Attention-deficit/hyperactivity Disorder Drugs Research Articles

Attention-Deficit/Hyperactivity Disorder Medications and Work Disability and Mental Health Outcomes

ImportanceIndividuals with attention-deficit/hyperactivity disorder (ADHD) often have comorbid psychiatric conditions. Relatively little is known about how specific ADHD medications are associated with overall treatment outcomes among these patients.ObjectiveTo investigate the association of the use of specific ADHD medications with hospitalization outcomes and work disability among adolescents and adults with ADHD.Design, Setting, and ParticipantsThis nationwide register-based cohort study identified individuals (aged 16-65 years) with ADHD from Swedish nationwide registers of inpatient health care, specialized outpatient health care, sickness absence, and disability pension during the years 2006 to 2021. Data analysis was performed from November 2022 to August 2023.ExposureUse of specific ADHD medications.Main Outcomes and MeasuresThe main outcome measure was psychiatric hospitalization, and secondary outcomes were suicide attempt and/or death by suicide, nonpsychiatric hospitalization, and work disability (ie, sickness absence or disability pension). The risk of outcomes between use vs nonuse periods of ADHD medications was compared in a within-individual design, where a person acts as their own control, and was analyzed with stratified Cox models.ResultsA total of 221 714 persons with ADHD were included in the study cohort (mean [SD] age, 25.0 [11.2] years; 120 968 male individuals [54.6%]). Methylphenidate was the most commonly used ADHD medication (151 837 individuals [68.5%]), followed by lisdexamphetamine (78 106 individuals [35.2%]) during the follow-up (mean [SD], 7.0 [4.7] years). The following medications were associated with a decreased risk of psychiatric hospitalization: amphetamine (adjusted hazard ratio [aHR], 0.74; 95% CI, 0.61-0.90), lisdexamphetamine (aHR, 0.80; 95% CI, 0.78-0.82), ADHD drug polytherapy (aHR, 0.85; 95% CI, 0.82-0.88), dexamphetamine (aHR, 0.88; 95% CI, 0.83-0.94), and methylphenidate (aHR, 0.93; 95% CI, 0.92-0.95). No associations were found for modafinil, atomoxetine, clonidine, and guanfacine. Decreased risk of suicidal behavior was associated with the use of dexamphetamine (aHR, 0.69; 95% CI, 0.53-0.89), lisdexamphetamine (aHR, 0.76; 95% CI, 0.68-0.84), and methylphenidate (aHR, 0.92; 95% CI, 0.86-0.98). None of the medications was associated with increased risk of nonpsychiatric hospitalization; instead, use of amphetamine, lisdexamphetamine, polytherapy, dexamphetamine, methylphenidate, and atomoxetine were associated with decreased risk of nonpsychiatric hospitalization. The results regarding work disability were significant only for the use of atomoxetine (aHR, 0.89; 95% CI, 0.82-0.97), especially among adolescents and young adults aged 16 to 29 years, (aHR, 0.82; 95% CI, 0.73-0.92).Conclusions and RelevanceIn this nationwide cohort study of adolescents and adults with ADHD, the use of ADHD medication was associated with fewer hospitalizations for both psychiatric and nonpsychiatric morbidity and lower suicidal behavior.

Trends in Incident Prescriptions for Behavioral Health Medications in the US, 2018-2022

