RESUMO
Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin-dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long-term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including calcium/calmodulin-dependent kinase II. Further studies demonstrated that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi-center double-blind randomized placebo-controlled 1-year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1-year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1-year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well-tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.
Assuntos
Síndrome de Angelman/tratamento farmacológico , Levodopa/uso terapêutico , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/fisiopatologia , Síndrome de Angelman/psicologia , Animais , Biomarcadores , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Modelos Animais de Doenças , Humanos , Levodopa/administração & dosagem , Potenciação de Longa Duração , Camundongos , Testes Neuropsicológicos , Resultado do TratamentoRESUMO
Angelman Syndrome is a rare neurodevelopmental disorder associated with significant developmental and communication delays, high risk for epilepsy, motor dysfunction, and a characteristic behavioral profile. While Angelman Syndrome is known to be associated with the loss of maternal expression of the ubiquitin-protein ligase E3A gene, the molecular sequelae of this loss remain to be fully understood. Amyloid precursor protein (APP) is involved in neuronal development and APP dysregulation has been implicated in the pathophysiology of other developmental disorders including fragile X syndrome and idiopathic autism. APP dysregulation has been noted in preclinical model of chromosome 15q13 duplication, a disorder whose genetic abnormality results in duplication of the region that is epigenetically silenced in Angelman Syndrome. In this duplication model, APP levels have been shown to be significantly reduced leading to the hypothesis that enhanced ubiquitin-protein ligase E3A expression may be associated with this phenomena. We tested the hypothesis that ubiquitin-protein ligase E3A regulates APP protein levels by comparing peripheral APP and APP derivative levels in humans with Angelman Syndrome to those with neurotypical development. We report that APP total, APP alpha (sAPPα) and A Beta 40 and 42 are elevated in the plasma of humans with Angelman Syndrome compared to neurotypical matched human samples. Additionally, we found that elevations in APP total and sAPPα correlated positively with peripheral brain derived neurotrophic factor levels previously reported in this same patient cohort. Our pilot report on APP protein levels in Angelman Syndrome warrants additional exploration and may provide a molecular target of treatment for the disorder. © 2016 Wiley Periodicals, Inc.
Assuntos
Precursor de Proteína beta-Amiloide/sangue , Síndrome de Angelman/sangue , Síndrome de Angelman/diagnóstico , Adolescente , Adulto , Síndrome de Angelman/genética , Biomarcadores , Caderinas/genética , Proteínas de Transporte/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Duplicação Cromossômica , Cromossomos Humanos Par 15 , Feminino , Humanos , Masculino , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Ubiquitina-Proteína Ligases/genética , Adulto JovemRESUMO
Angelman Syndrome (AS) is a rare neurodevelopmental disorder associated with developmental delay, speech impairment, gait ataxia, and a unique behavioral profile. AS is caused by loss of maternal expression of the paternally imprinted UBE3A gene. In this study we aim to contribute to understanding of the neurobehavioral phenotype of AS with particular focus on the neuropsychiatric presentation of the disorder. We also undertake initial exploration of brain-derived neurotrophic factor (BDNF) plasma levels in AS. Twelve individuals ages 3 years or older with a confirmed genetic diagnosis of AS underwent detailed medical history, phenotypic characterization, and BDNF plasma sampling. The results of this study demonstrate that individuals with AS suffer from significant developmental delay, impaired adaptive behavior, and sleep disruption. Additionally, hyperactivity/impulsivity appears to be the primary behavioral domain noted in these individuals. The majority of individuals in this project met criteria for autism spectrum disorder on the Autism Diagnostic Observation Schedule (ADOS); however, a negative correlation was noted between ADOS score and developmental age. BDNF plasma levels in AS individuals were significantly elevated compared to neurotypical controls. This is the first report of abnormal BDNF levels in AS, and one that necessitates larger future studies. The results provide a clue to understanding abnormal neuronal development in AS and may help guide future AS research.
