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Cannabis use during pregnancy is increasing; the study of adverse outcomes in cannabis-exposed pregnancies is therefore important. Previous articles in this series described increased risks of maternal adverse outcomes, fetal adverse outcomes, birth defects in newborns, and autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in childhood. This article examines neuropsychiatric adverse outcomes in offspring gestationally exposed to cannabis. Currently available research suggests that prenatal cannabis exposure is associated with increased risks of ASD, ADHD, psychosis proneness, psychotic like experiences, internalizing problems, externalizing problems, attention problems, thought-related problems, social problems, impaired executive function, and observed aggression. There is insufficient study of prenatal cannabis exposure and offspring IQ. Shortcomings in the existing literature are discussed; as examples, many outcomes were determined by screening rather than by formal assessment, prenatal cannabis exposure was ascertained retrospectively in some studies, childhood adverse experiences and exposures were seldom included as covariates, and details about cannabis use (source, potency, frequency, reasons) were unavailable. Curiously, the findings of adverse outcomes were inconsistent, and the effect sizes were small. Possible explanations are that women who use cannabis during pregnancy may not admit it and their pregnancy outcomes may then be misclassified into the control group, assessment of outcomes at too young an age or with insufficient accuracy may blur differences between exposed and unexposed groups, and adjustment for covariates may mask the full effects of cannabis. A last observation is that the studies reviewed were based on exposures that occurred decades ago. Given the increasing potency of currently available cannabis and the limitations of the existing research, it is possible that the available findings underestimate the breadth and severity of the risks. Cannabis is not a necessary substance for use during pregnancy, and so women who consider it safe might do well to guard against complacency and unnecessary exposure., (© Copyright 2025 Physicians Postgraduate Press, Inc.)

Up to 10% of women may use cannabis during pregnancy; this is of concern because constituents of cannabis cross the placental barrier and potentially influence neurodevelopment by acting on cannabinoid receptors in the developing fetal brain. In this context, a recent meta analysis of 13 observational studies found that gestational exposure to cannabis was associated with a small increase in the risk of autism spectrum disorder (ASD; relative risk [RR], 1.30) and with an even smaller increase in the risk of attention deficit/hyperactivity disorder (ADHD; RR, 1.13); the latter finding was probably supported by publication bias. In this meta-analysis, 4 studies provided information on ASD (pooled N = 178,565) and 10 on ADHD (pooled N = 203,783). In a large (n = 222,534) retrospectively ascertained cohort study published after the meta-analysis, cannabis use disorder (CUD) recorded before pregnancy, during pregnancy, and during pregnancy plus the year after delivery were associated with closely similar increased risks of ASD (RRs, 3.02-3.21). The risks were smaller in smokers (RRs, 1.74-1.87) than in nonsmokers (RRs, 4.55-4.83) but differed little between male (RRs, 3.01-3.06) and female (RRs, 2.71-2.85) offspring. Although the cohort study had many strengths, its limitations permitted only the conclusion that peri-pregnancy exposure to CUD is associated with a large increase in the risk of ASD in offspring; it remained possible that much of the risk was driven by genetic, environmental, or behavioral variables. The field is nascent; the total number of cannabis exposed pregnancies (with ASD and ADHD as the outcomes) in world literature is small. However, cannabis use during pregnancy is, at the very least, a clear marker for adverse neurodevelopmental outcomes, besides the adverse maternal, fetal, and neonatal outcomes identified in other studies. Healthcare providers who manage women who use cannabis during pregnancy need to be aware of these adverse outcomes., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Numerous studies have investigated environmental risk factors in ADHD, and Bisphenol A (BPA), an endocrine disruptor, is suspected by several reviews. However, the quality of the studies has never been carefully assessed, leading us to rigorously examine associations between BPA exposure and ADHD and associated symptoms in children. Using PRISMA criteria, we conducted a systematic review on the MEDLINE/PubMed, Web of Science, EBSCOhost, PsycINFO, PsycARTICLES and Cochrane databases. We used the ROBINS-E tool to assess the quality, and the GRADE Approach. This study was registered with PROSPERO, CRD42023377150. Out of 10446 screened articles, 46 were included. Unlike pre-existing reviews, most studies failed to find clear links with ADHD or associated symptoms, with a high risk of bias and a very low level of certainty. Our systematic review reveals insufficient evidence regarding the impact of BPA on ADHD, despite some behavioral results that cannot be generalized. Future studies will require improved consideration of confounding factors and more precise sampling methods. This study did not receive specific funding., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate the association between cannabis use during pregnancy and the risk for long-term neuropsychiatric pathology in the offspring., Data Sources: MEDLINE, EMBASE, and Cochrane library databases were systematically searched until January 22, 2024, with no language or date restrictions., Study Eligibility Criteria: Studies were eligible for inclusion if they reported quantitative data on any long-term neuropsychiatric outcome in offspring whose mothers used cannabis during pregnancy for medical or recreational use, by any route and at any trimester, in comparison to offspring of women who abstained from cannabis use during pregnancy. All observational study designs were included in the analysis., Study Appraisal and Synthesis Methods: A systematic review and meta-analysis were performed according to the PRISMA and MOOSE guidelines. The data was extracted independently by 2 reviewers. The following offspring outcomes were of interest: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, anxiety, psychotic disorders, as well as cannabis and other substance use. Odds ratios (OR) and 95% confidence intervals (CI) were pooled for each neuropsychiatric outcome in the offspring of women exposed to cannabis during pregnancy compared with nonexposed. Data were pooled using random-effects models., Results: Eighteen eligible observational studies were included in the systematic review, and 17 were included in the final quantitative analysis, representing 534,445 participants. After adjusting for confounders, the pooled OR for ADHD was 1.13 (95% CI 1.01-1.26); for ASD, the pooled OR was 1.04 (95% CI 0.74-1.46); for psychotic symptoms, the pooled OR was 1.29 (95% CI 0.97-1.72); for anxiety, the pooled OR was 1.34 (95% CI 0.79-2.29); for depression, the pooled OR was 0.72 (95% CI 0.11-4.57); and for offspring's cannabis use, the pooled OR was 1.20 (95% CI 1.01-1.42)., Conclusion: Prenatal cannabis exposure is not associated with an increased risk of ASD, psychotic symptoms, anxiety, or depression in offspring. However, it may slightly elevate the risk of ADHD and predispose offspring to cannabis consumption. Despite these findings, caution is warranted regarding cannabis use during pregnancy. Further research is imperative, especially given the increasing potency of cannabis in recent years., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Prenatal antidepressant exposure has been reported to be associated with adverse neurodevelopmental outcomes, yet studies considering confounding factors in Asian populations are lacking. This study utilized a nationwide data base in Taiwan, enrolling all liveborn children registered in the National Health Insurance system between 2004 and 2016. Subjects were divided into two groups: antidepressant-exposed (n = 55,707)) and antidepressant-unexposed group (n = 2,245,689). The effect of antidepressant exposure during different trimesters