The COVID-19 pandemic reportedly increased behavioral health needs and impacted treatment access. To assess changes in incident prescriptions dispensed for medications commonly used to treat depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), and opioid use disorder (OUD), before and during the COVID-19 pandemic. This was a cross-sectional study using comprehensive, population-level, nationally projected data from IQVIA National Prescription Audit on incident prescriptions (prescriptions dispensed to patients with no prior dispensing from the same drug class in the previous 12 months) dispensed for antidepressants, benzodiazepines, Schedule II (C-II) stimulants, nonstimulant medications for ADHD, and buprenorphine-containing medication for OUD (MOUD), from US outpatient pharmacies. Data were analyzed from April 2018 to March 2022. Incident prescriptions by drug class (by prescriber specialty, patient age, and sex) and drug. Interrupted time-series analysis to compare changes in trends in the monthly incident prescriptions dispensed by drug class and percentage changes in aggregate incident prescriptions dispensed between April 2018 and March 2022. Incident prescriptions dispensed for the 5 drug classes changed from 51 500 321 before the COVID-19 pandemic to 54 000 169 during the pandemic. The largest unadjusted percentage increase in incident prescriptions by prescriber specialty was among nurse practitioners across all drug classes ranging from 7% (from 1 811 376 to 1 944 852; benzodiazepines) to 78% (from 157 578 to 280 925; buprenorphine MOUD), whereas for patient age and sex, the largest increases were within C-II stimulants and nonstimulant ADHD drugs among patients aged 20 to 39 years (30% [from 1 887 017 to 2 455 706] and 81% [from 255 053 to 461 017], respectively) and female patients (25% [from 2 352 095 to 2 942 604] and 59% [from 395 678 to 630 678], respectively). Trends for C-II stimulants and nonstimulant ADHD drugs (slope change: 4007 prescriptions per month; 95% CI, 1592-6422 and 1120 prescriptions per month; 95% CI, 706-1533, respectively) significantly changed during the pandemic, exceeding prepandemic trends after an initial drop at the onset of the pandemic (level changes: -50 044 prescriptions; 95% CI, -80 202 to -19 886 and -12 876 prescriptions; 95% CI, -17 756 to -7996, respectively). Although buprenorphine MOUD dropped significantly (level change: -2915 prescriptions; 95% CI, -5513 to -318), trends did not significantly change for buprenorphine MOUD, antidepressants, or benzodiazepines. Incident use of many behavioral health medications remained relatively stable during the COVID-19 pandemic in the US, whereas ADHD medications, notably C-II stimulants, sharply increased. Additional research is needed to differentiate increases due to unmet need vs overprescribing, highlighting the need for further ADHD guideline development to define treatment appropriateness.

The effects of methylphenidate and atomoxetine on Drosophila brain at single-cell resolution and potential drug repurposing for ADHD treatment

The stimulant methylphenidate (MPH) and the non-stimulant atomoxetine (ATX) are frequently used for the treatment of attention-deficit/hyperactivity disorder (ADHD); however, the function of these drugs in different types of brain cells and their effects on related genes remain largely unknown. To address these questions, we built a pipeline for the simultaneous examination of the activity behavior and transcriptional responses of Drosophila melanogaster at single-cell resolution following drug treatment. We selected the Drosophila with significantly increased locomotor activities (hyperactivity-like behavior) following the administration of each drug in comparison with the control (same food as the drug-treated groups with 5% sucrose, yeast, and blue food dye solution) using EasyFlyTracker. Subsequently, single cell RNA sequencing (scRNASEQ) was used to capture the transcriptome of 82,917 cells, unsupervised clustering analysis of which yielded 28 primary cell clusters representing the major cell types in adult Drosophila brain. Indeed, both neuronal and glial cells responded to MPH and ATX. Further analysis of differentially expressed genes (DEGs) revealed distinct transcriptional changes associated with these two drugs, such as two well-studied dopamine receptor genes (Dop2R and DopEcR) were responsive to MPH but not to ATX at their optimal doses, in addition to genes involved in dopamine metabolism pathways such as Syt1, Sytalpha, Syt7, and Ih in different cell types. More importantly, MPH also suppressed the expression of genes encoding other neurotransmitter receptors and synaptic signaling molecules in many cell types, especially those for Glu and GABA, while the responsive effects of ATX were much weaker. In addition to monoaminergic neuronal transmitters, other neurotransmitters have also shown a similar pattern with respect to a stronger effect associated with MPH than with ATX. Moreover, we identified four distinct glial cell subtypes responsive to the two drugs and detected a greater number of differentially expressed genes associated with ensheathing and astrocyte-like glia. Furthermore, our study provides a rich resource of candidate target genes, supported by drug set enrichment analysis (P = 2.10E-4; hypergeometric test), for the further exploration of drug repurposing. The whole list of candidates can be found at ADHDrug (http://adhdrug.cibr.ac.cn/). In conclusion, we propose a fast and cost-efficient pipeline to explore the underlying molecular mechanisms of ADHD drug treatment in Drosophila brain at single-cell resolution, which may further facilitate drug repurposing applications.

