Potential disturbance of methylphenidate of gonadal hormones or pubescent development in patients with attention-deficit/hyperactivity disorder: A twelve-month follow-up study.

Several animal or case reports have demonstrated that methylphenidate (MPH) disrupts endogenous gonadal hormones and interferes with the pubescent development of children with attention-deficit/hyperactivity disorder (ADHD). Therefore, this prospective study examined the changes in gonadal hormones and pubescent development in children with ADHD undergoing 12-month MPH treatment. We recruited 146 patients with ADHD (mean age: 8.9 years, 76.7% males) and 70 healthy controls (mean age: 9.2 years, 65.7% males). Blood samples were obtained to measure the serum levels of sex hormone-binding globulin (SHBG), follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, testosterone, free testosterone, and prolactin in each child. The sex maturation of ADHD patients was evaluated using the Tanner Stage. Patients with ADHD (107 received MPH treatment and 39 were under natural observation) were followed up for 12 months, and we re-examined hormone levels and Tanner Stage at the endpoint. During a 12-month follow-up for all ADHD patients, the serum levels of SHBG and progesterone significantly decreased, while LH, FSH, and free-testosterone levels significantly increased. However, the duration, drug formulations, and doses of the MPH treatment did not significantly influence gonadal hormone trends or changes of Tanner Stage. This study provides evidence about gonadal hormone trends and pubescent development in children with ADHD who receive long-term MPH treatment in natural settings. We suggest that MPH treatment at usual doses does not significantly alter gonadal function trends in ADHD patients over the course of one year.

Validity of Visual and Auditory Attention Tests for Detecting ADHD.

Objective: This investigation examines the discriminative validity of visual and auditory attention tests for differentiating patients with ADHD from healthy control participants. Method: A total of 107 ADHD patients and 58 healthy control participants were recruited. Visual and auditory attention profiles were obtained using the Conners' Continuous Performance Test 3rd Edition (CPT3) and Conners' Continuous Auditory Test of Attention (CATA), respectively. Results: We found that ADHD patients underperformed healthy controls on all CPT3 and CATA indexes, except Response Style and Hit Reaction Time. The CPT3, CATA, and CPT3 plus CATA all significantly differentiate ADHD patients and controls. CPT3 plus CATA had a greater sensitivity (82.6%), specificity (76%), positive predictive value (88.8%), negative predictive value (65.5%), and overall correct classification rate (80.6%) than CPT3 or CATA alone. Conclusion: Neuropsychological tests CPT3 and CATA provide objective information about cases of ADHD and should be used routinely for clinical assessment.

Phthalates, Para-Hydroxybenzoic Acids, Bisphenol-A, and Gonadal Hormones' Effects on Susceptibility to Attention-Deficit/Hyperactivity Disorder.

This study aimed to examine whether endocrine-disrupting chemicals (EDCs), such as phthalates, para-hydroxybenzoic acids, and bisphenol-A (BPA), affect gonadal hormones and further link to the susceptibility to attention-deficit/hyperactivity disorder (ADHD). We recruited 98 boys with ADHD, 32 girls with ADHD, 42 boys without ADHD and any other psychiatric disorders, and 26 girls without ADHD and any other psychiatric disorders. Urine levels of EDCs, including mono-methyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoethylhexyl phthalate (MEHP), methylparaben (MP), ethylparaben (EP), propylparaben (PP), butylparaben (BP), and bisphenol A (BPA), were examined. Endocrine systems were evaluated by using the serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, free testosterone, estradiol, progesterone, sex hormone-binding globulin (SHBG), and prolactin. We found that boys with ADHD had higher levels of MnBP and EP than control boys. There were no significant differences regarding EDCs between the females with ADHD and control groups. No significant differences in testosterone, free testosterone, FSH, LH, estradiol, progesterone, or SHBG were found between the ADHD group and controls among either boys or girls. Among boys with ADHD, urine MBzP and MEHP levels were positively correlated with serum testosterone levels. Among girls, urine MEP levels were positively correlated with serum LH, testosterone, and free testosterone levels. The findings suggest that the possibility of an adverse impact of EDCs on gonadal hormones and neurodevelopment may exist. However, the results could be subject to potential selection bias, and the findings in this study should be interpreted with caution.