on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) was examined. Sibling controls and parallel comparisons by paternal exposure status were treated as negative controls. Additional sensitivity analyses were conducted to examine the effects of antidepressant exposure before and after pregnancy. Prenatal antidepressant exposure was associated with increased risks of ASD and ADHD in population-wide and adjusted analysis. However when comparing antidepressant-exposed children with their unexposed siblings, no differences were found for ASD (Hazard ratio [HR]: 1.04, 95% confidence interval [CI] 0.76-1.42 in first trimester; HR: 0.96, 95% CI 0.62-1.50 in second trimester; HR: 0.69, 95% CI 0.32-1.48 in third trimester) and ADHD (HR: 0.98, 95%CI 0.84-1.15 in first trimester; HR: 0.91, 95% CI 0.73-1.14 in second trimester; HR: 0.79, 95% CI 0.54-1.16 in third trimester). Increased risks for ASD and ADHD were also noted in paternal control, before and after pregnancy analyses. These results imply that the association between prenatal antidepressant exposure and ASD and ADHD is not contributed to by an intrauterine medication effect but more likely to be accounted for by maternal depression, genetic, and potential environmental factors., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests or financial support to disclose. Ethical standards: This study was approved by the Research Ethics Committee of China Medical University and Hospital (approval number: CMUH108-REC1-142) and was executed as per the Declaration of Helsinki. The requirement for informed consent was waived., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Chronic methamphetamine (METH) use, a prevalent psychostimulant, is known to impair attention, yet the cellular mechanisms driving these deficits remain poorly understood. Here, we employed a rat model of repeated passive METH injections and evaluated attentional performance using the 5-choice serial reaction time task (5-CSRTT). Using single-nucleus RNA sequencing, immunofluorescence and in situ hybridization, we characterized the response of neurons in the reticulotegmental nucleus (RtTg) to METH exposure. Our results indicate that METH exposure disrupts RtTg neurons at the transcriptional level and results in an increased activation ratio of RtTg under 5-CSRTT conditions. Crucially, chemogenetic inactivation of these neurons or RtTg lesion attenuated METH-induced attention deficits, whereas their activation reproduced the deficits. These findings underscore the critical role of RtTg neurons in mediating METH-induced attention deficits, positioning RtTg as a promising therapeutic target for the treatment of attention deficits linked to chronic METH use., Competing Interests: Declarations. Ethics approval and consent to participate: Animal ethics in this paper were approved by the Institutional Animal Care and Use Committee of the Center for Excellence in Brain Science and Intelligent Technology of the Chinese Academy of Sciences. Academy of Sciences in accordance with national guidelines. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Our previous studies have revealed a correlation between urinary phthalates (PAE) metabolites and parabens and PM 2.5 exposure and susceptibility to attention-deficit/hyperactivity disorder (ADHD) in school-age children. Our goal was to examine the relationships between urinary organophosphate flame retardants (OPFRs) and their metabolites and the susceptibility to ADHD in the same cohort of children. We recruited 186 school children, including 132 with ADHD and 54 normal controls, living in southern Taiwan to investigate five OPFRs (1,3-dichloro-2-propyl phosphate (TDCPP), tri-n-butyl phosphate (TnBP), tris (2-chloroethyl) phosphate (TCEP), tris(2-butoxyethyl) phosphate (TBEP), and triphenyl phosphate (TPHP)) and five OPFR metabolites (bis(1,3-dichloro-2-propyl) phosphate (BDCPP), di-n-butyl phosphate (DNBP), bis(2-chloroethyl) hydrogen phosphate (BCEP), di-(2-butoxyethyl) phosphate (DBEP), and diphenyl phosphate (DPHP)) in urine. ADHD patients' behavioral symptoms and neuropsychological function were assessed using the Swanson, Nolan, and Pelham Version IV Scale (SNAP-IV) and the Conners' Continuous Performance Test 3rd Edition (Conners CPT3), respectively. BCEP was predominant among urinary OPFRs and the metabolites in both the ADHD and control groups. ADHD children had significantly higher levels of urinary BDCPP, BCEP, DBEP, DPHP, TCEP, TBEP, TNBP, TPHP, and Σ 10 OPFR compared to the controls. After controlling for age, gender, body mass index, PM 2.5 exposure scenarios, and urinary phthalate metabolites, parabens, bisphenol-A and creatinine, levels of urinary BDCPP, TDCPP, and TBEP in ADHD children showed significant and dose-dependent effects on core behavioral symptoms of inattention. DNBP levels were positively correlated with neuropsychological deficits (CPT detectability, omission, and commission), while urinary DPHP in ADHD children were negatively related to CPT detectability and commission. Hyperactivity and impulsivity were not correlated with urinary OPFRs and their metabolites in ADHD children. In conclusion, the ADHD symptom of inattention and CPT performance may be closely associated with certain urinary OPFRs and their metabolites, independent of urinary PAE metabolites, parabens, and bisphenol-A in school-age-ADHD children., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: How-Ran Chao reports financial support was provided by National Science and Technology Council. How-Ran Chao reports a relationship with National Science and Technology Council that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Environmental lead exposure has been a much-discussed risk factor for the development of ADHD for decades. However, due to methodological shortcomings, the existing research on this topic is highly inconsistent. We will attempt to clarify this question by performing a meta-analysis based on a systematic literature search until February 2024 including different databases such as Pubmed and Google Scholar. The effects of environmental lead exposure were synthesized by odds ratios. A random effects model was deployed with a Paule-Mandel estimator using Hedges' invariance weighting. In addition, we carried out sensitivity analyses to examine the robustness of effects, including the detection of outliers, publication bias, p-hacking and moderating variables. In total, 14 studies with 14 effect sizes were included which had investigated the effects of lead exposure on the development of ADHD. The analyses were based on a final sample size of N = 7618 with n = 2554 ADHD cases (33,53 %) and n = 5064 healthy controls (66.47 %). Our results show that lead exposure was significantly associated with a higher risk of ADHD development. Regression analyses demonstrated that increased age of participants and increased lead significantly enhanced the risk of ADHD. Summing up we present novel results concerning the relationship between environmental lead exposure and the development of ADHD, while discussing underlying pathomechanisms as well as limitations. Finally, we provide recommendations for future studies and public health policies., Competing Interests: Declaration of competing interest The authors have no financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pesticides may impact children's neurodevelopment. As children's metabolic function and neural plasticity change throughout their growth and development, the effects of pesticide exposure may also vary., Objectives: We aimed to identify the trajectories of combined pesticide exposure during childhood, and to examine the associations of the exposure trajectories with children's neurobehavior at the age of 10., Methods: We involved repeated measurements of three pesticide metabolites [Pentachlorophenol (PCP), 3,5,6-Trichloro-2-pyridinol (TCPy), and Carbofuran phenol (CFP)], in urine samples collected from children in a cohort study at ages 1, 2, 3, 6, 7, 8, 9, and 10 years. The group-based multi-trajectory model (GBMT) and latent class analysis (LCA) were separately utilized to describe the distinct trajectories and patterns of pesticide mixture exposure during childhood. Meanwhile, the Strengths and Difficulties Questionnaire (SDQ) and attention deficit hyperactivity disorder (ADHD) Criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) list were applied to assess behavioral