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Sustained attention describes our ability to keep a constant focus on a given task. This ability is modulated by our physiological state of arousal. Although lapses of sustained attention have been linked with dysregulations of arousal, the underlying physiological mechanisms remain unclear. An emerging body of work proposes that the intrusion during wakefulness of sleep-like slow waves, a marker of the transition toward sleep, could mechanistically account for attentional lapses. This study aimed to expose, via pharmacological manipulations of the monoamine system, the relationship between the occurrence of sleep-like slow waves and the behavioural consequences of sustained attention failures. In a double-blind, randomised-control trial, 32 healthy human male participants received methylphenidate, atomoxetine, citalopram or placebo during four separate experimental sessions. During each session, electroencephalography (EEG) was used to measure neural activity whilst participants completed a visual task requiring sustained attention. Methylphenidate, which increases wake-promoting dopamine and noradrenaline across cortical and subcortical areas, improved behavioural performance whereas atomoxetine, which increases dopamine and noradrenaline predominantly over frontal cortices, led to more impulsive responses. Additionally, citalopram, which increases sleep-promoting serotonin, led to more missed trials. Based on EEG recording, citalopram was also associated with an increase in sleep-like slow waves. Importantly, compared to a classical marker of arousal such as alpha power, only slow waves differentially predicted both misses and faster responses in a region-specific fashion. These results suggest that a decrease in arousal can lead to local sleep intrusions during wakefulness which could be mechanistically linked to impulsivity and sluggishness.Significance StatementWe investigated whether the modulation of attention and arousal could not only share the same neuromodulatory pathways but also rely on similar neuronal mechanisms; for example, the intrusion of sleep-like activity within wakefulness. To do so, we pharmacologically manipulated noradrenaline, dopamine, and serotonin in a four-arm, randomised, placebo-controlled trial and examined the consequences on behavioural and EEG indices of attention and arousal. We showed that sleep-like slow waves can predict opposite behavioural signatures: impulsivity and sluggishness. Slow waves may be a candidate mechanism for the occurrence of attentional lapses since the relationship between slow-wave occurrence and performance is region-specific and the consequences of these local sleep intrusions are in line with the cognitive functions carried by the underlying brain regions.

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.

© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Objective: Although several genes have previously been studied about the treatment of Attention Deficit Hyperactivity Disorder (ADHD), the number of studies investigating the effects of genes on atomoxetine (ATX) treatment is very limited. In this study, we aimed to investigate the effect of CYP2C19 polymorphisms, which have a role in ATX biotransformation, on the treatment response and also to assess whether there is a relationship between BDNF and treatment response in children and adolescents with ADHD. Methods: One hundred children with ADHD and 100 healthy controls (HCs) were included in this study. The treatment response was assessed 2 months after the start of the ATX treatment. DNA samples from peripheral venous blood were replicated using PCR and analyzed using the ILLUMINA next-generation sequencing method. The resulting fastqs were analyzed using Basespace’s Variant Interpreter Program. Plasma BDNF levels were evaluated with ELISA kits. Results: Treatment response was found to be lower in both heterozygous and homozygous carriers of the c.681G > A (CYP2C19*2) polymorphism. When the BDNF level was compared, it was found to be significantly higher in the ADHD group compared to HCs. Also, BDNF has a stronger predictive value for assessing resistance to ATX treatment. Conclusions: To our knowledge, this is the first study to assess the effects of CYP2C19 polymorphisms and BDNF levels together on ATX treatment in children. Further studies with an extensive population are needed to better understand the effects of CYP2C19 polymorphisms on treatment and side effects, as well as the effects of BDNF levels.

