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Vitamin D deficiency during critical periods of development could lead to persistent brain alterations. We aimed to assess the association between maternal vitamin D-3, the major circulatory form of vitamin D, at pregnancy and neurodevelopmental outcomes during childhood, namely: behavioural problems, Attention Deficit and Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) symptoms, and social competence. This study included 2,107 mother-child pairs of a Spanish population-based birth cohort. Maternal plasma vitamin D-3 was measured in pregnancy. The outcomes were measured through questionnaires at 5, 8, 14, and 18 years old. We ran multivariate regression models adjusted for potential confounding variables. We found that per each 10 ng/mL increment of maternal vitamin D-3, children obtained higher social competence scores (coefficient =0.77; 95% CI=0.19, 1.35) at 5 years old. However, we observed null associations between maternal vitamin D-3 and total behavioural problems and ADHD and ASD symptoms in children from 5 to 18 years old. Further studies carried out in countries where the population is exposed to lower vitamin D levels are needed., The authors are grateful to all the teachers, parents and children who have participated in the INMA project for their generous collaborative efforts. We thank all the investigators who have collected information and samples from the participants. Menorca: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; 97/0588; 00/0021-2; PI061756; PS0901958; PI14/00677 incl. FEDER funds), CIBERESP, Beca de la IV convocatoria de Ayudas a la Investigacion en Enfermedades Neurodegenerativas de La Caixa, and EC Contract No. QLK4-CT-2000-00263. Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; CPII/00018), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR 2009 SGR 501, Fundacio La marato de TV3 (090430), EU Commission (261357). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Valencia: This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI11/01007, PI11/02591, PI11/02038, PI12/00610, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, and PI17/00663; Miguel Servet-FEDER CP11/00178, CP15/00025, and MSII16/00051), Generalitat Valenciana: FISABIO (UGP 15-230, UGP15-244, and UGP-15-249), and Alicia Koplowitz Foundation 2017. Asturias: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), FIS-PI042018, FIS-PI09/02311, FIS-PI13/02429, FIS-PI18/00909, CIBERESP, Obra Social Cajastur/Fundacion Liberbank and UNIVERSIDAD DE OVIEDO. Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867, FIS-PI09/00090 and FIS-PI13/02187), CIBERESP, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain).

Objectives A secondary objective of this head-to-head study of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) was to assess treatment response rates in children and adolescents with attention-deficit hyperactivity disorder (ADHD) and an inadequate response to methylphenidate (MPH). The primary efficacy and safety outcomes of the study, SPD489-317 (ClinicalTrials.gov NCT01106430), have been published previously. Methods In this 9-week, double-blind, active-controlled study, patients aged 6-17 years with a previous inadequate response to MPH were randomized (1:1) to dose-optimized LDX (30, 50 or 70 mg/day) or ATX (patients < 70 kg: 0.5-1.2 mg/kg/day, not to exceed 1.4 mg/kg/day; patients = 25, >= 30 or >= 50 %) or a Clinical Global Impressions (CGI)-Improvement (CGI-I) score of 1 or 2 throughout weeks 4-9. CGI-Severity (CGI-S) scores were also assessed, as an indicator of remission. Results A total of 