disorders in children. The associations between exposure trajectories and behavioral problem scores were then examined., Results: The GBMT model delineated three distinct trajectories of combined pesticide exposure among children: consistently low, higher levels in early childhood transitioning to lower levels during pre-school age, and lower levels in early childhood followed by higher levels in the middle childhood. The LCA model identified three similar longitudinal exposure patterns. Further, the children in the second trajectory group identified by GBMT, characterized by higher early childhood exposure levels, exhibited significantly elevated hyperactivity/inattention scores of the SDQ compared to the other two groups (β = 0.46, 95 %CI: 0.11, 0.81; β = 0.44, 95 %CI: 0.02, 0.86)., Conclusions: Our study revealed that exposure to pesticides during early childhood (especially before the age of two), rather than other age periods, was linked to hyperactivity/inattention problems in children aged 10 years. We also provided a novel perspective on characterizing the fluctuation in repeated measurements of multiple environmental chemicals and identifying the potential critical windows., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Human biomonitoring (HBM) data indicate that exposure to pyrethroids is widespread in Europe, with significantly higher exposure observed in children compared to adults. Epidemiological, toxicological, and mechanistic studies raise concerns for potential human health effects, particularly, behavioral effects such as attention deficit hyperactivity disorder (ADHD) in children at low levels of exposure. Based on an exposure-response function from a single European study and on available quality-assured and harmonized HBM data collected in France, Germany, Iceland, Switzerland, and Israel, a preliminary estimate of the environmental burden of disease for ADHD associated with pyrethroid exposure was made for individuals aged 0-19 years. The estimated annual number of prevalence-based disability-adjusted life years (DALYs) per million inhabitants were 27 DALYs for Israel, 21 DALYs for France, 12 DALYs for both Switzerland and Iceland, and 3 DALYs for Germany; while the annual ADHD cases per million inhabitants attributable to pyrethroids were 2189 for Israel, 1710 for France, 969 for Iceland, 944 for Switzerland, and 209 for Germany. Direct health costs related to ADHD ranged between 0.3 and 2.5 million EUR yearly per million inhabitants for the five countries. Additionally, a substantial number of ADHD cases, on average 18%, were associated with pyrethroid exposure. Yet, these figures should be interpreted with caution given the uncertainty of the estimation. A sensitivity analysis showed that by applying a different exposure-response function from outside the EU, the population attributable fraction decreased from an average of 18 to 7%. To ensure more robust disease burden estimates and adequate follow-up of policy measures, more HBM studies are needed, along with increased efforts to harmonize the design of epidemiological studies upfront to guarantee meta-analysis of exposure-response functions. This is particularly important for pyrethroids as evidence of potential adverse health effects is continuously emerging., (© 2024. The Author(s).)

Background: The associations between prenatal antibiotics exposure and attention-deficit/hyperactivity disorder (ADHD) in preschoolers, and the role of maternal vitamin D in these associations, remain to be explored., Objectives: To evaluate the relationships between multiple maternal urinary antibiotics levels and preschoolers' ADHD symptoms, and to identify the potential modifying effects of maternal vitamin D., Methods: Based on a prospective birth cohort, the present study included 2033 motherchild pairs. Maternal urine and serum samples were collected during all three trimesters to measure the urinary concentrations of 43 antibiotics (including two metabolites) and the serum vitamin D levels. The ADHD symptoms of preschoolers were assessed using the Diagnostic and Statistical Manual-oriented ADHD problems scale in the Achenbach Child Behavior Checklist. Multiple informant models in the form of logistic regression were conducted to investigate the associations between prenatal antibiotics exposure and preschooler ADHD symptoms, and these associations were stratified by child sex and maternal vitamin D status., Results: Compared with the lowest tertile concentrations, maternal exposure to the middle tertile concentrations of doxycycline and human antibiotics/preferred as human antibiotics (HAs/PHAs), and the highest tertile concentrations of doxycycline during the first trimester were associated with an increased risk of ADHD symptoms in children. An increased risk of ADHD symptoms was observed in girls exposed to the highest tertile levels of sulfamethazine during the second trimester. Furthermore, pregnant women with vitamin D deficiency have a greater risk of ADHD symptoms in their offspring after exposure to doxycycline in the first trimester., Conclusions: Maternal exposure to doxycycline and HAs/PHAs during the first trimester increases the risk of ADHD symptoms in preschoolers. Mid-pregnancy sulfamethazine exposure increases the risk of ADHD symptoms in girls. Maternal vitamin D deficiency during pregnancy may exacerbate the adverse effects of doxycycline exposure on ADHD symptoms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Organophosphate esters (OPEs) are a class of environmental chemicals with endocrine-disrupting properties. Epidemiologic studies have demonstrated that prenatal OPEs exposure is associated with neurodevelopmental disorders in offspring. However, studies assessing the effects of prenatal OPEs exposure on the dynamic changes in attention deficit hyperactivity disorder (ADHD) symptoms in preschoolers are scarce. Since vitamin D has been demonstrated to have a "neuroprotective" effect, the modifying effects of maternal vitamin D were estimated., Methods: The present study included 2410 pregnant women from the Ma'anshan Birth Cohort. The levels of OPEs in the mothers' urine were examined in the three trimesters. The Chinese version of the Conners Abbreviated Symptom Questionnaire was used to examine preschoolers' ADHD symptoms at 3, 5, and 6 years of age. ADHD symptom trajectories were fitted via group-based trajectory modeling. We used multinomial logistic regression, Bayesian kernel machine regression, quantile-based g-computation, and generalized linear models to assess individual and mixed relationships between OPEs during pregnancy and preschoolers' ADHD symptoms and trajectories., Results: Preschoolers' ADHD symptom scores were fitted to 3 trajectories, including the low-score, moderate-score, and high-score groups. First-trimester dibutyl phosphate (DBP), second-trimester bis(2-butoxyethyl) phosphate (BBOEP), and third-trimester diphenyl phosphate (DPHP) were associated with an increased risk in the high-score group (p < 0.05). BBOEP in the third trimester was associated with decreased risk in the moderate-score group (OR = 0.89, 95% CI: 0.79, 1.00). For mothers with 25(OH)D deficiency, a positive relationship was observed between OPEs during pregnancy and symptom trajectories. Our results did not reveal any mixed effects of OPEs on ADHD symptom trajectories., Conclusion: Prenatal exposure to OPEs had heterogeneous associations with ADHD symptom trajectories in preschoolers. Additionally, the effect of individual OPEs on symptom trajectories was intensified by vitamin D deficiency., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Triclosan (TCS) is an environmental pollutant. In recent years, there has been increasing level of concern regarding the potential toxicity of TCS in animals and humans, especially its effects on the nervous system. However, whether TCS induces ADHD-like behaviour and the mechanism by which it affects neural function are unclear. The impact of 60 days of continuous exposure to TCS on the behaviour of offspring rats was assessed in this research. According to the results of this study, TCS exposure led to ADHD-like behaviour in offspring rats and activated microglia in the prefrontal cortex (PFC), inducing inflammatory factor release. In vitro studies showed that TCS increased the levels of inflammatory cytokines, including interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α, in