Pituitary adenylate cyclase-activating polypeptide deficient mice show length abnormalities of the axon initial segment

We previously found that pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP−/−) mice exhibit dendritic spine morphology impairment and neurodevelopmental disorder (NDD)-like behaviors such as hyperactivity, increased novelty-seeking behavior, and deficient pre-pulse inhibition. Recent studies have indicated that rodent models of NDDs (e.g., attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder) show abnormalities in the axon initial segment (AIS). Here, we revealed that PACAP−/− mice exhibited a longer AIS length in layer 2/3 pyramidal neurons of the primary somatosensory barrel field compared with wild-type control mice. Further, we previously showed that a single injection of atomoxetine, an ADHD drug, improved hyperactivity in PACAP−/− mice. In this study, we found that repeated treatments of atomoxetine significantly improved AIS abnormality along with hyperactivity in PACAP−/− mice. These results suggest that AIS abnormalities are associated with NDDs-like behaviors in PACAP−/− mice. Thus, improvement in AIS abnormalities will be a novel drug therapy for NDDs.

Molecular Mechanisms Underlying NMDARs Dysfunction and Their Role in ADHD Pathogenesis.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, although the aetiology of ADHD is not yet understood. One proposed theory for developing ADHD is N-methyl-D-aspartate receptors (NMDARs) dysfunction. NMDARs are involved in regulating synaptic plasticity and memory function in the brain. Abnormal expression or polymorphism of some genes associated with ADHD results in NMDAR dysfunction. Correspondingly, NMDAR malfunction in animal models results in ADHD-like symptoms, such as impulsivity and hyperactivity. Currently, there are no drugs for ADHD that specifically target NMDARs. However, NMDAR-stabilizing drugs have shown promise in improving ADHD symptoms with fewer side effects than the currently most widely used psychostimulant in ADHD treatment, methylphenidate. In this review, we outline the molecular and genetic basis of NMDAR malfunction and how it affects the course of ADHD. We also present new therapeutic options related to treating ADHD by targeting NMDAR.

Safety profiles of methylphenidate, amphetamine, and atomoxetine: analysis of spontaneous reports submitted to the food and drug administration adverse event reporting system.

Background: Methylphenidate, atomoxetine, and Amphetamine are the three most commonly used medications approved by the United States Food and Drug Administration (FDA) for the treatment of attention deficit/hyperactivity disorder (ADHD). However, a comprehensive analysis of their safety profiles across various age groups and genders in real-world contexts has yet to be conducted. In this study, a pharmacovigilance analysis was performed using the FDA Adverse Event Reporting System (FAERS) database to examine differences in adverse events between methylphenidate, atomoxetine, and Amphetamine. Methods: From January 2014 to September 2022, FAERS reports listing "Methylphenidate," "Dexmethylphenidate," "Atomoxetine," "Amphetamine," "Lisdexamfetamine," "Dextroamphetamine," and "Methamphetamine" as primary suspects were analyzed after removing duplicate reports. We used the standardized Medical Dictionary for Regulatory Activities (MedDRA) query generalized search for adverse events at the preferred term level based on case reports. After filtering duplicate reports, disproportionality analysis was used to detect safety signals according to the proportional reporting ratio (PRR). In order to delve into potential safety concerns, we undertook a two-step analysis of the data. Initially, the data was segmented based on age cohorts: 0-5years, 6-12years, 13-18years, and individuals aged ≥19years. Following this, after partitioning the data into males and females within the 0-18years age group, and similarly for those aged ≥19years, further analysis was conducted. Results: The pharmacovigilance analysis uncovered substantial safety signals in the standardized MedDRA queries. Methylphenidate was associated with dyskinesia (PRR = 21.15), myocardial infarction (PRR = 12.32), and hypertension (PRR = 8.95) in children aged 0-5, 6-12, and 13-18years, respectively, as well as neonatal exposures via breast milk (PRR = 14.10) in adults aged ≥19years. Atomoxetine was linked to hostility/aggression (PRR = 15.77), taste and smell disorders (PRR = 6.75), and hostility/aggression (PRR = 6.74) in children aged 0-5, 6-12, and 13-18years, respectively, as well as hostility/aggression (PRR = 14.00) in adults aged ≥19years. Amphetamine was associated with psychosis and psychotic disorders (PRR = 16.78), hostility/aggression (PRR = 4.39), and Other ischaemic heart disease (PRR = 10.77) in children aged 0-5years, 6-12years, and 13-18years, respectively, and hostility/aggression in adults aged ≥19years (PRR = 9.16). Significant and noteworthy adverse event signals were also identified at the preferred term level. Specifically, methylphenidate was associated with myocardial infarction, acute myocardial infarction, coronary artery dissection, electrocardiogram QT prolonged, growth retardation, self-destructive behavior, suicidal ideation, and completed suicide. Atomoxetine was linked to electrocardiogram QT prolonged, growth retardation, and tic. Amphetamine was recorded for coronary artery dissection, suicidal ideation, and completed suicide. It was observed that male patients, including both children and adults, showed a more significant and frequent occurrence of adverse events compared to females, particularly in terms of cardiac disorders. The intensity and quantity of adverse event signals were distinctly different between the two genders, with males having a higher number of signals. All detected safety signals were confirmed using signals obtained from the disproportionality analysis. Conclusion: This pharmacovigilance analysis demonstrated significant variations in the safety profiles of methylphenidate, atomoxetine, and Amphetamine across different age groups and between different genders. Following an in-depth analysis of the FAERS database, we discerned prominent safety signals. Notably, the strength of the signals associated with coronary artery dissection induced by methylphenidate and amphetamine, as well as those related to suicide, demand particular attention. Consequently, it remains imperative to persist in monitoring these medications, assessing the associated risks, and carrying out comparative studies particularly geared towards ADHD drugs.

