RESUMEN
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.
Asunto(s)
Trastorno del Espectro Autista , Adolescente , Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/tratamiento farmacológico , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/tratamiento farmacológico , Niño , Preescolar , Método Doble Ciego , Humanos , Mirtazapina/uso terapéutico , Proyectos Piloto , Resultado del TratamientoRESUMEN
Patients with autism spectrum disorders and intellectual disability can be clinically complex and often have limited access to psychiatric care. Because little is known about post-graduate clinical education in autism spectrum disorder and intellectual disability, we surveyed training directors of child and adolescent psychiatry fellowship programs. On average, child and adolescent psychiatry directors reported lectures of 3 and 4 h per year in autism spectrum disorder and intellectual disability, respectively. Training directors commonly reported that trainees see 1-5 patients with autism spectrum disorder or intellectual disability per year for outpatient pharmacological management and inpatient treatment. Overall, 43% of directors endorsed the need for additional resources for training in autism spectrum disorder and intellectual disability, which, coupled with low didactic and clinical exposure, suggests that current training is inadequate.
Asunto(s)
Psiquiatría del Adolescente/educación , Trastorno Autístico/rehabilitación , Psiquiatría Infantil/educación , Educación de Postgrado en Medicina/métodos , Becas/métodos , Discapacidad Intelectual/rehabilitación , Adolescente , Psiquiatría del Adolescente/métodos , Psiquiatría del Adolescente/tendencias , Niño , Psiquiatría Infantil/métodos , Psiquiatría Infantil/tendencias , Educación de Postgrado en Medicina/tendencias , Becas/tendencias , Femenino , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
Individuals diagnosed with autism spectrum disorders (ASD) often exhibit serious behavioral disturbance (irritability) including severe tantrums, aggression, and self-injury that requires pharmacologic management. Research focused on the treatment of severe irritability has primarily involved the atypical antipsychotics, including risperidone and aripiprazole. Anticonvulsants have also been investigated for targeting serious behavioral disturbance; however findings have been mixed. Advances in the pharmacotherapy of irritability in ASD continue to inform practice. Research is needed to develop safer and more effective drug treatments for serious behavioral disturbance in this population.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Anticonvulsivantes/uso terapéutico , Antimaníacos/uso terapéutico , Antipsicóticos/uso terapéutico , Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Genio Irritable/efectos de los fármacos , Agresión/efectos de los fármacos , Trastornos Generalizados del Desarrollo Infantil/epidemiología , Trastornos Generalizados del Desarrollo Infantil/psicología , Ensayos Clínicos como Asunto , Terapia Combinada , Humanos , Conducta Autodestructiva/tratamiento farmacológicoRESUMEN
The current assessment of behaviors in the inventories to diagnose autism spectrum disorders (ASD) focus on observation and discrete categorizations. Behaviors require movements, yet measurements of physical movements are seldom included. Their inclusion however, could provide an objective characterization of behavior to help unveil interactions between the peripheral and the central nervous systems (CNSs). Such interactions are critical for the development and maintenance of spontaneous autonomy, self-regulation, and voluntary control. At present, current approaches cannot deal with the heterogeneous, dynamic and stochastic nature of development. Accordingly, they leave no avenues for real time or longitudinal assessments of change in a coping system continuously adapting and developing compensatory mechanisms. We offer a new unifying statistical framework to reveal re-afferent kinesthetic features of the individual with ASD. The new methodology is based on the non-stationary stochastic patterns of minute fluctuations (micro-movements) inherent to our natural actions. Such patterns of behavioral variability provide re-entrant sensory feedback contributing to the autonomous regulation and coordination of the motor output. From an early age, this feedback supports centrally driven volitional control and fluid, flexible transitions between intentional and spontaneous behaviors. We show that in ASD there is a disruption in the maturation of this form of proprioception. Despite this disturbance, each individual has unique adaptive compensatory capabilities that we can unveil and exploit to evoke faster and more accurate decisions. Measuring the kinesthetic re-afference in tandem with stimuli variations we can detect changes in their micro-movements indicative of a more predictive and reliable kinesthetic percept. Our methods address the heterogeneity of ASD with a personalized approach grounded in the inherent sensory-motor abilities that the individual has already developed.
