Early childhood exposures to phthalates in association with attention-deficit/hyperactivity disorder behaviors in middle childhood and adolescence in the ReCHARGE study.

BACKGROUND: Early-life exposure to phthalates alters behaviors in animals. However, epidemiological evidence on childhood phthalate exposure and attention-deficit/hyperactivity disorder (ADHD) behaviors is limited. METHODS: This study included 243 children from the ReCHARGE (Revisiting Childhood Autism Risks from Genetics and Environment) study, who were previously classified as having autism spectrum disorder (ASD), developmental delay, other early concerns, and typical development in the CHARGE case-control study. Twenty phthalate metabolites were measured in spot urine samples collected from children aged 2-5 years. Parents reported on children's ADHD symptoms at ages 8-18 years using Conners-3 Parent Rating Scale. Covariate-adjusted negative binomial generalized linear models were used to investigate associations between individual phthalate metabolite concentrations and raw scores. Weighted quantile sum (WQS) regression with repeated holdout validation was used to examine mixture effects of phthalate metabolites on behavioral scores. Effect modification by child sex was evaluated. RESULTS: Among 12 phthalate metabolites detected in >75% of the samples, higher mono-2-heptyl phthalate (MHPP) was associated with higher scores on Inattentive (ß per doubling = 0.05, 95% confidence interval [CI]: 0.02, 0.08) and Hyperactive/Impulsive scales (ß = 0.04, 95% CI: 0.00, 0.07), especially among children with ASD. Higher mono-carboxy isooctyl phthalate (MCiOP) was associated with higher Hyperactivity/Impulsivity scores (ß = 0.07, 95% CI: -0.01, 0.15), especially among typically developing children. The associations of the molar sum of high molecular weight (HMW) phthalate metabolites and a phthalate metabolite mixture with Hyperactivity/Impulsivity scores were modified by sex, showing more pronounced adverse associations among females. CONCLUSION: Exposure to phthalates during early childhood may impact ADHD behaviors in middle childhood and adolescence, particularly among females. Although our findings may not be broadly generalizable due to the diverse diagnostic profiles within our study population, our robust findings on sex-specific associations warrant further investigations.

Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability.

Importance: Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. Objective: To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. Design, Setting, and Participants: This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. Exposure: Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. Main Outcomes and Measures: Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. Results: In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. Conclusions and Relevance: Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

Perinatal exposure to polychlorinated biphenyls (PCBs) and child neurodevelopment: A comprehensive systematic review of outcomes and methodological approaches.

BACKGROUND: Polychlorinated biphenyls (PCBs), extensively used in various products, prompt ongoing concern despite reduced exposure since the 1970s. This systematic review explores prenatal PCB and hydroxylated metabolites (OH-PCBs) exposure's association with child neurodevelopment. Encompassing cognitive, motor development, behavior, attention, ADHD, and ASD risks, it also evaluates diverse methodological approaches in studies. METHODS: PubMed, Embase, PsycINFO, and Web of Science databases were searched through August 23, 2023, by predefined search strings. Peer-reviewed studies published in English were included. The inclusion criteria were: (i) PCBs/OH-PCBs measured directly in maternal and cord blood, placenta or breast milk collected in the perinatal period; (ii) outcomes of cognitive development, motor development, attention, behavior, attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) among children≤18 years old. Quality assessment followed the National Heart, Lung, and Blood Institute's tool. RESULTS: Overall, 87 studies were included in this review. We found evidence for the association between perinatal PCB exposure and adverse cognitive development and attention issues in middle childhood. There appeared to be no or negligible link between perinatal PCB exposure and early childhood motor development or the risk of ADHD/ASD. There was an indication of a sex-specific association with worse cognition and attention scores among boys. Some individual studies suggested a possible association between prenatal exposure to OH-PCBs and neurodevelopmental outcomes. There was significant heterogeneity between the studies in exposure markers, exposure assessment timing, outcome assessment, and statistical analysis. CONCLUSIONS: Significant methodological, clinical and statistical heterogeneity existed in the included studies. Adverse effects on cognitive development and attention were observed in middle childhood. Little or no apparent link on both motor development and risk of ADHD/ASD was observed in early childhood. Inconclusive evidence prevailed regarding other neurodevelopmental aspects due to limited studies. Future research could further explore sex-specific associations and evaluate associations at lower exposure levels post-PCB ban in the US. It should also consider OH-PCB metabolites, co-pollutants, mixtures, and their potential interactions.