Gut microbiota and dietary patterns in children with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, but the underlying pathophysiological mechanisms of ADHD remain unclear. Gut microbiota has been recognized to influence brain function and behaviors. Therefore, this study aimed to determine whether imbalanced gut microbiomes identified by a 16S rRNA sequencing approach are involved in the pathophysiology of ADHD. We recruited a total of 30 children with ADHD (mean age: 8.4 years) and a total of 30 healthy controls (mean age: 9.3 years) for this study. The dietary patterns of all participants were assessed with the food frequency questionnaire. The microbiota of fecal samples were investigated using 16S rRNA V3V4 amplicon sequencing, followed by bioinformatics and statistical analyses. We found that the gut microbiota communities in ADHD patients showed a significantly higher Shannon index and Chao index than the control subjects. Furthermore, the linear discriminant analysis effect size (LEfSe) analysis was used to identify differentially enriched bacteria between ADHD patients and healthy controls. The relative abundance of Bacteroides coprocola (B. coprocola) was decreased, while the relative abundance of Bacteroides uniformis (B. uniformis), Bacteroides ovatus (B. ovatus), and Sutterella stercoricanis (S. stercoricanis) were increased in the ADHD group. Of all participants, S. stercoricanis demonstrated a significant association with the intake of dairy, nuts/seeds/legumes, ferritin and magnesium. B. ovatus and S. stercoricanis were positively correlated to ADHD symptoms. In conclusion, we suggest that the gut microbiome community is associated with dietary patterns, and linked to the susceptibility to ADHD.

Gray matter volume and microRNA levels in patients with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder often characterized by gray matter (GM) volume reductions. MicroRNAs, which participate in regulating gene expression, potentially influence neurodevelopment. This study aimed to explore whether differential GM volume is associated with differential miRNA levels in ADHD patients. We recruited a total of 30 drug-naïve patients with ADHD (mean age 10.6 years) and 25 healthy controls (mean age 10.6 years) that underwent a single session of 3.0-T whole brain structural MRI scanning. RNA samples from the participants' white blood cells were collected to identify the ΔCt values of three miRNAs (miR-30e-5p, miR-126-5p, and miR-140-3p) using the real-time quantitative reverse transcription polymerase chain reaction. In comparison to the control group, ADHD patients demonstrated a significantly lower GM volume in the cingulate gyrus, left middle temporal gyrus, right middle occipital gyrus, left fusiform gyrus, and significantly higher ΔCt values of miR-30e-5p, miR-126-5p, and miR-140-3p. In the ADHD group, the GM volume of cingulate gyrus and left fusiform gyrus was negatively correlated with the ΔCt values of miR-30e-5p, miR-140-3p. The GM volume of left fusiform gyrus was negatively correlated to ADHD behavioral symptoms. Using structural equation modeling (SEM), we observed that the effect of miR-140-3p on hyperactivity/impulsivity symptoms was mediated by left fusiform gyrus. Our findings support that GM volume reduction and miRNA increases may be biomarkers for ADHD in children and adolescents. Expression levels of miRNAs may affect the development of brain structures and further participate in the pathophysiology of ADHD.

Peripheral Brain-Derived Neurotrophic Factor and Contactin-1 Levels in Patients with Attention-Deficit/Hyperactivity Disorder.

Brain-derived neurotrophic factor (BDNF) facilitates neuronal growth and plasticity, and is crucial for learning and memory. Contactin-1 (CNTN1) is a member of the subfamily of neural immunoglobulin and is involved in the formation of axon connections in the developing nervous system. This cross-sectional study investigates whether BDNF and CNTN1 affect susceptibility to attention deficit/hyperactivity disorder (ADHD). A total of 136 drug-naïve patients with ADHD (108 boys and 28 girls) and 71 healthy controls (45 boys and 26 girls) were recruited. Blood samples were obtained to measure the plasma levels of BDNF and CNTN1 in each child. We found that BDNF levels in the ADHD boys exceeded those in the control boys, but BDNF levels in the ADHD girls were lower than those in the control girls. Boys who had higher BDNF levels performed worse on the Wechsler Intelligence Scale for Children-Fourth Edition, but girls who had higher BDNF levels made fewer omission errors in the Conners' Continuous Performance Test. However, CNTN1 level did not differ significantly between patients and controls, and were not correlated to ADHD characteristics, regardless of gender. The findings suggest BDNF may influence sex-specific susceptibility to ADHD, but CNTN1 was not associated with ADHD pathophysiology.