RESUMEN
Current observational inventories used to diagnose autism spectrum disorders (ASD) apply similar criteria to females and males alike, despite developmental differences between the sexes. Recent work investigating the chronology of diagnosis in ASD has raised the concern that females run the risk of receiving a delayed diagnosis, potentially missing a window of opportunity for early intervention. Here, we retake this issue in the context of the objective measurements of natural behaviors that involve decision-making processes. Within this context, we quantified movement variability in typically developing (TD) individuals and those diagnosed with ASD across different ages. We extracted the latencies of the decision movements and velocity-dependent parameters as the hand movements unfolded for two movement segments within the reach: movements intended toward the target and withdrawing movements that spontaneously, without instruction, occurred incidentally. The stochastic signatures of the movement decision latencies and the percent of time to maximum speed differed between males and females with ASD. This feature was also observed in the empirically estimated probability distributions of the maximum speed values, independent of limb size. Females with ASD showed different dispersion than males with ASD. The distinctions found for females with ASD were better appreciated compared with those of TD females. In light of these results, behavioral assessment of autistic traits in females should be performed relative to TD females to increase the chance of detection.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/diagnóstico , Fenotipo , Desempeño Psicomotor , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Preescolar , Toma de Decisiones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Movimiento , Pruebas Neuropsicológicas , Factores SexualesRESUMEN
A Structured Observational Analog Procedure (SOAP), an analogue measure of parent-child interactions, was used to assess treatment outcome in children with Autism Spectrum Disorder and serious behavior problems. It served as a secondary outcome measure in a 24-week, randomized trial of risperidone (MED; N=49) versus risperidone plus parent training (COMB; n=75) (ages 4-13 years). At 24-weeks, there was 28 % reduction in child inappropriate behavior during a Demand Condition (p=.0002) and 12 % increase in compliance to parental requests (p=.004) for the two treatment conditions combined. Parents displayed 64 % greater use of positive reinforcement (p=.001) and fewer repeated requests for compliance (p<.0001). In the analysis of covariance (ANCOVA), COMB parents used significantly more positive reinforcement (p=.01) and fewer restrictive statements (p<.05) than MED parents. The SOAP is sensitive to change in child and parent behavior as a function of risperidone alone and in combination with PMT and can serve as a valuable complement to parent and clinician-based measures.
RESUMEN
OBJECTIVE: To follow up on a three-site, 24-week randomized clinical trial (N = 124) comparing antipsychotic medication alone (MED) with antipsychotic medication plus parent training in the behavior management (COMB) of children with autism spectrum disorders and severe behavior problems. The COMB treatment had shown a significant advantage for child behavioral noncompliance (p = .006, d = 0.34), irritability (p = .01, d = 0.48), and hyperactivity/noncompliance (p = .04, d = 0.55) with a lower medication dose. METHOD: One year after each participant's termination, the authors mailed an assessment packet with a return-addressed envelope; a telephone call alerted the family. Failure to return packets within 1 month elicited another contact and offers to resend. RESULTS: Eighty-seven of 124 families (70.2%) participated in the follow-up. The improvement difference between treatments attenuated from after treatment to follow-up for noncompliance (d = 0.32 to 0.12) and irritability (d = 0.46 to 0.03). The follow-up differences were nonsignificant (the noncompliance difference also was nonsignificant after treatment for these 87 families). Sixty-seven percent of the COMB group and 53% of the MED group were still taking risperidone, the original study medication. Most needed dose adjustments or additional medication, and the COMB group no longer had a significantly lower dose. All COMB families but only 39% of MED families reported seeking parent training after treatment. Improvements in daily living skills during treatment predicted noncompliance improvement at follow-up for the COMB children, but noncompliance deterioration and especially hyperactivity/noncompliance deterioration for the MED children. CONCLUSIONS: The study treatment experience/familiarity greatly influenced the follow-up treatment: those who had received parent training reported seeking it, whereas those who had not received it tended not to seek it. The superiority of COMB over MED after treatment attenuated by more than half at follow-up.