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Treatments for ADHD in Children and Adolescents: A Systematic Review.

CONTEXT: Effective treatment of attention-deficit/hyperactivity disorder (ADHD) is essential to improving youth outcomes. OBJECTIVES: This systematic review provides an overview of the available treatment options. DATA SOURCES: We identified controlled treatment evaluations in 12 databases published from 1980 to June 2023; treatments were not restricted by intervention content. STUDY SELECTION: Studies in children and adolescents with clinically diagnosed ADHD, reporting patient health and psychosocial outcomes, were eligible. Publications were screened by trained reviewers, supported by machine learning. DATA EXTRACTION: Data were abstracted and critically appraised by 1 reviewer and checked by a methodologist. Data were pooled using random-effects models. Strength of evidence and applicability assessments followed Evidence-based Practice Center standards. RESULTS: In total, 312 studies reported in 540 publications were included. We grouped evidence for medication, psychosocial interventions, parent support, nutrition and supplements, neurofeedback, neurostimulation, physical exercise, complementary medicine, school interventions, and provider approaches. Several treatments improved ADHD symptoms. Medications had the strongest evidence base for improving outcomes, including disruptive behaviors and broadband measures, but were associated with adverse events. LIMITATIONS: We found limited evidence of studies comparing alternative treatments directly and indirect analyses identified few systematic differences across stimulants and nonstimulants. Identified combination of medication with youth-directed psychosocial interventions did not systematically produce better results than monotherapy, though few combinations have been evaluated. CONCLUSIONS: A growing number of treatments are available that improve ADHD symptoms and other outcomes, in particular for school-aged youth. Medication therapies remain important treatment options but are associated with adverse events.

Early childhood exposure to environmental phenols and parabens, phthalates, organophosphate pesticides, and trace elements in association with attention deficit hyperactivity disorder (ADHD) symptoms in the CHARGE study.

BACKGROUND: A growing body of literature investigated childhood exposure to environmental chemicals in association with attention-deficit/hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay (DD), and typical development (TD). METHODS: A total of 549 children aged 2-5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study were administered the Aberrant Behavior Checklist (ABC). This study focused on the ADHD/noncompliance subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in > 70% samples were used to investigate their associations with ADHD symptoms. Negative binomial regression was used for single-chemical analysis, and weighted quantile sum regression with repeated holdout validation was applied for mixture analysis for each chemical class and all chemicals. The mixture analyses were further stratified by diagnostic group. RESULTS: A phthalate metabolite mixture was associated with higher ADHD/noncompliance scores (median count ratio [CR] = 1.10; 2.5th, 97.5th percentile: 1.00, 1.21), especially hyperactivity/impulsivity (median CR = 1.09; 2.5th, 97.5th percentile: 1.00, 1.25). The possible contributors to these mixture effects were di-2-ethylhexyl phthalate (DEHP) metabolites and mono-2-heptyl phthalate (MHPP). These associations were likely driven by children with ASD as these were observed among children with ASD, but not among TD or those with DD. Additionally, among children with ASD, a mixture of all chemicals was associated with ADHD/noncompliance and hyperactivity/impulsivity, and possible contributors were 3,4-dihydroxy benzoic acid, DEHP metabolites, MHPP, mono-n-butyl phthalate, and cadmium. CONCLUSIONS: Early childhood exposure to a phthalate mixture was associated with ADHD symptoms, particularly among children with ASD. While the diverse diagnostic profiles limited generalizability, our findings suggest a potential link between phthalate exposure and the comorbidity of ASD and ADHD.

A Randomized, Phase 3, Double-Blind, Crossover Comparison of Multilayer, Extended-Release Methylphenidate (PRC-063), and Lisdexamfetamine in the Driving Performance of Young Adults With ADHD.

OBJECTIVE: To compare PRC-063 (multilayer-release methylphenidate) and lisdexamfetamine dimesylate (LDX) on the driving performance of young adults with attention deficit hyperactivity disorder (ADHD) in a randomized, double-blind, crossover study. METHOD: Following up to 21 days of each treatment in each treatment course (PRC-063/LDX or LDX/PRC-063), subjects completed a 15-hour driving simulator laboratory assessment. The primary outcome measure was the Tactical Driving Quotient (TDQ) and the Clinical Global Impressions-Improvement (CGI-I) scale was a secondary outcome measure. RESULTS: Forty-four subjects completed the study. PRC-063 and LDX had equivalent effects on driving performance through a 15-hour time period (least square mean difference -0.3 [standard error 1.08], 95% confidence interval [-2.4, 1.8], p = .793). Consistent improvement in CGI-I was observed. The incidence of treatment-emergent adverse events was similar for each treatment sequence. CONCLUSIONS: PRC-063 and LDX had comparable effects on driving performance, from 1 through 15 hours, the last time point measured.