Mitochondrial-associated protein biomarkers in patients with attention-deficit/hyperactivity disorder.

This study aimed to determine the role of mitochondria-associated proteins (HtrA2, α-synuclein, and Park7) in attention deficit/hyperactivity disorder (ADHD). A total of 125 patients with ADHD (77.6% were males) and 66 healthy controls (66.7% were males) were recruited. We found that girls with ADHD demonstrated higher plasma HtrA2 level than control girls, and their HtrA2 levels were positively correlated with verbal comprehensive ability, and negatively correlated to behavior symptoms. Among boys, we observed no correlations between these mitochondrial proteins, neuropsychological findings, and clinical symptoms. Our findings suggest that an underlying gender-specific mitochondria pathway may influence with the pathophysiology of ADHD.

Dehydroepiandrosterone sulfate, free testosterone, and sex hormone-binding globulin on susceptibility to attention-deficit/hyperactivity disorder.

The neuroendocrine system may affect the pathophysiology of gender differences in attention deficit/hyperactivity disorder (ADHD). This study examines whether the relationships among dehydroepiandrosterone sulfate (DHEA-S), free testosterone, or sex hormone-binding globulin (SHBG) and ADHD presentations exhibit gender differences. A total of 113 boys and 35 girls with ADHD (all drug naïve) and 46 and 26 healthy control boys and girls, respectively, were recruited. Blood samples were obtained to measure the serum levels of DHEA-S, free testosterone, and SHBG in each child. The Swanson, Nolan, and Pelham Scale for ADHD Version IV (SNAP-IV) was used to evaluate behavioral symptoms and the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) and the Conners' Continuous Performance Test (CPT) were utilized to assess neurocognitive functions. Patients with ADHD had lower DHEA-S levels than male and female healthy control subjects, and no significant differences were observed in free testosterone and SHBG levels between the patients and the controls. DHEA-S levels were negatively correlated with children's impulsivity performance in the CPT. SHBG levels were negatively correlated with ADHD behavior symptoms among boys. Free testosterone levels were not significantly correlated with either ADHD clinical symptoms or neuropsychological functions. We propose that DHEA-S serves as a potential biomarker of ADHD and is consistently involved in the pathogenesis of ADHD in both boys and girls. SHBG may be involved in behaviors associated with ADHD in boys. Additional studies with basic scientific measures are warranted to elucidate the relationship between androgen hormones and clinical presentations of ADHD.

Maternal and Family Processes in Different Subgroups of Youth with Autism Spectrum Disorder.

We compared the maternal reports on mothering and family processes between 160 youth with autism spectrum disorder (ASD) and 160 age and gender-matched typically developing (TD) youth stratified by personal characteristics from Taiwan. The ASD groups consisted of 51 'typical autism' (TA), 52 'high-functioning autism' (HFA), and 57 'Asperger syndrome (AS).' Maternal reports showed that youth with ASD obtained less affection and more protection from the mother, and had less active mother-child interactions and more behavioral problems at home. Their mothers perceived less family support when compared to mothers of TD youth. Moreover, both TA and AS groups had more maternal protection and less maternal perceived family support, whereas HFA and co-occurring ADHD were only associated with more behavioral problems at home. The maternal and family process may vary across different ASD subgroups.

Symptoms of ADHD Affect Intrasubject Variability in Youths with Autism Spectrum Disorder: An Ex-Gaussian Analysis.

