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.

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.

[Attention deficit hyperactivity disorder in adults]. / Sindrom defitsita vnimaniya s giperaktivnost'yu u vzroslykh.

The article presents a review of scientific publications devoted to the study of the characteristics of the clinical picture and the dynamics of the main symptoms in adult patients with attention deficit hyperactivity disorder (ADHD). The authors present current data on the prevalence of this disease, leading clinical manifestations and the most common comorbid pathology. Research data on the impact of ADHD in adulthood on educational and professional activities are presented, and the economic and criminological aspects of ADHD are considered. The main methods of psychotherapeutic correction and pharmacological therapy are presented.

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant versus nonstimulant treatments on attentional processes.

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

Real-World Experience With Deutetrabenazine for Huntington Disease Chorea.

Huntington disease (HD) is a hereditary neurodegenerative disorder with a hallmark feature of chorea. While no disease-modifying therapies currently exist for HD, symptomatic treatment of HD-associated chorea includes US Food and Drug Administration-approved vesicular monoamine transporter type 2 inhibitors-tetrabenazine and deutetrabenazine. Deutetrabenazine was more recently approved (2017), and while structurally similar to tetrabenazine, deutetrabenazine has a unique pharmacokinetic profile that allows for a longer half-life, reduced plasma fluctuations, and less frequent dosing. In pivotal trials, deutetrabenazine seemed to have an improved safety and tolerability profile over tetrabenazine but real-world data to confirm this are lacking. Here, we evaluate our real-world clinical experience with deutetrabenazine for HD-associated chorea. We performed a retrospective chart review of all patients with HD who initiated treatment with deutetrabenazine from January 2017 to May 2019 at the University of Alabama at Birmingham. Total maximal chorea scores, patient-reported subjective efficacy, dosing information, and subjective reports of adverse events (AEs) were abstracted for each patient. Our review included 58 patients with a mean length of treatment of 476.4 days. In the reviewed time period, the mean treatment difference in total maximal chorea scores was 4.4. The combined total rate of occurrence of any AEs was relatively low, at 32.8%, and the most commonly reported AEs were sedation (15.5%), insomnia (6.9%), and diarrhea (3.4%). Our real-world data support current literature indicating that deutetrabenazine is an effective and well-tolerated treatment for HD-associated chorea. Further studies repeating this on a larger scale, across a greater geography and practice pattern, are needed.

The Dose-Response Relationship of Atomoxetine for the Treatment of Children With ADHD: A Systematic Review and Dose-Response Meta-Analysis of Double-Blind Randomized Placebo-Controlled Trials.

OBJECTIVES: The present study aimed to meta-analytically estimate the dose-response relationship of atomoxetine for treating children with ADHD. METHODS: We systematically searched double-blind randomized placebo-controlled trials that evaluated the effectiveness of atomoxetine for treating ADHD in children. The search was carried out in PubMed, Cochrane Library, CINHAL, and ClinicalTrials.gov databases, covering articles from their inception until January 20, 2023. In addition, a dose-response meta-analysis was conducted. RESULTS: In this dose-response meta-analysis, 12 double-blind randomized placebo-controlled trials involving 2,250 patients were included. The efficacy of atomoxetine increased up to a dosage of 1.4 mg/kg, after which it reached a plateau. CONCLUSIONS: The first dose-response meta-analysis of atomoxetine dosing for children with ADHD conducted here enhances the robustness of the Food and Drug Administration and the European Medicines Agency dose recommendations.

Cardiovascular Safety of Atomoxetine and Methylphenidate in Patients With Attention-Deficit/Hyperactivity Disorder in Japan: A Self-Controlled Case Series Study.