267 patients were enrolled (LDX, n = 133; ATX, n = 134) and 200 completed the study (LDX, n = 99; ATX, n = 101). By week 9, significantly (p < 0.01) greater proportions of patients receiving LDX than ATX met the response criteria of a reduction from baseline in ADHD-RS-IV total score of at least 25 % (90.5 vs. 76.7 %), 30 % (88.1 vs. 73.7 %) or 50 % (73.0 vs. 50.4 %). Sustained response rates were also significantly (p < 0.05) higher among LDX-treated patients (ADHD-RS-IV >= 25, 66.1 %; ADHD-RS-IV >= 30, 61.4 %; ADHD-RS-IV >= 50, 41.7 %; CGI-I, 52.0 %) than among ATX-treated individuals (ADHD-RS-IV >= 25, 51.1 %; ADHD-RS-IV >= 30, 47.4 %; ADHD-RS-IV >= 50, 23.7 %; CGI-I, 39.3 %). Finally, by week 9, 60.7 % of patients receiving LDX and 46.3 % of those receiving ATX had a CGI-S score of 1 (normal, not at all ill) or 2 (borderline mentally ill), and greater proportions of patients in the LDX group than the ATX group experienced a reduction from baseline of at least one CGI-S category. Conclusions Both LDX and ATX treatment were associated with high levels of treatment response in children and adolescents with ADHD and a previous inadequate response to MPH. However, within the parameters of the study, LDX was associated with significantly higher treatment response rates than ATX across all response criteria examined. In addition, higher proportions of patients in the LDX group than the ATX group had a CGI-S score of 1 or 2 by week 9, indicating remission of symptoms. Both treatments were generally well tolerated, with safety profiles consistent with those observed in previous studies., This study was supported by funding from Shire. The authors thank the patients and their parents, and the investigators who took part in the study. Esther Cardo, David R. Coghill, Ralf W. Dittmann and Peter Nagy were principal investigators in this clinical study. Colleen S. Anderson, Beatriz Caballero, Richard Civil, Ralf W. Dittmann and Paul Hodgkins contributed to the study design. Ben Adeyi was responsible for the statistical analysis. All authors were involved in the discussion and interpretation of the data, critically revised the article and approved the manuscript before submission. Dr Tamzin Gristwood and Dr Eric Southam of Oxford PharmaGenesis (TM) Ltd provided writing and editing assistance, collated the comments of the authors and edited the manuscript for submission, with funding from Shire. Ben Adeyi, Colleen S. Anderson and Beatriz Caballero are employees of Shire and own stock/stock options. Richard Civil is a former employee of Shire. Paul Hodgkins is a former employee of Shire and a current employee of Vertex Pharmaceuticals. The following authors have received compensation for serving as consultants or speakers, or they, or the institutions they work for, have received research support or royalties from the companies or organizations indicated: Esther Cardo (Eli Lilly, Health Spanish Ministry Research Fund, Ministry of Education Grant Research, Shire, UCB); David R. Coghill (Flynn Pharma, Janssen-Cilag, Lilly, Medice, Novartis, Otsuka, Oxford University Press, Pfizer, Schering-Plough, Shire, UCB, Vifor Pharma); Ralf W. Dittmann (Ferring, Janssen-Cilag, Lilly, Otsuka, Shire, German Research Foundation [DFG], German Ministry of Education and Research [BMBF], Ministry of Health/German Regulatory Body [BfArM], European Union [EU FP7 program], US National Institute of Mental Health (NIMH), and he is a former employee and stock-holder of Eli Lilly and Co.); Peter Nagy (Tourette Syndrome Association of USA, Hungarian Ministry of Education, National Development Agency of Hungary, Otsuka, Shire).