HMC3 cells. More importantly, we found that TCS regulated the STAT3 pathway by upregulating PKM2 via hnRNPA1. In summary, this study suggested that TCS can induce ADHD-like behaviour in offspring rats and continuously activate HMC3 microglia through the hnRNPA1-PKM2-STAT3 feedback loop, promoting inflammatory cytokine secretion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In recent years, exposure to triclosan (TCS) has been linked to an increase in psychiatric disorders. Nonetheless, the precise mechanisms of this occurrence remain elusive. Therefore, this study developed a long-life TCS-exposed rat model, an SH-SY5Y cell model, and an atomoxetine hydrochloride (ATX) treatment model to explore and validate the neurobehavioral mechanisms of TCS from multiple perspectives. In the long-life TCS-exposed model, pregnant rats received either 0 mg/kg (control) or 50 mg/kg TCS by oral gavage throughout pregnancy, lactation, and weaning of their offspring (up to 8 weeks old). In the ATX treatment model, weanling rats received daily injections of either 0 mg/kg (control) or 3 mg/kg ATX via intraperitoneal injection until they reached 8 weeks old. Unlike the TCS model, ATX exposure only occurred after the pups were weaned. The results indicated that long-life TCS exposure led to attention-deficit hyperactivity disorder (ADHD)-like behaviors in male offspring rats accompanied by dopamine-related mRNA and protein expression imbalances in the prefrontal cortex (PFC). Moreover, in vitro experiments also confirmed these findings. Mechanistically, TCS reduced dopamine (DA) synthesis, release, and transmission, and increased reuptake in PFC, thereby reducing synaptic gap DA levels and causing dopaminergic deficits. Additional experiments revealed that increased DA concentration in PFC by ATX effectively alleviated TCS-induced ADHD-like behavior in male offspring rats. These findings suggest that long-life TCS exposure causes ADHD-like behavior in male offspring rats through dopaminergic deficits. Furthermore, ATX treatment not only reduce symptoms in the rats, but also reveals valuable insights into the neurotoxic mechanisms induced by TCS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Air pollution stands as an environmental risk to child mental health, with proven relationships hitherto observed only in urban areas. Understanding the impact of pollution in rural settings is equally crucial. The novelty of this article lies in the study of the relationship between air pollution and behavioural and developmental disorders, attention deficit hyperactivity disorder (ADHD), anxiety, and eating disorders in children below 15 living in a rural area. The methodology combines spatio-temporal models, Bayesian inference and Compositional Data (CoDa), that make it possible to study areas with few pollution monitoring stations. Exposure to nitrogen dioxide (NO 2 ), ozone (O 3 ), and sulphur dioxide (SO 2 ) is related to behavioural and development disorders, anxiety is related to particulate matter (PM 10 ), O 3 and SO 2 , and overall pollution is associated to ADHD and eating disorders. To sum up, like their urban counterparts, rural children are also subject to mental health risks related to air pollution, and the combination of spatio-temporal models, Bayesian inference and CoDa make it possible to relate mental health problems to pollutant concentrations in rural settings with few monitoring stations. Certain limitations persist related to misclassification of exposure to air pollutants and to the covariables available in the data sources used., (© 2024. The Author(s).)

Introduction: Benzodiazepine (BDZP) and/or z-hypnotic dispensing during pregnancy has increased globally, as have rates of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This systematic review and meta-analysis aimed to estimate the association between gestational exposure to BDZP and/or z-hypnotics and diagnosis of ASD or ADHD in offspring., Methods: We searched MEDLINE, EMBASE, and SCOPUS from inception till December 2023 for relevant English-language articles. Outcomes of interest were risk of ASD and ADHD, two independent primary outcomes, in children exposed anytime during pregnancy to BDZP and/or z-hypnotics versus those unexposed. Secondary outcomes were trimester-wise analyses. Using a random effects model, we pooled the overall and trimester-wise hazard ratios (HRs), with 95% confidence intervals (CIs), separately for risk of ASD and ADHD., Results: We found six eligible retrospective cohort studies and no case-control studies. There was no increased risk of ASD associated with anytime gestational BDZP and/or z-hypnotic exposure (primary outcome, HR, 1.10; 95% CI, 0.81-1.50; 4 studies; n = 3,783,417; 80,270 exposed, 3,703,147 unexposed) nor after first trimester exposure (HR, 1.15; 95% CI, 0.83-1.58; 3 studies; n = 1,539,335; 70,737 exposed, 1,468,598 unexposed) or later trimester exposures. A very small but significantly increased risk of ADHD was noted with anytime gestational exposure to these drugs (primary outcome, HR, 1.07; 95% CI, 1.03-1.12; 4 studies; n = 2,000,777; 78,912 exposed, 1,921,865 unexposed) and also with (only) second trimester exposure (HR, 1.07; 95% CI, 1.03-1.12; 3 studies; n = 1,539,281; 33,355 exposed, 1,505,926 unexposed). Findings were consistent in sensitivity analyses., Conclusion: Gestational exposure to benzodiazepines or z-hypnotics was not associated with an increased risk of ASD and with only a marginally increased risk of ADHD in offspring. Given the likelihood of confounding by indication and by unmeasured variables in the original studies, our findings should reassure women who need these medications for severe anxiety or insomnia during pregnancy., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Attention-Deficit/Hyperactivity Disorder (ADHD) is a recognized neurodevelopmental disorder with a complex, multifactorial origin. Lead (Pb) and mercury (Hg) are highly toxic substances that can potentially impair brain development and have been implicated in the development of ADHD. This systematic review aims to analyze the epidemiological literature regarding the association between Pb and Hg exposure and the diagnosis of ADHD., Methods: From November 1983 to June 2, 2023, a comprehensive search was conducted in multiple databases and search engines, including PubMed, Web of Science, Scopus, and Google Scholar. Observational studies (case-control, cohort, and cross-sectional) measuring Pb and Hg levels in various biological samples (blood, hair, urine, nail, saliva, teeth, and bone) of children with ADHD or their parents and their association with ADHD symptoms were included., Results: Out of 2059 studies, 87 met the inclusion criteria and were included in this systematic review. Approximately two-thirds of the 74 studies investigating Pb levels in different biological samples reported associations with at least one subtype of ADHD. However, most studies examining Hg levels in various biological samples found no significant association with any ADHD subtype, although there were variations in exposure periods and diagnostic criteria., Conclusion: The evidence gathered from the included studies supports an association between Pb exposure and the diagnosis of ADHD, while no significant association was found with Hg exposure. Importantly, even low levels of Pb were found to elevate the risk of ADHD. Further research is needed to explore the comprehensive range of risk factors for ADHD in children, considering its significance as a neurodevelopmental disorder., (© 2024. The Author(s).)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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 (β = -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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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 (β per doubling = 0.05, 95% confidence interval [CI]: 0.02, 0.08) and Hyperactive/Impulsive scales (β = 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 (β = 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., Competing Interests: Declaration of competing interest Rebecca J. Schmidt consults for the Beasley Law Firm. Rebecca J. Schmidt and Deborah H. Bennett consult for Linus Biotechnology, Inc. Other authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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.