OBJECTIVE: To investigate the association between atomoxetine or methylphenidate use and arrhythmia, heart failure (HF), stroke, and myocardial infarction (MI) in attention-deficit/hyperactivity disorder (ADHD) patients mainly focused on the people of working age. METHODS: In a self-controlled case series study using a Japanese claims database, we identified events of arrhythmia, HF, stroke, and MI among 15,472 atomoxetine new users and 12,059 methylphenidate new users. Adjusted incidence rate ratios (aIRRs) of outcome events were estimated using multivariable conditional Poisson regression. RESULTS: An increased risk of arrhythmia was observed during the first 7 days after the initial atomoxetine exposure (aIRR 6.22, 95% CI [1.90, 20.35]) and in the subsequent exposure (3.23, [1.58, 6.64]). No association was found between methylphenidate exposure and arrhythmia, nor between atomoxetine or methylphenidate exposure and HF. The limited number of stroke and MI cases prevented thorough analysis. CONCLUSIONS: Clinicians should consider monitoring for arrhythmia after patients initiating or re-initiating atomoxetine.

Population Pharmacokinetic Analysis of Atomoxetine and its Metabolites in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

Atomoxetine (ATX) is a non-stimulant used to treat attention-deficit/hyperactivity disorder (ADHD) and systemic exposure is highly variable due to polymorphic cytochrome P450 2D6 (CYP2D6) activity. The objective of this study was to characterize the time course of ATX and metabolites (4-hydroxyatomoxetine (4-OH); N-desmethylatomoxetine (NDA); and 2-carboxymethylatomoxetine (2-COOH)) exposure following oral ATX dosing in children with ADHD to support individualized dosing. A nonlinear mixed-effect modeling approach was used to analyze ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles obtained over 24-72 hours from children with ADHD (n = 23) following a single oral ATX dose. Demographics and CYP2D6 activity score (AS) were evaluated as covariates. Simulations were performed to explore the ATX dosing in subjects with various CYP2D6 AS. A simultaneous pharmacokinetic modeling approach was used in which a model for ATX, 4-OH, and NDA in plasma and urine, and 2-COOH in urine was developed. Plasma ATX, 4-OH, and NDA were modeled using two-compartment models with first-order elimination. CYP2D6 AS was a significant determinant of ATX apparent oral clearance (CL/F), fraction metabolized to 4-OH, and systemic exposure of NDA. CL/F of ATX varied almost 7-fold across the CYP2D6 AS groups: AS 2: 20.02 L/hour; AS 1: 19.00 L/hour; AS 0.5: 7.47 L/hour; and AS 0: 3.10 L/hour. The developed model closely captures observed ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles. Application of the model shows the potential for AS-based dosing recommendations for improved individualized dosing.

Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2.

Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood1. Dysfunction of monoaminergic circuits has been implicated in various neurodegenerative and neuropsychiatric disorders2. Vesicular monoamine transporters (VMATs) pack monoamines into vesicles for synaptic release and are essential to neurotransmission3-5. VMATs are also therapeutic drug targets for a number of different conditions6-9. Despite the importance of these transporters, the mechanisms of substrate transport and drug inhibition of VMATs have remained elusive. Here we report cryo-electron microscopy structures of the human vesicular monoamine transporter VMAT2 in complex with the antichorea drug tetrabenazine, the antihypertensive drug reserpine or the substrate serotonin. Remarkably, the two drugs use completely distinct inhibition mechanisms. Tetrabenazine binds VMAT2 in a lumen-facing conformation, locking the luminal gating lid in an occluded state to arrest the transport cycle. By contrast, reserpine binds in a cytoplasm-facing conformation, expanding the vestibule and blocking substrate access. Structural analyses of VMAT2 also reveal the conformational changes following transporter isomerization that drive substrate transport into the vesicle. These findings provide a structural framework for understanding the physiology and pharmacology of neurotransmitter packaging by synaptic vesicular transporters.

Extended-Release Viloxazine Compared with Atomoxetine for Attention Deficit Hyperactivity Disorder.