Asunto(s)
Antipsicóticos/farmacología , Trastornos Generalizados del Desarrollo Infantil/terapia , Padres/educación , Educación del Paciente como Asunto/métodos , Adolescente , Adulto , Antipsicóticos/administración & dosificación , Aripiprazol , Niño , Trastornos de la Conducta Infantil/tratamiento farmacológico , Trastornos de la Conducta Infantil/epidemiología , Trastornos de la Conducta Infantil/terapia , Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Trastornos Generalizados del Desarrollo Infantil/epidemiología , Preescolar , Terapia Combinada , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Educación del Paciente como Asunto/tendencias , Piperazinas/administración & dosificación , Piperazinas/farmacología , Quinolonas/administración & dosificación , Quinolonas/farmacología , Risperidona/administración & dosificación , Risperidona/farmacología , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Antipsicóticos/efectos adversos , Síndrome de Asperger/tratamiento farmacológico , Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Piperazinas/efectos adversos , Quinolonas/efectos adversos , Adolescente , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Aripiprazol , Síndrome de Asperger/fisiopatología , Niño , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Preescolar , Relación Dosis-Respuesta a Droga , Electrocardiografía , Femenino , Humanos , Genio Irritable/efectos de los fármacos , Masculino , Proyectos Piloto , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Estudios Prospectivos , Quinolonas/administración & dosificación , Quinolonas/uso terapéuticoRESUMEN
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.
Asunto(s)
Antipsicóticos/uso terapéutico , Trastorno Autístico/tratamiento farmacológico , Genio Irritable/efectos de los fármacos , Isoxazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Antipsicóticos/administración & dosificación , Trastorno Autístico/psicología , Niño , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Esquema de Medicación , Femenino , Humanos , Isoxazoles/administración & dosificación , Masculino , Palmitato de Paliperidona , Proyectos Piloto , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Pirimidinas/administración & dosificación , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Children with Pervasive Developmental Disorders (PDDs) have social interaction deficits, delayed communication, and repetitive behaviors as well as impairments in adaptive functioning. Many children actually show a decline in adaptive skills compared with age mates over time. METHOD: This 24-week, three-site, controlled clinical trial randomized 124 children (4 through 13 years of age) with PDDs and serious behavioral problems to medication alone (MED; n = 49; risperidone 0.5 to 3.5 mg/day; if ineffective, switch to aripiprazole was permitted) or a combination of medication plus parent training (PT) (COMB; n = 75). Parents of children in COMB received an average of 11.4 PT sessions. Standard scores and Age-Equivalent scores on Vineland Adaptive Behavior Scales were the outcome measures of primary interest. RESULTS: Seventeen subjects did not have a post-randomization Vineland assessment. Thus, we used a mixed model with outcome conditioned on the baseline Vineland scores. Both groups showed improvement over the 24-week trial on all Vineland domains. Compared with MED, Vineland Socialization and Adaptive Composite Standard scores showed greater improvement in the COMB group (p = .01 and .05, and effect sizes = 0.35 and 0.22, respectively). On Age Equivalent scores, Socialization and Communication domains showed greater improvement in COMB versus MED (p = .03 and 0.05, and effect sizes = 0.33 and 0.14, respectively). Using logistic regression, children in the COMB group were twice as likely to make at least 6 months' gain (equal to the passage of time) in the Vineland Communication Age Equivalent score compared with MED (p = .02). After controlling for IQ, this difference was no longer significant. CONCLUSION: Reduction of serious maladaptive behavior promotes improvement in adaptive behavior. Medication plus PT shows modest additional benefit over medication alone. Clinical trial registration information-RUPP PI PDD: Drug and Behavioral Therapy for Children With Pervasive Developmental Disorders; http://www.clinicaltrials.gov; NCT00080145.