The selective norepinephrine reuptake inhibitor atomoxetine is potentially among the first-line pharmacotherapy options for ADHD. Therapeutic drug monitoring (TDM) with the quantification and interpretation of atomoxetine serum concentrations is used to determine an individual dose followed by an optimal effectiveness and minimal side effects. The aim of this retrospective pharmacokinetic–pharmacodynamic analysis was to derive age-appropriate recommendations for the implementation of TDM to improve the efficacy and tolerability of atomoxetine in children and adolescents. Using the analytical method of high-performance liquid chromatography with UV detection, 94 serum concentrations of 74 patients between 6 and 21 years of age were determined. Therapeutic effectiveness and side effects were evaluated according to the categories “low”, “moderate”, and “significant”. As part of TDM, a time interval with maximum concentrations of 1–3 h after the administration of atomoxetine was determined for blood sampling. In this time interval, a significant correlation between the weight-normalized dose and the serum concentrations was found. The efficacy as well as the tolerability proved to be mainly moderate or significant. A preliminary therapeutic reference range was between 100 and 400 ng/ml. Naturalistic studies have limitations. Therefore, and due to a limited study population, the results have to be regarded as preliminary observations that must be confirmed in further studies. The preliminary therapeutic reference range for children and adolescents proved to be narrower than the reference range for adult patients. However, due to good efficacy and tolerability an exact reference range remained difficult to determine.

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.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).Atomoxetine treated patients had greater reductions in ADHD symptoms as defined by total scores on the CAARS-S:S (FIn Veterans with ADHD comorbid with PTSD, atomoxetine demonstrated modest efficacy for ADHD symptoms; quality of life measures and PTSD symptoms were not affected.

In this study, we aimed for the first time to evaluate the effectiveness of atomoxetine (Strattera) in the treatment of cognitive impairment and aphasia after stroke in a large sample.We reviewed the data of 106 patients with poststroke aphasia and cognitive impairment (atomoxetine treatment group = 55 patients vs control group = 51 patients), including scores of the Korean version of the Mini-Mental State Examination (K-MMSE) and the Korean version of the Western Aphasia Battery. Wilcoxon signed-rank tests were used to compare the initial and follow-up K-MMSE and Korean version of the Western Aphasia Battery scores. Mann-Whitney U tests were used to compare the degree of improvement in K-MMSE and Aphasia Quotient (AQ) scores between the atomoxetine and control groups.Baseline characteristics including age, years of education, and scores of the initial Functional Independence Measure, Korean version of the Modified Barthel Index, Hamilton Depression Rating Scale, K-MMSE, and AQ did not differ significantly between the 2 groups. Follow-up K-MMSE and AQ scores were significantly better than the initial scores in both the treatment and control groups. However, improvements in K-MMSE scores were significantly greater in the treatment group than in the control group. In addition, the atomoxetine group had significantly higher AQ scores than the control group, especially for auditory verbal comprehension and naming.Atomoxetine has been shown to significantly improve cognitive function and language in patients with poststroke aphasia. It is also the first study to report improvement in auditory comprehension and naming by administration of atomoxetine.

Atomoxetine (ATO) is a second line medication for attention-deficit hyperactivity disorder (ADHD). We proposed that part of the therapeutic profile of ATO may be through circadian rhythm modulation. Thus, the aim of this study was to investigate the circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after ATO exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with a diagnosis of ADHD. Circadian preference was evaluated with German Morningness-Eveningness-Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After ex vivo exposure to different ATO concentrations in HDF cultures, the rhythmicity of circadian gene expression was analyzed via qRT-PCR. No statistical significant effect of both groups (healthy controls, ADHD group) for mid-sleep on weekend days, mid-sleep on weekdays, social jetlag, sleep WASO and total number of wake bouts was observed. D-MEQ scores indicated that healthy controls had no evening preference, whereas subjects with ADHD displayed both definitive and moderate evening preferences. ATO induced the rhythmicity of Clock in the ADHD group. This effect, however, was not observed in HDF cultures of healthy controls. Bmal1 and Per2 expression showed a significant ZT × group interaction via mixed ANOVA. Strong positive correlations for chronotype and circadian genes were observed for Bmal1, Cry1 and Per3 among the study participants. Statistical significant different Clock, Bmal1 and Per3 expressions were observed in HDFs exposed to ATO collected from ADHD participants exhibiting neutral and moderate evening preference, as well as healthy participants with morning preferences. The results of the present study illustrate that ATO impacts on circadian function, particularly on Clock, Bmal1 and Per2 gene expression.