Attention deficit hyperactivity disorder - symptoms, diagnosis and therapy among children and adults.

Introduction: The prevalence of Attention Deficit Hyperactivity Disorder (ADHD) in the world is estimated at about 5%. Among adults, it occurs with a frequency of 2.5%. This syndrome can significantly impair functioning in various areas of life. There is a treatment to reduce the symptoms. Aim of the study: The aim of the study was to collect and analyze publications on attention deficit hyperactivity disorder - symptoms, diagnosis and therapy, taking into account the differences among children and adults. Material and methods: We reviewed the literature available in the PubMed database using the keywords: "ADHD"; "Attention deficit hyperactivity disorder"; '' ADHD diagnosis', ''ADHD therapy'; ‘’ADHD drug therapy’, ‘’Methylphenidate’, ‘’Atomoxetine” Results: The clinical presentation of the disorder changes over the years. The main symptoms among children are related to inattention and impulsiveness, while among adults, hyperactivity can turn into a feeling of inner fear. Among children, frequent accompanying disorders are behavioral and oppositional-defiant disorders, and among adults, sleep disorders, personality, mood and anxiety disorders. ADHD treatment is based on a multimodal approach that uses cognitive behavioral therapy and effective stimulants (methylphenidate) and non-stimulants (atomoxetine) among children and adults. Conclusions: There are differences in symptoms, comorbidities and diagnosis of ADHD among children and adults. Pharmacotherapy is carried out using the same drugs that are safe and effective. Diagnosis of the disorder and both non-pharmacological and pharmacological help are important due to the risk of increased mortality in patients.

Necessity of an Integrative Animal Model for a Comprehensive Study of Attention-Deficit/Hyperactivity Disorder.

Animal models of attention-deficit/hyperactivity disorder (ADHD) have been used to study and understand the behavioral, neural, and physiological mechanisms underlying ADHD. These models allow researchers to conduct controlled experiments and manipulate specific brain regions or neurotransmitter systems to investigate the underlying causes of ADHD and test potential drug targets or treatments. However, it is essential to note that while these models can provide valuable insights, they do not ideally mimic the complex and heterogeneous nature of ADHD and should be interpreted cautiously. Additionally, since ADHD is a multifactorial disorder, environmental and epigenetic factors should be considered simultaneously. In this review, the animal models of ADHD reported thus far are classified into genetic, pharmacological, and environmental models, and the limitations of the representative models are discussed. Furthermore, we provide insights into a more reliable alternative model for the comprehensive study of ADHD.