Increased intrasubject variability in reaction times (RT-ISV) is frequently found in individuals with autism spectrum disorder (ASD). However, how dimensional attention deficit/hyperactivity disorder (ADHD) symptoms impact RT-ISV in individuals with ASD remains elusive. We assessed 97 high-functioning youths with co-occurring ASD and ADHD (ASD+ADHD), 124 high-functioning youths with ASD only, 98 youths with ADHD only, and 249 typically developing youths, 8-18 years of age, using the Conners Continuous Performance Test (CCPT). We compared the conventional CCPT parameters (omission errors, commission errors, mean RT and RT standard error (RTSE) as well as the ex-Gaussian parameters of RT (mu, sigma, and tau) across the four groups. We also conducted regression analyses to assess the relationships between RT indices and symptoms of ADHD and ASD in the ASD group (i.e., the ASD+ADHD and ASD-only groups). The ASD+ADHD and ADHD-only groups had higher RT-ISV than the other two groups. RT-ISV, specifically RTSE and tau, was significantly associated with ADHD symptoms rather than autistic traits in the ASD group. Regression models also revealed that sex partly accounted for RT-ISV variance in the ASD group. A post hoc analysis showed girls with ASD had higher tau and RTSE values than their male counterparts. Our results suggest that RT-ISV is primarily associated with co-occurring ADHD symptoms/diagnosis in children and adolescents with ASD. These results do not support the hypothesis of response variability as a transdiagnostic phenotype for ASD and ADHD and warrant further validation at a neural level.

Prenatal and perinatal risk factors and the clinical implications on autism spectrum disorder.

Prenatal and perinatal factors may increase the risk of autism spectrum disorder. However, little is known about whether unaffected siblings of probands with autism spectrum disorder also share the phenomenon and whether the prenatal/perinatal factors are related to the clinical severity of autistic symptoms. We compared the frequency of prenatal and perinatal factors among 323 probands with autism spectrum disorder (mean age ± standard deviation, 10.7 ± 3.5 years; males, 91.0%), 257 unaffected siblings (11.7 ± 4.5; 42.8%), and 1504 typically developing controls (8.9 ± 1.6 years; 53.1%); and investigated their effects on the severity of autistic symptoms. We found that probands with autism spectrum disorder and their unaffected siblings had more prenatal/perinatal events than typically developing controls with higher numbers of prenatal/perinatal factors in probands than in unaffected siblings. The prenatal/perinatal events were associated with greater stereotyped behaviors, social-emotional problems, socio-communication deficits, and overall severity. We also found that six prenatal/perinatal factors (i.e. preeclampsia, polyhydramnios, oligoamnios, placenta previa, umbilical cord knot, and gestational diabetes) were associated with the severity of autistic symptoms, particularly stereotyped behaviors and socio-communication deficits. Our findings suggest that prenatal and perinatal factors may potentially moderate the clinical expression of autism spectrum disorder. The underlying mechanism warrants further research.

Social adjustment and family function after drug switch from IR-methylphenidate to OROS-methylphenidate in patients with attention-deficit/hyperactivity disorder.

PURPOSE: This prospective, single-arm, open-label, 8-week, multicenter study investigated the effectiveness of switching from immediate-release methylphenidate (IR-MPH) to osmotic controlled-release methylphenidate (OROS-MPH) in patients with attention-deficit/hyperactivity disorder (ADHD). PATIENTS AND METHODS: Overall, 296 patients with ADHD (mean age: 9.5 years) already on IR-MPH treatment were enrolled. Upon enrollment, a flexible dose of OROS-MPH was administered, replacing IR-MPH. Patients were assessed at baseline and weeks 2, 4, and 8 using the Swanson, Nolan, and Pelham version IV scale (SNAP-IV) and the Clinical Global Impression for ADHD symptoms. The Social Adjustment Inventory for Children and Adolescents assessed social functions, and the Chinese Health Questionnaire (CHQ) and Family Adaptation, Partnership, Growth, Affection, and Resolve evaluated parental and family functions. RESULTS: Switching from IR-MPH to OROS-MPH yielded significant improvements in all ADHD symptoms, as rated by parents, teachers (SNAP-IV), and study investigators (Clinical Global Impression). CHQ scores and all Social Adjustment Inventory for Children and Adolescents subscores except spare time scores improved significantly. Patients with poor IR-MPH adherence had greater improvements in teacher-rated SNAP-IV and mothers' mental health (CHQ) after switching. CONCLUSION: Switching from IR-MPH to OROS-MPH improved patients' behavioral ADHD symptoms and social adjustment, and mental health of patients' mothers. This was most evident in patients who previously exhibited poor IR-MPH adherence.

Dietary and nutrient status of children with attention-deficit/ hyperactivity disorder: a case-control study.