Aim To assess label compliance in prescription of medications approved for treatment of attention‐deficit/hyperactivity disorder (ADHD) in Japan at the time of this study: methylphenidate (MPH), atomoxetine, and guanfacine. Methods Retrospective descriptive study was conducted in prevalent‐user cohorts from the Japan Medical Data Center database. Patients who were prescribed a study drug between January 1, 2013 and September 30, 2018 and were in the database for ≥30 days were included. A prescription was considered compliant if all 4 criteria were satisfied: appropriate age, daily dose not exceeding the approved maximum, no contraindicated concurrent medications, and no contraindicated conditions. Results Among 17 418 patients who were prescribed a study drug during 2013‐2018, 73% were male and 53% were children (aged 85% of patients, all prescriptions were label‐compliant for dose, and for approximately 80%, all prescriptions were label‐compliant for contraindicated conditions. We did not find evidence of widespread abuse or noncompliant use of prescribed ADHD medications., To assess label compliance in prescription of medications approved for the treatment of ADHD in Japan at the time of this study (2013‐2018), a retrospective descriptive cohort study was conducted in patients from the JMDC database who were prescribed a study drug (methylphenidate, atomoxetine, or guanfacine) and were in the database for at least 30 days. Among 17 418 patients eligible for the study, nearly all prescriptions were label‐compliant for age; for more than 85% of patients, all prescriptions were label‐compliant for dose, and for approximately 80%, all prescriptions were label‐compliant for contraindicated conditions. We did not find evidence of widespread abuse or noncompliant use of prescribed ADHD medications.

Background and objective Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). Methods Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. Results The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H2 O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. Conclusion Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.

The combination of the noradrenergic agent atomoxetine plus the antimuscarinic oxybutynin has recently been shown to improve upper airway physiology and reduce obstructive sleep apnea (OSA) severity. However, the effects of different antimuscarinics when combined with atomoxetine is limited. This study aimed to determine the effects of atomoxetine combined with two different antimuscarinics with varying M-subtype receptor selectivity on OSA severity and upper airway physiology. Ten people with predominantly severe OSA completed a double-blind, randomized, placebo-controlled, cross-over trial. Participants completed three overnight in-laboratory sleep studies after either 80 mg atomoxetine + 5 mg solifenacin succinate (ato-sol) or 80 mg atomoxetine + 2 mg biperiden hydrochloride (ato-bip) or placebo. OSA severity, ventilatory stability (loop gain), respiratory-arousal threshold (via epiglottic manometry), next-day subjective sleepiness [Karolinska Sleepiness Scale (KSS)], and alertness were compared between conditions. Neither drug combination altered the apnea/hypopnea index versus placebo (P = 0.63). Ato-sol caused a shift toward milder respiratory events with reduced frequency of obstructive apneas (13 ± 14 vs. 22 ± 17 events/h; means ± SD, P = 0.04) and increased hypopneas during nonrapid eye movement (NREM) (38 ± 21 vs. 24 ± 18 events/h, P = 0.006) with improved nadir oxygenation versus placebo (83 ± 4 vs. 80 ± 8%, P = 0.03). Both combinations reduced loop gain by ∼10% versus placebo; sleep efficiency and arousal threshold were unaltered. Ato-bip reduced next-day sleepiness versus placebo (KSS = 4.3 ± 2.2 vs. 5.6 ± 1.6, P = 0.03). Atomoxetine + biperiden hydrochloride reduces perceived sleepiness, and atomoxetine + solifenacin modestly improves upper airway function in people with OSA but to a lesser extent versus recently published atomoxetine + oxybutynin (broad M-subtype receptor selectivity) findings. These results provide novel mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA. NEW & NOTEWORTHY In contrast to recent findings of major reductions in OSA severity when atomoxetine is combined with a nonspecific antimuscarinic, oxybutynin (broad M-subtype receptor selectivity), addition of solifenacin succinate (M2 and M3 muscarinic receptor selectivity) or biperiden (M1 muscarinic receptor selectivity) with atomoxetine had modest effects on upper airway function during sleep, which provide mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.