Assuntos
Síndrome de Angelman/genética , Comportamento , Encéfalo/patologia , Síndrome de Angelman/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Estudos de Casos e Controles , Pré-Escolar , Humanos , Lactente , FenótipoRESUMO
OBJECTIVE: This pilot study compared the pharmacologic treatment history and clinical outcomes observed in pediatric outpatients with psychiatric disorders exposed to drugs of abuse in utero to those of an age-matched, sex-matched and psychiatric disorder-matched, non-drug-exposed group. METHODS: In this matched cohort study, medical records of children treated at an academic, child and adolescent psychiatry outpatient clinic were reviewed. Children with caregiver-reported history of prenatal drug exposure were compared with a non-drug-exposed control group being cared for by the same providers. Patients were rated with the Clinical Global Impressions-Severity scale (CGI-S) throughout treatment. The changes in pre-treatment and post-treatment CGI-S scores and the total number of medication trials were determined between groups. RESULTS: The drug-exposed group (n = 30) had a higher total number of lifetime medication trials compared with the non-drug-exposed group (n = 28) and were taking significantly more total medications, at their final assessment. Unlike the non-drug-exposed group, the drug-exposed group demonstrated a lack of clinical improvement. CONCLUSIONS: These results suggest that in utero drug-exposed children may be more treatment-refractory to or experience greater side effects from the pharmacologic treatment of psychiatric disorders than controls, although we cannot determine if early environment or drugs exposure drives these findings.
Assuntos
Drogas Ilícitas/efeitos adversos , Transtornos Mentais/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal , Transtornos Relacionados ao Uso de Substâncias/complicações , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Transtornos Mentais/etiologia , Transtornos Mentais/fisiopatologia , Projetos Piloto , Gravidez , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants. METHODS: Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living skills. The Cox Proportional Hazard model was applied to analyze differences in the probability of achievement of skills at various ages among five molecular subtypes of AS. RESULTS: Almost all individuals, regardless of molecular subtype, were able to walk with support by five years of age. By age 15, those with a deletion had at least a 50% probability of acquiring 17 out of 30 skills compared to 25 out of 30 skills among those without a deletion. Overall, fine and gross motor skills such as holding and reaching for small objects, sitting, and walking with support were achieved within a fairly narrow range of ages, while toileting, feeding, and hygiene skills tend to have greater variability in the ages at which these skills were achieved. Those without a deletion had a higher probability (25-92%) of achieving daily living skills such as independently toileting and dressing compared to those with a deletion (0-13%). Across all molecular subtypes, there was a low probability of achieving independence in bathing and brushing teeth. CONCLUSION: Individuals with AS without a deletion are more likely to achieve developmental milestones and daily living skills at an earlier age than those with a deletion. Many individuals with AS are unable to achieve daily living skills necessary for independent self-care.
Assuntos
Atividades Cotidianas , Síndrome de Angelman , Desenvolvimento Infantil , Humanos , Síndrome de Angelman/fisiopatologia , Síndrome de Angelman/genética , Síndrome de Angelman/complicações , Feminino , Pré-Escolar , Masculino , Criança , Adolescente , Lactente , Desenvolvimento Infantil/fisiologia , Estudos Longitudinais , Destreza Motora/fisiologia , Deficiências do Desenvolvimento/etiologia , Adulto , Adulto JovemRESUMO