Attention-deficit/hyperactivity disorder (ADHD) is associated with functional impairments in multiple domains of patients' lives. A secondary objective of this randomized, active-controlled, head-to-head, double-blind, dose-optimized clinical trial was to compare the effects of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) on functional impairment in children and adolescents with ADHD. Patients aged 6-17 years with an ADHD Rating Scale IV total score a parts per thousand yen28 and an inadequate response to methylphenidate treatment (judged by investigators) were randomized (1:1) to once-daily LDX or ATX for 9 weeks. Parents/guardians completed the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at baseline and at week 9 or early termination. p values were nominal and not corrected for multiple comparisons. Of 267 randomized patients, 200 completed the study (LDX 99, ATX 101). At baseline, mean WFIRS-P total score in the LDX group was 0.95 [standard deviation (SD) 0.474; 95 % confidence interval (CI) 0.87, 1.03] and in the ATX group was 0.91 (0.513; 0.82, 1.00). Scores in all WFIRS-P domains improved from baseline to endpoint in both groups, with least-squares mean changes in total score of -0.35 (95 % CI -0.42, -0.29) for LDX and -0.27 (-0.33, -0.20) for ATX. The difference between LDX and ATX was statistically significant (p < 0.05) for the Learning and School (effect size of LDX vs ATX, 0.43) and Social Activities (0.34) domains and for total score (0.27). Both treatments reduced functional impairment in children and adolescents with ADHD; LDX was statistically significantly more effective than ATX in two of six domains and in total score., Study SPD489-317 was funded by Shire Development LLC. Shire develops and markets drugs to treat psychiatric disorders, including ADHD. The authors thank the patients and their parents/guardians and the investigators who took part in the study, including the coordinating principal investigator, Professor Ralf W Dittmann (Paediatric Psychopharmacology, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany). E Cardo, DR Coghill, A Hage, and P Nagy were investigators or principal investigators in this clinical study. CS Anderson, B Caballero, and V Sikirica contributed to the study design. B Adeyi was responsible for the statistical analysis. All authors were involved in discussion and interpretation of the data, critically revised the article, and approved the manuscript for submission. Shire International GmbH provided funding to Oxford PharmaGenesis (TM) Ltd for writing and editorial support for this publication. Dr T Gristwood and Dr E Southam of Oxford PharmaGenesis (TM) Ltd provided writing assistance under the direction of the authors. Editorial assistance in editing, fact checking, formatting, proofreading, and submission was also provided by Oxford PharmaGenesis (TM) Ltd.

The aim of this study was to compare the efficacy and safety of the prodrug psychostimulant lisdexamfetamine dimesylate (LDX) and the non-stimulant noradrenergic compound atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who had previously responded inadequately to methylphenidate (MPH). This 9-week, head-to-head, randomized, double-blind, active-controlled study (SPD489-317; ClinicalTrials.gov NCT01106430) enrolled patients (aged 6-17 years) with at least moderately symptomatic ADHD and an inadequate response to previous MPH therapy. Patients were randomized (1:1) to an optimized daily dose of LDX (30, 50 or 70 mg) or ATX (patients < 70 kg, 0.5-1.2 mg/kg with total daily dose not to exceed 1.4 mg/kg; patients a parts per thousand yen70 kg, 40, 80 or 100 mg). The primary efficacy outcome was time (days) to first clinical response. Clinical response was defined as a Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved). Secondary efficacy outcomes included the proportion of responders at each study visit and the change from baseline in ADHD Rating Scale (ADHD-RS-IV) and CGI-Severity scores. Tolerability and safety were assessed by monitoring treatment-emergent adverse events (TEAEs), height and weight, vital signs and electrocardiogram parameters. Endpoint was defined as the last post-baseline, on-treatment visit with a valid assessment. Of 267 patients randomized (LDX, n = 133; ATX, n = 134), 200 (74.9 %) completed the study. The median time to first clinical response [95 % confidence interval (CI)] was significantly shorter for patients receiving LDX [12.0 days (8.0-16.0)] than for those receiving ATX [21.0 days (15.0-23.0)] (p = 0.001). By week 9, 81.7 % (95 % CI 75.0-88.5) of patients receiving LDX had responded to treatment compared with 63.6 % (95 % CI 55.4-71.8) of those receiving ATX (p = 0.001). Also by week 9, the difference between LDX and ATX in least-squares mean change from baseline (95 % CI) was significant in favour of LDX for the ADHD-RS-IV total