RESUMO
This study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5-45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p < 0.001). The improvement in PARS score for mirtazapine versus placebo was clinically meaningful but not statistically significant (ES = 0.63, p = 0.64). Forty-seven percent of participants assigned to mirtazapine (95% CI 22%: 74%) and 20% assigned to placebo (95% CI 2%: 60%) were rated "much improved" (CGI-I = 2) or "very much improved" (CGI-I = 1) for anxiety, p = 0.46. No statistically significant differences in mean 10-week changes between mirtazapine and placebo occurred on any outcome measure. There were no statistically significant differences in adverse effect frequency between mirtazapine and placebo. The results are consistent with mirtazapine's safety and tolerability and meet three of four pre-specified indicators of efficacy (statistically significant change in total PARS score for mirtazapine, numerically greater reduction in total PARS score for mirtazapine than placebo, numerically higher number of responders to mirtazapine than placebo, but not greater than 50% of participants receiving mirtazapine rated as responders). Implementation of a larger randomized controlled trial of mirtazapine for the treatment of anxiety in this population is supported.Clinical trial registration information: Mirtazapine Treatment of Anxiety in Children and Adolescents with Pervasive Developmental Disorders; https://clinicaltrials.gov ; NCT01302964.
Assuntos
Transtorno do Espectro Autista , Adolescente , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/tratamento farmacológico , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/tratamento farmacológico , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Mirtazapina/uso terapêutico , Projetos Piloto , Resultado do TratamentoRESUMO
BACKGROUND: d-Cycloserine (DCS) enhances extinction learning across species, but it has proven challenging to identify consistent benefit of DCS when added to therapeutic interventions. We conducted a placebo-controlled trial of DCS to potentiate social skills training in autism spectrum disorder (ASD) but found substantial improvement in both the DCS and placebo groups at the conclusion of active treatment. Here, we assess the impact of DCS 11 weeks following active treatment to evaluate the impact of DCS on treatment response durability. METHODS: Study participants included 60 outpatient youth with ASD, ages 5-11 years, all with IQ above 70, and significantly impaired social functioning who completed a 10-week active treatment phase during which they received weekly single doses of 50 mg of DCS or placebo administered 30 min prior to group social skills training. Following the 10-week active treatment phase, blinded follow-up assessments occurred at week 11 and week 22. The primary outcome measure for our durability of treatment evaluation was the parent-rated social responsiveness scale (SRS) total raw score at week 22. RESULTS: Analysis of the SRS total raw score demonstrated significant decrease for the DCS group compared to the placebo group (p = 0.042) indicating greater maintenance of treatment effect in the DCS group. DCS was well tolerated, with irritability being the most frequently reported adverse effect in both groups. CONCLUSIONS: The findings of this study suggest that DCS may help youth with ASD to maintain skills gained during sort-term social skills training. Larger-scale studies with longer follow-up will be necessary to further understand the long-term impact of DCS paired with structured social skills training. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01086475.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Ciclosserina/administração & dosagem , Aprendizagem/efeitos dos fármacos , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Ciclosserina/farmacologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Comportamento Social , Resultado do TratamentoRESUMO
BACKGROUND: Social impairment is a defining feature of autism spectrum disorder (ASD) with no demonstrated effective pharmacologic treatments. The goal of this study was to evaluate efficacy, safety, and tolerability of oral N-acetylcysteine (NAC), an antioxidant whose function overlaps with proposed mechanisms of ASD pathophysiology, targeting core social impairment in youth with ASD. METHODS: This study was a 12-week randomized, double-blind, placebo-controlled trial of oral NAC in youth with ASD. Study participants were medically healthy youth age 4 to 12 years with ASD, weighing ≥15 kg, and judged to be moderately ill based on the Clinical Global Impressions Severity scale. The participants were randomized via computer to active drug or placebo in a 1:1 ratio, with the target dose of NAC being 60 mg/kg/day in three divided doses. The primary outcome measure of efficacy was the Clinical Global Impressions Improvement (CGI-I) scale anchored to core social impairment. To investigate the impact of NAC on oxidative stress markers in peripheral blood, venous blood samples were collected at screen and week 12. RESULTS: Thirty-one patients were enrolled (NAC = 16, placebo = 15). Three participants were lost to follow-up, and three left the trial due to adverse effects. The average daily dose of NAC at week 12 was 56.2 mg/kg (SD = 9.7) with dose ranging from 33.6 to 64.3 mg/kg. The frequency of adverse events was so low that comparisons between groups could not be conducted. At week 12, there was no statistically significant difference between the NAC and placebo groups on the CGI-I (p > 0.69) but the glutathione (GSH) level in blood was significantly higher in the NAC group (p < 0.05). The oxidative glutathione disulfide (GSSG) level increased in the NAC group, however only at a trend level of significance (p = 0.09). There was no significant difference between the NAC and placebo groups in the GSH/GSSG ratio, DNA strand break and oxidative damage, and blood homocysteine levels at week 12 (ps > 0.16). CONCLUSIONS: The results of this trial indicate that NAC treatment was well tolerated, had the expected effect of boosting GSH production, but had no significant impact on social impairment in youth with ASD. TRIAL REGISTRATION: Clinicaltrials.gov NCT00453180.