OBJECTIVE: Extracellular signal-regulated kinase (ERK1/2) is a conserved central intracellular signaling cascade involved in many aspects of neuronal development and plasticity. Converging evidence support investigation of ERK1/2 activity in autism spectrum disorder (ASD). We previously reported enhanced baseline lymphocytic ERK1/2 activation in autism, and now we extend our work to investigate the early phase kinetics of lymphocytic ERK1/2 activation in idiopathic ASD. METHOD: Study participants included 67 individuals with ASD (3-25 years of age), 65 age- and sex-matched typical developing control (TDC) subjects, and 36 age-, sex-, and IQ-matched developmental disability control (DDC) subjects matched to those with ASD and IQ <90. We completed an additional analysis comparing results from ASD, TDC, and DDC groups with data from 37 individuals with Fragile X syndrome (FXS). All subjects had blood lymphocyte samples analyzed by flow cytometry following stimulation with phorbol ester and sequentially analyzed for ERK1/2 activation (phosphorylation) at several time points. RESULTS: The ASD group (mean = 5.81 minutes; SD = 1.5) had a significantly lower (more rapid) mean ERK1/2 T1/2 activation value than both the DDC group (mean = 6.78 minutes; SD = 1.6; p = .00078) and the TDC group (mean = 6.4 minutes; SD = 1.5; p = .025). More rapid ERK1/2 T1/2 activation times did correlate with increased social impairment across all study groups including the ASD cohort. Differences in ERK1/2 T1/2 activation were more pronounced in younger than in older individuals in the primary analysis. The ASD group additionally had more rapid activation times than the FXS group, and the FXS group activation kinetics did not differ from those of the TDC and DDC groups. CONCLUSION: Our findings indicate that lymphocytic ERK1/2 activation kinetics are dysregulated in persons with ASD, marked by more rapid early phase activation. Group differences in ERK1/2 activation kinetics appear to be driven by findings from the youngest children analyzed. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Síndrome do Cromossomo X Frágil , Masculino , Criança , Feminino , Humanos , Idoso , MAP Quinases Reguladas por Sinal Extracelular , LinfócitosRESUMO
Dysregulation of glutamate neurotransmission plays a critical role in autism spectrum disorder (ASD) pathophysiology and is a primary target for core deficit research treatment trials. The mechanism of action of ketamine has striking overlap with the theory of ASD as a disorder of synaptic communication and neuronal networks. This two-dose, double-blind, placebo controlled, cross-over pilot trial of intranasal (IN) ketamine targeting core social impairment included individuals with ASD (N = 21) between 14 and 29 years. Participants were randomized to received two doses of IN ketamine (30 and 50 mg) and two doses of matching placebo. No significant impact was noted on the Aberrant Behavior Checklist Social Withdraw subscale. The IN ketamine was well tolerated, with only transient mild adverse effects.
Assuntos
Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/administração & dosagem , Administração Intranasal , Adolescente , Adulto , Transtorno do Espectro Autista/psicologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Projetos Piloto , Resultado do Tratamento , Adulto JovemRESUMO
IMPORTANCE OF THE FIELD: Autism spectrum disorders, or pervasive developmental disorders (PDDs), are neurodevelopmental disorders defined by qualitative impairment in social interaction, impaired communication and stereotyped patterns of behavior. The most common forms of PDD are autistic disorder (autism), Asperger's disorder and PDD not otherwise specified. Recent surveillance studies reveal an increase in the prevalence of autism and related PDDs. The use of pharmacologic agents in the treatment of these disorders can reduce the impact of interfering symptoms, providing relief for affected individuals and their families. AREAS COVERED IN THIS REVIEW: This review examines results from neurobiologic research in an attempt to both elucidate the pathophysiology of autism and guide the development of pharmacologic agents for the treatment of associated symptoms. The safety and efficacy data of drugs currently in clinical use for the treatment of these symptoms, as well as pharmaceuticals currently under development, are discussed. WHAT THE READER WILL GAIN: This comprehensive review will deepen the reader's current understanding of the research guiding the pharmacologic treatment of symptoms associated with autism and related PDDs. Areas of focus for future research are also discussed. The need for large-scale investigation of some commonly used pharmacologic agents, in addition to the development of drugs with improved efficacy and safety profiles, is made evident. TAKE HOME MESSAGE: Despite progress in the development of pharmacologic treatments for a number of interfering symptom domains associated with autism and other PDDs, a great deal of work remains.
