Pharmacological Treatment For Attention-deficit/hyperactivity Disorder Research Articles

Diagnosis and pharmacological management of attention deficit hyperactivity disorder in adults with and without intellectual disability: cohort study using electronic health records.

Attention deficit hyperactivity disorder (ADHD) is increasingly diagnosed in adults. People with intellectual disability have higher rates of ADHD yet there is little evidence on the presentation and pharmacological treatment of ADHD in this population or how this differs from the general population. Retrospective cohort study using data from electronic health records. Adults with intellectual disability newly diagnosed with ADHD between 2007 and 2022 were matched to adults with ADHD without intellectual disability and their clinical features and treatments were compared. A total of 159 adults with ADHD and intellectual disability and 648 adults with ADHD without intellectual disability formed the dataset. Adults with intellectual disability had higher rates of psychiatric co-morbidity and spent more time under mental health services than those without intellectual disability. They were more likely to have recorded agitation, aggression, hostility, and mood instability, and less likely to have poor concentration recorded in the 12 months prior to the diagnosis of ADHD. Following diagnosis, people with intellectual disability were significantly less likely to be prescribed any medication for ADHD than controls without intellectual disability (adjusted odds ratio 0.60, 95% confidence interval 0.38-0.91), and were less likely to be prescribed stimulants (27.7% v 46.0%, p < 0.001). The presence of behaviors that challenge in adults with intellectual disability may indicate co-occurring ADHD. Further work to define the safety and efficacy of medication for ADHD in adults with intellectual disability is needed to understand differences in prescription rates and to avoid inequities in care outcomes.

Systematic Review and Meta-Analysis: Effects of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Quality of Life

We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to understand whether this effect differs between stimulants and non-stimulants. From the dataset of a published network meta-analysis (Cortese etal., 20181), updated on 27th February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 years or more with a diagnosis of ADHD based on the DSM (from third to fifth editions) or the International Classification of Diseases (ICD; ninth or tenth revision), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multi-level meta-analytic models were conducted with R 4.3.1. We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedges g= 0.51, 95% CI= 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, and did not differ between children/adolescents and adults. In addition to being efficacious in reducing ADHD core symptom severity, both stimulant and non-stimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether, and to what degree, combining pharmacological and non-pharmacological interventions is likely to further improve QoL in people with ADHD. Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/;qvgps.

Qualitative study of the lived experience of methylphenidate prescribed for children with a fetal alcohol spectrum disorder.

Fetal Alcohol Spectrum Disorders (FASD) refer to physical, cognitive, and behavioural symptoms in an individual whose mother consumed alcohol during pregnancy. It is the leading cause of non-genetic avoidable mental disability, with an estimated worldwide prevalence of 1%. Attention Deficit Hyperactivity Disorder (ADHD) diagnostic criteria are met for 50-80% of patients with FASD. Methylphenidate (MPH) is the first-line pharmacological treatment for ADHD. This study aims to explore the lived experience of children with FASD taking MPH and their caregivers to adapt prescribing modalities by considering different ways to administer the drugs. We hope to improve the therapeutic alliance between the children and their caregivers by gaining an insiders' view of the medication perception. Semi-structured interviews with children and their caregivers were conducted in this qualitative study. Data collection by purposive sampling continued until we reached theoretical sufficiency. Data were analysed using interpretative phenomenological analysis. We conducted 16 semi-structured interviews: 8 with the children aged 7-12, 5 boys and 3 girls and 8 with their caregivers. The analysis showed that inadequate palatability and capsule form experiences were the leading causes of children's non-adherence to the treatment. MPH appeared to be a valuable aid for caregivers even if they had concerns about its potential toxicity. However, it is necessary to identify caregivers' expectations concerning MPH to adapt the prescription in terms of choice of specialty and intake modalities. Regular support was required to reduce caregivers' fears of dependence, personality transformation and long-term adverse effects. Information on palatability should be given when prescribing MPH to children with ADHD as well as its possible side effects or toxicity. It highlights the need for further studies of the experience of palatability of drugs prescribed to children. When prescribing a treatment, children should be more involved in medical counselling and it is necessary to understand the child's perspectives to co-construct common representations for better therapeutical adherence.