The paucity of evidence regarding the safety of gestational antipsychotic exposure has led to treatment discontinuation in pregnant women with severe mental health conditions. This systematic review and meta-analysis aimed to summarise the current evidence on the association between gestational antipsychotic exposure and attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children (Study protocol registered in PROSPERO:CRD42022311354). Five studies included in our meta-analysis with around 8.6 million pregnancy episodes in nine different countries/regions. Results from our meta-analysis indicate that the heightened risks of ASD and ADHD in children gestationally exposed to antipsychotics appear to be attributable to maternal characteristics, rather than having a causal relationship with the antipsychotic exposure during pregnancy. The results underscore the importance of meticulously monitoring the neurodevelopment of children born to mothers with mental illnesses, which can facilitate early interventions and provide requisite support., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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 α2 A 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Vishal Madaan: In his current role, Dr. Madaan is an employee with the American Psychiatric Association and has no current disclosures to make. In his prior role as a University of Virginia Health System employee, he received research support from Supernus, Allergan, Boehringer Ingelheim, Pfizer, Purdue, and the NICHD at the time the original manuscript was prepared. Daniel Cox: Dr Cox has received research support as a University of Virginia Health System employee from the National Institutes of Health, Eli Lilly, Purdue, Johnson & Johnson, Dexcom, and Abbott. Graeme Donnelly is an employee of Purdue Pharma (Canada). Sailaja Bhaskar: Sailaja Bhaskar is currently employed at Imbrium Therapeutics L.P., a subsidiary of Purdue Pharma L.P.

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/RR 1/3 ). 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., (© 2024. American College of Medical Toxicology.)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Larissa Helena Torres reports financial support was provided by Coordination of Superior Level Staff Improvement - Brazil (CAPES, Finance Code 001). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: It is plausible that exposure to cannabis in-utero could be associated with an increased risk of neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) during childhood and adolescence; however, mixed results have been reported. This study investigated whether there is an association between prenatal cannabis use and ADHD symptoms and ASD in offspring using a systematic review and meta-analysis methodology., Methods: A systematic literature search was conducted in PubMed/Medline, Scopus, EMBASE, Web of Science, Psych-Info, and Google Scholar to identify relevant studies. The study protocol has been preregistered in the Prospective Register of Systematic Reviews (PROSPERO) (CRD42022345001), and the Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the methodological quality of included studies. An inverse variance weighted random effect meta-analysis was conducted to pool the overall effect estimates from the included studies., Results: Fourteen primary studies, consisting of ten on ADHD and four on ASD, with a total of 203,783 participants, were included in this study. Our meta-analysis underscores an increased risk of ADHD symptoms and/or disorder [β = 0.39: 95 % CI (0.20-0.58), I 2  = 66.85 %, P = 0.001)] and ASD [RR = 1.30: 95 % CI (1.03-1.64), I 2  = 45.5 %, P = 0.14] associated with in-utero cannabis exposure in offspring compared to their non-exposed counterparts. Additionally, our stratified analysis highlighted an elevated risk of ADHD symptoms [β = 0.54: 95 % CI (0.26-0.82)] and a marginally significant increase in the risk of diagnostic ADHD among exposed offspring compared to non-exposed counterparts [RR = 1.13, 95 % CI (1.01, 1.26)]., Conclusion: This study indicated that maternal prenatal cannabis exposure is associated with a higher risk of ADHD symptoms and ASD in offspring., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AH has received compensation for serving as consultant or speaker for Shire–Takeda and Medice, unrelated to this work. KKCM reports grants from the CW Maplethorpe Fellowship, the UK National Institute for Health and Care Research (NIHR), the EU Horizon 2020 Framework, and the Hong Kong Research Grant Council, and personal fees from IQVIA Holdings, outside the submitted work. JB has been in the past 3 years a consultant, member of advisory board, or speaker for Takeda–Shire, Roche, Medice, Angelini, Janssen, and Servier. SC reports collaboration on projects from the EU Seventh Framework Programme and on clinical trials sponsored by Shire Pharmaceutical Company, Lundbeck, Otsuka, Janssen-Cilag, and Angelini. MD has received research funding from Takeda–Shire, outside the submitted work. RWD—For the past 3 years, he has no conflicts of interest to report. As a former company employee, he has been a stock holder of Eli Lilly & Co. BF has been a consultant or speaker for Abbvie, Actelion, Allergan, Almirall, Alnylam, Amgen, Astellas, Astrazeneca, Bayer, Biogen, Biopecs, Bioproject, Biotronik, BMS, Boehringer, Celgène, Daiichi-Sankyio, Ethypharm, Forestlab, Genevrier, Genzyme, Gilead, Grünenthal, GSK, Idorsia, IMS, Indivior, IQVIA, JNJ, Léo, Lilly, Lundbeck, Menarini, MSD, Novartis, Novonordisk, Otsuka, Pfizer, Pierre-Frabre, Recordati, Roche, SANOFI, Servier, Takeda, UCB, ViiV, and Wellmera. CH reports research funding from the NIHR including the Health Technology Assessment SATURN trial (grant ref: NIHR128472) comparing MPH with guanfacine for children and young people with ADHD and tics. CH was chair of the NICE Guideline (CG155) for psychosis and schizophrenia in children and young people; member of the NICE ADHD Guideline Update committee (NG87) and is a member of Eunethydis and the European ADHD Guideline Group. SM reports speaker’s fee, travel support, and research support from Shire, outside the submitted work. AN reports research funding from the EU, the German Ministry of Health, and the German Federal Joint Committee, outside the submitted work. PN has been a consultant or speaker for Medice, Servier, and Egis Pharmaceuticals, outside the submitted work. ER received speaker’s fee and travel support from Shire, outside the submitted work. ESB has received in the last 3 years speakers fees from Takeda and Medice and research support from QBTech. AZ served in an advisory or consultancy role for Angelini, EduPharma, Servier; received conference support or speaker’s fee from Angelini and Janssen; participated in clinical trials conducted by Angelini, Janssen, Lundbeck, Otsuka, Roche, Servier, and Shire; and received royalties from Giunti OS and Oxford University Press. ICKW reports research and educational funding from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the Hong Kong Innovation and Technology Commission, the NIHR, the EU, and the Australian National Health and Medical Research Council, and the expert testimony payment from the Hong Kong Court of Final Appeal; outside the submitted work. DC reports, in the past 3 years, a consultant, member of advisory board, or speaker role for Takeda–Shire, Medice, Novartis, and Servier. He has received royalties from Oxford University Press and Cambridge University Press; research support from the Australian National Health and Medical Research Council and the Royal Children’s Hospital Foundation; and funding for the current study from the European Commission. All other authors declare no competing interests. TB served in an advisory or consultancy role for Eyelevel, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg, Roche, and Takeda; received conference support or speaker’s fee from Jansen, Medice, and Takeda; and royalities from Hogrefe, Kohlhammer, CIP Medien, and Oxford University Press; outside the submitted work.