Prenatal caffeine consumption and neurobehavioral disorders - A systematic review.

Studies have suggested associations between gestational exposure to caffeine and adverse outcomes, however the evidence is still limited. Therefore, a systematic review was conducted to investigate the association between prenatal caffeine exposure and neurobehavioral disorders. The MEDLINE (PubMed), EMBASE, Scopus, Web of Science, and LILACS databases were searched. Observational studies involving women with documented caffeine consumption during pregnancy were eligible for inclusion. The outcomes evaluated were behavioral and intellectual development, Attention Deficit Hyperactivity Disorder, and related behaviors. The data were analyzed by qualitative synthesis. The ROBINS-I tool was employed to assess the risk of bias, and the certainty of evidence was evaluated using GRADE (PROSPERO: CRD42023421164). The search yielded fourteen studies that met the inclusion/exclusion criteria. The sample size among pregnant women ranged from 173 to 64,189, and among children ranged from 88 to 49,190. Maternal caffeine consumption during pregnancy ranged from 0 to 1000 mg/day, with the highest levels observed during mid-pregnancy. Seven studies indicated a potential association between prenatal caffeine exposure and neurobehavioral/neurodevelopment deficits, one study showed that prenatal caffeine exposure improved peer problems, and six studies did not show a significant effect of prenatal caffeine consumption on neurobehavioral disorders. The included studies were classified as moderate for the risk of bias and with very low certainty of evidence. Thus, the evidence is insufficient to confirm with certainty that the prenatal caffeine exposure leads to neurobehavioral disorders. Studies heterogenicity, as well as their variable quality and the presence of several confounding factors, generate uncertainty.

Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD.

Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (GD 3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1-21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning.

Sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood.

Externalizing disorders, such as attention-deficit/hyperactivity disorder (ADHD), account for the majority of the child/adolescent referrals to mental health services and increase risk for later-life psychopathology. Although the expression of externalizing disorders is more common among males, few studies have addressed how sex modifies associations between metal exposure and adolescent externalizing symptoms. This study aimed to examine sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood. Among 150 adolescents and young adults (55% female, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study in Brescia, Italy, we measured five metals (manganese (Mn), lead (Pb), copper (Cu), chromium (Cr), nickel (Ni)) in four biological matrices (blood, urine, hair, and saliva). Externalizing symptoms were assessed using the Achenbach System of Empirically Based Assessment (ASEBA) Youth Self-Report (YSR) or Adult Self Report (ASR). Using generalized weighted quantile sum (WQS) regression, we investigated the moderating effect of sex (i.e., assigned at birth) on associations between the joint effect of exposure to the metal mixture and externalizing symptoms, adjusting for age and socioeconomic status. We observed that metal mixture exposure was differentially associated with aggressive behavior in males compared to females (ß = -0.058, 95% CI [-0.126, -0.009]). In males, exposure was significantly associated with more externalizing problems, and aggressive and intrusive behaviors, driven by Pb, Cu and Cr. In females, exposure was not significantly associated with any externalizing symptoms. These findings suggest that the effect of metal exposure on externalizing symptoms differs in magnitude between the sexes, with males being more vulnerable to increased externalizing symptoms following metal exposure. Furthermore, our findings support the hypothesis that sex-specific vulnerabilities to mixed metal exposure during adolescence/young adulthood may play a role in sex disparities observed in mental health disorders, particularly those characterized by externalizing symptoms.

An Industry-Relevant Metal Mixture, Iron Status, and Reported Attention-Related Behaviors in Italian Adolescents.

