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.

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.

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.

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.

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.

Atomoxetine in comorbid ADHD/PTSD: A randomized, placebo controlled, pilot, and feasibility study.

BACKGROUND: PTSD and ADHD often occur comorbidly. Research indicates that the cognitive deficits in PTSD may be related to the same disturbance of fronto-temporal systems as observed in ADHD, and ADHD has been shown to impact PTSD treatment outcomes. The presented study evaluated the safety and efficacy of atomoxetine in Veterans with comorbid ADHD/PTSD. METHODS: A double blind, randomized, placebo controlled, cross-over pilot and feasibility study was conducted. Atomoxetine was examined as an adjunctive treatment over this 10 weeks, two phase, crossover study which compared treatment with atomoxetine 80 mg daily to placebo daily. The primary outcome was improvement in ADHD symptoms as measured by the Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S), the Barkley Adult ADHD Rating Scale-IV (BAARS-IV), and the Adult ADHD Quality of Life-29 (AAQoL-29). Secondary outcomes included the Clinician Administered PTSD Scale (CAPS), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the response inhibition task Go/NoGo (GNG). RESULTS: Atomoxetine treated patients had greater reductions in ADHD symptoms as defined by total scores on the CAARS-S:S (F(1, 29) = 6.37, p = .017); both the BAARS-IV (F(1, 26) = 3.16, p = .087); and GNG overall errors test (F(1, 29) = 3.88, p = .06), reached a trend level of significance. No significant differences were noted in quality of life assessments, GNG latency periods, or CAPS scores. Atomoxetine was well-tolerated with no serious adverse events observed. CONCLUSIONS: In Veterans with ADHD comorbid with PTSD, atomoxetine demonstrated modest efficacy for ADHD symptoms; quality of life measures and PTSD symptoms were not affected.

Role of the norepinephrine transporter polymorphisms in atomoxetine treatment: From response to side effects in children with ADHD.

OBJECTIVE: Atomoxetine (ATX), one of the most commonly used drugs after stimulants in attention deficit hyperactivity disorder (ADHD) treatment, is an inhibitor of the norepinephrine transporter (NET/SLC6A2), which is also associated with the etiology of ADHD. In this study, we aimed to investigate the effect of NET gene polymorphisms on response to ATX treatment and to find the answers to the questions about whether there is a relationship between the severity of the disorder and the observed side effects in children with ADHD. METHOD: About 100 children with ADHD and 80 healthy controls (HCs) were included in this study. The dose of ATX was started at 0.5 mg/kg/day and titrated at 1.2 mg/kg/day. Response to treatment of 78 patients was evaluated 2 months after the beginning of the treatment. After whole blood samples were obtained, DNAs were isolated, and samples were stored at -80°C. Two single-nucleotide polymorphisms (SNPs) (rs12708954 and rs3785143) were analyzed by real-time quantitative PCR (qRT-PCR). RESULTS: The patients with both rs12708954 and rs3785143 heterozygous genotype had better treatment response and more side effects than patients with wild type. There was not found any association between any of the investigated NET polymorphisms and ADHD severity. CONCLUSION: It was, however, found that the NET rs12708954 and rs3785143 genotypes affect the treatment response to ATX in our study; thus, further studies with a large population are needed to understand the effects of NET polymorphisms on treatment, side effects, and also the severity of ADHD.

Long-Term Safety and Efficacy of Deutetrabenazine in Younger and Older Patients With Tardive Dyskinesia.