Support for primary care prescribing for adult ADHD in England: national survey.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with effective pharmacological treatments that improve symptoms and reduce complications. NICE guidelines recommend primary care practitioners prescribe medication for adult ADHD under shared care agreements with adult mental health services (AMHS). However, provision remains uneven, with some practitioners reporting a lack of support. This study aimed to describe supportive elements (prescribing, shared care, AMHS availability) of primary care prescribing for adult ADHD medication in England, to inform service improvement and improve access for this underserved population. Three interlinked cross-sectional surveys asked every integrated care board (ICB) in England (Commissioners), and convenience samples of healthcare professionals (HP) and people with lived experience (LE), about elements supporting pharmacological treatment of ADHD in primary care. Descriptive analyses used percentages and confidence intervals to summarise responses by stakeholder group. Variations in reported provision and practice were explored and displayed visually using mapping software. Data from 782 respondents (42 Commissioners; 331 HP; 409 LE) revealed differences in reported provision by stakeholder group, including for prescribing (94.6% of HP vs 62.6% of LE). Over 40% of respondents reported extended AMHS waiting times of two years or more. There was some variability by NHS region, for example London had highest rates of HP reported prescribing (100%), and lowest reported extended waiting times (25.0%). Elements supporting appropriate shared care prescribing of ADHD medication via primary care are not universally available in England. Co-ordinated approaches are needed to address these gaps.

ADHD medications use and risk of mortality and unintentional injuries: a population-based cohort study

We assessed the association between the use of medications for attention-deficit/hyperactivity disorder (ADHD) and the risk of all-cause mortality and unintentional injuries leading to emergency department (ED) or hospital admission in individuals aged ≤24 years with ADHD. We conducted a population-based retrospective cohort study between 2000 and 2021 using Quebec health administrative data. Individuals were followed from the first ADHD diagnosis or ADHD medication claim until turning 25, death, or study end. Exposure was defined as mutually exclusive episodes of ADHD medication use and/or coverage under the public provincial drug plan (PDP): 1) covered and not treated with ADHD medication; 2) covered and treated with ADHD medication; and 3) not covered under the PDP. The risk of all-cause mortality and unintentional injuries associated with exposure episodes was estimated using multivariable survival analyses. The cohort included n = 217 192 individuals aged 1–24 years with a male to female ratio of close to 2:1. Compared to non-medication use, episodes of ADHD medication use, overall, were associated with reduced all-cause mortality (adjusted hazard ratio, aHR 0.61, 95% CI 0.48–0.76) and unintentional injury leading to ED (0.75, 0.74–0.77) or hospitalisation (0.71, 0.68–0.75). Episodes of stimulants were associated with a lower risk of all-cause mortality and reduced risk of unintentional injuries, while episodes with non-stimulants and with both stimulants and non-stimulants concomitantly were associated with reduced risk of unintentional injuries, but not of all-cause mortality. Although residual confounding cannot be excluded, stimulants may have a protective effect in terms of risk of all-cause mortality and both stimulants and non-stimulants for ADHD may reduce the risk of unintentional injuries. The findings of the current study should inform clinical decision making on the choice of starting a pharmacological treatment for ADHD, when a balance needs to be struck between expected benefits and possible risks.

Pharmacotherapy for ADHD in children and adolescents: A summary and overview of different European guidelines.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. It is the most common neurodevelopmental disorder presenting to pediatric services, and pediatricians are often involved in the early assessment, diagnosis, and treatment of children with ADHD. The treatment of ADHD typically involves a multimodal approach that encompasses a combination of psychoeducation, parent/teacher training, psychosocial/psychotherapeutic interventions, and pharmacotherapy. Concerning pharmacotherapy, guidelines vary in drug choice and sequencing, with psychostimulants, such as methylphenidate and (lis)dexamfetamine, generally being the favored initial treatment. Alternatives include atomoxetine and guanfacine. Pharmacotherapy has been proven effective, but close follow-up focusing on physical growth, cardiovascular monitoring, and the surveillance of potential side effects including tics, mood fluctuations, and psychotic symptoms, is essential. This paper presents an overview of current pharmacological treatment options for ADHD and explores disparities in treatment guidelines across different European countries. Conclusion: Pharmacological treatment options for ADHD in children and adolescents are effective and generally well-tolerated.Pharmacotherapy for ADHDis alwayspart of a multimodal approach.While there is a considerableconsensus among European guidelines on pharmacotherapy for ADHD, notable differences exist, particularly concerning the selection and sequencing of various medications. What is Known: • There is a significant base of evidence for pharmacological treatment for ADHD in children and adolescents. • Pediatricians are often involved in assessment, diagnosis and management of children with ADHD. What is New: • Our overview of different European guidelines reveals significant agreement in the context of pharmacotherapy for ADHD in children and adolescents. • Discrepancies exist primarily in terms of selection and sequencing of different medications.