BACKGROUND: Exposure to environmental metals has been consistently associated with attention and behavioral deficits in children, and these associations may be modified by coexposure to other metals or iron (Fe) status. However, few studies have investigated Fe status as a modifier of a metal mixture, particularly with respect to attention-related behaviors. METHODS: We used cross-sectional data from the Public Health Impact of Metals Exposure study, which included 707 adolescents (10-14 years of age) from Brescia, Italy. Manganese, chromium, and copper were quantified in hair samples, and lead was quantified in whole blood, using inductively coupled plasma mass spectrometry. Concentrations of Fe status markers (ferritin, hemoglobin, transferrin) were measured using immunoassays or luminescence assays. Attention-related behaviors were assessed using the Conners Rating Scales Self-Report Scale-Long Form, Parent Rating Scales Revised-Short Form, and Teacher Rating Scales Revised-Short Form. We employed Bayesian kernel machine regression to examine associations of the metal mixture with these outcomes and evaluate Fe status as a modifier. RESULTS: Higher concentrations of the metals and ferritin were jointly associated with worse self-reported attention-related behaviors: metals and ferritin set to their 90th percentiles were associated with 3.0% [ß=0.03; 95% credible interval (CrI): -0.01, 0.06], 4.1% (ß=0.04; 95% CrI: 0.00, 0.08), and 4.1% (ß=0.04; 95% CrI: 0.00, 0.08) higher T-scores for self-reported attention deficit/hyperactivity disorder (ADHD) index, inattention, and hyperactivity, respectively, compared with when metals and ferritin were set to their 50th percentiles. These associations were driven by hair manganese, which exhibited nonlinear associations with all self-reported scales. There was no evidence that Fe status modified the neurotoxicity of the metal mixture. The metal mixture was not materially associated with any parent-reported or teacher-reported scale. CONCLUSIONS: The overall metal mixture, driven by manganese, was adversely associated with self-reported attention-related behavior. These findings suggest that exposure to multiple environmental metals impacts adolescent neurodevelopment, which has significant public health implications. https://doi.org/10.1289/EHP12988.

Methylphenidate and Sleep Difficulties in Children and Adolescents With ADHD: Results From the 2-Year Naturalistic Pharmacovigilance ADDUCE Study.

OBJECTIVE: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. METHODS: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children's-Sleep-Habits-Questionnaire (CSHQ). RESULTS: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. CONCLUSION: Our findings support that sleep-problems are common in ADHD, but don't suggest significant negative long-term effects of MPH on sleep.

QT-Interval Prolongation Associated with Supratherapeutic Guanfacine Concentration: A Case Report.

INTRODUCTION: Guanfacine, an alpha-2 adrenergic agonist, is used to treat attention deficit hyperactivity disorder (ADHD). Although cardiovascular effects including hypotension and bradycardia are common adverse effects of guanfacine, the effect of guanfacine on QT intervals remains unclear. The association between the serum concentration of guanfacine and its toxicity has also not been fully investigated. CASE REPORT: This is a case of a 21-year-old woman with ADHD who developed repeated presyncope 1 day before admission. She was taking 3 mg of extended-release guanfacine and 50 mg of sertraline. On admission, she had bradycardia and hypotension. An electrocardiogram (ECG) showed a QT interval of 0.68 s and a QTcF interval of 0.648 s. The QT intervals were manually measured and corrected by the Fridericia formula (QTcF = QT/RR1/3). Although she denied taking an overdose of guanfacine and other drugs, we suspected guanfacine toxicity. The serum guanfacine concentration was 13.0 ng/mL on admission and decreased to 3.2 ng/mL on day 1 and 0.4 ng/mL on day 2. Changes in QTcF intervals and her vital signs correlated with serum guanfacine concentrations. CONCLUSION: Supratherapeutic serum guanfacine concentrations may induce QT prolongation.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children.

Importance: Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. Objective: To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. Design, Setting, and Participants: This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Exposures: Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Main Outcomes and Measures: Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. Results: The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. Conclusions and Relevance: The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.

Methylphenidate alleviates cognitive dysfunction caused by early manganese exposure: Role of catecholaminergic receptors.

Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same dysfunctions in a rat model. Methylphenidate (MPH) lessens impairments in attention, impulse control, and psychomotor function in children, but it is unknown whether MPH ameliorates these dysfunctions when induced by developmental Mn exposure. Here, we sought to (1) determine whether oral MPH treatment ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure, and (2) elucidate the mechanism(s) of Mn neurotoxicity and MPH effectiveness. Rats were given 50 mg Mn/kg/d orally over PND 1-21 and assessed as adults in a series of attention, impulse control and sensorimotor tasks during oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d). Subsequently, selective catecholaminergic receptor antagonists were administered to gain insight into the mechanism(s) of action of Mn and MPH. Developmental Mn exposure caused persistent attention and sensorimotor impairments. MPH treatment at 0.5 mg/kg/d completely ameliorated the Mn attentional dysfunction, whereas the sensorimotor deficits were ameliorated by the 3.0 mg/kg/d MPH dose. Notably, the MPH benefit on attention was only apparent after prolonged treatment, while MPH efficacy for the sensorimotor deficits emerged early in treatment. Selectively antagonizing D1, D2, or α2A receptors had no effect on the Mn-induced attentional dysfunction or MPH efficacy in this domain. However, antagonism of D2R attenuated the Mn sensorimotor deficits, whereas the efficacy of MPH to ameliorate those deficits was diminished by D1R antagonism. These findings demonstrate that MPH is effective in alleviating the lasting attentional and sensorimotor dysfunction caused by developmental Mn exposure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and psychomotor deficits in children is often unknown, these findings have implications for the treatment of environmentally induced attentional and psychomotor dysfunction in children more broadly.

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

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

Susceptible windows of prenatal and postnatal fine particulate matter exposures and attention-deficit hyperactivity disorder symptoms in early childhood.

Few prior studies have explored windows of susceptibility to fine particulate matter (PM2.5) in both the prenatal and postnatal periods and children's attention-deficit/hyperactivity disorder (ADHD) symptoms. We analyzed data from 1416 mother-child pairs from the Spanish INMA (INfancia y Medio Ambiente) Study (2003-2008). Around 5 years of age, teachers reported the number of ADHD symptoms (i.e., inattention, hyperactivity/impulsivity) using the ADHD Diagnostic and Statistical Manual of Mental Disorders. Around 7 years of age, parents completed the Conners' Parent Rating Scales, from which we evaluated the ADHD index, cognitive problems/inattention, hyperactivity, and oppositional subscales, reported as age- and sex-standardized T-scores. Daily residential PM2.5 exposures were estimated using a two-stage random forest model with temporal back-extrapolation and averaged over 1-week periods in the prenatal period and 4-week periods in the postnatal period. We applied distributed lag non-linear models within the Bayesian hierarchical model framework to identify susceptible windows of prenatal or postnatal exposure to PM2.5 (per 5-µg/m3) for ADHD symptoms. Models were adjusted for relevant covariates, and cumulative effects were reported by aggregating risk ratios (RRcum) or effect estimates (ßcum) across adjacent susceptible windows. A similar susceptible period of exposure to PM2.5 (1.2-2.9 and 0.9-2.7 years of age, respectively) was identified for hyperactivity/impulsivity symptoms assessed ~5 years (RRcum = 2.72, 95% credible interval [CrI] = 1.98, 3.74) and increased hyperactivity subscale ~7 years (ßcum = 3.70, 95% CrI = 2.36, 5.03). We observed a susceptibility period to PM2.5 on risk of hyperactivity/impulsivity symptoms ~5 years in gestational weeks 16-22 (RRcum = 1.36, 95% CrI = 1.22, 1.52). No associations between PM2.5 exposure and other ADHD symptoms were observed. We report consistent evidence of toddlerhood as a susceptible window of PM2.5 exposure for hyperactivity in young children. Although mid-pregnancy was identified as a susceptible period of exposure on hyperactivity symptoms in preschool-aged children, this association was not observed at the time children were school-aged.