BACKGROUND AND OBJECTIVE: In our outpatient pediatric and adult psychiatry centers, we reserve psychostimulants for predominantly inattentive attention deficit hyperactivity disorder (ADHD) due to the potential for appetite and growth suppression, insomnia, wear off, exacerbation of mood, anxiety, and tics, or misuse. We utilize extended-release (ER) alpha-2 agonists primarily for hyperactivity/impulsivity but find them less effective for inattention, and they can cause sedation and hypotension. Oftentimes, we need to combine an alpha-2 agonist for behavior with psychostimulants for inattention. We employ atomoxetine or viloxazine ER (VER) for combined ADHD. However, our patients' insurers mandate a trial of generic atomoxetine prior to covering branded VER. The objective of this study was to determine whether pediatric and adult patients taking atomoxetine for DSM-5-TR ADHD combined type would experience improvement in ADHD symptoms following voluntary, open-label switch to VER. METHODS: 50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after a 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to US Food and Drug Administration (FDA) guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine, and 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; the same protocol was used after treatment with VER. We conducted a blinded, de-identified, retrospective review of charts from these 50 patients in the regular course of outpatient practice. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p < 0.05. RESULTS: From the baseline total ADHD-RS-5 mean score (40.3 ± 10.3), improvements were greater on VER (13.9 ± 10.2) than atomoxetine (33.1 ± 12.1; t = - 10.12, p < 0.00001) in inattention (t = - 8.57, p < 0.00001) and in hyperactivity/impulsivity (t = - 9.87, p < 0.00001). From the baseline total AISRS mean score (37.3 ± 11.8), improvements were greater on VER (11.9 ± 9.4) than atomoxetine (28.8 ± 14.9; t = - 4.18, p = 0.0009) in inattention (t = - 3.50, p < 0.004) and in hyperactivity/impulsivity (t = - 3.90, p < 0.002). Of patients on VER, 86% reported positive response by 2 weeks versus 14% on atomoxetine. A total of 36% discontinued atomoxetine for side effects, including gastrointestinal (GI) upset (6 patients), irritability (6), fatigue (5), and insomnia (1), versus 4% who discontinued VER due to fatigue. A total of 96% preferred VER over atomoxetine, with 85% (22 out of 26) choosing to taper psychostimulants following stabilization on VER. CONCLUSIONS: Pediatric and adult ADHD patients who have experienced less than optimal response to atomoxetine demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on extended-release viloxazine.

Prescribing patterns for attention deficit hyperactivity disorder among children and adolescents in Taiwan from 2004 to 2017.

This study documented the prescribing patterns of methylphenidate and atomoxetine among patients aged 3 to 18 in Taiwan diagnosed with attention deficit hyperactivity disorder (ADHD) between 2004 and 2017. Initial treatment for ADHD, the time between the first diagnosis and the first prescription, and medication-switching patterns were investigated. The final cohort consisted of 256,882 patients, and 147,210 (57.3%) of them received medication treatment. Most of the patients (98.2%) received methylphenidate. Atomoxetine use increased from 0.1% in 2007 to 5.5% in 2017. The median time between the ADHD diagnosis and the first prescription was 21 days (IQR: 0-212 days). In patients who initiated methylphenidate, 12,406 (8.4%) patients switched to atomoxetine; 850 (31.3%) of the children began with atomoxetine and switched to methylphenidate. In conclusion, methylphenidate was the predominant treatment for ADHD in 2004-2017. However, the prevalence of pharmacotherapy for ADHD was relatively low. Further investigation on the reasons behind this pattern is recommended.

Effect of atomoxetine on ADHD-pain hypersensitization comorbidity in 6-OHDA lesioned mice.