Long-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study

Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. Although many randomised controlled trials support short-term efficacy, tolerability, and safety, data on long-term safety and tolerability are scarce. The aim of this study was to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health, and cardiovascular function in children and adolescents. We conducted a naturalistic, longitudinal, controlled study as part of the ADDUCE research programme in 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary. Participants aged 6-17 years were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group), and a control group without ADHD. Children with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who scored less than 1·5 on average on the Swanson, Nolan, and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (<6) were eligible for inclusion. Participants were excluded if they had previously taken any ADHD medications but remained eligible if they had previously taken or were currently taking other psychotropic drugs. The primary outcome was height velocity (height velocity SD score; estimated from at least two consecutive height measurements, and normalised with reference to the mean and SD of a population of the same age and sex). Between Feb 01, 2012, and Jan 31, 2016, 1410 participants were enrolled (756 in methylphenidate group, 391 in no-methylphenidate group, and 263 in control group). 1070 (76·3%) participants were male, 332 (23·7%) were female, and for eight gender was unknown. The average age for the cohort was 9·28 years (SD 2·78; IQR 7-11). 1312 (93·0%) of 1410 participants were White. The methylphenidate and no-methylphenidate groups differed in ADHD symptom severity and other characteristics. After controlling for the effects of these variables using propensity scores, there was little evidence of an effect on growth (24 months height velocity SD score difference -0·07 (95% CI -0·18 to 0·04; p=0·20) or increased risk of psychiatric or neurological adverse events in the methylphenidate group compared with the no-methylphenidate group. Pulse rate and systolic and diastolic blood pressure were higher in the methylphenidate group compared with the no-methylphenidate group after 24 months of treatment. No serious adverse events were reported during the study. Our results suggest that long-term treatment with methylphenidate for 2 years is safe. There was no evidence to support the hypothesis that methylphenidate treatment leads to reductions in growth. Methylphenidate-related pulse and blood pressure changes, although relatively small, require regular monitoring. EU Seventh Framework Programme.

Diagnosis and treatment of intractable idiopathic orofacial pain with attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP.

Abnormalities of axon initial segments in mice with attention-deficit hyperactivity disorder (ADHD)-like behavior are recovered along with behavioral abnormalities by the drug for ADHD.

Abnormalities of axon initial segments in mice with attention-deficit hyperactivity disorder (ADHD)-like behavior are recovered along with behavioral abnormalities by the drug for ADHD.

The use of attention-deficit hyperactivity disorder medications in cardiac disease.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset usually in childhood characterized by inattention, impulsivity, and hyperactivity causing a functional impairment. Untreated ADHD, or treatment delay is associated with adverse outcomes and poor quality of life. Although conservative management strategies such as behavioral and psychological interventions are important, pharmacological treatment has a strong evidence base with improved outcomes. ADHD medications are broadly divided into stimulant and non-stimulant medications. Stimulant medications are generally more effective than non-stimulants. Cardiovascular safety of ADHD medication has been a matter of debate for decades. Treatment guidelines advise the careful consideration of risks and benefits in people with cardiovascular diseases such as congenital heart disease or cardiomyopathy. Although stimulants can increase systemic blood pressure and heart rate, no significant associations were found between their use and serious cardiovascular events. Concerns regarding QT effects and attendant sudden cardiac death risks deter clinicians from initiating much-needed ADHD medications in patients with heart disease. This overly cautious approach is potentially depriving low-risk individuals from significant benefits associated with timely ADHD drug treatment. This review discusses the cardiovascular risks reportedly associated with ADHD medications, the evidence base for their safe usage in persons with established cardiovascular disease, and highlights future research directions.

The orphan receptor GPR88 controls impulsivity and is a risk factor for Attention-Deficit/Hyperactivity Disorder.

The neural orphan G protein coupled receptor GPR88 is predominant in the striatum and cortex of both rodents and humans, and considered a potential target for brain disorders. Previous studies have shown multiple behavioral phenotypes in Gpr88 knockout mice, and human genetic studies have reported association with psychosis. Here we tested the possibility that GPR88 contributes to Attention Deficit Hyperactivity Disorder (ADHD). In the mouse, we tested Gpr88 knockout mice in three behavioral paradigms, best translatable between rodents and humans, and found higher motor impulsivity and reduced attention together with the reported hyperactivity. Atomoxetine, a typical ADHD drug, reduced impulsivity in mutant mice. Conditional Gpr88 knockout mice in either D1R-type or D2R-type medium spiny neurons revealed distinct implications of the two receptor populations in waiting and stopping impulsivity. Thus, animal data demonstrate that deficient GPR88 activity causally promotes ADHD-like behaviors, and identify circuit mechanisms underlying GPR88-regulated impulsivity. In humans, we performed a family-based genetic study including 567 nuclear families with DSM-IV diagnosis of ADHD. There was a minor association for SNP rs2036212 with diagnosis, treatment response and cognition. A stronger association was found for SNP rs2809817 upon patient stratification, suggesting that the T allele is a risk factor when prenatal stress is involved. Human data therefore identify GPR88 variants associated with the disease, and highlight a potential role of life trajectories to modulate GPR88 function. Overall, animal and human data concur to suggest that GPR88 signaling should be considered a key factor for diagnostic and treatment of ADHD.