Noradrenaline (NE) is closely related to attentive performance and impulsive control. However, the potential sex differences regarding attention and impulsivity under the noradrenergic modulation have been largely neglected. Therefore, our study aimed to investigate whether male and female rats exhibit differential responses to NE-related drugs during the five-choice serial reaction time task (5CSRT). Male and female rats were trained in 5CSRT and administered with different NE drugs after obtaining stable baseline performance: atipamezole, a highly selective α2 receptor antagonist; prazosin, an α1 receptor antagonist; and atomoxetine, a selective NE reuptake inhibitor. Later, prazosin was selected to co-administration with atomoxetine. Male and female rats exhibited equal learning speed, and no significant baseline differences were found as measured by the 5CSRT. Atomoxetine decreased premature responses in both sexes, but the extent of this reduction was different, with the reduction greater in males. Besides, atomoxetine (1.8 mg/kg) increased the error of omissions in females. The high dose of prazosin (0.5 mg/kg) decreased the accuracy only in male rats, but this was ameliorated by the co-administration with atomoxetine. Atomoxetine showed significant improvement in impulsivity, but atomoxetine had less beneficial effects on impulsive control in females than in males, and it even impaired attentional performance in female rats. The α1 receptors were mainly responsible for NE drug-related sex differences in attention rather than impulsivity. The results obtained in this study indicate that the sex differences exist in both attention and impulsivity by the modulation of noradrenaline and raise the concern to improve sex-specific treatments.

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.Written informed consent for publication was obtained from the patient and his parents, and their identities were concealed for ethical reasons.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.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.

Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can continue into adulthood. The abuse of ADHD-related drugs to improve mental performance for studying, working and everyday life is also rising. The potentially high number of subjects with controlled or uncontrolled use of such substances increases the impact of possible side effects. It has been shown before that the early ADHD drug methylphenidate influences bone metabolism negatively. This study focused on the influence of three more recent cognitive enhancers, modafinil, atomoxetine and guanfacine, on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Human mesenchymal stem cells (hMSCs) were incubated with a therapeutic plasma dosage of modafinil, atomoxetine and guanfacine. Gene expression analyses revealed a high beta-2 adrenoreceptor expression in hMSC, suggesting it as a possible pathway to stimulate action. In bone formation assays, all three cognitive enhancers caused a significant decrease in the mineralized matrix and an early slight reduction of cell viability without triggering apoptosis or necrosis. While there was no effect of the three substances on early differentiation, they showed differing effects on the expression of osterix (OSX), receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in the later stages of osteoblast development, suggesting alternative modes of action. All three substances significantly inhibited hMSC migration. This effect could be rescued by a selective beta-blocker (Imperial Chemical Industries ICI-118,551) in modafinil and atomoxetine, suggesting mediation via beta-2 receptor stimulation. In conclusion, modafinil, atomoxetine and guanfacine negatively influence hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.

Objective: Dysregulated emotional behavior occurs often in adults with ADHD. Analysis of clinical trials may guide clinical intervention and future research. Method: Controlled trials of adult ADHD measuring emotional behavior were included if another study offered a comparable analysis of the same treatment method. Standardized Mean Difference (SMD) of effects were calculated, and the size of effects for emotional and non-emotional ADHD behavior were compared. Results: 13 out of 14 studies of methylphenidate, atomoxetine, and lisdexamfetamine demonstrated significant improvement in emotional behavior measures, with small to high SMDs. The proportional effect on emotional versus non-emotional behavior ranged from 46% to 110% for methylphenidate, 56% to 129% for atomoxetine, and 36% to 96% for lisdexamfetamine. Conclusion: Psychopharmacological treatments for ADHD are likely to improve emotional behavior, and available scales are sensitive to these effects. Studies dedicated to treatment of this domain of function can further refine clinical approaches.