BACKGROUND: Methylphenidate and atomoxetine are used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Our previous studies established the validity of the 6-hydroxydopamine (6-OHDA) mouse model of ADHD and demonstrated hypersensitivity to pain, in line with clinical reports in ADHD patients. Acute methylphenidate treatment reduces hyperactivity and increases attention, but does not affect pain behaviors in this mouse model. Whereas atomoxetine has been shown to be effective against some symptoms of ADHD, nothing is known about its possible action on comorbid pain hypersensitivity. The objectives of the present research are (1) to investigate the effects of acute and chronic treatment with atomoxetine on ADHD-like symptoms and nociceptive thresholds, and (2) to explore the catecholaminergic systems underlying these effects. METHODS: Sham and 6-OHDA cohorts of male mice were tested for hyperactivity (open field), attention and impulsivity (5-choice serial reaction time task test), and thermal (hot plate test) and mechanical (von Frey test) thresholds after acute or repeated treatment with vehicle or atomoxetine (1, 3 or 10 mg/kg). RESULTS: Acute administration of atomoxetine (10 mg/kg) reduced the hyperactivity and impulsivity displayed by 6-OHDA mice, without affecting attention or nociception. However, atomoxetine administered at 3 mg/kg/day for 7 days alleviated the ADHD-like core symptoms and attenuated the hyperalgesic responses. Furthermore, hyperlocomotion and anti-hyperalgesic activity were antagonized with phentolamine, propranolol, and sulpiride pre-treatments. CONCLUSION: These findings demonstrated that when administered chronically, atomoxetine has a significant effect on ADHD-associated pain hypersensitization, likely mediated by both α- and ß-adrenergic and D2/D3 dopaminergic receptors, and suggest new indications for atomoxetine that will need to be confirmed by well-designed clinical trials.

Reduced attentional lapses in male rats following a combination treatment of low-dose D-serine and atomoxetine.

BACKGROUND: Goal-directed attention involves the selective processing of behaviorally relevant sensory information. This selective processing is thought to be supported by glutamatergic and noradrenergic systems. Pharmacotherapies that simultaneously target these systems could therefore be effective treatments for impaired attention. AIMS: We first tested an N-methyl-D-aspartate (NMDA) receptor co-agonist (D-serine) for effects on attention (processing speed and attentional lapses). NMDA receptor activation is thought to support noradrenergic effects on sensory processing; therefore, we tested a combination treatment comprising D-serine and a norepinephrine reuptake inhibitor (atomoxetine). METHODS: D-serine was first tested in rats performing a two-choice visuospatial discrimination task. Combination treatments comprising relatively low doses of D-serine and atomoxetine were then tested in a separate group. RESULTS: In experiment 1, D-serine reduced the skew of initiation time (IT) distributions (IT devmode) at the highest dose tested (300 mg/kg). In experiment 2, low-dose D-serine (125 mg/kg) had no effect, while low-dose atomoxetine (0.3 mg/kg) reduced IT devmode and slowed movement speed. Importantly, the combination of these relatively low doses of D-serine and atomoxetine reduced IT devmode more than either drug alone without further slowing movement speed. CONCLUSIONS: IT devmode is thought to reflect attentional lapses; therefore, D-serine's effects on IT devmode suggest that NMDA receptors are involved in the preparatory deployment of attention. Greater effects following a combination of D-serine and atomoxetine suggest that preparatory attention can be facilitated by targeting glutamatergic and noradrenergic systems simultaneously. These results could inform the development of improved treatments for individuals with ADHD who experience abnormally high attentional lapses.

[A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring]. / æ‰˜èŽ«è¥¿æ±€åœ¨æ³¨æ„åŠ›ç¼ºé™·å¤šåŠ¨éšœç¢æ‚£å„¿ä¸­çš„ç²¾å‡†è¯å­¦ç ”ç©¶ï¼šCYP2D6åŸºå› æ£€æµ‹å’Œæ²»ç–—è¯ç‰©ç›‘æµ‹.

Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.