Assuntos
Acetilcisteína/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Acetilcisteína/farmacologia , Administração Oral , Criança , Pré-Escolar , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Glutationa/sangue , Homocisteína/sangue , Humanos , Masculino , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Projetos Piloto , Efeito Placebo , Comportamento SocialRESUMO
BACKGROUND: Researchers have demonstrated that d-cycloserine (DCS) can enhance the effects of behavioral interventions in adults with anxiety and enhances prosocial behavior in animal models of autism spectrum disorders (ASD). This study extended upon this background by combining DCS with behavioral social skills therapy in youth with ASD to assess its impact on the core social deficits of ASD. We hypothesized that DCS used in combination with social skills training would enhance the acquisition of social skills in children with ASD. METHODS: A 10-week, double-blind, placebo-controlled trial of DCS (50 mg) given 30 min prior to weekly group social skills training was conducted at two sites. Children with ASD were randomized to receive 10 weeks (10 doses) of DCS or placebo in a 1:1 ratio. RESULTS: No statistically significant difference attributable to drug treatment was observed in the change scores for the primary outcome measure, the Social Responsiveness Scale (SRS), total score (p = 0.45), or on secondary outcome measures. CONCLUSIONS: The results of this trial demonstrated no drug-related short-term improvement on the primary outcome measure, or any of the secondary outcome measures. However, an overall significant improvement in SRS total raw score was observed from baseline to end of treatment for the entire group of children with ASD. This suggests a need to further study the efficacy of the social skills training protocol. Limitations to the current study and areas for future research are discussed. TRIAL REGISTRATION: ClinicalTrials.govNCT01086475.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Terapia Comportamental , Ciclosserina/uso terapêutico , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Habilidades Sociais , Transtorno do Espectro Autista/psicologia , Transtorno do Espectro Autista/terapia , Criança , Pré-Escolar , Ciclosserina/efeitos adversos , Método Duplo-Cego , Agonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Humanos , Relações Interpessoais , Aprendizagem/efeitos dos fármacos , Masculino , Pais/psicologia , Índice de Gravidade de Doença , Falha de TratamentoRESUMO
OBJECTIVE: Risperidone has demonstrated efficacy for acute (8 week) and intermediate length (6 month) management of severe irritability and aggression in children and adolescents with autism. Less is known about the long-term effects of risperidone exposure in this population. We examined the tolerability, safety, and therapeutic benefit of risperidone exposure over a 1-2 year follow-up period. METHODS: In a naturalistic study, 84 children and adolescents 5-17 years of age (from an original sample of 101) were assessed an average of 21.4 months after initial entry into a placebo-controlled 8 week trial of risperidone for children and adolescents with autism and severe irritability. They were assessed at baseline and at follow-up on safety and tolerability measures (blood, urinalysis, electrocardiogram [ECG], medical history, vital signs, neurological symptoms, other adverse events), developmental measures (adaptive behavior, intelligence quotient [IQ]), and standardized rating instruments. Treatment over the follow-up period, after completion of protocol participation, was uncontrolled. Statistical analyses assessed outcome over time with or without prolonged