Psychostimulants Modafinil, Atomoxetine and Guanfacine Impair Bone Cell Differentiation and MSC Migration

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.

Ascorbic acid derived carbon dots promote circadian rhythm and contribute to attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children, and ADHD patients always display circadian abnormalities. While, the ADHD drugs currently used in clinic have strong side effects, such as psychosis, allergic reactions, and heart problems. Here, we demonstrated carbon dots derived from the ascorbic acid (VCDs) could strongly rescue the hyperactive and impulsive behaviour of a zebrafish ADHD disease model caused by per1b mutation. VCDs prolonged the circadian period of zebrafish for more than half an hour. In addition, the amplitude and circadian phase were also changed. The dopamine level was specifically increased, which may be caused by stimulation of the dopaminergic neuron development in the midbrain. Notably, it was found that the serotonin level was not altered by VCDs treatments. Also, the gene transcriptome effects of VCDs were discussed in present work. Our results provided the dynamic interactions of carbon dots with circadian system and dopamine signaling pathway, which illustrates a potential application of degradable and bio-safe VCDs for the treatment of the attention deficient and hyperactive disorder through circadian intervention.

Utilization of Drugs for Attention-Deficit Hyperactivity Disorder Among Young Patients in China, 2010-2019.

ObjectiveThe use of attention-deficit hyperactivity disorder (ADHD) medication is increasing worldwide, but its status in China is unknown. This research aimed to assess the trends of ADHD medication use in young Chinese patients between 2010 and 2019.MethodsDispensing data related to ADHD medication use were extracted from the Hospital Prescription Analysis Cooperative Project of China. The trends in the yearly prescription number of ADHD drugs and corresponding cost were analyzed. We further stratified the data by age, sex, and specific drug.ResultsFrom 2010 to 2019, sampled prescriptions for ADHD medication increased from 902 to 4531, and the total expenditure increased rapidly from 276,580 to 2,412,308 Chinese Yuan. Prescriptions for males were almost fourfold more than that for females. Patients aged 6–11 years had the highest number of prescriptions for ADHD medication each year, accounting for more than 50% of the total number of prescriptions. The percentage of methylphenidate prescriptions decreased from 91.9% in 2010 to 76.9% in 2019, and the corresponding cost declined from 77.3% to 66.8%. In contrast, atomoxetine prescriptions increased progressively and accounted for about 24.5% of the total prescriptions at the end of the study.ConclusionsThe use of ADHD drugs and the corresponding cost increased rapidly in China, and methylphenidate was the most frequently prescribed medicine. The increase in ADHD prescriptions requires attention to ensure that it reflects appropriate use, especially in patients aged 6–11 years.

New Drugs to Treat ADHD: Opportunities and Challenges in Research and Development.

Since the landmark MTA (Multimodal Treatment of ADHD) trial unequivocally demonstrated the efficacy of methylphenidate, catecholaminergic drugs, especially stimulants, have been the therapeutic mainstay in treatment of Attention-Deficit Hyperactivity Disorder (ADHD). We review the new drugs which have entered the ADHD formulary. The lessons learned from drug-candidates that have succeeded in clinical trialstogether with those that have not have also been considered. What emerges confirms and consolidates the hypothesis that clinically effective ADHD drugs indirectly or directly increase catecholaminergic neurotransmission in the prefrontal cortex (PFC). Attempts to enhance catecholaminergic signalling through modulatory neurotransmitter systems or cognitive-enhancing drugs have all failed. New drugs approved for ADHD are catecholaminergic reuptake inhibitors and releasing agents, or selective noradrenaline reuptake inhibitors. Triple reuptake inhibitors with preferential effects on dopamine have not been successful. The substantial number of failures probably accounts for a continued focus on developing novel catecholaminergic and noradrenergic drugs, and a dearth of drug-candidates with novel mechanisms entering clinical development. However, substantial improvements in ADHD pharmacotherapy have been achieved by the almost exclusive use of once-daily medications and prodrugs, e.g. lisdexamfetamine and Azstarys®, which improve compliance, deliver greater efficacy and reduce risks for diversion and abuse.