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

PURPOSE: There is marked heterogeneity in treatment response of atomoxetine in patients with attention deficit/hyperactivity disorder (ADHD), especially for the pediatric population. This review aims to evaluate current evidence to characterize the dose-exposure relationship, establish clinically relevant metrics for systemic exposure to atomoxetine, define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD. METHODS: A comprehensive search was performed across electronic databases (PubMed and Embase) covering the period of January 1, 1985 to July 10, 2022, to summarize recent advances in the pharmacokinetics, pharmacogenomics/pharmacogenetics (PGx), therapeutic drug monitoring (TDM), physiologically based pharmacokinetics (PBPK), and population pharmacokinetics (PPK) of atomoxetine in children with ADHD. RESULTS: Some factors affecting the pharmacokinetics of atomoxetine were summarized, including food, CYP2D6 and CYP2C19 phenotypes, and drug‒drug interactions (DDIs). The association between treatment response and genetic polymorphisms of genes encoding pharmacological targets, such as norepinephrine transporter (NET/SLC6A2) and dopamine ß hydroxylase (DBH), was also discussed. Based on well-developed and validated assays for monitoring plasma concentrations of atomoxetine, the therapeutic reference range in pediatric patients with ADHD proposed by several studies was summarized. However, supporting evidence on the relationship between systemic atomoxetine exposure levels and clinical response was far from sufficient. CONCLUSION: Personalizing atomoxetine dosage may be even more complex than anticipated thus far, but elucidating the best way to tailor the non-stimulant to a patient's individual need will be achieved by combining two strategies: detailed research in linking the pharmacokinetics and pharmacodynamics in pediatric patients, and better understanding in nature and causes of ADHD, as well as environmental stressors.

Meta-analysis on the efficacy of the norepinephrine reuptake inhibitors reboxetine and atomoxetine for the treatment of schizophrenia and attention deficit hyperactivity disorder.

BACKGROUND: Norepinephrine transporter inhibitors that can alter the level of neurotransmitter in the brain are used to treat neurological disorders. However, a number of studies have reported their limited significance as a result of their slow onset of action and moderate efficacy. OBJECTIVES: To determine the effects of norepinephrine reuptake inhibitors (NRIs), reboxetine and atomoxetine on schizophrenia and attention deficit hyperactivity disorder (ADHD). MATERIAL AND METHODS: Relevant articles published between 2000 and 2022 were searched in the MEDLINE, CINAHL (via Ebsco), Web of Science and Scopus databases. Among the various NRIs, studies concerning the 2 potent drugs - reboxetine and atomoxetine - were selected for analysis. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated, along with the exploration of heterogeneity and publication bias, using RevMan software. RESULTS: A total of 14 eligible studies with a combined sample size of 970 patients were included. Using a random effects model, an OR of 0.55 (0.32-0.94), a Tau2 value of 0.23, a ÷2 value of 12.31, 8 degrees of freedom (df), an I2 of 35%, a Z value of 2.19, and a p-value of 0.03 were recorded for reboxetine. Atomoxetine had an OR of 0.35 (0.13-0.97), a Tau2 value of 0.58, a ÷2 value of 7.31, 4 df, an I2 of 45%, a Z value of 1.53, and a p-value of 0.04. All results were statistically significant with a low risk of publication bias, as was evident from the p-values >0.05 derived from the Egger's test and the Begg's test. These drugs provided comparable changes to control drugs in Hamilton Depression Rating Scale (HAM-D) scores, Positive and Negative Syndrome Scale (PANSS) scores and ADHD ratings. This confirms the efficacy of reboxetine for the treatment of schizophrenia and atomoxetine for the treatment of ADHD. CONCLUSION: The present meta-analysis suggests that NRIs are efficacious and therefore they are potential candidate drugs for the treatment of schizophrenia and ADHD.

A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring / 中国当代儿科杂志

Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.

A Case of Priapism in a Child With Autism Spectrum Disorder, Possibly Due to Risperidone Treatment With Addition of Atomoxetine.