risperidone therapy. RESULTS: Two-thirds of the 84 subjects continued to receive risperidone (mean 2.47 mg/day, S.D. 1.29 mg). At follow-up, risperidone was associated with more enuresis, more excessive appetite, and more weight gain, but not more adverse neurological effects. No clinically significant events were noted on blood counts, chemistries, urinalysis, ECG, or interim medical history. Regardless of drug condition at follow-up, there was considerable improvement in maladaptive behavior compared with baseline, including core symptoms associated with autism. Height and weight gains were elevated with risperidone. Social skills on Vineland Adaptive Behavior Scale (VABS) improved with risperidone. Parent-rated Aberrant Behavior Checklist (ABC) Irritability subscale scores were reduced in those taking risperidone at follow-up. Several other measures of maladaptive behavior (some related to socialization) also showed improved functioning in association with risperidone on the ABC or on the Modified Real Life Rating Scale. CONCLUSIONS: Increased appetite, weight gain, and enuresis are risks associated with long-term risperidone. Our data suggest that these risks were balanced by longer-term behavioral and social benefits for many children over 1.8 years of ongoing treatment.
Assuntos
Antipsicóticos/uso terapêutico , Transtorno Autístico/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Risperidona/uso terapêutico , Adolescente , Agressão/efeitos dos fármacos , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Criança , Pré-Escolar , Método Duplo-Cego , Enurese/induzido quimicamente , Feminino , Seguimentos , Humanos , Masculino , Risperidona/administração & dosagem , Risperidona/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Aumento de Peso/efeitos dos fármacosRESUMO
OBJECTIVES: Psychotropic medications, including the atypical antipsychotics, have historically been scrutinized for cardiac effects and risk of sudden death. Aripiprazole is an atypical antipsychotic approved for pediatric use in schizophrenia, bipolar I disorder, and autistic disorder. Adult studies have evaluated aripiprazole's effects on electrocardiograms, but no pediatric studies have been published to date. METHODS: Electrocardiographic data were collected from children and adolescents participating in a 14-week, prospective, open-label study (n=25) of aripiprazole for irritability in pervasive developmental disorder not otherwise specified and Asperger's disorder. A 12-lead electrocardiogram was obtained at the baseline and end point visits. The electrocardiograms were evaluated for abnormal findings, and the PR, QRS, QT(c), and RR intervals were recorded. The QT interval was corrected using Bazett's, United States Food and Drug Administration (FDA) Pharmacology Division, and Fridericia's formulas. RESULTS: Twenty-four subjects received both baseline and posttreatment electrocardiograms. The mean age was 8.6 years (range 5-17 years). The average final aripiprazole dose was 7.8 mg/day (range 2.5-15 mg/day). There were no significant differences noted with the PR, QRS, RR, and QT(c) intervals after aripiprazole therapy. Also, there was no significant correlation between the dose given and the percent change in the QT(c). No post-treatment QT(c) exceeded 440 ms. CONCLUSIONS: To our knowledge, this is the first systematic evaluation of the cardiac effects of aripiprazole in children and adolescents. The results are consistent with previously published literature in adults that aripiprazole has no significant cardiac effects and can be deemed a low risk for causing sudden death. It will be important to confirm these findings in a randomized controlled trial.