Introduction:The prevalence of attention deficit/hyperactivity disorder in the general population is common and is now diagnosed in 4%–12% of children. Children with CHD have been shown to be at increased risk for attention deficit/hyperactivity disorder. Case reports have led to concern regarding the use of attention deficit/hyperactivity disorder medications in children with underlying CHD. We hypothesised that medical therapy for patients with CHD and attention deficit/hyperactivity disorder is safe.Methods:A single-centre, retrospective chart review was performed evaluating for adverse events in patients aged 4–21 years with CHD who received attention deficit/hyperactivity disorder therapy over a 5-year span. Inclusion criteria were a diagnosis of CHD and concomitant medical therapy with amphetamines, methylphenidate, or atomoxetine. Patients with trivial or spontaneously resolved CHD were excluded from analysis.Results:In 831 patients with CHD who received stimulants with a mean age of 12.9 years, there was only one adverse cardiovascular event identified. Using sensitivity analysis, our median follow-up time was 686 days and a prevalence rate of 0.21% of adverse events. This episode consisted of increased frequency of supraventricular tachycardia in a patient who had this condition prior to initiation of medical therapy; the condition improved with discontinuation of attention deficit/hyperactivity disorder therapy.Conclusion:The incidence of significant adverse cardiovascular events in our population was similar to the prevalence of supraventricular tachycardia in the general population. Our single-centre experience demonstrated no increased risk in adverse events related to medical therapy for children with attention deficit/hyperactivity disorder and underlying CHD. Further population-based studies are indicated to validate these findings.

The aim of this study was to investigate the effects of paroxetine, a potent inhibitor of CYP2D6, on the pharmacokinetics of atomoxetine and its two metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine, in different CYP2D6 genotypes. Twenty-six healthy subjects were recruited and divided into CYP2D6*wt/*wt (*wt=*1 or *2, n = 10), CYP2D6*wt/*10 (n = 9), and CYP2D6*10/*10 groups (n = 7). In atomoxetine phase, all subjects received a single oral dose of atomoxetine (20 mg). In paroxetine phase, after administration of a single oral dose of paroxetine (20 mg) for six consecutive days, all subjects received a single oral dose of atomoxetine with paroxetine. Plasma concentrations of atomoxetine and its metabolites were determined up to 24 h after dosing. During atomoxetine phase, there were significant differences in Cmax and AUC0−24 of atomoxetine and N-desmethylatomoxetine among three genotype groups, whereas significant differences were not found in relation to CYP2D6*10 allele after administration of paroxetine. AUC ratios of 4-hydroxyatomoxetine and N-desmethylatomoxetine to atomoxetine were significantly different among three genotype groups during atomoxetine phase (all, P

This study analyzed the pattern of attention-deficit/hyperactivity disorder (ADHD) medication initiation in adult patients with ADHD after the reimbursement criteria change and identified the influencing factors associated with it using the claim data. We identified 243 adult patients with ADHD who had not been prescribed ADHD drugs before 1 September 2016. We conducted Kaplan-Meier survival analysis to calculate the time to initial prescription of ADHD medications, and Cox proportional hazard regression analysis to estimate the influencing factors. Approximately one-third of the patients (n = 76, 31.3%) were first prescribed ADHD medications after reimbursement approval, and 40 of them (16.5%) started treatment with osmotic release oral system methylphenidate. The patient's age group (30-39 years) and the status of diagnosis before the index date were associated with early initiation of pharmacotherapy. The odds of starting ADHD medications increased approximately 2.7-fold in the 30-39 age group and 0.2-fold in the case of patients who were diagnosed before the approval. Our findings show that both diagnosis and treatment of adult ADHD remains inadequate despite the change in reimbursement criteria. Improving awareness of adult ADHD among both the public and the professionals is essential to increase its chances of diagnosis and treatment.

ADHD causes significant distress and functional impairment in multiple domains of daily life. Therefore, diagnosis and treatment are important to improve the quality of life of people. The pharmacotherapy for ADHD is well established but needs systematic evaluation in Intellectual Disability (ID) populations.This paper reviews the ADHD pharmacological treatment in people with ID using the PRISMA guidance for scoping reviews to help identify the nature and strength of evidence.In the last 20 years, seven randomized controlled trials have evaluated pharmacotherapies for ADHD in people with ID; five looking at methylphenidate. Generally, studies were underpowered; all but two had less than 25 participants. Of the two larger trials one was single blinded and therefore open to bias. Only two used a parallel-group method, the remainder were mostly short crossover trials; not ideal when measuring behavioral and psychological parameters which are long standing. The remaining evidence is made up of observational studies. Methylphenidate and atomoxetine, particularly at higher doses, have shown clear benefits in people with ID. Most people with ID tolerated ADHD medications well. Benefits were seen in behavioral and/or cognitive domains. The evidence base is limited, though promising, for dexamfetamine, clonidine, and guanfacine.