Few prior studies have explored windows of susceptibility to fine particulate matter (PM 2.5 ) 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 PM 2.5 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 PM 2.5 (per 5-μg/m 3 ) for ADHD symptoms. Models were adjusted for relevant covariates, and cumulative effects were reported by aggregating risk ratios (RR cum ) or effect estimates (β cum ) across adjacent susceptible windows. A similar susceptible period of exposure to PM 2.5 (1.2-2.9 and 0.9-2.7 years of age, respectively) was identified for hyperactivity/impulsivity symptoms assessed ~5 years (RR cum  = 2.72, 95% credible interval [CrI] = 1.98, 3.74) and increased hyperactivity subscale ~7 years (β cum  = 3.70, 95% CrI = 2.36, 5.03). We observed a susceptibility period to PM 2.5 on risk of hyperactivity/impulsivity symptoms ~5 years in gestational weeks 16-22 (RR cum  = 1.36, 95% CrI = 1.22, 1.52). No associations between PM 2.5 exposure and other ADHD symptoms were observed. We report consistent evidence of toddlerhood as a susceptible window of PM 2.5 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., Competing Interests: Declaration of competing interest All authors declare they have no actual or potential competing financial interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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% [ β = 0.03 ; 95% credible interval (CrI): - 0.01 , 0.06], 4.1% ( β = 0.04 ; 95% CrI: 0.00, 0.08), and 4.1% ( β = 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.

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Y.Z. is an employee of Takeda Pharmaceutical Company Limited; however, Takeda Pharmaceutical Company Limited was not involved in this study. T.F. has been employed by the Department of Digital Health and Epidemiology, an Industry-Academia Collaboration Course supported by Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Real World Data Co., Ltd., and Mitsubishi Corporation; and has received consulting fees from Real World Data Co., Ltd. and speaker fees from Asahi Kasei Pharma Corporation and EPS Corporation. F.Y. declares no conflict of interest. M.T. received consulting fees from Eisai Co., Ltd. K.K. received research grants from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., OMRON Corporation, and Toppan Inc.; consulting fees from Advanced Medical Care Inc., JMDC Inc., and Shin Nippon Biomedical Laboratories Ltd.; executive compensation from Cancer Intelligence Care Systems, Inc.; honoraria from Chugai Pharmaceutical Co., Ltd., and Pharma Business Academy.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The growing population of survivors of childhood brain tumors present the challenge of long-term quality of survival. The domains most affected by tumor and treatment are those implicated in development of typical intellectual functions: attention, working memory, and processing speed, with consequent effects upon function and quality of life. In this paper we present service evaluation data on the 12-month effect upon processing speed, visual and auditory attentional domains in 29 patients receiving methylphenidate aged 5-16 years (Mean=10.6)., Methods: Patients received immediate-release methylphenidate and were converted to modified-release as appropriate. Mean optimal dose of immediate-release methylphenidate was 0.34 mg/kg per dose (range 0.2-0.67)., Results: Patients showed a significant positive impact of methylphenidate on attention in all tests of selective visual attention from the Test of Everyday Attention for Children 2. A significant improvement was also shown on response time. Significant change was not found on psychometric measures of sustained auditory or visual attention, or selective auditory attention. Ratings of Health-Related Quality of Life showed a positive benefit of methylphenidate at 12 months. Side effects were minimal and not statistically significant., Conclusions: Survivors of childhood brain tumor with attentional and processing speed deficit show clinical benefit from methylphenidate.

Perfluorooctane sulfonic acid (PFOS) is one of the main residual environmental pollutants that threaten human health. PFOS exposure is positively correlated with the prevalence of attention deficit hyperactivity disorder (ADHD); however, the underlying mechanism is unknown. Given that dopamine (DA) is a crucial target for PFOS and that its dysfunction is a key role in ADHD development, it is speculated that PFOS exposure contributes to the occurrence of ADHD to some extent by disrupting DA homeostasis. To establish the relationship between PFOS exposure, DA dysfunction, and ADHD-like behavior, adult zebrafish were exposed to PFOS for 21 days using PFOS concentrations in the serum of patients with ADHD as the reference exposure dose. Results showed that PFOS caused ADHD-like behaviors, with the presence of the slightly elevated percentage of time spent in movement and prolonged time spent in reaching the target zone in the T-maze. Hyperactivity and cognitive ability impairment were more severe with increasing PFOS concentrations. Further investigation showed that PFOS exposure resulted in a decrease in the DA content, accompanied by a decrease in the number of dopaminergic neurons and a disturbance in the transcription profiles of genes associated with the dopaminergic system. Treatment with Ritalin effectively alleviated PFOS-induced ADHD-like behavior and restored DA levels, number of dopaminergic neurons, and expression of DA metabolism-related genes, suggesting that PFOS exposure induced ADHD-like behavior by triggering DA secretion disorder. This study enriches our understanding of the pathogenic mechanisms underlying ADHD development and emphasizes the importance of focusing on the health risks pertaining to environmental exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The neurotoxic effects of certain heavy metals are well established, but only a few studies have investigated the joint effect of concurrent exposure to multiple ones. The study aims to evaluate the association between mixed exposure to neurotoxic metals and the psychosocial behavior of preschool children. Using a stratified sampling strategy, we recruited participants from 105 kindergartens in 41 townships of Taiwan and excluded those with blood lead levels ≥ 3.5 µg/L. The first-morning void urines were collected and analyzed for cadmium, manganese, arsenic, chromium, lead, and nickel concentrations using inductively coupled plasma mass spectrometry. We applied the parentally reported Strengths and Difficulties Questionnaire (SDQ) and Swanson, Nolan, and Pelham IV (SNAP-IV) scales to evaluate the psychosocial behaviors. Multiple linear regressions were utilized to evaluate the associations between each heavy metal and the outcomes, while the mixed effect of concurrent exposure was estimated by using a Quantile g-computation approach. A total of 977 preschool children were included in the study, and the mean (SD) age was 5.7 (0.7) years old. In single pollutant models, we observed adverse effects of urinary manganese, nickel, arsenic, and lead on the specific subsets of SDQ. Furthermore, the combined effect of six heavy metals significantly affected the hyperactivity/inattention symptoms (beta = 0.46, 95% CI: 0.13-0.78, with all metals increased by one quartile), and chromium and lead were the two major contributors. Similar detrimental effects of urinary cadmium and lead were also observed in the SNAP-IV subsets, although the joint effect analysis was not significant. The study provided evidence that concurrent exposure to multiple heavy metals may exert increased risks of hyperactivity/inattention in children compared to single pollutant exposure. Further studies are needed to verify our findings regarding mixed exposure to multiple neurotoxic metals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate choroidal vascularity in children with attention-deficit/hyperactivity disorder (ADHD) who were not receiving therapy, children with ADHD who were regularly taking methylphenidate (MPH), and healthy controls., Methods: The study included three groups: patients with newly diagnosed ADHD without treatment, patients diagnosed as having ADHD who were already being treated with oral MPH, and controls. Both choroidal vascularity index (CVI) and choroidal thickness were measured using an enhanced-depth imaging mode of spectral-domain optical coherence tomography (EDIOCT) (Spectralis; Heidelberg Engineering GmbH)., Results: There was a significant difference in CVI and stromal area between groups. Post-hoc univariate analysis showed that CVI was significantly lower in patients with ADHD treated with MPH compared with the other groups ( P < .001, for each); however, there was no difference between the treatment-free ADHD group and controls ( P = .305). In contrast, stromal area was significantly higher in patients with ADHD treated with MPH than the other groups ( P < .001, for each group). The correlation of CVI with MPH treatment duration in patients with ADHD treated with MPH showed a significant, moderate negative correlation ( P = .01, r = - 0.66)., Conclusions: CVI is reduced in patients with ADHD treated with MPH, and the decrease in CVI becomes significant with increasing duration of MPH treatment. This result reflects an indirect effect of MPH treatment on choroidal vascular structures. [ J Pediatr Ophthalmol Strabismus . 2023;60(6):411-416.] .

