Tratamiento farmacológico y no farmacológico en el T. Espectro Autista

Tratamiento farmacológico y no farmacológico en el T. Espectro Autista
Dra Carolina Garcés Q Psiquiatra Infanto Juvenil UV Unidad de neuropsiquiatría Hospital Gustavo Fricke

Objetivos de aprendizaje:
TEA Generalidades Y DSM 5 Abordaje terapeutico Fármacos y síntomas a tratar Terapias farmacológicas Terapias no farmacológicas Terapias complementarias

Generalidades: Tr. Espectro autista (TEA)
Un grupo de T. Neuropsiquiátricos heterogéneos en los que se encuentra alterada de manera grave y generalizada múltiples areas del desarrollo Inicio en los primeros años de vida y Etiología multifactorial Alteración dinámica del Desarrollo cerebral (fx y morfología) pre y postnatal Clínica varía con la edad. Curso crónico Se asocia a RM frecuentemente No existen tratamientos que lo curen, pero si que mejoran la calidad de vida y pronóstico A. Deficit en la comunicación y en la interacción social B. Patrones de comportamiento repetitivos e intereses fijos Retraso en fx psicológicas Additional characteristics include onset early in life, delay and/or deviance of development of key psychological functions, multifactorial etiology in which several as yet unknown genetic risk factors interact with each other and with environmental factors, change and mitigation of symptomatic expression by age and, despite this, a chronic course with strong persistence of handicaps over time. However, it is equally true that ASD are clinically very heterogeneous conditions. A main factor that determines diversity is variation in level of cognitive functioning and language skills. There is a large difference between a severely intellectually impaired person with autism who is unable to speak and who engages in motor stereotypies and self-injury, and a highly skilled computer engineer with Asperger disorder or with high functioning autism who is fluent in his one-sided exchange of excessive and obsessive preoccupations about, for example, the constellation of the planets and stars. Other aspects of diversity concern age, severity of cardinal features, coexisting somatic conditions including epilepsy, and coexisting psychiatric conditions. Over the past decades, clinical and research interest has moved from a focus on a more narrowly defined group of subjects with severe manifestations of the three cardinal features (i.e., “typical autism”) to a broader and more prevalent category with more subtle and less severe symptoms, usually classified as atypical autism or pervasive developmental disorder not otherwise specified (PDD-NOS). Although most of our knowledge about ASD is still derived from research in typical autism, this chapter takes a perspective on the whole range of severity of ASD. Recent findings indicate that ASD can be conceptualized as disorders of early brain development. Functional and mor- phological abnormalities of the brain, induced by both static persistent processes that started in utero and dynamic processes that change over time and continue to change in postnatal life, underlie the complex behavioral and cognitive manifestations of ASD Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - k Stigler- Child Adolesc Psychiatric Clin N Am 23 (2014) 73–82 Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187

TEA: Espectro amplio heterogéneo s/: desarrollo cognitivo
habilidades lingüisticas Severidad de síntomas cardinales Coexistencia de tr. Psiquiátrico./ Genéticos (RM, epilepsia) STIGLER 2014 Autism spectrum disorders (ASD) are lifelong neuropsychiatric disorders characterized by impairment in social interaction and communication, as well as repetitive behaviors. The therapeutic approach to the management of ASD is multimodal, often including speech therapy, occupational therapy, social skills training, and physical therapy. In addition to these nonpharmacological treatment modalities, medication is often required to decrease specific target symptoms such as irritability (severe tantrums, aggression, self-injury). Research into the pharmacotherapy of ASD began with the typical antipsychotics in the 1960s. Numerous well-designed studies investigated the high-potency antipsychotic haloperidol, finding the drug effective for serious behavioral disturbance in youth with autism.1–3 Although beneficial, the drug’s potent dopamine D2 receptor antagonism often led to acute dystonic reactions, as well as drug-induced and withdrawal-related dyskinesias.4 Concerns regarding the typical antipsychotics led researchers toward the development of the atypical antipsychotics, which has been the most studied drug class in ASD to date. At this time, risperidone and aripiprazole are the only US Food and Drug Administration (FDA)–approved medications to treat irritability in children and adolescents with autism (aged 5–16 years and 6–17 years, respectively). However, in clinical practice, many pharmacologic agents are being prescribed to diminish serious behavioral disturbance in individuals with ASD. Trastorno espectro autista  conjunto de enf. Heterogéneas con comp. Moderado - severo Síntomas centrales: Alt. Interacciones sociales Alt. De la comunicación Patrones repetitivos y estereotipias de conducta e intereses Rutter recently wrote “.studies have been striking (and surprising) in their evidence on no clinically meaningful benefits with respect to the core symptoms of autism behavioral and educational approaches, reviewed elsewhere in this issue, is the cornerstone of a comprehensive treatment plan for ASD core symptoms and delays A main factor that determines diversity is variation in level of cognitive functioning and language skills. There is a large difference between a severely intellectually impaired person with autism who is unable to speak and who engages in motor stereotypies and self-injury, and a highly skilled computer engineer with Asperger disorder or with high functioning autism who is fluent in his one-sided exchange of excessive and obsessive preoccupations about, for example, the constellation of the planets and stars. Other aspects of diversity concern age, severity of cardinal features, coexisting somatic conditions including epilepsy, and coexisting psychiatric conditions. Over the past decades, clinical and research interest has moved from a focus on a more narrowly defined group of subjects with severe manifestations of the three cardinal features (i.e., “typical autism”) to a broader and more prevalent category with more subtle and less severe symptoms, usually classified as atypical autism or pervasive developmental disorder not otherwise specified (PDD-NOS). Although most of our knowledge about ASD is still derived from research in typical autism, this chapter takes a perspective on the whole range of severity of ASD. Recent findings indicate that ASD can be conceptualized as disorders of early brain development. Functional and mor- phological abnormalities of the brain, induced by both static persistent processes that started in utero and dynamic processes that change over time and continue to change in postnatal life, underlie the complex behavioral and cognitive manifestations of ASD