Asunto(s)
Adaptación Psicológica/efectos de los fármacos , Antipsicóticos/uso terapéutico , Trastornos de la Conducta Infantil/terapia , Trastornos Generalizados del Desarrollo Infantil/terapia , Educación , Risperidona/uso terapéutico , Adolescente , Antipsicóticos/efectos adversos , Síndrome de Asperger/diagnóstico , Síndrome de Asperger/psicología , Síndrome de Asperger/terapia , Trastorno Autístico/diagnóstico , Trastorno Autístico/psicología , Trastorno Autístico/terapia , Lista de Verificación , Niño , Trastornos de la Conducta Infantil/diagnóstico , Trastornos de la Conducta Infantil/psicología , Trastornos Generalizados del Desarrollo Infantil/diagnóstico , Trastornos Generalizados del Desarrollo Infantil/psicología , Preescolar , Terapia Combinada , Comunicación , Conducta Cooperativa , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Risperidona/efectos adversos , SocializaciónRESUMEN
The Research Units on Pediatric Psychopharmacology--Autism Network reported additional benefit when adding parent training (PT) to antipsychotic medication in children with autism spectrum disorders and serious behavior problems. The intent-to-treat analyses were rerun with putative predictors and moderators. The Home Situations Questionnaire (HSQ) and the Hyperactivity/Noncompliance subscale of the Aberrant Behavior Checklist were used as outcome measures. Candidate predictors and moderators included 21 demographics and baseline measures of behavior. Higher baseline HSQ scores predicted greater improvement on the HSQ regardless of treatment assignment, but no other predictors of outcome were observed. None of the variables measured in this study moderated response to PT. Antipsychotic medication plus PT appears to be equally effective for children with a wide range of demographic and behavioral characteristics.
Asunto(s)
Trastornos de la Conducta Infantil/psicología , Trastornos Generalizados del Desarrollo Infantil/psicología , Relaciones Padres-Hijo , Padres/educación , Adolescente , Antipsicóticos/uso terapéutico , Niño , Trastornos de la Conducta Infantil/tratamiento farmacológico , Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Preescolar , Femenino , Humanos , Masculino , Padres/psicología , Valor Predictivo de las Pruebas , Risperidona/uso terapéutico , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
To date, placebo-controlled drug trials targeting the core social impairment of autistic disorder (autism) have had uniformly negative results. Given this, the search for new potentially novel agents targeting the core social impairment of autism continues. Acamprosate is U.S. Food and Drug Administration-approved drug to treat alcohol dependence. The drug likely impacts both gamma-aminobutyric acid and glutamate neurotransmission. This study describes our initial open-label experience with acamprosate targeting social impairment in youth with autism. In this naturalistic report, five of six youth (mean age, 9.5 years) were judged treatment responders to acamprosate (mean dose 1,110 mg/day) over 10 to 30 weeks (mean duration, 20 weeks) of treatment. Acamprosate was well tolerated with only mild gastrointestinal adverse effects noted in three (50%) subjects.
Asunto(s)
Trastorno Autístico/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Antagonistas del GABA/uso terapéutico , Trastorno de la Conducta Social/tratamiento farmacológico , Taurina/análogos & derivados , Acamprosato , Trastorno Autístico/complicaciones , Niño , Antagonistas de Aminoácidos Excitadores/efectos adversos , Antagonistas del GABA/efectos adversos , Humanos , Proyectos Piloto , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Trastorno de la Conducta Social/complicaciones , Taurina/efectos adversos , Taurina/uso terapéuticoAsunto(s)
Ansiolíticos/uso terapéutico , Bruxismo/tratamiento farmacológico , Buspirona/uso terapéutico , Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Bruxismo/complicaciones , Niño , Trastornos Generalizados del Desarrollo Infantil/complicaciones , Humanos , MasculinoAsunto(s)
Trastorno Autístico/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/farmacología , Riluzol/farmacología , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitadores/efectos adversos , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Humanos , Masculino , Riluzol/efectos adversos , Riluzol/uso terapéutico , Resultado del Tratamiento , Adulto JovenAsunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Guanfacina/uso terapéutico , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Niño , Preescolar , Preparaciones de Acción Retardada , Femenino , Guanfacina/administración & dosificación , Humanos , Masculino , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Antipsicóticos/uso terapéutico , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Piperazinas/uso