score [-6.5 (-9.3 to -3.6); p < 0.001; effect size 0.56], inattentiveness subscale score [-3.4 (-4.9 to -1.8); p < 0.001; effect size 0.53] and the hyperactivity/impulsivity subscale score [-3.2 (-4.6 to -1.7); p < 0.001; effect size 0.53]. TEAEs were reported by 71.9 and 70.9 % of patients receiving LDX and ATX, respectively. At endpoint, both treatments were associated with mean (standard deviation) increases in systolic blood pressure [LDX, +0.7 mmHg (9.08); ATX, +0.6 mmHg (7.96)], diastolic blood pressure [LDX, +0.1 mmHg (8.33); ATX, +1.3 mmHg (8.24)] and pulse rate [LDX, +3.6 bpm (10.49); ATX, +3.7 bpm (10.75)], and decreases in weight [LDX, -1.30 kg (1.806); ATX, -0.15 kg (1.434)]. LDX was associated with a faster and more robust treatment response than ATX in children and adolescents with at least moderately symptomatic ADHD who had previously responded inadequately to MPH. Both treatments displayed safety profiles consistent with findings from previous clinical trials., This study was supported by funding from Shire. The authors thank the patients and their parents, and the investigators who took part in the study.; C. S. Anderson, R. Bloomfield, B. Caballero, R. Civil, N. Higgins, P. Hodgkins and A. Lyne are employees of Shire and own stock/stock options. The following authors have received compensation for serving as consultants or speakers, or they or the institutions they work for have received research support or royalties from the companies or organizations indicated: E. Cardo (Eli Lilly, Health Spanish Ministry Research Fund, Ministry of Education Grant Research, Shire, UCB); D. Coghill (Flynn Pharma, Janssen-Cilag, Lilly, Medice, Novartis, Otsuka, Oxford University Press, Pfizer, Schering-Plough, Shire, UCB, Vifor Pharma); R. W. Dittmann (Ferring, Janssen-Cilag, Lilly, Otsuka, Shire, the German Research Foundation [DFG], the German Ministry of Education and Research [BMBF], the Ministry of Health/the German Regulatory Body [BfArM], the European Union [EU FP7 program], the US National Institute of Mental Health NIMH, and he is a former employee and stockholder of E. Lilly and Co.); P. Nagy (Tourette Syndrome Association of USA, Hungarian Ministry of Education, National Development Agency of Hungary, Otsuka, Shire).

There are at present very few studies of the effects of polybromodiphenyl ethers (PBDEs), used as flame retardants in consumer products, on neurodevelopment or thyroid hormone levels in humans. The present study aims to examine the association between pre and postnatal PBDE concentrations and neurodevelopment and thyroid hormone levels in children at age 4 years and isolate the effects of PBDEs from those of PCBs, DDT, DDE and HCB. A prospective birth cohort in Menorca (Spain) enrolled 482 pregnant mothers between 1997 and 1998. At 4 years, children were assessed for motor and cognitive function (McCarthy Scales of Children's Abilities), attention-deficit, hyperactivity and impulsivity (ADHD-DSM-IV) and social competence (California Preschool Social Competence Scale). PBDE concentrations were measured in cord blood (N=88) and in serum of 4 years olds (N=244). Among all congeners analyzed only PBDE 47 was quantified in a reasonable number of samples (LOQ=0.002 ng/ml). Exposure to PBDE 47 was analyzed as a dichotomous variable: concentrations above the LOQ (exposed) and concentrations below (referents). Scores for cognitive and motor functions were always lower in children pre and postnatally exposed to PBDE47 than in referents, but none of these associations was statistically significant (beta coefficient (95% CI) of the total cognition score: -2.7 (-7.0, 1.6) for postnatal exposure, and -1.4 (-92.6.5) for prenatal exposure). Postnatal exposure to PBDE 47 was statistically significantly related to an increased risk of symptoms on the attention deficit subscale of ADHD symptoms (RR (95%CI) = 1.8 (1.0, 3.2)) but not to hyperactivity symptoms. A statistically significant higher risk of poor social competence symptoms was observed as a consequence of postnatal PBDE 47 exposure (RR (95% CI) = 2.6 (1.2, 5.9)). Adjustment for other organochlorine compounds did not influence the results. Levels of thyroid hormones were not associated to PBDE exposure. This study highlights the importance of assessing the effects of PBDE exposure not just prenatally but also during the early years of life. In the light of current evidence a precautionary approach towards PBDE exposure of both mothers and children seems warranted., This study was supported by Instituto de Salud Carlos III, Red de Grupos INMA (G03/176). It has also been partially supported by the Fundacio La Caixa (00/077-00), the Instituto de Salud Carlos III, Red de Centros RCESP (C03/09) and FIS 041436, 061756 and 091958. Finally the authors would like to be grateful to the families and schools in Menorca participating in the study.

