1. Anagnostou E, Aman MG, Handen BL, Sanders KB, Shui A, Hollway JA, Brian J, Arnold LE, Capano L, Hellings JA, Butter E, Mankad D, Tumuluru R, Kettel J, Newsom CR, Hadjiyannakis S, Peleg N, Odrobina D, McAuliffe-Bellin S, Zakroysky P, Marler S, Wagner A, Wong T, Macklin EA, Veenstra-VanderWeele J. {{Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial}}. {JAMA Psychiatry}. 2016.
Importance: Atypical antipsychotic medications are indicated for the treatment of irritability and agitation symptoms in children with autism spectrum disorder (ASD). Unfortunately, these medications are associated with weight gain and metabolic complications that are especially troubling in children and with long-term use. Objective: To evaluate the efficacy of metformin for weight gain associated with atypical antipsychotic medications in children and adolescents with ASD (defined in the protocol as DSM-IV diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified), aged 6 to 17 years. Design, Setting, and Participants: A 16-week, double-blind, placebo-controlled, randomized clinical trial was conducted at 4 centers in Toronto, Ontario, Canada; Columbus, Ohio; Pittsburgh, Pennsylvania; and Nashville, Tennessee. In all, 209 potential participants were screened by telephone, 69 individuals provided consent, and 61 participants were randomized to receive metformin or placebo between April 26, 2013, and June 24, 2015. Interventions: Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years. Main Outcomes and Measures: The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication. Results: Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005). Conclusions and Relevance: Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD. Trial Registration: clinicaltrials.gov Identifier: NCT01825798.
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3. Buchele G, Becker C, Cameron ID, Auer R, Rothenbacher D, Konig HH, Rapp K. {{Fracture risk in people with developmental disabilities: results of a large claims data analysis}}. {Osteoporos Int}. 2016.
Age- and sex-specific fracture rates of 18,000 people with developmental disabilities aged 0-69 years were compared to the general population. Age-standardized incidence of femoral fracture was 4.8- and 7.1-fold higher in women and men, respectively. Comparable fracture risks to the general population occurred 10-15 years earlier in females and 20-40 years earlier in males. INTRODUCTION: Previous studies suggested that fracture risks in people with developmental disabilities (DD) may be higher than in people in the general population. However, there are no current sufficiently large studies to compare age- and sex-specific fracture rates of single fracture types. METHODS: People with DD and incident fractures were identified by routine data of a health insurance company. Fractures in the general population were derived from the official fracture statistics. Age-specific and age-standardized fracture incidences were analyzed. To compare fracture risks in people with DD with that of the general population incidence ratios were calculated. RESULTS: Between 2008 and 2010, 148 femoral fractures and 469 other fractures were observed in nearly 18,000 people with DD aged 0-69 years. The three most frequent fracture types leading to hospital admission were fractures of the femur, lower leg/ankle, and shoulder/arm. For femoral fractures, a particularly high risk was observed in children and adolescents with DD. In adults with DD, the risk of femoral fractures increased with increasing age. Even if the youngest age category was not considered, the age-standardized incidence was 4.8- and 7.1-fold higher in women and men, respectively. For all other fracture types, except fractures of forearm/hand and of pelvis, people with DD had also higher fracture incidences than the general population. CONCLUSIONS: People with DD have a high fracture burden. Comparable risks of femoral fracture, for example, occurred about 10-15 years earlier in females and even 20-40 years earlier in males with DD than in the general population.
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5. Happe FG, Mansour H, Barrett P, Brown T, Abbott P, Charlton RA. {{Demographic and Cognitive Profile of Individuals Seeking a Diagnosis of Autism Spectrum Disorder in Adulthood}}. {J Autism Dev Disord}. 2016.
Little is known about ageing with autism spectrum disorder (ASD). We examined the characteristics of adults referred to a specialist diagnostic centre for assessment of possible ASD, 100 of whom received an ASD diagnosis and 46 did not. Few demographic differences were noted between the groups. Comorbid psychiatric disorders were high in individuals with ASD (58 %) and non-ASD (59 %). Individuals who received an ASD diagnosis had higher self-rated severity of ASD traits than non-ASD individuals. Within the ASD group, older age was associated with higher ratings of ASD traits and better cognitive performance. One interpretation is that general cognitive ability and the development of coping strategies across the lifespan, do not necessarily reduce ASD traits but may mitigate their effects.
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7. Jeddi MZ, Janani L, Memari AH, Akhondzadeh S, Yunesian M. {{The role of phthalate esters in autism development: A systematic review}}. {Environ Res}. 2016; 151: 493-504.
BACKGROUND: Available evidence implicates environmental factors in the pathogenesis of autism spectrum disorders (ASD). However, the role of specific environmental chemicals such as phthalate esters that influence ASD risk remains elusive. This paper systematically reviews published evidences on association between prenatal and/or childhood exposure to phthalate and ASD. METHODS: Studies pertaining to systematic literature search from Scopus, PubMed, PsycInfo and Web of Science prior to December 2015 were identified. The authors included studies which assessed the effect of exposure to phthalates on occurrence of ASD. This comprehensive bibliographic search identified five independent studies. Each eligible paper was summarized with respect to its methods and results with particular attention to study design and exposure assessment. Because of the heterogeneity in the type of included studies, different methods of assessing exposure to phthalates and the use of different statistics for summarizing the results, meta-analysis could not be used to combine the results of included studies. RESULTS: The results of this systematic review have revealed the limited number of studies conducted and assessed phthalate exposure. Seven studies were regarded as relevant to the objectives of this review. Two of them did not measure phthalate exposure directly and did not result in quantitative results. Out of the five studies in which phthalate exposure was mainly measured by the examining biomarkers in biological samples, two were cohort studies (one with positive results and another one with not clear association). Among the three case control studies, two of them showed a significant relation between exposure to phthalate and ASD and the last case control study had negative results. Indeed, this case control studies showed a compromised phthalate metabolite glucuronidation pathway, as a probable explanation of mechanism of the relation between phthalate exposure and ASD. CONCLUSIONS: This review reveals evidence showing a connection between exposure to phthalates and ASD. Nevertheless, further research is needed with appropriate attention to exposure assessment and relevant pre and post-natal cofounders.