OBJECTIVES: To assess long-term safety and efficacy of deutetrabenazine in younger (<55 years) and older (≥55 years) adult participants with tardive dyskinesia (TD). DESIGN: Three-year, single-arm, open-label extension (OLE) study enrolling participants who completed the 12-week, pivotal ARM-TD or AIM-TD studies. SETTING: Seventy-six centers in the United States and Europe. PARTICIPANTS: A total of 337 participants with TD (119 younger and 218 older). INTERVENTION: Deutetrabenazine was initiated at 12 mg/day and titrated once weekly by 6 mg/day using a response-driven dosing regimen until adequate dyskinesia control was reached or a clinically significant adverse event occurred. MEASUREMENTS: This post hoc analysis assessed change and percent change from baseline in total motor Abnormal Involuntary Movement Scale (AIMS) score, response rates for ≥50% AIMS improvement, Clinical Global Impression of Change (CGIC), Patient Global Impression of Change (PGIC), and safety in younger and older participants with TD. RESULTS: After 3 years of open-label treatment, mean deutetrabenazine dose was ∼39.5 mg/day in both groups. Mean±SE changes from baseline in total motor AIMS score were -6.7 ± 0.62 and -6.5 ± 0.47 in younger and older participants, respectively (percent changes: -61.4% ± 4.10% and -54.6% ± 3.01%); 76% of younger and 62% of older participants achieved ≥50% AIMS response. Most younger and older participants achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%). Deutetrabenazine was generally well tolerated in both groups. CONCLUSIONS: Deutetrabenazine treatment was associated with sustained improvements in total motor AIMS score, treatment success, and improved quality of life, and was well tolerated in younger and older adults with TD in this 3-year OLE study.

Methylphenidate and atomoxetine treatment negatively affect physical growth indexes of school-age children and adolescents with attention-deficit/hyperactivity disorder.

AIM: To determine the effects of drug therapy on the physical growth of school-age children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHOD: The medical records of 86 participants (average age: 8.9 ± 2.2 years) with ADHD prescribed methylphenidate (MPH) or atomoxetine (ATX) for ≥24 weeks from the Children's Hospital of Chongqing Medical University were analysed. RESULTS: The Z-scores of height, weight and body mass index (BMI) of children with ADHD decreased significantly over the first six months of MPH treatment (P < 0.001). The slopes of the fitting lines after the first six months of MPH (-0.18, -0.58 and -0.69, respectively) returned over the entire treatment (the slopes changed to -0.027, -0.26 and -0.20, respectively). For ATX, the Z-scores of height of children decreased significantly over the first six months (P < 0.001), but the Z-scores of weight and BMI did not (P > 0.05). The slopes of the fitting lines after the first six months of ATX (-0.058, -0.032 and 0.0094, respectively) changed over the entire treatment (slopes were 0.16, 0.52 and 0.26, respectively). Children taking MPH were more likely to report decreased appetite (P < 0.05). The weight and BMI of the children receiving MPH were significantly correlated with decreased appetite (P < 0.01). CONCLUSION: The physical growth indexes (PGIs) of school-age children and adolescents with ADHD were negatively affected while taking MPH, and these effects were gradually mitigated with continued treatment. ATX hardly had negative effects on weight and BMI. Neither MPH nor ATX had a significant negative effect on the height of children in long-term ADHD treatment. It is necessary for clinicians to consider children's diet during treatment.

A Phase 3, Placebo-Controlled Trial of Once-Daily Viloxazine Extended-Release Capsules in Adolescents With Attention-Deficit/Hyperactivity Disorder.

PURPOSE: This phase 3 clinical trial evaluated the efficacy and safety of viloxazine extended-release capsules (VLX-ER) as a monotherapy for attention-deficit/hyperactivity disorder (ADHD) in adolescents (12-17 years). METHODS: Eligible subjects (n = 310) were randomized to receive once-daily 200 and 400 mg VLX-ER, or placebo for 6 weeks. The primary efficacy end point was change from baseline (CFB) at the end of study (EOS) in ADHD Rating Scale-5 Total score. Key secondary end points were Clinical Global Impression-Improvement score at EOS, CFB at EOS in Conners 3-Parent Short Form Composite T-score, and CFB at EOS in Weiss Functional Impairment Rating Scale-Parent Total average score. RESULTS: In the 200-mg/d and 400-mg/d VLX-ER treatment groups, a significant improvement was found in the CFB at EOS in ADHD Rating Scale-5 Total (P = 0.0232, P = 0.0091) and Inattention (P = 0.0424, P = 0.0390) and Hyperactivity/Impulsivity (P = 0.0069, P = 0.0005) subscale scores versus placebo. The Clinical Global Impression-Improvement score was significantly improved at EOS in the 200-mg/d and 400-mg/d VLX-ER groups versus placebo (P = 0.0042, P = 0.0003). The Conners 3-Parent Short Form composite T-score and Weiss Functional Impairment Rating Scale-Parent Total average score exhibited improvement in both VLX-ER groups; however, the difference versus placebo was not statistically significant. The most common treatment-related adverse events were somnolence, headache, decreased appetite, nausea, and fatigue. The adverse event-related discontinuation rates were <5% in all groups. CONCLUSIONS: Viloxazine extended-release demonstrated statistically significant and clinically meaningful improvement in ADHD symptoms in adolescents and was generally well tolerated.

Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN-812 (Viloxazine Extended-Release) Pharmacokinetics in Healthy Adults.

SPN-812 (viloxazine extended-release) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Given that SPN-812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN-812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single-sequence, 3-treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN-812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN-812 and paroxetine (period 3). Blood samples were collected for 72 hours post-SPN-812 dosing and analyzed for viloxazine and its primary metabolite, 5-HVLX-gluc. Twenty-two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN-812 and paroxetine was assessed using analysis of variance on the log-transformed pharmacokinetic parameters Cmax , AUC0-t , and AUCinf . The least-squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN-812 alone) Cmax , 116.04%; 90%CI, 109.49%-122.99%; AUC0-t , 134.65%; 90%CI, 127.65-142.03; and AUCinf , 134.80%; 90%CI, 127.94%-142.03%. CYP2D6 inhibition resulted in a modest change (<35%) on viloxazine AUCs with no change in Cmax . All adverse events were mild in severity.

Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status.

Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

Activation Syndrome in a Patient With Attention-Deficit/Hyperactivity Disorder Treated With Atomoxetine: A Case Report.

ABSTRACT: "Activation syndrome" represents a cluster of symptoms of excessive emotional arousal or behavioral activation, which emerges after the first few weeks of antidepressant treatment or a dose increase and resolves with dose reduction or cessation of treatment. It was reported after treatment with selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor group of agents, but no case of activation syndrome has been reported with the norepinephrine reuptake inhibitor group. Atomoxetine is a norepinephrine reuptake inhibitor and nonstimulant and is used to manage symptoms of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine-related symptoms of mania and hypomania were reported in literature previously. Here, we report a case of activation syndrome arising after atomoxetine (ATX) dose titration in a prepubertal male child with ADHD. Differentiation of activation symptoms from mania/hypomania symptoms after treatment with ATX may be important for the clinicians to manage the adverse effects and understand the risk factors behind activation syndrome with use of ATX in children and adolescents diagnosed with ADHD.

Sex differences in depressive symptoms and tolerability after treatment with selective serotonin reuptake inhibitor antidepressants: Secondary analyses of the GENPOD trial.

BACKGROUND: Differences in serotonergic neurotransmission could lead to sex differences in depressive symptoms and tolerability after treatment with selective serotonin reuptake inhibitors (SSRIs). AIMS: We investigated whether women have greater reductions in depressive symptoms than men after treatment with an SSRI (citalopram) compared with a noradrenaline reuptake inhibitor (reboxetine) control, and after antidepressant treatment irrespective of class. We also investigated tolerability and the influence of menopausal status. METHODS: Secondary analyses of the GENPOD (GENetic and clinical Predictors Of treatment response in Depression) trial. Six hundred and one people with depression were recruited from UK primary care and randomized to citalopram or reboxetine. Beck Depression Inventory (BDI-II) score at 6 weeks was the primary outcome. Secondary outcomes included BDI-II score at 12 weeks, and physical symptoms and treatment discontinuation. We calculated main effects and interaction terms using linear and logistic regression models. RESULTS: There was no evidence that women experienced greater reductions in depressive symptoms than men when treated with citalopram compared with reboxetine. We also found no evidence of sex differences at six or 12 weeks (irrespective of antidepressant class): men scored -0.31 (95% confidence interval (CI) -2.23 to 1.62) BDI-II points lower than women at six weeks and -0.44 (95% CI -2.62 to 1.74) points lower at 12 weeks. There was no evidence of sex differences in physical symptoms or treatment discontinuation and no evidence for an influence of menopausal status. CONCLUSION: Citalopram was not more effective in women compared with men and there was no difference in tolerability. Women and men had similar prognosis after SSRI treatment and similar prognosis regardless of antidepressant class. Findings were unaltered by menopausal status.