Targeting Catecholamines to Develop New Drugs for Attention Deficit Hyperactivity Disorder

The prevalence of attention deficit hyperactivity disorder (ADHD), a developmental neuropsychiatric disorder, is high among children and adolescents. The pathogenesis of ADHD is mediated with genetic, biological, and environmental factors. Most therapeutic drugs for ADHD have so far targeted biological causes, primarily by regulating catecholaminergic neurotransmitters. However, ADHD drugs that are clinically treated have various problems in their addictiveness and drug stability; thus, it is recommended that efficacy and safety should be secured through simultaneous prescription of multiple drugs rather than a single drug treatment. Accordingly, it is necessary to develop drugs that newly target pathogenic mechanisms of ADHD. In this study, we attempt to confirm the possibility of developing new drugs by reviewing dopamine-related developmental mechanisms of neurons and their correlation with ADHD. Histone deacetylase inhibitors (HDACi) can regulate the concentration of intracellular dopamine in neurons by expressing vesicular monoamine transporter 2 and inducing the exocytosis of neurotransmitters to the synaptic cleft, thereby promoting the development of neurons and signal transmission. This cellular modulation of HDACi is expected to treat ADHD by regulating endogenous catecholamines such as dopamine. Although studies are still in the preclinical stage, HDAC inhibitors clearly have potential as a therapeutic agent with low addictiveness and high efficacy for ADHD treatment.

Effects of Parent-Teacher Training on Academic Performance and Parental Anxiety in School-Aged Children With Attention-Deficit/Hyperactivity Disorder: A Cluster Randomized Controlled Trial in Shanghai, China.

Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common chronic neurodevelopmental disorder in childhood, placing a heavy burden on family and society. The treatment of school-aged children with ADHD emphasizes multimodal interventions, but most current research focuses solely on parent training and family functioning. The aim of this study was to examine the effect of parent-teacher training on academic performance and parental anxiety. In an open-label cluster randomized controlled trial from January 2018 to January 2019, 14 primary schools in Shanghai were randomly assigned into the intervention group and the control group, and ADHD screening was conducted for students from grades one to five. Children in both groups received medication as prescribe by their pediatricians. In the intervention group, families and teachers also received parent-teacher training. The training included ADHD behavioral interventions for parents, as well as classroom management skills for teachers. This study screened 9,295 students, 99 children in the control group and 105 children in the intervention group were included in the analysis. The intervention group demonstrated significant improvement in ADHD symptoms and academic performance and decreases in parent stress compared to that in the control group (P < 0.05). This training improved the parents’ perception of ADHD knowledge, treatment options, and drug side effects awareness (P < 0.05). Our study aims to underscore the suitability of such programs in the local nuances of the Chinese context, show application feasibility to pediatricians and psychiatrists, and provide supporting evidence for their utilization within the country’s health and educational systems.

General practitioner prescribing trends among pediatric patients in the United Kingdom: 1998-2018.

To describe the prescribing trends of 17 therapeutic drug categories and the specific drug classes of systemic antibiotics, analgesics, and antidepressants in children and adolescents in the United Kingdom between 1998 and 2018. A population-based retrospective cohort study including children and adolescents aged 018 years. Overall and annual prescription rates per 10 000 person-years and corresponding 95% confidence intervals (CIs) were calculated. Rate ratios and 95% CIs were calculated to assess changes in prescription rates during the study period using Poisson regression. Among 4 075 527 children and adolescents during the study period from 1998 to 2018, the prescribing rates increased by 15% for attention deficit hyperactivity disorder drugs (rate ratio: 1.15, 95% CI: 1.12-1.18), 14% for anxiolytics and hypnotics (rate ratio: 1.14, 95% CI: 1.13-1.16), and 8% for drugs for gastroesophageal reflux disease (GERD) (rate ratio: 1.08, 95% CI: 1.07-1.09). Prescribing rates decreased by 6% for cough preparations (rate ratio: 0.94, 95% CI: 0.92-0.95) and by 3% for analgesics (rate ratio: 0.97, 95% CI: 0.96-0.99). No meaningful changes were observed for systemic antibiotics (rate ratio: 1.02, 95% CI: 0.99-1.04). Among specific drug classes, prescribing rates decreased for broad-spectrum penicillins and cephalosporins, and they increased for selective serotonin reuptake inhibitors, opioids, and drugs for migraine. Between 1998 and 2018, the prescribing of centrally acting drugs and drugs for GERD increased among pediatric patients, whereas prescribing of cough preparations and analgesics declined in this population.