OBJECTIVES: Risperidone is an effective drug used for the treatment of irritability in children with autism spectrum disorder (ASD). Atomoxetine (ATX) is a well-tolerated drug used in first-line therapy in children with attention-deficit/hyperactivity disorder (ADHD). However, uncommon adverse effects of risperidone and ATX are a concern among mental health professionals. To our knowledge, this is the first case report of priapism after addition of ATX upon existing treatment with risperidone. METHODS: Written informed consent for publication was obtained from the patient and his parents, and their identities were concealed for ethical reasons. RESULTS: Here, we report a case of priapism as an adverse effect of ATX and risperidone treatment in a 7-year-old boy with ASD and comorbid ADHD. In this case, priapism was not observed with risperidone until ATX was added. CONCLUSIONS: Priapism is a condition viewed as a medical emergency. Although risperidone-induced priapism is a rare phenomenon, it is advised for clinicians to consider the drug interactions in treatment of ASD and ADHD in terms of early diagnosis and intervention.

A systematic review of the use of atomoxetine for management of comorbid anxiety disorders in children and adolescents with attention-deficit hyperactivity disorder.

BACKGROUND: Anxiety disorders are among the most common comorbid mental disorders in children and adolescents with attention-deficit hyperactivity disorder (ADHD). While the role of atomoxetine, a non-stimulant medication, is well-established in the management of ADHD symptoms since two decades, there is a dearth of evidence regarding its efficacy in the management of anxiety disorders in children and adolescents with ADHD. AIMS: We aimed to provide insights into (1) the comparative efficacy of atomoxetine in children and adolescents with comorbid ADHD and anxiety disorders, (2) change in severity of anxiety symptoms based on patients', parents', and clinicians' ratings, (3) tolerability and side effects. METHODS: We searched PubMed, EMBASE, and PsycINFO for clinical trials that addressed the efficacy of atomoxetine for anxiety symptoms in children and adolescents with ADHD. All published literature was systematically reviewed. RESULTS: We included four studies, out of which two specifically addressed comorbid ADHD and anxiety disorder. The studies suggested that atomoxetine did not exacerbate and in fact reduced anxiety symptoms in young patients with comorbid ADHD. CONCLUSIONS AND IMPLICATIONS: Overall, atomoxetine demonstrates good efficacy in improving anxiety symptoms in children and adolescents with ADHD. Further studies are needed to shed light on atomoxetine's efficacy for anxiety subtypes in ADHD.

Shared and Unique Effects of Long-Term Administration of Methylphenidate and Atomoxetine on Degree Centrality in Medication-Naïve Children With Attention-Deficit/Hyperactive Disorder.

BACKGROUND: Although methylphenidate (MPH) and atomoxetine (ATX) can improve clinical symptoms and functional impairments in attention deficit/hyperactive disorder (ADHD), the underlying psychopharmacological mechanisms have not been clearly elucidated. Therefore, we aimed to explore the shared and unique neurologic basis of these 2 medications in alleviating the clinical symptoms and functional impairments observed in ADHD. METHODS: Sixty-seven ADHD and 44 age-matched children with typical development were included and underwent resting-state functional magnetic resonance imaging scans at baseline. Then patients were assigned to MPH, ATX, or untreated subgroups, based on the patients' and their parents' choice, for a 12-week follow-up and underwent a second functional magnetic resonance imaging scan. The treatment effect on degree centrality (DC) was identified and correlated with clinical symptoms and functional impairments in the ADHD group. RESULTS: Both MPH and ATX normalized the DC value in extensive brain regions mainly involving fronto-cingulo-parieto-cerebellum circuits. However, ATX showed limited significant effects on the cerebellum compared with ADHD at baseline. The improvements in clinical symptoms were correlated with increased DC in the right inferior temporal gyrus in both MPH and ATX subgroups but showed opposite effects. The alleviation of functional impairments in the school/learning domain negatively correlated with decreased DC in the bilateral cerebellum after MPH treatment, and the family functional domain positively correlated with decreased DC in the cerebellum and negatively correlated with decreased DC in the postcentral gyrus after ATX treatment. CONCLUSIONS: Both MPH and ATX can normalize abnormal brain functions that mainly involve the fronto-cingulo-parieto-cerebellum circuit in ADHD. Furthermore, the 2 medications showed shared and unique effects on brain functions to alleviate clinical symptoms and functional impairment.