BACKGROUND AND OBJECTIVES: Nutritional and dietary habits may affect children's behaviors and learning. The etiology of attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental disorder in children, may be associated with unhealthy diets or nutrients deficiencies. The purpose of this study was to examine whether children with ADHD exhibited different dietary habits or nutrient profiles from healthy control subjects. METHODS AND STUDY DESIGN: We recruited 42 patients with ADHD (mean age: 8.1 years) and 36 healthy children as the control group (mean age: 9.8 years). We adopted the ADHD Rating Scale and the Swanson, Nolan, and Pelham Version IV Scale to interview both the ADHD patients and the control subjects and then evaluated participants' dietary intake with a food frequency questionnaire. Logistic regression models were utilized to produce a composite dietary/nutrient score, while receiver operating characteristic (ROC) was adopted to differentiate between the two participant groups. RESULTS: Compared to the control children, children with ADHD demonstrated a higher intake proportion of refined grains (p=0.026) and a lower proportion of dairy (p=0.013), calcium (p=0.043), and vitamin B-2 (p=0.024). We observed that the composite score of dietary and nutrient could significantly distinguish patients with ADHD from healthy controls (p<0.001). The composite dietary/nutrient score demonstrated a significant correlation with the severity of ADHD clinical symptoms (p<0.05). CONCLUSIONS: ADHD children and healthy controls have different dietary patterns and that dietary and nutrient factors may play a role in the pathophysiology of ADHD. Clinicians should consider dietary habits and specific nutrients in the routine assessment of children with ADHD.

Impact of Drug Adherence on Oppositional Defiant Disorder and Conduct Disorder Among Patients With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) may be a predecessor of oppositional defiant disorder (ODD) and conduct disorder (CD), and medication is an effective treatment option for ADHD. This study aims to examine whether adherence to medication treatment is associated with developing ODD and CD among youths with ADHD. METHODS: A total of 33,835 youths (4 years ≤ age of diagnosis ≤ 18 years) with ADHD (ICD-9-CM code 314.X) undergoing medication treatment for at least 90 days were selected from Taiwan's National Health Insurance Research Database during the period of January 2000 through December 2009. Patients' medical records were monitored through December 31, 2011, or until they had a diagnosis of ODD or CD. We categorized participants as compliant or noncompliant on the basis of a medication possession ratio (MPR) of 50%. RESULTS: The patients with better drug adherence (MPR ≥ 50%) exhibited a significantly decreased probability of developing ODD (53% reduction, P < .001) or CD (58% reduction, P < .001) when compared to the patients with poor drug adherence (MPR < 50%). The results in our sensitivity analyses showed that good drug adherence consistently exerted protective effects on ODD or CD, irrespective of patients' characteristics. Moreover, the patients with the best drug adherence (MPR ≥ 75%) had the lowest risks of developing ODD or CD. CONCLUSION: Among patients with ADHD undergoing drug therapy, a better drug adherence is associated with a lower likelihood of their developing ODD or CD in later life.

Heavy Metals' Effect on Susceptibility to Attention-Deficit/Hyperactivity Disorder: Implication of Lead, Cadmium, and Antimony.

Background: Heavy metals are known to be harmful for neurodevelopment and they may correlate to attention deficit/hyperactivity disorder (ADHD). In this study, we aim to explore the relationships between multiple heavy metals (manganese, lead, cadmium, mercury, antimony, and bismuth), neurocognitive function, and ADHD symptoms. Methods: We recruited 29 patients with ADHD inattentive type (ADHD-I), 47 patients with ADHD hyperactivity/impulsivity type (ADHD-H/I), and 46 healthy control children. Urine samples were obtained to measure the levels of the aforementioned heavy metals in each child. Participants’ cognitive function and clinical symptoms were assessed, respectively. Results: We found ADHD-H/I patients demonstrated the highest antimony levels (p = 0.028), and ADHD-I patients demonstrated the highest cadmium levels (p = 0.034). Antimony levels were positively correlated with the severity of ADHD symptoms that were rated by teachers, and cadmium levels were negatively correlated with the Full Scale Intelligence Quotient. Lead levels were negatively correlated with most indices of the Wechsler Intelligence Scale for Children⁻Fourth Edition (WISC-IV), but positively correlated with inattention and hyperactivity/impulsivity symptoms (p < 0.05). Conclusion: Lead, cadmium and antimony were associated with susceptibility to ADHD and symptom severity in school-age children. Eliminating exposure to heavy metals may help to prevent neurodevelopmental disorders in children.