Assuntos
Fármacos do Sistema Nervoso Central/uso terapêutico , Transtornos Globais do Desenvolvimento Infantil/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Adulto , Animais , Fármacos do Sistema Nervoso Central/efeitos adversos , Fármacos do Sistema Nervoso Central/farmacologia , Criança , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Desenho de Fármacos , HumanosRESUMO
OPINION STATEMENT: Pervasive developmental disorders (PDDs), including autistic disorder (autism), Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD NOS), are neurodevelopmental disorders of childhood onset. These disorders persist throughout the lifespan of affected individuals and are characterized by impaired social behavior and communication, along with repetitive, stereotypic behaviors. Early diagnosis and subsequent behavioral therapy have been shown to improve outcomes for these individuals. Risperidone and aripiprazole have been approved by the United States Food and Drug Administration (FDA) for treatment of irritability associated with autism in children and adolescents. Despite their efficacy, use of these medications is limited by their side effects. In individuals with severe irritability, the first-line treatment is often risperidone. Because of its relatively lower risk of weight gain and metabolic side effects, aripiprazole may be used initially if there is a personal or family history of obesity or diabetes. Monitoring of body mass index and metabolic profiles is indicated with both medications. Stereotypic behaviors associated with autism, though clearly driven by neurobiologic processes, can also be understood as coping mechanisms used to decrease anxiety. From this perspective, therapies targeting reduction of these symptoms may be contraindicated. However, when these symptoms are severe and interfering, pharmacotherapy may be necessary. Serotonin reuptake inhibitors are of limited efficacy in children and adolescents, but risperidone and aripiprazole have been shown to reduce these symptoms. There remains a need for further safety and efficacy research in this area. Hyperactivity and inattention are currently treated with a variety of medications, including guanfacine, which has a relatively benign side effect profile. Stimulant medications are generally avoided as first-line treatment for hyperactivity because of concerns about increased irritability. Currently, social impairment is best addressed through behavioral therapy and social skills training. Novel pharmacotherapies to improve social impairment are in the early stages of research.
RESUMO
Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition affecting an estimated one in 36 children. Youth with ASD may have severe behavioral disturbances including irritability, aggression, and hyperactivity. Currently, there are only two medications (risperidone and aripiprazole) approved by the US Food and Drug Administration (FDA) for the treatment of irritability associated with ASD. Pharmacologic treatments are commonly used to target ASD-associated symptoms including irritability, mood lability, anxiety, and hyperactivity. However, evidence for the efficacy of many commonly used treatments is limited by the lack of large placebo-controlled trials of these medications in this population. Research into the pathophysiology of ASD has led to new targets for pharmacologic therapy including the neuroimmune system, the endocannabinoid system, and the glutamatergic neurotransmitter system. The goal of this review is to provide an overview of the current evidence base for commonly used treatments, as well as emerging treatment options for common behavioral disturbances seen in youth with ASD.
Assuntos
Comportamento do Adolescente/efeitos dos fármacos , Antipsicóticos/uso terapêutico , Transtorno do Espectro Autista/tratamento farmacológico , Comportamento Infantil/efeitos dos fármacos , Adolescente , Agressão/efeitos dos fármacos , Ansiedade/tratamento farmacológico , Transtorno do Espectro Autista/psicologia , Criança , Humanos , Hipercinese/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Transtornos do Sono-Vigília/tratamento farmacológicoRESUMO
To date, health related quality of life (QoL) has not been systematically evaluated in youth with fragile X syndrome (FXS), the most common single gene cause of autism and the most common inherited form of developmental disability. We describe QoL data gathered using the Pediatric Quality of Life Inventory (PedsQL) completed online by 364 parents of youth with FXS. Parents consistently reported across all gender and age groups that their children experienced the highest QoL in Physical functioning and the lowest QoL in Cognitive functioning. Overall, older children with FXS had increase QoL ratings in the domains of School and Cognitive function.
Assuntos
Síndrome do Cromossomo X Frágil/epidemiologia , Qualidade de Vida , Inquéritos e Questionários , Adolescente , Adulto , Criança , Cognição , Síndrome do Cromossomo X Frágil/patologia , Humanos , Pais/psicologia , Aptidão FísicaRESUMO
Individuals with Autism Spectrum Disorder (ASD) and/or intellectual and developmental disabilities (DD) often struggle with behavior management and emotion-regulation (ER). In this manuscript, we describe the results of a chart review examining a group treatment program designed to address ER deficits in youth with ASD and/or DD. The intensive 5 week program utilizes cognitive behavior, applied behavior analysis, and mindfulness techniques and includes biweekly child and parent groups. Results indicate that this program is feasible and associated with high caregiver satisfaction. Pre-and-post outcome results indicate statistically significant improvement on behavioral measures, but did not demonstrate significant improvment on the Pediatric Quality of Life Family Impact Module. Based on overall positive outcomes, a randomized controlled trial of the program is indicated.