Practical clinical guidelines and pharmacological treatment for attention-deficit hyperactivity disorder in Asia.

Attention-deficit hyperactivity disorder (ADHD) is characterized by persistent symptoms of inattention, hyperactivity, and impulsivity. Both, stimulant and nonstimulant medications have been approved for the treatment of this disorder. Several Western guidelines recommend the use of prescribed Food and Drug Administration (FDA)-approved medications for ADHD along with parental training in behavior management and behavioral classroom intervention. In 2022, new Japanese guidelines for ADHD were issued, which recommended school environment management and psychosocial treatment as the first-line treatment, with pharmacological treatment added as the second-line treatment. Although Japanese guidelines, including pharmacological treatments, have been established, the guidelines and utilization of ADHD medications across Asian regions are unclear. Therefore, to appropriately evaluate the strategy of pharmacological treatments for ADHD, we investigated Asian regional guidelines for ADHD medication in children. We also reviewed the guidelines in Malaysia, Singapore, India, and the Republic of Korea and found that these guidelines differ from Western guidelines.

Factors associated with pharmacological treatment in children with attention-deficit/hyperactivity disorders: a retrospective study of a series of 77 cases in a single third-level reference Centre in Apulia region

BackgroundThe present study analysed data on children and adolescents with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) who were referred to the ADHD reference centre of Scientific Institute IRCCS E. Medea (Brindisi, Italy) for ADHD pharmacotherapy initiation and monitoring overtime. The main aim of the study was to examine differences in pharmacological treatment status (i.e., treatment continuation vs discontinuation) between patients.MethodsSeventy-seven children and adolescents (mean age at pharmacotherapy initiation = 9.5, standard deviation = 2.6) with ADHD received drugs treatment for ADHD at the reference center between January, 2013 and May, 2022. Demographic and clinical data were obtained from the Italian Registry for ADHD and medical records. Child Behavior Checklist (CBCL) available data were used.ResultsPharmacological treatment status was examined for patients (n = 63) with at least 12 months of follow-up after the first pharmacological treatment for ADHD. After starting pharmacotherapy treatment, 77.8% (n = 49) patients were still on treatment whereas 22.2% (n = 14) discontinued it. No between group difference were observed in demographic and clinical data except for the intelligence quotient/intellectual disability and rule-breaking behavior (n = 40).ConclusionsThis study stressed the need of periodical assessments, monitoring difficulties with treatment and/or reasons for poor treatment compliance to provide individualized care.

Attention-deficit/hyperactivity disorder and inflammation: natural product-derived treatments-a review of the last ten years.