terapéutico , Quinolonas/uso terapéutico , Adolescente , Adulto , Agresión/efectos de los fármacos , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Aripiprazol , Niño , Femenino , Síndrome del Cromosoma X Frágil/psicología , Humanos , Masculino , Proyectos Piloto , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Estudios Prospectivos , Pruebas Psicológicas , Quinolonas/administración & dosificación , Quinolonas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Glutamatergic dysregulation is implicated in the pathophysiology of fragile X syndrome (FXS). Riluzole is hypothesized to have an inhibitory effect on glutamate release, block excitotoxic effects of glutamate, and potentiate postsynaptic GABA(A) receptor function. Extracellular signal-related kinase (ERK) activation is known to be delayed in humans with FXS and knockout animal models of FXS. Correction of delayed ERK activation is a potential biomarker of treatment response in FXS. We conducted a six-week open-label prospective pilot study of riluzole (100 mg/day) in six adults with FXS. METHODS: Riluzole was started at 50mg every evening and then increased to 50mg twice daily at week 2. The dose was kept constant for the final 4 weeks of the trial. Clinical response was determined by a score of 1 "very much improved" or 2 "much improved" on the Clinical Global Impressions Improvement (CGI-I) scale and a≥25% improvement on the Children's Yale-Brown Obsessive Compulsive Scale modified for Pervasive Developmental Disorders. The primary target of treatment in this study was repetitive, compulsive behavior that commonly occurs in persons with FXS. The study incorporated an ERK activation biomarker assay. Potential adverse effects were assessed in a systematic manner at all clinic visits and by phone between visits. RESULTS: Riluzole treatment was associated with clinical response in 1 of 6 subjects (17%). Among a number of secondary outcome measures employed, significant improvement was only noted on the ADHD Rating Scale-IV (became non-significant when corrected for multiple comparisons). Riluzole use was associated with significant correction in ERK activation time in all subjects (mean change from 3.82±0.27 (baseline) to 2.99±0.26 (endpoint) minutes; p=0.007). Riluzole was well tolerated; mean increases in liver function tests occurred but drug discontinuation was not required. CONCLUSION: Overall, riluzole use was not associated with significant clinical improvement despite uniform correction of peripheral ERK activation. Future directions of study include testing of riluzole in animal models of FXS and assessment of psychotropic monotherapy on ERK activation.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Riluzol/administración & dosificación , Niño , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Trastornos Generalizados del Desarrollo Infantil/psicología , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/efectos adversos , Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/fisiopatología , Humanos , Masculino , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/efectos adversos , Proyectos Piloto , Estudios Prospectivos , Riluzol/efectos adversos , Adulto JovenRESUMEN
The neurobiology of autism spectrum disorders (ASDs) has become increasingly understood since the advent of magnetic resonance imaging (MRI). Initial observations of an above-average head circumference were supported by structural MRI studies that found evidence of increased total brain volume and early rapid brain overgrowth in affected individuals. Subsequent research revealed consistent abnormalities in cortical gray and white matter volume in ASDs. The structural integrity and orientation of white matter have been further elucidated via diffusion tensor imaging methods. The emergence of functional MRI techniques led to an enhanced understanding of the neural circuitry of ASDs, demonstrating areas of dysfunctional cortical activation and atypical cortical specialization. These studies have provided evidence of underconnectivity in distributed cortical networks integral to the core impairments associated with ASDs. Abnormalities in the default-mode network during the resting state have also been identified. Overall, structural and functional MRI research has generated important insights into the neurobiology of ASDs. Additional research is needed to further delineate the underlying brain basis of this constellation of disorders.
Asunto(s)
Encéfalo/anomalías , Encéfalo/patología , Trastornos Generalizados del Desarrollo Infantil/patología , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Imagen por Resonancia Magnética/métodos , Encéfalo/fisiopatología , Niño , Preescolar , Humanos , Lactante , Modelos NeurológicosRESUMEN
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.