Attention deficit/hyperactivity disorder (ADHD) is the most prevalent psychiatric childhood disorder, characterized by hyperactivity, impulsivity and impaired attention, treated most frequently with methylphenidate (MPH). For children and adults with ADHD who do not respond satisfactorily or do not tolerate well stimulants such as MPH or D-Amphetamine, for them the alternative is to use Atomoxetine (ATX), a norepinephrine (NE) transporter inhibitor that increase extracellular NE. We examined the effects of ATX on behavior and hippocampal synaptic plasticity in the murine prenatal nicotine exposure (PNE) model of ADHD. ADHD symptoms were measured using behavioral tests, open field for hyperactivity and the Y-maze for spatial working memory. Further, ATX effects on long-term potentiation (LTP) in hippocampal slices at the CA3-CA1 synapse were assessed. PNE mice exhibited the behavioral deficits of ADHD, hyperactivity and spatial memory impairment. Intraperitoneal injection of ATX (2 mg/kg/day) normalized these behaviors significantly after 7 days. In PNE mice LTP was reduced (110.6 ± 4.5% %; n = 7) compared to controls (148.9 ± 5.2%; n = 7; p 0.05). ATX administration (5 µM) reestablished the LTP in PNE mice to levels similar to the controls (157.7 ± 6.3%; n = 7). Paired-pulse ratios (PPR) were not significantly different for any condition. These results indicate that administration of ATX in a PNE model of ADHD reestablishes TBS-dependent LTP in CA3-CA1 synapses. The results suggest postsynaptic changes in synaptic plasticity as part of the mechanisms that underlie improvement of ADHD symptoms induced by ATX.

The bitterness of a drug is a major challenge for patient acceptability and compliance, especially for children. Due to the toxicity of medication, a human taste panel test has certain limitations. Atomoxetine hydrochloride (HCl), which is used for the treatment of attention deficit/hyperactivity disorder (ADHD), has an extremely bitter taste. The aim of this work is to quantitatively predict the bitterness of atomoxetine HCl by a biosensor system. Based on the mechanism of detection of the electronic tongue (E-tongue), the bitterness of atomoxetine HCl was evaluated, and it was found that its bitterness was similar to that of quinine HCl. The bitterness threshold of atomoxetine HCl was 8.61 µg/ml based on the Change of membrane Potential caused by Adsorption (CPA) value of the BT0 sensor. In this study, the taste-masking efficiency of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) was assessed by Euclidean distances on a principle component analysis (PCA) map with the SA402B Taste Sensing System, and the host–guest interactions were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR) spectroscopy and scanning electron microscopy (SEM). Biosensor evaluation and characterization of the inclusion complex indicated that atomoxetine HCl could actively react with 2-hydroxypropyl-β-cyclodextrin., Graphical abstract The quantitative bitterness of atomoxetine hydrochloride was measured by a biosensor system using quinine hydrochloride as a reference. HP-β-CyD/atomoxetine hydrochloride inclusion complex was prepared to mask the bitter taste, and the efficiency of bitterness suppression by HP-β-CyD was evaluated by biosensor system. Following DSC, X-ray, H-NMR and SEM analysis, it was found that atomoxetine hydrochloride actively reacted with HP-β-CyD.Image, graphical abstract

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.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.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.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.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.