Assuntos
Antipsicóticos/efeitos adversos , Síndrome de Asperger/tratamento farmacológico , Transtornos Globais do Desenvolvimento Infantil/tratamento farmacológico , Piperazinas/efeitos adversos , Quinolonas/efeitos adversos , Adolescente , Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Aripiprazol , Síndrome de Asperger/fisiopatologia , Criança , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Pré-Escolar , Relação Dose-Resposta a Droga , Eletrocardiografia , Feminino , Humanos , Humor Irritável/efeitos dos fármacos , Masculino , Projetos Piloto , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Estudos Prospectivos , Quinolonas/administração & dosagem , Quinolonas/uso terapêuticoRESUMO
RATIONALE: Individuals with autistic disorder (autism) frequently exhibit significant irritability marked by severe tantrums, aggression, and self-injury. Despite advances in the treatment of this symptom domain in autism, there remains an ongoing need for more effective and better tolerated pharmacotherapies. OBJECTIVES: The aim of this study is to determine the effectiveness and tolerability of paliperidone for irritability in autism. METHODS: This is a prospective, 8-week open-label study of paliperidone in 25 adolescents and young adults with autism. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) Scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Concomitant medications (except antipsychotics) were permitted if dosages were stable for ≥2 months. RESULTS: Twenty-one (84 %) of 25 subjects ages 12-21 years (mean 15.3 years) responded to paliperidone, based on a CGI-I Scale score of 1 or 2 (very much or much improved) and ≥25 % improvement on the ABC-I. The mean final dosage of paliperidone was 7.1 mg/day (range 3-12 mg/day). Two subjects discontinued paliperidone prior to study completion (moderate sedation, n = 1; nonresponse, n = 1). Mild-to-moderate extrapyramidal symptoms were recorded in four subjects. A mean weight gain of 2.2 ± 2.6 kg (range -3.6 to +7.9 kg) was recorded. Mean age- and sex-normed body mass index increased from 23.6 to 24.2 (p ≤ 0.001). Mean serum prolactin increased from 5.3 to 41.4 ng/mL (p ≤ 0.0001). CONCLUSIONS: Paliperidone treatment was associated with significant improvement in irritability and was generally well tolerated. Larger scale, placebo-controlled studies are needed to elucidate the efficacy and tolerability of paliperidone in this population.
Assuntos
Antipsicóticos/uso terapêutico , Transtorno Autístico/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Isoxazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Antipsicóticos/administração & dosagem , Transtorno Autístico/psicologia , Criança , Manual Diagnóstico e Estatístico de Transtornos Mentais , Esquema de Medicação , Feminino , Humanos , Isoxazóis/administração & dosagem , Masculino , Palmitato de Paliperidona , Projetos Piloto , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Pirimidinas/administração & dosagem , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemAssuntos
Síndrome de Asperger/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Adolescente , Síndrome de Asperger/complicações , Síndrome de Asperger/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Masculino , Memantina/efeitos adversos , Memantina/farmacologia , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/fisiopatologia , Resultado do TratamentoAssuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Transtornos Globais do Desenvolvimento Infantil/tratamento farmacológico , Guanfacina/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Criança , Pré-Escolar , Preparações de Ação Retardada , Feminino , Guanfacina/administração & dosagem , Humanos , Masculino , Resultado do TratamentoRESUMO
RATIONALE: Fragile X syndrome (FXS) is the most common inherited form of developmental disability and most common single gene cause of autism. Persons with FXS frequently exhibit irritable behavior marked by aggression, self-injury, and severe tantrums. Despite frequent clinical use of atypical antipsychotic drugs to target this behavioral cluster, no systematic trials to date have assessed the efficacy and safety of these drugs in persons with FXS. METHODS: We conducted a prospective open-label 12-week trial of aripiprazole in 12 persons aged 6-25 years (mean age, 14.3 years) with FXS who were free of concomitant psychoactive drugs. RESULTS: Aripiprazole use (mean dose, 9.8 mg/day) was associated with treatment response (defined by a Clinical Global Impressions-Improvement scale score of much improved or very much improved and a ≥ 25% improvement on the Aberrant Behavior Checklist-Irritability subscale) in 10 of 12 (87%) persons. Two individuals (13%) discontinued aripiprazole prior to study completion due to adverse events. One discontinuation was due to akathisia, mild drooling, and mild tiredness and the other due to moderate tiredness and moderate drooling. No significant changes in vital signs including weight or laboratory measures occurred during treatment with aripiprazole. CONCLUSIONS: Aripiprazole was generally safe and well tolerated and was associated with significant improvement in irritable behavior. Given these findings, a double-blind, placebo-controlled study of aripiprazole in FXS is warranted.