Blood-Bourne MicroRNA Biomarker Evaluation in Attention-Deficit/Hyperactivity Disorder of Han Chinese Individuals: An Exploratory Study.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a highly genetic neurodevelopmental disorder, and its dysregulation of gene expression involves microRNAs (miRNAs). The purpose of this study was to identify potential miRNAs biomarkers and then use these biomarkers to establish a diagnostic panel for ADHD. Design and methods: RNA samples from white blood cells (WBCs) of five ADHD patients and five healthy controls were combined to create one pooled patient library and one control library. We identified 20 candidate miRNAs with the next-generation sequencing (NGS) technique (Illumina). Blood samples were then collected from a Training Set (68 patients and 54 controls) and a Testing Set (20 patients and 20 controls) to identify the expression profiles of these miRNAs with real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). We used receiver operating characteristic (ROC) curves and the area under the curve (AUC) to evaluate both the specificity and sensitivity of the probability score yielded by the support vector machine (SVM) model. Results: We identified 13 miRNAs as potential ADHD biomarkers. The ΔCt values of these miRNAs in the Training Set were integrated to create a biomarker model using the SVM algorithm, which demonstrated good validity in differentiating ADHD patients from control subjects (sensitivity: 86.8%, specificity: 88.9%, AUC: 0.94, p < 0.001). The results of the blind testing showed that 85% of the subjects in the Testing Set were correctly classified using the SVM model alignment (AUC: 0.91, p < 0.001). The discriminative validity is not influenced by patients' age or gender, indicating both the robustness and the reliability of the SVM classification model. Conclusion: As measured in peripheral blood, miRNA-based biomarkers can aid in the differentiation of ADHD in clinical settings. Additional studies are needed in the future to clarify the ADHD-associated gene functions and biological mechanisms modulated by miRNAs.

ADHD-related symptoms and attention profiles in the unaffected siblings of probands with autism spectrum disorder: focus on the subtypes of autism and Asperger's disorder.

BACKGROUND: The presence of attention-deficit/hyperactive disorder (ADHD) symptoms and impaired attention performance are commonly noted in individuals with autism spectrum disorder (ASD). However, little is known about attention performance in their unaffected siblings. This study aimed to investigate the ADHD-related traits and attention performance in unaffected siblings of probands with autism and Asperger syndrome (AS), as well as the clinical correlates of ADHD-related traits. METHODS: We assessed the intention, hyperactivity-impulsivity, and oppositional symptoms, and attention profiles of 199 probands with a diagnosis of ASD (122 autism, 77 AS), their unaffected siblings, and 196 typically developing controls (TD) by their parents' reports on the ADHD-related symptoms and the Connors' Continuous Performance Test (CCPT), respectively. RESULTS: Compared to TD, unaffected siblings of ASD probands were more hyperactive/impulsive and oppositional, particularly unaffected siblings of AS probands. In CCPT, unaffected siblings of AS have intermediate levels of performance between probands with AS and TD on focused attention and sustained attention but were not statistically different from AS probands or TD in these attention profiles. In contrast, unaffected siblings of autism probands have significantly better CCPT performance when compared to autism probands but not to TD. In addition, stereotyped behaviors predicted ADHD-related traits in both sibling groups, but distinctive patterns of other correlates for ADHD-related traits were found between the two sibling groups. CONCLUSIONS: This work suggested that unaffected siblings of AS, but not autism, have more hyperactive/impulsive traits and a trend of pervasive attention deficits assessed by CCPT which might serve as potential endophenotypes for genetic studies in AS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01582256.

Potential role of pre- and postnatal testosterone levels in attention-deficit/hyperactivity disorder: is there a sex difference?

