or systematic reviews was prioritized� If there were no HTAs or systematic reviews identified for a condition , the findings from primary clinical studies (both randomized and nonrandomized) were described� There are many gene-drug association studies that examine the relationship between genetic polymorphisms and response to pharmacotherapies for various disorders, including depression, [57][58][59] bipolar disorder, 60,61 substance use disorders, [62][63][64][65] schizophrenia spectrum disorders, 66 ADHD, [67][68][69] obsessive-compulsive disorder, 70 anxiety disorders, 71,72 autism spectrum disorder, 73,74 post-traumatic stress disorder (PTSD), 75 and alcohol withdrawal syndrome� 76 Although these studies may be informative for the development of pharmacogenomic tests because they identify genes of potential interest, these studies were not reviewed in this report� This Horizon Scan report is not a systematic review of the evidence, the studies included were not critically appraised, and it does not endorse any information, pharmacogenomic test, or technology�…”

Section: Summary Of the Evidencementioning

confidence: 99%

An Overview of Pharmacogenomic Testing for Psychiatric Disorders

Young¹,

MacDougall²

2023

cjht

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Pharmacogenomic testing is a precision medicine technology that examines genetic variation in medication metabolism. Selected for inclusion in CADTH’s 2023 Watch List, pharmacogenomic testing has the potential to significantly influence the landscape of health care in Canada over the next 5 years. By analyzing an individual’s unique genetic profile, this testing aims to guide personalized treatment strategies that improve therapeutic outcomes, optimize the medication selection process, and enhance patient experiences. The integration of pharmacogenomic testing into clinical practice may pave the way for a more efficient and effective delivery of mental health care. Pharmacogenomic tests for psychiatric disorders that are available in Canada include direct-to-consumer tests — which are paid out of pocket — and tests that are offered as a laboratory service (which may or may not be paid out of pocket). These tests are quite different from each other, including the types and number of genes examined, cost of testing, and methods used for sample collection and analysis. Despite being available for approximately 20 years and that numerous guideline-developing groups and regulators have issued recommendations about the types of pharmacogenomic information that should be used to guide prescribing decisions, pharmacogenomic testing has yet to be integrated into most psychiatric care practices in Canada and worldwide. Although some studies suggest pharmacogenomic testing provides benefits over treatment as usual, the evidence is often conflicting and of limited quality. Concerns related to risk of bias, inconsistency across studies, reproducibility, and generalizability do not allow a clear and consistent interpretation of the results. This Horizon Scan provides an overview of information related to pharmacogenomic testing for psychiatric disorders, a description of some of the published studies, and a summary of some important considerations related to clinician education and training, privacy and confidentiality of health data, health equity, and laboratory capacity should testing become more widely used in Canada.

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“…Medications approved by the FDA comprise stimulants (like amphetamines and methylphenidate), generally recommended as the first-line pharmacologic treatment, and nonstimulants (like atomoxetine and extended-release clonidine and guanfacine), always taken as the second-line therapy [ 2 ]. However, the 2014 Japanese clinical guidelines and the 2015 Chinese guidelines recommend both the nonstimulants and the stimulants as first-line pharmacological treatment for children and adolescents with ADHD [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…In another scenario, some other children experienced low doses and low exposures, tolerated the drug very well but showed poor clinical efficacy. In these cases, alternative medications were chosen instead of adjusting the dosage regimen [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together

Guo,

Wu,

et al. 2024

Transl Psychiatry

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Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children’s Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.

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Personalizing atomoxetine dosing in children with ADHD: what can we learn from current supporting evidence

Cited by 5 publications

References 157 publications

Atomoxetine Treatment of Attention Deficit/Hyperactivity Disorder Symptoms in 3–6-Year-Old Children with Autism Spectrum Disorder: A Retrospective Cohort Study

Atomoxetine Treatment of Attention Deficit/Hyperactivity Disorder Symptoms in 3–6-Year-Old Children with Autism Spectrum Disorder: A Retrospective Cohort Study

An Overview of Pharmacogenomic Testing for Psychiatric Disorders

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together

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