Attention-deficit hyperactivity disorder (ADHD) is a psychiatric disorder characterized by symptoms of inattention, hyperactivity, and impulsivity. Stimulant medication is the main pharmacological treatment for ADHD. However, the traditional pharmacological treatments may have significant side effects; therefore, non-pharmacological approaches are needed. Thus, there has been growing interest in alternative herbal treatments. The aim of this review was to comprehensively assess the current evidence for plant-based treatment of ADHD in human and animal models, as well as their ability to modulate the inflammatory process. This study was an integrative review of the current evidence for the plant-based treatment of ADHD. The research involved using literature available on PubMed and Scopus databases. Spontaneously hypersensitive rats treated with baicalin exhibited significant reductions in locomotion, increased spatial learning skills, and increased levels of dopamine in the striatum. Supplementation with Sansonite improved memory and attention capacity. In human studies, Ginkgo biloba significantly improved the symptoms of inattention and reduced memory impairment. In studies conducted using Korean Red ginseng, Klamath, and Crocus sativus L., the patients showed significant improvements in symptoms of inattention and hyperactivity/impulsivity. Furthermore, we demonstrated that the identified plants modulate the inflammatory process through pro-inflammatory and anti-inflammatory cytokines, nitric oxide, Th cells, Toll-like receptor 4, and mitogen-activated protein kinases. All the studies included in this review focused on plants with demonstrated potential against inflammatory processes, positioning them as promising candidates for ADHD treatment, due to their potential to attenuate or even prevent neuroinflammatory mechanisms.

Effect of Pharmacological Treatment of Attention-Deficit/Hyperactivity Disorder on Criminality

Criminality rates are higher among persons with attention-deficit/hyperactivity disorder (ADHD), and evidence that medication reduces crime is limited. Medication rates between clinics vary widely even within universal health care systems, partly because of providers' treatment preferences. We used this variation to estimate causal effects of pharmacological treatment of ADHD on 4-year criminal outcomes. We used Norwegian population-level registry data to identify all unique patients aged 10 to 18 years diagnosed with ADHD between 2009 and 2011 (n= 5,624), their use of ADHD medication, and subsequent criminal charges. An instrumental variable design, exploiting variation in provider preference for ADHD medication between clinics, was used to identify causal effects of ADHD medication on crime among patients on the margin of treatment, that is, patients who receive treatment because of their provider's preference. Criminality was higher in patients with ADHD relative to the general population. Medication preference varied between clinics and strongly affected patients' treatment. Instrumental variable analyses supported a protective effect of pharmacological treatment on violence-related and public-order-related charges with numbers needed to treat of 14 and 8, respectively. There was no evidence for effects on drug-, traffic-, sexual-, or property-related charges. This is the first study to demonstrate causal effects of pharmacological treatment of ADHD on some types of crimes in a population-based natural experiment. Pharmacological treatment of ADHD reduced crime related to impulsive-reactive behavior in patients with ADHD on the margin of treatment. No effects were found on crimes requiring criminal intent, conspiracy, and planning. The ADHD controversy project: Long-term effects of ADHD medication; https://www.isrctn.com/; 11891971.

Increased fracture risk among children diagnosed with attention- deficit/hyperactivity disorder: a large matched cohort study.

To analyse the risk of fractures among children with attention-deficit/hyperactivity disorder (ADHD) compared with matched children without ADHD; and to evaluate the impact of pharmacological treatment. This registry-based cohort study included 31,330 children diagnosed with ADHD and a comparison group of 62,660 children matched by age, sex, population sector and socioeconomic status. Demographic and clinical information was extracted from the electronic database of Meuhedet, a health maintenance organization. Fracture events between 2-18years of age were identified by coded diagnoses. The overall fracture incidence rate was 334 per 10,000 patient-years (PY) in the ADHD group and 284 per 10,000 PY in the comparison group (p < 0.001). Among boys, the fracture incidence rates were 388 per 10,000 PY and 327 per 10,000 PY (p < 0.001), for the respective groups. Among girls, the rates were lower in both groups compared to boys, but higher in the ADHD compared to the matched group (246 vs 203 per 10,000 PY, p < 0.001). Among the children with ADHD, the hazard ratios (HR) to have a fracture were similar in boys (1.18, 95%CI 1.15-1.22, p < 0.001) and girls (1.22, 95%CI 1.16-1.28, p < 0.001). Children with ADHD were also at increased risk for two and three fractures; the hazard ratios (HRs) were 1.32 (95%CI 1.26-1.38, p < 0.001) and 1.35 (95%CI 1.24-1.46, p < 0.001), respectively. In a multivariable model of the children with ADHD, pharmacological treatment was associated with reduced fracture risk (HR 0.90, 95%CI 0.82-0.98, p < 0.001) after adjustment for sex, resident socioeconomic status and population sector. Conclusion: Children with ADHD had greater fracture risk than a matched group without ADHD. Pharmacological treatment for ADHD may decrease this risk. What is Known: • Children with attention-deficit/hyperactivity disorder (ADHD) may be more prone to injuries and fractures than children without ADHD. What is New: • Children with ADHD were 1.2 times more likely to have a fracture than children with similar characteristics, without ADHD.The increased risk for fractures was even greater for two and three fractures (hazard ratios 1.32 and 1.35, respectively). • Our study suggests a positive effect of pharmacological treatment for ADHD in reducing fracture risk.