Objectives: Exposure to environmental toxic agents in the prenatal and/or postnatal periods may play in the acquired development of attention-deficit/hyperactivity disorder (ADHD) in groups with genetic risks. Bisphenol A (BPA) is a widely used industrial chemical with neurotoxic effects. This study examined the relationship between exposure to BPA and clinical ADHD., Methods: This cross-sectional, case-controlled clinical study compared 45 drug-naive children and adolescents with ADHD and 30 healthy controls in terms of serum BPA levels. Psychiatric comorbidities in the ADHD group were determined using the "Schedule for Affective Disorders and Schizophrenia for school-aged children, lifetime version." The Child Behavior Checklist (CBCL) was also administered to all participants., Results: Serum BPA levels were significantly higher in the ADHD group than in the healthy control group. In addition, significant, weak positive correlation was found between BPA levels and CBCL attention and CBCL total problem scores., Conclusions: Our results show that BPA may be an environmental toxic agent with a potential role in the etiology of ADHD and particularly attention deficiency. Preventive interventions can be developed if this can be confirmed with longitudinal studies and repeated measurements., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Although heritability estimates suggest a role for genetic components, environmental risk factors have been described as relevant in the etiology of attention deficit/hyperactivity disorder (ADHD). Several studies have investigated the role of toxicological pollution, i.e., air pollution, heavy metals, POPs, and phthalates. Clear evidence for association of ADHD and environmental factors has not been provided yet. To answer this, we have assessed all available systematic reviews and meta-analyses that focused on the association between pollutant exposure and either ADHD diagnosis or symptoms. More than 1800 studies were screened of which 14 found eligible. We found evidence of a significant role for some pollutants, in particular heavy metals and phthalates, in the increased risk of developing ADHD symptoms. However, at the current stage, data from existing literature also do not allow to weight the role of the different environmental pollutants. We also offer a critical examination of the reviews/meta-analyses and provide indications for future studies in this field. PROSPERO registration: CRD42022341496., (© 2023. The Author(s).)

Background: Health concerns about the potential impact of exposure to fluoride via drinking water (DW) on neuropsychological development include behavioral outcomes such as ADHD., Objective: We aimed to examine the association between prenatal maternal urinary fluoride and symptoms associated with attention-deficit/hyperactivity disorder (ADHD) at the age of 8 and 11 years., Method: Data from 255 to 236 mother-child pairs from the "Infancia y Medio Ambiente" (INMA) birth cohort (Gipuzkoa; Spain) with maternal urinary F adjusted for creatinine (MUFcr) during pregnancy (first and third trimester) and child assessments of ADHD-like symptoms reported by Conners' Rating Scales-Revised at age of 8 and 11 years was available. Clinical approach was also used: cut off criteria (T > 66). Multiple linear regression models were fitted when outcomes were analyzed as continuous, and logistic regression models when the outcomes were analyzed with a categorical clinical approach. Covariates related to maternal characteristics, birth outcomes, childhood, quality of family context and biomarkers of neuro-toxicants were used., Results: No association was found between MUFcr levels during pregnancy and cognitive problems-inattention, hyperactivity or ADHD index score of symptoms at 8 or 11 years. When results were analyzed from the perspective of a clinical approach, at the age of 11 years, there were significant inverse association between MUFcr and being categorized as a cognitive problems-inattention case. ORs were also indicative of a lower risk, although not significant, for ADHD index at age 11. Sensitivity analyses, taking into consideration quality of family context or the levels of other toxicants during pregnancy showed similar results., Conclusions: Higher levels of MUFcr in pregnant women were associated with a lower risk of cognitive problems-inattention at 11 years. These findings are inconsistent with those from previous studies and indicate the need for other population-based studies to confirm or overturn these results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate treatment patterns for ADHD in Sweden., Method: Observational retrospective study of patients with ADHD from the Swedish National Patient Register and Prescribed Drug Register, 2018 to 2021. Cross-sectional analyses included incidence, prevalence, and psychiatric comorbidities. Longitudinal analyses (newly diagnosed patients) included medication, treatment lines, duration, time-to-treatment initiation, and switching., Results: Of 243,790 patients, 84.5% received an ADHD medication. Psychiatric comorbidities were common, particularly autism among children, and depression in adults. Most frequent first-/second-line treatments were methylphenidate (MPH; 81.6%) and lisdexamfetamine dimesylate (LDX; 46.0%), respectively. In the second-line, LDX was most frequently prescribed (46.0%), followed by MPH (34.9%), then atomoxetine (7.7%). Median treatment duration was longest for LDX (10.4 months), followed by amphetamine (9.1 months)., Conclusion: This nationwide registry study provides real-life insights into the current epidemiology of ADHD and the changing treatment landscape for patients in Sweden.