The combination of the noradrenergic atomoxetine plus the anti-muscarinic oxybutynin acutely increased genioglossus activity and reduced obstructive sleep apnoea (OSA) severity. However, oxybutynin has shorter half-life than atomoxetine and side effects that might discourage long-term usage. Accordingly, we aimed to test the combination of atomoxetine and fesoterodine (Ato-Feso), a newer anti-muscarinic with extended release formulation, on OSA severity and endotypes.Twelve subjects with OSA underwent a randomized, double-blind, crossover trial comparing one night of atomoxetine plus fesoterodine (80-4 mg) to placebo. Parameters of OSA severity (e.g., apnoea-hypopnoea index [AHI], nadir oxygen desaturation and hypoxic burden) were calculated from two clinical, in-lab polysomnographic studies. OSA endotypes (including collapsibility per VCompared to placebo, Ato-Feso did not reduce the AHI (34.2 ± 19.1 vs. 30.1 ± 28.2 events/h, p = 0.493), but reduced the apnoea index (12.9 [28.8] vs. 1.8 [9.1] events/h, median [interquartile range], p = 0.027) and increased nadir desaturation (76.8 [8.0] vs. 82.2 [8.8] %, p = 0.003); a non-significant trend for improved hypoxic burden was observed (52.4 [50.5] vs. 29.7 [78.9] %min/h, p = 0.093). Ato-Feso lowered collapsibility (raised VWhile inefficacious in unselected patients, Ato-Feso administered for one night suppressed OSA in patients with milder collapsibility. Ato-Feso may hold some promise as an alternative OSA treatment in certain subgroups of individuals.

In this issue, Rodrigues et al. (2020) present a systematic review with meta-analyses that reports the efficacy of five treatments for children with attention-deficit hyperactivity disorder symptoms in the context of autism spectrum disorder - (a) methylphenidate; (b) atomoxetine; (c) guanfacine; (d) aripiprazole; and (e) risperidone. In this commentary, we highlight the contrast between the scarce evidence base of treatment for ADHD in the context of autism and other subpopulations, such as tic disorders and intellectual disability, and the extensive evidence base of treatment for ADHD in general. The commentary weighs about the conundrum clinicians face of whether to rely on the limited evidence base of treatment for ADHD in subpopulation, or to derive conclusions from the larger body of evidence of treatment for ADHD in general. The commentary also discusses potential avenues for future research to address this clinical problem.

There is a paucity of clinical trials for the treatment of pediatric insomnia. This study was designed to predict the doses of trazodone to guide dosing in a clinical trial for pediatric insomnia using physiologically-based pharmacokinetic (PBPK) modeling. Data on the pharmacokinetics of trazodone in children are currently lacking. The interaction potential between trazodone and atomoxetine was also predicted. Doses predicted in the following age groups, with exposures corresponding to adult dosages of 30, 75, and 150 mg once a day (q.d.), respectively, were: (i) 2- to 6-year-old group, doses of 0.35, 0.8, and 1.6 mg/kg q.d.; (ii) >6- to 12-year-old group, doses of 0.4, 1.0, and 1.9 mg/kg q.d.; (iii) >12- to 17-year-old group, doses of 0.4, 1.1, and 2.1 mg/kg q.d. An interaction between trazodone and atomoxetine was predicted to be unlikely. Clinical trials based on the aforementioned predicted dosing are currently in progress, and pharmacokinetic data obtained will enable further refinement of the PBPK models.

Recent behavioural modelling and pupillometry studies suggest that neuromodulatory arousal systems play a role in regulating decision formation but neurophysiological support for these observations is lacking. We employed a randomised, double-blinded, placebo-controlled, crossover design to probe the impact of pharmacological enhancement of catecholamine levels on perceptual decision making. Catecholamine levels were manipulated using the clinically relevant drugs methylphenidate (MPH) and atomoxetine (ATM) and their effects were compared to those of citalopram (CIT), and placebo (PLA). Participants performed a classic EEG oddball paradigm which elicits the P3b, a centro-parietal potential that has been shown to trace evidence accumulation, under each of the four drug conditions. We found that MPH and ATM administration shortened RTs to the oddball targets. The neural basis of this behavioural effect was an earlier P3b peak latency, driven specifically by an increase in its build-up rate without any change in its time of onset or peak amplitude. This study provides neurophysiological evidence for the catecholaminergic enhancement of a discrete aspect of human decision making, i.e. evidence accumulation. Our results also support theoretical accounts suggesting that catecholamines may enhance cognition via increases in neural gain.