Pharmacological Treatment of Children and Adolescents Diagnosed with Attention-deficit/hyperactivity Disorder at Mental Health Services in Qatar: A Retrospective Study

Background: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common mental disorders affecting children. The consequences of ADHD could seriously impact the patient’s life, and thus parental training, behavioral therapies, and pharmacological interventions are the main therapeutic options applied. This study was conducted to explore the trends of prescribing pharmacological medications used in ADHD and identify the reasons for discontinuation of such medications. Methodology: A retrospective chart review for patients diagnosed with ADHD at Child and Adolescent Mental Health Services (CAMHS) in Qatar from January 2019 to December 2019 was carried out. Patients less than 18 years old, diagnosed with ADHD as per the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and were on pharmacological treatment for ADHD were suitable to be included. Patients who were not on anti-ADHD medications were excluded from the study. Results: Ninety-two patients were eligible to be included in the study. Autism Spectrum Disorder (ASD) was found to be the most coexisting condition in addition to ADHD in 16.3%. Methylphenidate was the most prescribed medication (68.5%), followed by atomoxetine (30.4%). None of the participants were found on modafinil, guanfacine, bupropion, or benzodiazepines, and none exceeded the maximum licensed dose of either methylphenidate or atomoxetine. Half (50%) of the sample on atomoxetine discontinued treatment compared to 14.2% in the methylphenidate group. Conclusion: The clinical practice of prescribing pharmacological options for ADHD was thoroughly in alignment with international guidelines. The effects of long-term use of these psychotropics in this particular group of patients on their neurobiological, behavioral, and physical health should be studied further.

Improvement of attention deficit/hyperactivity disorder (ADHD) in three adult men during testosterone treatment: a case series

BackgroundAttention deficit/hyperactivity disorder (ADHD) entails inattention, impulsivity, and restlessness at a disabling level. The pharmacological treatment of ADHD rests on the use of centrally acting stimulants, such as methylphenidate and D-amphetamine. In some patients, these drugs cause side effects that preclude their use.Case presentationWe present three adult male, Caucasian, ADHD patients (24, 37, and 43 years old) whose ADHD symptoms improved during treatment with testosterone. The first patient experienced loss of libido during treatment with methylphenidate; for this, he was offered a trial of testosterone. Unexpectedly, his ADHD symptoms improved with testosterone treatment, and this effect continued with testosterone as monotherapy. The two other patients, who also had side effects from centrally acting stimulants, received testosterone monotherapy with similar results. The effect has now continued for 4.5–5 years at the same doses: 10–60 mg testosterone/day, administered as a skin gel. Prior to testosterone treatment, the patients had serum levels of testosterone in the low–normal range: 12–16 nmol/L (age-specific reference range: 10.4–32.6 nmol/L). The testosterone/sex hormone-binding globulin ratio was low in two patients (0.32 and 0.34; age-specific reference range: 0.38–1.1), suggesting low free serum levels of testosterone. Serum testosterone levels and testosterone/sex hormone-binding globulin ratios increased with testosterone treatment in all patients, but remained within reference values.ConclusionThese cases suggest that a moderately reduced serum level of free testosterone may contribute to the ADHD symptoms of some adult male ADHD patients, and that testosterone treatment may be of value for these patients.

Risk prediction model for cardiovascular diseases in adults initiating pharmacological treatment for attention-deficit/hyperactivity disorder

BackgroundAvailable prediction models of cardiovascular diseases (CVDs) may not accurately predict outcomes among individuals initiating pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD).ObjectiveTo improve the predictive accuracy of traditional CVD risk factors...