Assuntos
Antipsicóticos/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Piperazinas/uso terapêutico , Quinolonas/uso terapêutico , Adolescente , Adulto , Agressão/efeitos dos fármacos , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Aripiprazol , Criança , Feminino , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Masculino , Projetos Piloto , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Estudos Prospectivos , Testes Psicológicos , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Autism spectrum disorders (ASDs) are childhood onset developmental disorders characterized by impairment of social skills and repetitive behavior, and also for classic autistic disorder, a significant impairment of communication. In addition to these core symptom domains, persons with ASDs frequently exhibit interfering behavioral symptoms, including irritability marked by aggression, self-injurious behavior, and severe tantrums. Aripiprazole is an atypical or newer generation antipsychotic with a unique mechanism of action impacting dopaminergic and serotonergic neurotransmission. The drug has been found efficacious for several indications, including most recently for use targeting irritability associated with autistic disorder in youth. Fragile X syndrome is the most common inherited cause of developmental disability and the most common known single gene cause of ASDs. As in idiopathic ASDs, irritable behavior is often exhibited by persons with fragile X syndrome. However, research to date in this disorder has not focused on this target symptom cluster. An initial pilot study has begun to assess the impact of aripiprazole on irritability in youth with fragile X syndrome.
Assuntos
Antipsicóticos/uso terapêutico , Transtornos Globais do Desenvolvimento Infantil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Piperazinas/uso terapêutico , Quinolonas/uso terapêutico , Aripiprazol , Criança , HumanosRESUMO
OBJECTIVE/BACKGROUND: The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritability in autistic disorder. This paper explores moderators and mediators of this effect. METHOD: Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results. RESULTS: Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5'-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo. CONCLUSION: The benefit-risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems nonspecifically predict better outcome. Mineral interactions with risperidone deserve further study.
Assuntos
Transtorno Autístico/tratamento farmacológico , Biomarcadores Farmacológicos/metabolismo , Antagonistas de Dopamina/uso terapêutico , Humor Irritável/efeitos dos fármacos , Risperidona/uso terapêutico , Adolescente , Transtorno Autístico/complicações , Transtorno Autístico/metabolismo , Criança , Pré-Escolar , Ensaios Clínicos Controlados como Assunto , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Adesão à Medicação , Risperidona/farmacologiaAssuntos
Agressão/efeitos dos fármacos , Antipsicóticos/uso terapêutico , Transtorno Autístico/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Isoxazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Agressão/psicologia , Antipsicóticos/administração & dosagem , Transtorno Autístico/diagnóstico , Transtorno Autístico/psicologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Relação Dose-Resposta a Droga , Humanos , Isoxazóis/administração & dosagem , Masculino , Palmitato de Paliperidona , Pirimidinas/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Aripiprazole was recently US FDA-approved to treat irritability in children and adolescents with autistic disorder aged 6-17 years. There are currently only two psychotropics approved by the FDA to treat irritability in the autistic population. This drug profile will discuss available studies of aripiprazole in individuals with pervasive developmental disorders, two of which led to its recent FDA approval. We will discuss the efficacy, as well as the safety and tolerability of the drug documented in these studies. In addition, the chemistry, pharmacokinetics, metabolism and mechanism of action of aripiprazole will be reviewed.