Dsm 5: Trastorno espectro autista
A. Deficit persistentes en la comunicación y en la interacción social en ≠ contextos: Alt. reciprocidad socioemocional fracaso en acercamiento, en compartir emociones Alt. conductas comunicativas no verbales de la interacción social poco integrada. Alt. contacto visual y del lenguaje corporal, poca expresión facial Deficit en el desarrollo, mantenimiento y comprensión de las relaciones Deficiencias persistentes en la comunicación social y en la interacción social en diversos contextos, manifestado por lo siguiente, actualmente o por los antecedentes (los ejemplos son ilustrativos pero no exhaustivos): 1. Las deficiencias en la reciprocidad socioemocional, varían, por ejemplo, desde un acercamiento social anormal y fracaso de la conversación normal en ambos sentidos pasando por la disminución en intereses, emociones o afectos compartidos hasta el fracaso en iniciar o responder a interacciones sociales. 2. Las deficiencias en las conductas comunicativas no verbales utilizadas en la interacción social, varían, por ejemplo, desde una comunicación verbal y no verbal poco integrada pasando por anomalías del contacto visual y del lenguaje corporal o deficiencias de la comprensión y el uso de gestos, hasta una falta total de expresión facial y de comunicación no verbal. 3. Las deficiencias en el desarrollo, mantenimiento y comprensión de las relaciones, varían, por ejemplo, desde dificultades para ajustar el comportamiento en diversos contextos sociales pasando por dificultades para compartir juegos imaginativos o para hacer amigos, hasta la ausencia de interés por otras personas. Especificar la gravedad actual: La gravedad se basa en deterioros de la comunicación social y en patrones de comportamiento restringidos y repetitivos (véase la Tabla 2).

Dsm 5: TEA B. Patrones restrictivos y repetitivos
de comportamiento, intereses o actividades: 1. Movimientos, uso objetos, habla estereotipados 2. Insistencia en la monotonía, excesiva inflexibilidad de rutinas o patrones ritualizados 3. Intereses muy restringidos y fijos de forma anormal 4. Hiper o hiporeactividad a los estimulos sensoriales Especificar la gravedad actual 1. Movimientos, utilización de objetos o habla estereotipados o repetitivos (p. ej., estereotipias motoras simples, alineación de los juguetes o cambio de lugar de los objetos, ecolalia, frases idiosincrásicas). 2. Insistencia en la monotonía, excesiva inflexibilidad de rutinas o patrones ritualizados de comportamiento verbal o no verbal (p. ej., gran angustia frente a cambios pequeños, dificultades con las transiciones, patrones de pensamiento rígidos, rituales de saludo, necesidad de tomar el mismo camino o de comer los mismos alimentos cada día). 3. Intereses muy restringidos y fijos que son anormales en cuanto a su intensidad o foco de interés (p. ej., fuerte apego o preocupación por objetos inusuales, intereses excesivamente circunscritos o perseverantes). 4. Hiper- o hiporeactividad a los estimulos sensoriales o interés inhabitual por aspectos sensoriales del entorno (p. ej., indiferencia aparente al dolor/temperatura, respuesta adversa a sonidos o texturas específicos, olfateo o palpación excesiva de objetos, fascinación visual por las luces o el movimiento). Especificar la gravedad actual: La gravedad se basa en deterioros de la comunicación social y en patrones de comportamiento restringidos y repetitivos (véase la Tabla 2). C. Los síntomas han de estar presentes en las primeras fases del período de desarrollo (pero pueden no manifestarse totalmente hasta que la demanda social supera las capacidades limitadas, o pueden estar enmascarados por estrategias aprendidas en fases posteriores de la vida). D. Los síntomas causan un deterioro clínicamente significativo en lo social, laboral u otras áreas importantes del funcionamiento habitual. E. Estas alteraciones no se explican mejor por la discapacidad intelectual (trastorno del desarrollo intelectual) o por el retraso global del desarrollo. La discapacidad intelectual y el trastorno del espectro del autismo con frecuencia coinciden; para hacer diagnósticos de comorbilidades de un trastorno del espectro del autismo y discapacidad intelectual, la comunicación social ha de estar por debajo de lo previsto para el nivel general de desarrollo.