Exposure to chlorpyrifos and pyrethroid insecticides and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in preschool children from the Odense Child Cohort.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood psychiatric disorder with severe and lifelong impact on mental health and socioeconomic achievements. Environmental factors may play a role in the increasing incidens rates. Previous studies on associations between prenatal and childhood exposure to organophosphate and pyrethroid insecticides and ADHD symptoms have yielded mixed findings. OBJECTIVES: To investigate associations between prenatal and childhood exposure to chlorpyrifos and pyrethroids and ADHD symptoms in 5-year-old children from the Odense Child Cohort. METHODS: Spot urine samples from pregnant women in gestational week 28 (n = 614) and offspring at 5 years of age (n = 814) were collected and analyzed for the specific metabolite of chlorpyrifos, TCPY (3,5,6-trichloro-2-pyridinol), as well as the generic pyrethroid metabolite, 3-PBA (3-phenoxybenzoic acid). Offspring ADHD symptoms were assessed at age 5 years using the parent reported "ADHD scale" from the "Child Behavior Checklist 1½-5" (n = 1114). Associations between insecticide exposure variables and an ADHD score ≥90th percentile were analyzed using logistic regression for all children and stratified by sex. RESULTS: Most pregnant women had detectable concentrations of 3-PBA (93%) and TCPY (91%) with median concentrations of 0.20 µg/L and 1.62 µg/L, respectively. In children, 3-PBA and TCPY concentrations were detectable in 88% and 82% of the samples, and the median concentrations were 0.17 and 1.16 µg/L. No statistically significant associations were observed between insecticide metabolites and an ADHD score ≥90th percentile at age 5. CONCLUSION: In this relatively large Danish birth cohort study with mainly low dietary insecticide exposure, we found no statistically significant associations between prenatal or childhood exposure to chlorpyrifos or pyrethroids, and excess ADHD-symptom load, in 5-year-old children. Prospective studies with multiple urine samples across vulnerable windows of neurodevelopment is warranted to improve assessment of safe exposure levels, which is particularly relevant for pyrethroids, since their use is increasing.

A Systematic Review and Meta-analysis of Chemical Exposures and Attention-Deficit/Hyperactivity Disorder in Children.

Exposure to certain chemicals prenatally and in childhood can impact development and may increase risk for attention-deficit/hyperactivity disorder (ADHD). Leveraging a larger set of literature searches conducted to synthesize results from longitudinal studies of potentially modifiable risk factors for childhood ADHD, we present meta-analytic results from 66 studies that examined the associations between early chemical exposures and later ADHD diagnosis or symptoms. Studies were eligible for inclusion if the chemical exposure occurred at least 6 months prior to measurement of ADHD diagnosis or symptomatology. Included papers were published between 1975 and 2019 on exposure to anesthetics (n = 5), cadmium (n = 3), hexachlorobenzene (n = 4), lead (n = 22), mercury (n = 12), organophosphates (n = 7), and polychlorinated biphenyls (n = 13). Analyses are presented for each chemical exposure by type of ADHD outcome reported (categorical vs. continuous), type of ADHD measurement (overall measures of ADHD, ADHD symptoms only, ADHD diagnosis only, inattention only, hyperactivity/impulsivity only), and timing of exposure (prenatal vs. childhood vs. cumulative), whenever at least 3 relevant effect sizes were available. Childhood lead exposure was positively associated with ADHD diagnosis and symptoms in all analyses except for the prenatal analyses (odds ratios (ORs) ranging from 1.60 to 2.62, correlation coefficients (CCs) ranging from 0.14 to 0.16). Other statistically significant associations were limited to organophosphates (CC = 0.11, 95% confidence interval (CI): 0.03-0.19 for continuous measures of ADHD outcomes overall), polychlorinated biphenyls (CC = 0.08, 95% CI: 0.02-0.14 for continuous measures of inattention as the outcome), and both prenatal and childhood mercury exposure (CC = 0.02, 95% CI: 0.00-0.04 for continuous measures of ADHD outcomes overall for either exposure window). Our findings provide further support for negative impacts of prenatal and/or childhood exposure to certain chemicals and raise the possibility that primary prevention and targeted screening could prevent or mitigate ADHD symptomatology. Furthermore, these findings support the need for regular review of regulations as our scientific understanding of the risks posed by these chemicals evolves.

Stimulant Treatment and Potential Adverse Outcomes in Pediatric Populations With Bipolar Disorder: A Systematic Review of the Literature.

OBJECTIVE: To explore outcomes of stimulant treatment for ADHD in pediatric populations with particular attention to bipolar disorder (BPD). METHOD: We conducted a literature search of PubMed articles published prior to August 25, 2022 that focused on BPD, mania, and psychosis prior to, or as result of, stimulant treatment. We excluded studies: (1) unrelated to stimulants, (2) general stimulant research, (3) articles older than 40 years, (4) study protocols, or (5) case reports. RESULTS: A total of 11 articles met all inclusion/exclusion criteria. Some reports found stimulant treatment safe and well-tolerated in children with comorbid BPD and ADHD. Others found evidence of treatment-emergent mania (TEM), discontinuation, and other adverse events with stimulant treatment. CONCLUSION: Poor outcomes associated with stimulant treatment in pediatric populations with BPD necessitate work to identify patients at risk of serious stimulant-related adverse events. Our results were limited by automated search filters and a pediatric, primarily male sample.