Assuntos
Assistência Ambulatorial/psicologia , Transtorno do Espectro Autista/psicologia , Emoções/fisiologia , Pacientes Ambulatoriais/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Psicoterapia de Grupo , Adolescente , Assistência Ambulatorial/métodos , Assistência Ambulatorial/tendências , Transtorno do Espectro Autista/terapia , Criança , Deficiências do Desenvolvimento , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pais/psicologia , Psicoterapia de Grupo/métodos , Psicoterapia de Grupo/tendências , Qualidade de Vida/psicologiaRESUMO
BACKGROUND: Fragile X syndrome (FXS) is the leading inherited cause of autism spectrum disorder, but there remains debate regarding the clinical presentation of social deficits in FXS. The aim of this study was to compare individuals with FXS to typically developing controls (TDC) and individuals with idiopathic autism spectrum disorder (ASD) across two social eye tracking paradigms. METHODS: Individuals with FXS and age- and gender-matched TDC and individuals with idiopathic ASD completed emotional face and social preference eye tracking tasks to evaluate gaze aversion and social interest, respectively. Participants completed a battery of cognitive testing and caregiver-reported measures for neurobehavioral characterization. RESULTS: Individuals with FXS exhibited reduced eye and increased mouth gaze to emotional faces compared to TDC. Gaze aversive findings were found to correlate with measures of anxiety, social communication deficits, and behavioral problems. In the social interest task, while individuals with idiopathic ASD showed significantly less social preference, individuals with FXS displayed social preference similar to TDC. CONCLUSIONS: These findings suggest fragile X syndrome social deficits center on social anxiety without the prominent reduction in social interest associated with autism spectrum disorder. Specifically designed eye tracking techniques clarify the nature of social deficits in fragile X syndrome and may have applications to improve phenotyping and evaluate interventions targeting social functioning impairments.
Assuntos
Ansiedade/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Comportamento de Escolha/fisiologia , Reconhecimento Facial/fisiologia , Fixação Ocular/fisiologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Comportamento Problema , Transtorno de Comunicação Social/fisiopatologia , Percepção Social , Adolescente , Adulto , Ansiedade/etiologia , Transtorno do Espectro Autista/complicações , Criança , Pré-Escolar , Emoções/fisiologia , Medições dos Movimentos Oculares , Feminino , Síndrome do Cromossomo X Frágil/complicações , Humanos , Masculino , Fenótipo , Transtorno de Comunicação Social/etiologia , Adulto JovemRESUMO
The neural correlates distinguishing youth with Autism Spectrum Disorder (ASD-) and ASD with co-occurring Attention Deficit Hyperactivity Disorder (ASD+) are poorly understood despite significant phenotypic and prognostic differences. Paired-pulse transcranial magnetic stimulation (TMS) measures, including intracortical facilitation (ICF), short interval cortical inhibition (SICI), and cortical silent period (CSP) were measured in an age matched cohort of youth with ASD- (n = 20), ASD + (n = 29), and controls (TDC) (n = 24). ASD- and ASD+ groups did not differ by IQ or social functioning; however, ASD+ had significantly higher inattention and hyperactivity ratings. ICF (higher ratio indicates greater facilitation) in ASD+ (Mean 1.0, SD 0.19) was less than ASD- (Mean 1.3, SD 0.36) or TDC (Mean 1.2, SD 0.24) (F2,68 = 6.5, p = 0.003; post-hoc tests, ASD+ vs either TDC or ASD-, p ≤ 0.05). No differences were found between groups for SICI or age corrected active/resting motor threshold (AMT/RMT). Across all ASD youth (ASD- and ASD+), ICF was inversely correlated with worse inattention (Conners-3 Inattention (r = -0.41; p < 0.01) and ADHDRS-IV Inattention percentile (r = -0.422, p < 0.01) scores. ICF remains intact in ASD- but is impaired in ASD+. Lack of ICF is associated with inattention and executive function across ASD. Taken with the present findings, ADHD may have a distinct electrophysiological "signature" in ASD youth. ICF may constitute an emerging biomarker to study the physiology of ADHD in ASD, which may align with disease prognosis or treatment response.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Potencial Evocado Motor , Córtex Motor/fisiopatologia , Adolescente , Adulto , Comorbidade , Eletromiografia , Feminino , Humanos , Masculino , Nervo Mediano/fisiologia , Inibição Neural , Estimulação Magnética TranscranianaRESUMO
Using a dataset involving 415 individuals with irritability, aggression, agitation and self-injury (IAAS) behaviors from the fragile X syndrome (FXS) FORWARD database, we describe the psychopharmacologic management of IAAS and features of the population of persons with FXS treated with drug therapy for IAAS. Among those with FXS exhibiting IAAS, individuals with FXS receiving drug treatment of IAAS were older, more predominantly male, have more significant intellectual disability, more like to have comorbid autism, hyperarousal, and social impairments. The most commonly utilized medications for IAAS in FXS are antipsychotic medications, specifically aripiprazole and risperidone (37% and 27%, respectively). The majority of subjects (63%) experienced no side effects noted from the use of their psychopharmacologic medications.