Methylphenidate remediates aberrant brain network dynamics in children with attention‐deficit/hyperactivity disorder: A randomized controlled trial

Methylphenidate is a widely used first-line treatment for attention deficit/hyperactivity disorder (ADHD), but the underlying circuit mechanisms are poorly understood. Here we investigate whether a single dose of osmotic release oral system methylphenidate can remediate attention deficits and aberrancies in functional circuit dynamics in cognitive control networks, which have been implicated in ADHD. In a randomized placebo-controlled double-blind crossover design, 27 children with ADHD were scanned twice with resting-state functional MRI and sustained attention was examined using a continuous performance task under methylphenidate and placebo conditions; 49 matched typically-developing (TD) children were scanned once for comparison. Dynamic time-varying cross-network interactions between the salience (SN), frontoparietal (FPN), and default mode (DMN) networks were examined in children with ADHD under both administration conditions and compared with TD children. Methylphenidate improved sustained attention on a continuous performance task in children with ADHD, when compared to the placebo condition. Children with ADHD under placebo showed aberrancies in dynamic time-varying cross-network interactions between the SN, FPN and DMN, which were remediated by methylphenidate. Multivariate classification analysis confirmed that methylphenidate remediates aberrant dynamic brain network interactions. Furthermore, dynamic time-varying network interactions under placebo conditions predicted individual differences in methylphenidate-induced improvements in sustained attention in children with ADHD. These findings suggest that a single dose of methylphenidate can remediate deficits in sustained attention and aberrant brain circuit dynamics in cognitive control circuits in children with ADHD. Findings identify a novel brain circuit mechanism underlying a first-line pharmacological treatment for ADHD, and may inform clinically useful biomarkers for evaluating treatment outcomes.

Viloxazine in the Treatment of Attention Deficit Hyperactivity Disorder.

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children. Over the past twenty years, research on the disease and its characteristics and treatment options has grown exponentially. The first-line pharmacologic treatment of ADHD is stimulants, which have a response rate of ~70%. With the support of four phase 3 studies involving more than 1,000 pediatric patients 6–17 years old, the FDA has approved the non-stimulant, serotonin-norepinephrine modulating agent (SNMA) viloxazine in an extended-release capsule (viloxazine ER) for treatment of ADHD in children aged 6–17. Viloxazine modulates serotonergic activity as a selective 5-HT22B receptor antagonist and 5-HT2C receptor agonist and moderately inhibits norepinephrine transporter (NET), thus blocking the reuptake of norepinephrine. A phase 2 study by Johnson et al. found that once-daily dosing of viloxazine ER in 200, 300, or 400 mg dosages in children with ADHD for eight weeks resulted in a statistically significant reduction of ADHD-RS-IV total score. A post hoc analysis of data from four phase 3, randomized, placebo-controlled, double-blind, three-arm, clinical trials by Faraone et al. found that early response to viloxazine treatment, defined as a change in ADHD-RS-5 total score at week 2, best predicted the treatment response at week 6 [75% positive predictive power (PPP), 75% sensitivity]. Proper treatment of the symptoms and comorbidities associated with ADHD is crucial in improving a patient's quality of life, cognitive function, and overall therapeutic outcomes. Viloxazine's mechanism of action, clinical effects, and limited side effect profile point toward the drug's relevance in the treatment of ADHD.

Methylphenidate for attention-deficit/hyperactivity disorder in patients with Smith\u2013Magenis syndrome: protocol for a series of N-of-1 trials

BackgroundSmith–Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Often, patients with SMS are diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations.Methods and analysisWe will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged ≥ 6 years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level.ConclusionsThis study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care.Trial registration This study is registered in the Netherlands Trial Register (NTR9125).

Lifetime evolution of ADHD treatment.