OBJECTIVE: Both prenatal testosterone (T) exposure and postnatal T levels have been associated with developing neural circuitry and behavioral systems. This study examined the potential correlation between pre- and postnatal T levels and behavioral and neurocognitive profiles of children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Two hundred ADHD patients with a mean age of 8.7±2.0 years (158 boys and 42 girls) were recruited. The ratio of the length of the right index finger (2D) to that of the right ring finger (4D) (2D/4D ratio) served as a surrogate of prenatal T exposure, and postnatal T was determined using salivary T concentration. Behavioral symptoms were evaluated using the Swanson, Nolan, and Pelham - Version IV Scale for ADHD (SNAP-IV). Neurocognitive function was assessed using the Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV) and Conners' Continuous Performance Test (CPT). RESULTS: Lower 2D/4D ratios were associated with comorbid disruptive behavior disorders (t=2.15, P=0.033) in all participants. Among the boys with ADHD, neither 2D/4D ratios nor salivary T levels were associated with behavioral symptoms or neurocognitive function. Among the girls with ADHD, the salivary T level was positively correlated with the Perceptual Reasoning Index of the WISC-IV (r=0.48, P=0.001) and the Confidence Index (r=0.37, P=0.017) and Omission Errors of the CPT (r=0.62, P<0.001). CONCLUSION: Findings suggest that a higher prenatal T exposure is associated with a greater risk of developing disruptive behavior disorders, and T may exert differential neurocognitive effects between boys and girls with ADHD. However, the neurobiological mechanisms of T involved in the pathogenesis of ADHD warrant further investigation.

Polymorphisms of STS gene and SULT2A1 gene and neurosteroid levels in Han Chinese boys with attention-deficit/hyperactivity disorder: an exploratory investigation.

This study examined the relationships among polymorphisms of the STS gene and SULT2A1 gene, dehydroepiandrosterone (DHEA) and its sulfated form (DHEA-S), and characteristics of attention-deficit/hyperactivity disorder (ADHD). We used cheek swabs to obtain the genomic DNA of 200 ADHD male probands (mean age: 8.7 years), 192 patients' mothers and 157 patients' fathers. Three SNPs in the STS gene (rs6639786, rs2270112, and rs17268988) and one SNP in the SULT2A1 gene (rs182420) were genotyped. Saliva samples were collected from the ADHD patients to analyze DHEA and DHEA-S levels. The behavioral symptoms were evaluated with the Swanson, Nolan, and Pelham, and Version IV Scale for ADHD (SNAP-IV), and the neuropsychological function was assessed using the Conners' Continuous Performance Tests (CPT). We found the C allele of rs2270112 within the STS gene to be over-transmitted in males with ADHD. Polymorphisms of rs182420 within the SULT2A1 gene were not associated with ADHD. In addition, the C allele carriers of rs2270112 demonstrated significantly higher DHEA-S levels than the G allele carriers. Levels of DHEA were positively correlated with attention as measured by the CPT. These findings support a potential role in the underlying biological pathogenesis of ADHD with regard to STS polymorphisms and neurosteroid levels.

Does Methylphenidate Reduce Testosterone Levels in Humans? A Prospective Study in Children with Attention-Deficit/Hyperactivity Disorder.

Background: Animal studies and case reports have suggested that methylphenidate exerts adverse effects on gonadal hormones. This study aimed to determine whether methylphenidate alters testosterone levels in children with attention-deficit/hyperactivity disorder through comparison of those with or without methylphenidate treatment. Methods: This 4-week, nonrandomized, prospective study conducted in Taiwan included 203 attention-deficit/hyperactivity disorder patients with a mean age of 8.7 years (boys: 75.8%). After the initial recruitment, 137 received daily methylphenidate treatment (medicated group) and 66 were assessed through naturalistic observation (nonmedicated group). The saliva samples of attention-deficit/hyperactivity disorder patients were used to quantify testosterone levels at baseline and the endpoint by using the chemiluminescence immunoassay. At the 4th week, 86 patients in the medicated group and 46 patients in the nonmedicated group were eligible for statistical analyses. Results: During the study period, salivary testosterone levels did not significantly change in the medicated group (P=.389) or in the nonmedicated group (P=.488). After correction for the potential confounding effects of age and sex, salivary testosterone levels still remained unchanged in the medicated and nonmedicated groups during the 4-week follow-up. In the medicated group, changes in salivary testosterone levels over 4 weeks were not significantly correlated with the methylphenidate daily dose (mean daily dose: 18.1 mg). Conclusions: Findings suggest that short-term treatment with methylphenidate at usual doses does not significantly alter salivary testosterone levels in attention-deficit/hyperactivity disorder patients. Future studies should clarify whether long-term methylphenidate treatment disrupts testosterone production as well as the function of the reproductive system.