Assuntos
Agressão/efeitos dos fármacos , Antipsicóticos/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Agitação Psicomotora/tratamento farmacológico , Comportamento Autodestrutivo/tratamento farmacológico , Adolescente , Adulto , Agressão/fisiologia , Agressão/psicologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antipsicóticos/farmacologia , Criança , Comorbidade , Estudos Transversais , Feminino , Síndrome do Cromossomo X Frágil/epidemiologia , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Humor Irritável/fisiologia , Masculino , Pessoa de Meia-Idade , Agitação Psicomotora/epidemiologia , Agitação Psicomotora/psicologia , Risperidona/farmacologia , Risperidona/uso terapêutico , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/psicologia , Adulto JovemRESUMO
OBJECTIVE: The goal of this study was to assess the effectiveness of risperidone monoantipsychotic therapy targeting irritability in patients with Fragile X syndrome (FXS) in a naturalistic outpatient clinical setting. METHODS: We examined the use of risperidone, predominantly in combination with other nonantipsychotic psychotropic agents, targeting irritability in 21 male patients with FXS with a retrospective analysis of a prospectively collected large developmental disabilities-specific treatment database. Mean age at start of treatment, treatment duration, final dose, body mass index (BMI), and Clinical Global Impressions-Improvement (CGI-I) Scale score at final visit were determined, and changes with treatment were analyzed using paired t-tests. RESULTS: Mean age at start of treatment was 14.0 years. The final mean dose of risperidone was 2.5 mg/day. The mean duration of treatment was 22 months. Seven (33.33%) participants were considered treatment responders based on the CGI-I. Change in BMI between initiation and cessation of treatment episode was not significant, however, these data were only available for a subset (n = 11) of patients. CONCLUSIONS: Risperidone may be effective in the treatment of irritability in males with FXS. The overall effectiveness of monoantipsychotic treatment with risperidone was limited in this study compared with previous published reports; however, this may be the result of differences in outcome measures as well as a reflection of the level of functioning and severity of irritability in this sample.
Assuntos
Antipsicóticos/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Humor Irritável/efeitos dos fármacos , Risperidona/uso terapêutico , Adolescente , Adulto , Antipsicóticos/administração & dosagem , Criança , Pré-Escolar , Quimioterapia Combinada , Síndrome do Cromossomo X Frágil/psicologia , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Psicotrópicos/administração & dosagem , Estudos Retrospectivos , Risperidona/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
Riluzole is a glutamatergic modulator of particular interest in autism spectrum disorder (ASD). In this 12-week randomized, double-blind, placebo-controlled, crossover pilot study we evaluated the safety and tolerability of 5-week of adjunctive riluzole treatment (vs. 5-week of placebo, with 2-week washout period) targeting ASD-associated drug-refractory irritability in eight individuals age 12-25 years. All participants tolerated riluzole 200 mg per day, however there were no statistically significant findings for the overall treatment effect, the treatment effect by week within period of the study, or a cross-over effect across the periods of the study on the Clinical Global Impression Improvement Scale or the Aberrant Behavior Checklist Irritability subscale. The results of this trial indicate that 5-week of riluzole treatment was well tolerated, but had no significant effect on the target symptoms. Trial Registration ClinicalTrials.gov Identifier NCT02081027, Registered 5 August 2013, First participant enrolled 19 September 2013.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/psicologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humor Irritável/efeitos dos fármacos , Riluzol/uso terapêutico , Adolescente , Adulto , Transtorno do Espectro Autista/diagnóstico , Criança , Estudos Cross-Over , Método Duplo-Cego , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Humanos , Humor Irritável/fisiologia , Masculino , Projetos Piloto , Riluzol/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