Dsm 5: TEA C. Desde el desarrollo temprano
D. Deterioro clínicamente significativo E. No se explican mejor por la discapacidad intelectual o por el retraso del desarrollo Especificar: Severidad  nivel de apoyo requerido Con/ sin déficit intelectual, Deterioro del lenguaje Asociado a: afección médica o genética Factor ambiental conocidos trastorno del desarrollo neurológico, mental o del comportamiento Con catatonía Ev verbal y no verbal Especificar: sin déficit intelectual acompañante Con o sin deterioro del lenguaje acompañante Asociado a una afección médica o genética, o a un factor ambiental conocidos (Nota de codificación: Utilizar un código adicional para identificar la afección médica o genética asociada.) Asociado a otro trastorno del desarrollo neurológico, mental o del comportamiento (Nota de codificación: Utilizar un código(s) adicional(es) para identificar el trastorno(s) del desarrollo neurológico, mental o del comportamiento asociado[s].) Con catatonía (véanse los criterios de catatonía asociados a otro trastorno mental; para la definición, véanse las págs. 65– 66). (Nota de codificación: Utilizar el código adicional [F06.1] catatonía asociada a trastorno del espectro del autismo para indicar la presencia de la catatonía concurrente). . La discapacidad intelectual y el trastorno del espectro del autismo con frecuencia coinciden; para hacer diagnósticos de comorbilidades de un trastorno del espectro del autismo y discapacidad intelectual, la comunicación social ha de estar por debajo de lo previsto para el nivel general de desarrollo. Nota: A los pacientes con un diagnóstico bien establecido según el DSM-IV de trastorno autista, enfermedad de Asperger o trastorno generalizado del desarrollo no especificado de otro modo, se les aplicará el diagnóstico de trastorno del espectro del autismo. Los pacientes con deficiencias notables de la comunicación social, pero cuyos síntomas no cumplen los criterios de trastorno del espectro del autismo,deben ser evaluados para diagnosticar el trastorno de la comunicación social (pragmática). Especificar si: Con o sin déficit intelectual acompañante Procedimientos de registro Para el trastorno del espectro del autismo que está asociado a una afección médica o genética conocida, a un factor ambiental o a otro trastorno del desarrollo neurológico, mental, o del comportamiento, se registrará el trastorno del espectro del autismo asociado a (nombre de la afección, trastorno o factor) (p. ej., trastorno del espectro de autismo asociado al síndrome de Rett). La gravedad se registrará de acuerdo con el grado de ayuda necesaria para cado uno de los dominios psicopatológicos de la Tabla 2 (p. ej., “necesita apoyo muy notable para deficiencias en la comunicación social y apoyo notable para comportamientos restringidos y repetitivos”). A continuación, se debe especificar “con deterioro intelectual acompañante” o “sin deterioro intelectual acompañante”. Después se hará constar la especi ficación de la deterioro del lenguaje. Si existe un deterioro del lenguaje acompañante, se registrará el grado actual de funcionamiento verbal (p. ej., “con deterioro del lenguaje acompañante-habla no inteligible” o “con deterioro del lenguaje acompañante-habla con frases”). Si existe catatonía, se registrará por separado “catatonía asociada a trastorno del espectro del autismo.”