Introduction: Attention deficit hyperactivity disorder (ADHD) is a mental disorder that was once thought to occur only in children. Meanwhile, it is known that adults can also be affected. The first-line drug in children and adults to treat symptoms of inattention, impulsivity, lack of self-regulation, and hyperactivity is methylphenidate (MPH). Known adverse effects of MPH include cardiovascular problems, such as elevated blood pressure and heart rate. Therefore, biomarkers to monitor potential cardiovascular side effects of MPH are needed. The l-Arginine/Nitric oxide (Arg/NO) pathway is involved in noradrenaline and dopamine release as well as in normal cardiovascular functioning and is therefore a prime candidate for the search of biomarkers. The aim of the present study was to investigate the Arg/NO pathway as well as oxidative stress in adult ADHD patients in plasma and urine and the potential influence of MPH medication., Methods: In plasma and urine samples of 29 adults with ADHD (39.2 ± 10.9 years) and 32 healthy adults serving as controls (CO) (38.0 ± 11.6 years) the major NO metabolites nitrite and nitrate, Arg, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) as well as malondialdehyde (MDA) were measured by gas chromatography-mass spectrometry., Results: Of the 29 patients with ADHD 14 were currently without MPH treatment (-MPH) and 15 were treated with MPH (+MPH). Plasma nitrate concentrations were significantly higher in patients not treated with MPH vs. CO (-MPH 60.3 μM [46.2-76.0] vs. CO 44.4 μM [35.0-52.7]; p = 0.002), while plasma nitrite tended to be higher in -MPH patients (2.77 μM [2.26-3.27]) vs. CO (2.13 μM [1.50-2.93]; p = 0.053). Additionally, plasma creatinine concentrations were significantly different, with -MPH showing significantly higher concentrations than the other two groups (-MPH 141 μM [128-159]; +MPH 96.2 μM [70.2-140]; Co 75.9 μM [62.0-94.7]; p < 0.001). Urinary creatinine excretion tended to be lowest in -MPH group vs. +MPH and CO (-MPH 11.4 ± 8.88 mM; +MPH 20.7 ± 9.82 mM; 16.6 ± 7.82 mM; p = 0.076). None of the other metabolites, including MDA, a marker of oxidative stress, showed a difference between the groups., Conclusion: Adult patients with ADHD, who are not treated with MPH (-MPH), showed varied Arg/NO pathway, but Arg bioavailability seemed to be consistent over the groups. Our findings imply that urinary reabsorption may be increase and/or excretion of nitrite and nitrate may be decreased in ADHD, resulting in an increase in the plasma concentration of nitrite. MPH seems to partially reverse these effects by not yet known mechanisms, and does not affect oxidative stress., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abnormal growth hormones and thyroid function may be linked to pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Phthalates and bisphenol-A (BPA), two endocrine-disrupting chemicals (EDCs), may affect the human endocrine system. In this study, we aimed to perform a comprehensive investigation of whether growth hormone, thyroid function, and EDCs exhibited differential levels between ADHD patients and healthy controls. In total, 144 children with ADHD and 70 healthy control subjects were enrolled. Their endocrine systems were evaluated using the serum levels of insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and Free T4. The urinary levels of EDCs, including monoethyl phthalate (MEP), mono-methyl phthalate (MMP), monoethylhexyl phthalate (MEHP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), and BPA, were also examined. Patients with ADHD had lower IGF-1 levels than healthy controls (p = 0.003), but we observed no significant difference in IGFBP-3, TSH, T3, T4, or Free T4. Compared to the control group, patients with ADHD demonstrated higher MEHP levels (p = 0.043), MnBP (p = 0.033), and MBzP (p = 0.040). Furthermore, MEHP levels (p < 0.001) and BPA levels (p = 0.041) were negatively correlated with IGF-1 levels, while IGF-1 levels were negatively correlated with principal components consisting of ADHD clinical symptoms and neuropsychological performance variables. We suggest that MEHP exposure may be associated with decreased serum levels of IGF-1 and increased risk of ADHD. The mechanism underlying this association may be important for protecting children from environmental chemicals that adversely affect neurodevelopment., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

There is evidence that exposure to perfluoroalkyl substances (PFAS) is associated with attention-deficit/hyperactivity disorder (ADHD) symptoms. Previous studies have focused on prenatal exposure to PFAS, and only few studies have examined the associations of early-childhood exposure, especially at low exposure levels. This study explored the association between early-childhood exposure to PFAS and ADHD symptoms later in childhood. In 521 children, we measured the serum levels of six PFAS in peripheral blood at the ages of 2 and 4 years, including perfluorooctanoate (PFOA), perfluornonanoicacid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonate (PFOS). The ADHD Rating Scale IV (ARS) was utilized to measure ADHD traits at 8 years of age. We explored the relationship between PFAS and ARS scores using Poisson regression models after adjusting for potential confounders. Levels of exposure to individual PFAS and the summed value were divided into quartiles to examine possible nonlinear relationships. All six PFAS exhibited inverted U-shaped curves. Children in the 2nd and 3rd quartile levels of each PFAS showed higher ARS scores than those in the1 st quartile level. Below the 3rd quartile of the summed levels of six PFAS (ΣPFAS), a doubling of the ΣPFAS was associated with an 20.0 % (95 % CI: 9.5 %, 31.5 %) increase in ADHD scores. However, at the age of 4 years, none of the evaluated PFAS exhibited linear or nonlinear associations with the ARS scores. Thus, school-aged children may be vulnerable to the neurotoxic effects of exposure to PFAS at age 2 that contribute to ADHD, particularly at low to mid-levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have inappropriately influenced the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Exposure to ambient noise and air pollution may affect the manifestation and severity of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). However, evidence is limited, and most studies solely assessed environmental exposures during pregnancy and early childhood., Objective: To examine the longitudinal effects of ambient noise and air pollutants on ASD and ADHD symptom severity during adolescence and early adulthood., Methods: Using a longitudinal design, we included 2750 children between 10 and 12 years old from the TRacking Adolescents' Individual Lives Survey (TRAILS) in the Netherlands, who were assessed in 6 waves from 2001 to 2017. ASD was measured by the Children's Social Behavior Questionnaire and the Adult Social Behavior Questionnaire. ADHD was measured by Child Behavior Checklist and the Adult Behavior Checklist. Ambient noise and air pollution exposures, including Ozone (O 3 ), soot, sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ), particulate matter 2.5 (PM 2.5 ), and PM 10 were modeled at the residential level according to standardized protocols. The longitudinal associations between exposures and symptom outcomes were examined using linear mixed models., Results: We found evidence that higher levels of exposure to PM were associated with more severe ASD and ADHD symptoms. This association decreased over time. We did not observe any other consistent associations of noise or other air pollutants with ASD and ADHD severity., Conclusion: The current study provides evidence for the negative impact of PM on ASD and ADHD symptoms. We did not find evidence of the negative health impact of other air pollutants and noise exposures on ASD or ADHD symptoms. Our study adds more evidence on the presence of associations between PM air pollution and neurodevelopmental diseases among adolescents and young adults., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Antibiotics represent the most common type of medication used during pregnancy and infancy. Antibiotics have been proposed as a possible factor in changes in microbiota composition, which may play a role in the aetiology of autism and attention deficit/hyperactivity disorder (ADHD). Our aim was to investigate the association between maternal and early-life antibiotic use and autism and ADHD in childhood., Methods: This Swedish nation-wide population-based cohort study included all first live singleton births (N = 483,459) between January 2006 and December 2016. The association of dispensed antibiotics with autism and ADHD in children aged ≤ 11 years was estimated by applying multivariable logistic regression and generalised estimating equations models., Results: Of the mothers, 25.9% (n = 125,106) were dispensed ≥1 antibiotic during the exposure period (from 3 months pre-conception to delivery), and 41.6% (n = 201,040) of the children received ≥ 1 antibiotic in early life (aged ≤ 2 years). Penicillin was the most prescribed antibiotic class (17.9% of mothers, 38.2% of children). Maternal antibiotic use was associated with an increased risk of autism [odds ratio (OR) = 1.16, 95% confidence interval (CI) 1.09-1.23] and ADHD (OR = 1.29, 95% CI 1.21-1.36) in childhood. Early-life exposure to antibiotics showed an even stronger association [autism (OR = 1.46, 95% CI 1.38-1.55); ADHD (OR = 1.90, 95% CI 1.80-2.00)]. Both maternal and childhood-exposure sub-analyses suggested a dose-response relationship., Conclusion: Maternal and early-life antibiotic use was associated with an increased risk of autism and ADHD in childhood. However, differences were noted by exposure period and antibiotic classes., (© 2023. The Author(s).)