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9. Kosaka H, Okamoto Y, Munesue T, Yamasue H, Inohara K, Fujioka T, Anme T, Orisaka M, Ishitobi M, Jung M, Fujisawa TX, Tanaka S, Arai S, Asano M, Saito DN, Sadato N, Tomoda A, Omori M, Sato M, Okazawa H, Higashida H, Wada Y. {{Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial}}. {Transl Psychiatry}. 2016; 6(8): e872.
Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than 21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for 21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.
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11. Pedersen AL, Pettygrove S, Lu Z, Andrews J, Meaney FJ, Kurzius-Spencer M, Lee LC, Durkin MS, Cunniff C. {{DSM Criteria that Best Differentiate Intellectual Disability from Autism Spectrum Disorder}}. {Child Psychiatry Hum Dev}. 2016.
Clinical characteristics of autism spectrum disorder (ASD) and intellectual disability (ID) overlap, creating potential for diagnostic confusion. Diagnostic and statistical manual of mental disorders (DSM) criteria that best differentiate children with ID and some ASD features from those with comorbid ID and ASD were identified. Records-based surveillance of ASD among 8-year-old children across 14 US populations ascertained 2816 children with ID, with or without ASD. Area under the curve (AUC) was conducted to determine discriminatory power of DSM criteria. AUC analyses indicated that restricted interests or repetitive behaviors best differentiated between the two groups. A subset of 6 criteria focused on social interactions and stereotyped behaviors was most effective at differentiating the two groups (AUC of 0.923), while communication-related criteria were least discriminatory. Matching children with appropriate treatments requires differentiation between ID and ASD. Shifting to DSM-5 may improve differentiation with decreased emphasis on language-related behaviors.
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13. Soto T, Giserman Kiss I, Carter AS. {{SYMPTOM PRESENTATIONS AND CLASSIFICATION OF AUTISM SPECTRUM DISORDER IN EARLY CHILDHOOD: APPLICATION TO THE DIAGNOSTIC CLASSIFICATION OF MENTAL HEALTH AND DEVELOPMENTAL DISORDERS OF INFANCY AND EARLY CHILDHOOD (DC:0-5)}}. {Infant Ment Health J}. 2016.
Over the past 5 years, a great deal of information about the early course of autism spectrum disorder (ASD) has emerged from longitudinal prospective studies of infants at high risk for developing ASD based on a previously diagnosed older sibling. The current article describes early ASD symptom presentations and outlines the rationale for defining a new disorder, Early Atypical Autism Spectrum Disorder (EA-ASD) to accompany ASD in the new revision of the ZERO TO THREE Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood (DC:0-5) (in press) alternative diagnostic classification manual. EA-ASD is designed to identify children who are 9 to 36 months of age presenting with a minimum of (a) two social-communication symptoms and (b) one repetitive and restricted behavior symptom as well as (c) evidence of impairment, with the intention of providing these children with appropriately tailored services and improving the likelihood of optimizing their development.
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15. Yoshimura Y, Kikuchi M, Hiraishi H, Hasegawa C, Takahashi T, Remijn GB, Oi M, Munesue T, Higashida H, Minabe Y. {{Synchrony of auditory brain responses predicts behavioral ability to keep still in children with autism spectrum disorder: Auditory-evoked response in children with autism spectrum disorder}}. {Neuroimage Clin}. 2016; 12: 300-5.
The auditory-evoked P1m, recorded by magnetoencephalography, reflects a central auditory processing ability in human children. One recent study revealed that asynchrony of P1m between the right and left hemispheres reflected a central auditory processing disorder (i.e., attention deficit hyperactivity disorder, ADHD) in children. However, to date, the relationship between auditory P1m right-left hemispheric synchronization and the comorbidity of hyperactivity in children with autism spectrum disorder (ASD) is unknown. In this study, based on a previous report of an asynchrony of P1m in children with ADHD, to clarify whether the P1m right-left hemispheric synchronization is related to the symptom of hyperactivity in children with ASD, we investigated the relationship between voice-evoked P1m right-left hemispheric synchronization and hyperactivity in children with ASD. In addition to synchronization, we investigated the right-left hemispheric lateralization. Our findings failed to demonstrate significant differences in these values between ASD children with and without the symptom of hyperactivity, which was evaluated using the Autism Diagnostic Observational Schedule, Generic (ADOS-G) subscale. However, there was a significant correlation between the degrees of hemispheric synchronization and the ability to keep still during 12-minute MEG recording periods. Our results also suggested that asynchrony in the bilateral brain auditory processing system is associated with ADHD-like symptoms in children with ASD.