Nearly 11% of youth with Autism Spectrum Disorder (ASD) undergo psychiatric hospitalization, and 65% are treated with psychotropic medication. Here we characterize psychotropic medication usage in subjects enrolled in the Autism Inpatient Collection. Participant psychotropic medication usage rates topped 90% at admission and discharge, though there was a decline at 2-month follow-up. Antipsychotics, ADHD medications, and sleep aids were the most commonly reported classes of medications. The impact of age, gender, and non-verbal IQ on medication usage rates was minimal, though age and IQ may play a role in prescribing practices. Future work is indicated to explore medication usage trends, the impact of clinical factors on medication use rates, and the safety of psychotropic medications in youth with ASD.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Uso de Medicamentos/estatística & dados numéricos , Pacientes Internados/estatística & dados numéricos , Psicotrópicos/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Hospitais Pediátricos/estatística & dados numéricos , Hospitais Psiquiátricos/estatística & dados numéricos , Humanos , Masculino , Psicotrópicos/uso terapêutico , Adulto JovemRESUMO
OBJECTIVE: The purpose of this study was to explore the use of multiple antipsychotic medications in patients with autism spectrum disorder (ASD) by reviewing the longitudinal medication management of 1100 patients consecutively treated for behavioral symptoms associated with ASD at a tertiary care specialty clinic. METHODS: We identified all patients with ASD treated with daily doses of two or more antipsychotics for at least two visits at our clinic. For each patient meeting inclusion criteria, diagnostic and demographic data were collected. To evaluate clinical need and effectiveness of antipsychotic medications in this sample, we reviewed symptoms targeted with each antipsychotic medication and concomitant medications prescribed. Clinical Global Impressions-Severity (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) scale ratings had been completed at the time of each visit, and the duration of treatment with antipsychotic medications was determined. To evaluate the safety and tolerability of antipsychotic medication use in ASD, we reviewed reported adverse effects and calculated body mass index (BMI) change with treatment. RESULTS: Seventy patients met the inclusion criteria (6.4% of our sample). The majority of patients were moderately to severely ill Caucasian males, as determined by baseline mean CGI-S of 4.7 (SD = 0.8), and were diagnosed with autistic disorder and comorbid intellectual disability. The mean age was 15.1 years (SD = 10.9), the primary targeted symptoms were agitation/irritability, physical aggression, and self-injury. The majority of patients remained on two or more antipsychotics for >1 year. In this population, patients demonstrated greater symptomatic improvement and generally tolerated treatment without significant adverse effects. CONCLUSIONS: The use of two or more antipsychotic medications may be increasingly common in patients with ASD. This retrospective study demonstrates that this treatment approach may be of some clinical benefit, and is generally well tolerated. Prospective studies focusing on the efficacy and safety of concomitant antipsychotic medication usage in ASD should be considered.
Assuntos
Antipsicóticos/administração & dosagem , Transtorno do Espectro Autista/tratamento farmacológico , Adolescente , Adulto , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Transtorno do Espectro Autista/fisiopatologia , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Estudos Longitudinais , Masculino , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
In this study, we present an eye-tracking paradigm, adapted from previous work with toddlers, for assessing social-interaction looking preferences in youth ages 5-17 with ASD and typically-developing controls (TDC). Videos of children playing together (Social Scenes, SS) were presented side-by-side with animated geometric shapes (GS). Participants with ASD demonstrated reduced SS preferences compared to TDC, results also represented continuously by associations between higher SS preferences and fewer social difficulties across the combined sample. Exploratory analyses identified associations between increased SS preferences and higher Vineland Daily Living Skills in ASD and suggested SS preferences in TDC females might drive ASD versus TDC between-group differences. These findings describe potentially sex-linked couplings between preferences for social information and social functioning in school-aged children.