The dopaminergic neural system plays a crucial role in motor regulation as well as regulation of anxiety-related behaviors. Although rats with neonatal dopamine depletion exhibit motor hyperactivity and have been utilized as animal models of attention deficit hyperactivity disorder, characterization of their behavior under anxiogenic conditions is lacking. In the present study, we investigated behavioral responses to anxiogenic stimuli in young adult rats with neonatal dopamine depletion using the open field (OF), elevated plus maze (EPM), and light/dark (L/B) box tests. The OF and EPM tests were performed under low-light and bright-light conditions. The ameliorative effects of pretreatment with methamphetamine (MAP) or atomoxetine (ATX) on abnormal behaviors induced by neonatal dopamine depletion were also assessed. Rats that underwent 6-hydroxydopamine treatment 4 day after birth showed significant increases in motor activity and decreases in anxiety-related behaviors in OF tests under both conditions and in EPM tests under bright-light conditions. Furthermore, rats with neonatal dopamine depletion did not show normal behavioral responsiveness to changes in the intensity of anxiogenic stimuli. Pretreatment with MAP (4 mg/kg) and ATX (1.2 mg/kg/day) ameliorated motor hyperactivity but not abnormal anxiety-related behaviors. These results suggest that the dopaminergic system plays a crucial role in the development of neural networks involved in locomotion as well as in those involved in anxiety-related behavior. The results indicate that the mechanisms underlying the abnormal anxiolytic responses partially differ from those underlying motor hyperactivity.

Attention Deficit Hyperactivity Disorder is a neurodevelopmental disorder with three presentations: inattentive, hyperactive/impulsive and combined. These may represent an independent disease entity. Therefore, the therapeutic approach must be focused on their neurobiological, psychological and social characteristics. To date, there is no comprehensive analysis of the efficacy of different treatments for each presentation of ADHD and each stage of development. This is as narrative overview of scientific papers that summarize the most recent findings and identify the most effective pharmacological and psychosocial treatments by ADHD presentation and age range. Evidence suggests that methylphenidate is the safest and most effective drug for the clinical management of children, adolescents and adults. Atomoxetine is effective in preschoolers and maintains similar efficacy to methylphenidate in adults, whereas guanfacine has proven to be an effective monotherapy for adults and is a worthy adjuvant for the management of cognitive symptoms. The psychosocial treatments with the best results in preschoolers are behavioral interventions that include training of primary caregivers. In adolescents, the combination of cognitive and cognitive-behavioral therapies has shown the best results, whereas cognitive-behavioral interventions are the most effective in adults. Pharmacological and psychosocial treatments must be adjusted to the ADHD presentation and its neurocognitive characteristics through the patient’s development.

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that affects approximately 2-7 % of children globally and is associated with a myriad of difficulties that have long-term consequences. Most children and adolescents live in low- and middle-income countries (LMICs), but there are few reports and no consolidation of findings on ADHD treatment outcomes in this population. We conducted a review of ADHD treatment literature for children and adolescents living in LMICs.Studies were identified using databases (PsychoINFO, Pubmed, MEDLINER, EMBASE, Global Health, Academic Search Complete, Google Scholar). The initial search produced 139 articles. These were filtered for language, title, abstract, and full-text keyword identification to yield a final 20 articles to be included in this review.Reports on outcomes of both psychological and pharmacological treatment were relatively sparse, particularly the former, which mostly referred to parent training and multimodal programs in pre-school children. Most evidence exists for the benefit of methylphenidate-IR with a few reports on other agents, including clonidine, atomoxetine, and lisdexamfetamine. Methylphenidate is the most common agent to treat ADHD in youth in LMICs. Younger age, combined subtype, and comorbid oppositional defiant disorder were associated with poorer treatment outcome.Access to treatment for ADHD is overall limited in LMICs and varied among individual countries. Pharmacological treatments were generally more available than psychological interventions. Several barriers including stigma, cost, and lack of resources were reported to impact treatment acceptance. More research in LMICs is needed to improve and expand mental health services in these regions.