4 pages, 4 tables.-- PMID: 17431497 [PubMed].-- PMCID: PMC1849941., [Background] Hexachlorobenzene (HCB) is an organochlorine chemical that has been used in agriculture and industrial processes. Behavioral impairment after HCB exposure has been described in animal models, but little information is available in humans., [Objectives] Our goal was to study the association of prenatal exposure to HCB with the social behavior of preschool children., [Methods] Two birth cohorts in Ribera d’Ebre and Menorca (Spain) were set up between 1997 and 1999 (n = 475). The California Preschool Social Competence Scale and the Attention-Deficit Hyperactivity Disorder (ADHD) were scored by each 4-year-old child’s teacher. Organochlorine compounds were measured in cord serum. Children’s diet and parental sociodemographic information were obtained through questionnaire., [Results] Children with concentrations of HCB > 1.5 ng/mL at birth had a statistically significant increased risk of having poor Social Competence [relative risk (RR) = 4.04; 95% confidence interval (CI), 1.76–9.58] and ADHD (RR = 2.71; 95% CI, 1.05–6.96) scores. No association was found between HCB and the cognitive and psychomotor performance of these children., [Conclusions] Prenatal exposure to current concentrations of HCB in Spain is associated with a decrease in the behavioral competence at preschool ages. These results should be considered when evaluating the potential neurotoxicologic effects of HCB., This study was funded by grants from the Spanish Ministry of Health (FIS-97/1102, FIS-PI041436), Instituto de Salud Carlos III (Red RCESP C03/09 and Red INMA G03/176), Fundació “la Caixa” (97/009-00 and 00/077-00), and the Generalitat de Catalunya-CIRIT (1999SGR 00241).

Background Current standardized treatments for cognitive impairment in attention-deficit/hyperactivity disorder remain limited and their efficacy restricted. Transcranial direct current stimulation (tDCS) is a promising tool for enhancing cognitive performance in several neuropsychiatric disorders. Nevertheless, the effects of tDCS in reducing cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD) have not yet been investigated. Methods A parallel, randomized, double-blind, sham-controlled trial was conducted to examine the efficacy of tDCS on the modulation of inhibitory control in adults with ADHD. Thirty patients were randomly allocated to each group and performed a go/no-go task before and after a single session of either anodal stimulation (1 mA) over the left dorsolateral prefrontal cortex or sham stimulation. Results A nonparametric two-sample Wilcoxon rank-sum (Mann-Whitney) test revealed no significant differences between the two groups of individuals with ADHD (tDCS vs. sham) in regard to behavioral performance in the go/no go tasks. Furthermore, the effect sizes of group differences after treatment for the primary outcome measures-correct responses, impulsivity and omission errors-were small. No adverse events resulting from stimulation were reported. Conclusion According to these findings, there is no evidence in support of the use of anodal stimulation over the left dorsolateral prefrontal cortex as an approach for improving inhibitory control in ADHD patients. To the best of our knowledge, this is the first clinical study to assess the cognitive effects of tDCS in individuals with ADHD. Further research is needed to assess the clinical efficacy of tDCS in this population., The authors received no specific funding for this trial. CC and PM received scholarship from CAPES/Brazil.