RESUMO
OBJECTIVE: The aim of this study was to determine the effectiveness and tolerability of aripiprazole for irritability in pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger's disorder. METHOD: This is a 14-week, prospective, open-label investigation of aripiprazole in 25 children and adolescents diagnosed with PDD-NOS or Asperger's disorder. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). RESULTS: Twenty-five subjects, ages 5-17 years (mean 8.6 years) received a mean final aripiprazole dosage of 7.8 mg/day (range 2.5-15 mg/day). Full-scale intelligence quotient (IQ) scores ranged from 48 to 122 (mean 84). Twenty-two (88%) of 25 subjects were responders in regard to interfering symptoms of irritability, including aggression, self-injury, and tantrums, with a final CGI-I of 1 or 2 (very much or much improved) and a 25% or greater improvement on the ABC-I. The final mean CGI-I was 1.6 (p Assuntos
Antipsicóticos/uso terapêutico
, Síndrome de Asperger/tratamento farmacológico
, Transtornos Globais do Desenvolvimento Infantil/tratamento farmacológico
, Piperazinas/uso terapêutico
, Quinolonas/uso terapêutico
, Adolescente
, Antipsicóticos/efeitos adversos
, Aripiprazol
, Síndrome de Asperger/fisiopatologia
, Índice de Massa Corporal
, Criança
, Transtornos Globais do Desenvolvimento Infantil/fisiopatologia
, Pré-Escolar
, Feminino
, Humanos
, Humor Irritável/efeitos dos fármacos
, Masculino
, Projetos Piloto
, Piperazinas/efeitos adversos
, Prolactina/efeitos dos fármacos
, Prolactina/metabolismo
, Estudos Prospectivos
, Escalas de Graduação Psiquiátrica
, Psicometria
, Quinolonas/efeitos adversos
, Índice de Gravidade de Doença
RESUMO
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
Assuntos
Transtorno Autístico/genética , Dosagem de Genes/genética , Variação Genética/genética , Genoma Humano/genética , Neurônios/metabolismo , Ubiquitina/metabolismo , Estudos de Casos e Controles , Moléculas de Adesão Celular Neuronais/genética , Estudos de Coortes , Europa (Continente)/etnologia , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos TestesRESUMO
This report examined the effect of methylphenidate on social communication and self-regulation in children with pervasive developmental disorders and hyperactivity in a secondary analysis of RUPP Autism Network data. Participants were 33 children (29 boys) between the ages of 5 and 13 years who participated in a four-week crossover trial of placebo and increasing doses of methylphenidate given in random order each for one week. Observational measures of certain aspects of children's social communication, self-regulation, and affective behavior were obtained each week. A significant positive effect of methylphenidate was seen on children's use of joint attention initiations, response to bids for joint attention, self-regulation, and regulated affective state. The results go beyond the recent literature and suggest that methylphenidate may have positive effects on social behaviors in children with PDD and hyperactivity.
Assuntos
Estimulantes do Sistema Nervoso Central/uso terapêutico , Transtornos Globais do Desenvolvimento Infantil/tratamento farmacológico , Transtornos Globais do Desenvolvimento Infantil/psicologia , Metilfenidato/uso terapêutico , Comportamento Social , Controles Informais da Sociedade , Adolescente , Síndrome de Asperger/tratamento farmacológico , Síndrome de Asperger/psicologia , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Agitação Psicomotora/tratamento farmacológico , Resultado do TratamentoRESUMO
Objective To evaluate gastrointestinal (GI) problems in a large, well-characterized sample of children with pervasive developmental disorders (PDDs). Methods One hundred seventy two children entering one of two trials conducted by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network were assessed comprehensively prior to starting treatment and classified with regard to GI symptoms. Results Thirty nine (22.7%) were positive for GI problems, primarily constipation and diarrhea. Those with GI problems were no different from subjects without GI problems in demographic characteristics, measures of adaptive functioning, or autism symptom severity. Compared to children without GI problems, those with GI problems showed greater symptom severity on measures of irritability, anxiety, and social withdrawal. Those with GI problems were also less likely to respond to treatment.
Assuntos
Ansiedade/psicologia , Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Constipação Intestinal/fisiopatologia , Diarreia/fisiopatologia , Transtornos do Comportamento Social/psicologia , Adaptação Psicológica , Adolescente , Transtorno Autístico/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Índice de Gravidade de DoençaRESUMO
There are many challenges to studying drug effects on core social and language impairment in autism. Drugs such as fenfluramine, naltrexone, and secretin do not appear to be efficacious for these core symptoms. Risperidone has led to improvement in some aspects of social relatedness when used to treat irritability in autism. More research is needed on the utility of selective serotonin reuptake inhibitors, cholinergic drugs, glutamatergic drugs, and oxytocin for core autistic symptoms.