Attention-deficit hyperactivity disorder (ADHD), has been traditionally considered a neurodevelopmental disorder affecting children and adolescents characterized by inattention, hyperactivity, disruptive behavior, and impulsivity. Although still debated, it is evident that ADHD is also present in adulthood, but this diagnosis is rarely carried out, mainly forthe frequent comorbidity with other psychiatric and/or substance abuse disorders. Given the need to shed more light on the pharmacological treatment of ADHD, we performed a naturalistic review to review and comment on the available literature of ADHD treatment across the lifespan. Indeed, stimulants are endowed of a prompt efficacy and safety, whilst non-stimulants,although requiring some weeks to be fully effective, are useful when a substance abuse history is detected. In any case, the pharmacological management of ADHD appears to be still largely influenced by the individual experience of the clinicians. Further longitudinal studies with a careful and detailed characterization of participants across different phases of the lifespan are also required to provide relevant confirmations (or denials) regarding pharmacological treatments amongst the different age groups.

Overdiagnosis of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents

Reported increases in attention-deficit/hyperactivity disorder (ADHD) diagnoses are accompanied by growing debate about the underlying factors. Although overdiagnosis is often suggested, no comprehensive evaluation of evidence for or against overdiagnosis has ever been undertaken and is urgently needed to enable evidence-based, patient-centered diagnosis and treatment of ADHD in contemporary health services. To systematically identify, appraise, and synthesize the evidence on overdiagnosis of ADHD in children and adolescents using a published 5-question framework for detecting overdiagnosis in noncancer conditions. This systematic scoping review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension for Scoping Reviews and Joanna Briggs Methodology, including the PRISMA-ScR Checklist. MEDLINE, Embase, PsychINFO, and the Cochrane Library databases were searched for studies published in English between January 1, 1979, and August 21, 2020. Studies of children and adolescents (aged ≤18 years) with ADHD that focused on overdiagnosis plus studies that could be mapped to 1 or more framework question were included. Two researchers independently reviewed all abstracts and full-text articles, and all included studies were assessed for quality. Of the 12 267 potentially relevant studies retrieved, 334 (2.7%) were included. Of the 334 studies, 61 (18.3%) were secondary and 273 (81.7%) were primary research articles. Substantial evidence of a reservoir of ADHD was found in 104 studies, providing a potential for diagnoses to increase (question 1). Evidence that actual ADHD diagnosis had increased was found in 45 studies (question 2). Twenty-five studies showed that these additional cases may be on the milder end of the ADHD spectrum (question 3), and 83 studies showed that pharmacological treatment of ADHD was increasing (question 4). A total of 151 studies reported on outcomes of diagnosis and pharmacological treatment (question 5). However, only 5 studies evaluated the critical issue of benefits and harms among the additional, milder cases. These studies supported a hypothesis of diminishing returns in which the harms may outweigh the benefits for youths with milder symptoms. This review found evidence of ADHD overdiagnosis and overtreatment in children and adolescents. Evidence gaps remain and future research is needed, in particular research on the long-term benefits and harms of diagnosing and treating ADHD in youths with milder symptoms; therefore, practitioners should be mindful of these knowledge gaps, especially when identifying these individuals and to ensure safe and equitable practice and policy.

Functional validation of CHMP7 as an ADHD risk gene

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood with a strong genetic component. Despite the success of mapping ADHD risk loci, little work has been done to experimentally verify the contribution of these loci to ADHD phenotypes. Meta-analysis of four genome-wide association studies in ADHD suggested CHMP7 as a predisposing gene for ADHD. A DNA variant (rs2294123) mapped to CHMP7 has been shown (via bioinformatic analysis) to have a high likelihood for functionality and correlate with reduced transcript levels. We used CRISPR-Cas9 genome editing to generate a chmp7 zebrafish model for ADHD. chmp7+/− fish showed comparable reductions in mRNA levels to individuals homozygous for the CHMP7 ADHD risk allele. These fish displayed significant hyperactivity over a 24-h period at 6 days post-fertilisation compared to chmp7+/+, but this effect did not persist into juvenile and adulthood stages. In addition, chmp7+/− fish had significantly smaller total brain volumes than chmp7+/+ fish. Finally, the hyperactivity at 6 days post-fertilisation was significantly reduced through the application of methylphenidate, a mainstay pharmacological treatment for ADHD. Overall, this study highlights an important role for CHMP7 in the neurodevelopment of ADHD, and demonstrates the utility of zebrafish for modelling the functional effects of genes conferring risk to ADHD.