Objetivos del Tratamiento en N y A con TEA:
Minimizar los deficit principales y asociados Maximizar la independencia, funcionalidad y calidad de vida Aliviar la angustia del paciente y familia Facilitar el desarrollo y el aprendizaje Promover la socialización Reducir las conductas desadaptativas Educar y apoyar a las familias : fo, T.O., Entrenam. Habilidades sociales, terapia física Facilitar el desarrollo y el aprendizaje Promover la socialización Reducir las conductas desadaptativas Educar y apoyar a las familias STIGLER 2014 Autism spectrum disorders (ASD) are lifelong neuropsychiatric disorders characterized by impairment in social interaction and communication, as well as repetitive behaviors. The therapeutic approach to the management of ASD is multimodal, often including speech therapy, occupational therapy, social skills training, and physical therapy. In addition to these nonpharmacological treatment modalities, medication is often required to decrease specific target symptoms such as irritability (severe tantrums, aggression, self-injury). Research into the pharmacotherapy of ASD began with the typical antipsychotics in the 1960s. Numerous well-designed studies investigated the high-potency antipsychotic haloperidol, finding the drug effective for serious behavioral disturbance in youth with autism.1–3 Although beneficial, the drug’s potent dopamine D2 receptor antagonism often led to acute dystonic reactions, as well as drug-induced and withdrawal-related dyskinesias.4 Concerns regarding the typical antipsychotics led researchers toward the development of the atypical antipsychotics, which has been the most studied drug class in ASD to date. At this time, risperidone and aripiprazole are the only US Food and Drug Administration (FDA)–approved medications to treat irritability in children and adolescents with autism (aged 5–16 years and 6–17 years, respectively). However, in clinical practice, many pharmacologic agents are being prescribed to diminish serious behavioral disturbance in individuals with ASD. Trastorno espectro autista  conjunto de enf. Heterogéneas con comp. Moderado - severo Síntomas centrales: Alt. Interacciones sociales Alt. De la comunicación Patrones repetitivos y estereotipias de conducta e intereses Rutter recently wrote “.studies have been striking (and surprising) in their evidence on no clinically meaningful benefits with respect to the core symptoms of autism behavioral and educational approaches, reviewed elsewhere in this issue, is the cornerstone of a comprehensive treatment plan for ASD core symptoms and delays Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - K Stigler- Child Adolesc Psychiatric Clin N Am 23 (2014)–82 Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187

Tratamiento del TEA: Características de tto Efectivo: Temprano
Abordaje multimodal e interdisciplinario Individualizado, persp. Evolutiva, adaptado a entorno y necesidades Inclusivo: flia –colegio-terapeutas  generalización de aprendizajes Estructurado: Diseño de actividades necesarias para logro objetivos claros Fomente capacidad lingüística, cognitiva, social, comunicacional Tratamiento temprano e interdisciplinario con enfoque evolutivo e individualizado que permita mejorar su funcionamiento y adaptación, que fomenten las competencias sociales y comunicacionales : fo, T.O., Entrenam. Habilidades sociales, terapia física Facilitar el desarrollo y el aprendizaje Promover la socialización Reducir las conductas desadaptativas Educar y apoyar a las familias STIGLER 2014 Autism spectrum disorders (ASD) are lifelong neuropsychiatric disorders characterized by impairment in social interaction and communication, as well as repetitive behaviors. The therapeutic approach to the management of ASD is multimodal, often including speech therapy, occupational therapy, social skills training, and physical therapy. In addition to these nonpharmacological treatment modalities, medication is often required to decrease specific target symptoms such as irritability (severe tantrums, aggression, self-injury). Research into the pharmacotherapy of ASD began with the typical antipsychotics in the 1960s. Numerous well-designed studies investigated the high-potency antipsychotic haloperidol, finding the drug effective for serious behavioral disturbance in youth with autism.1–3 Although beneficial, the drug’s potent dopamine D2 receptor antagonism often led to acute dystonic reactions, as well as drug-induced and withdrawal-related dyskinesias.4 Concerns regarding the typical antipsychotics led researchers toward the development of the atypical antipsychotics, which has been the most studied drug class in ASD to date. At this time, risperidone and aripiprazole are the only US Food and Drug Administration (FDA)–approved medications to treat irritability in children and adolescents with autism (aged 5–16 years and 6–17 years, respectively). However, in clinical practice, many pharmacologic agents are being prescribed to diminish serious behavioral disturbance in individuals with ASD. Trastorno espectro autista  conjunto de enf. Heterogéneas con comp. Moderado - severo Síntomas centrales: Alt. Interacciones sociales Alt. De la comunicación Patrones repetitivos y estereotipias de conducta e intereses Rutter recently wrote “.studies have been striking (and surprising) in their evidence on no clinically meaningful benefits with respect to the core symptoms of autism behavioral and educational approaches, reviewed elsewhere in this issue, is the cornerstone of a comprehensive treatment plan for ASD core symptoms and delays Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - K Stigler- Child Adolesc Psychiatric Clin N Am 23 (2014)–82 Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187

Farmacoterapia en TEA:
Objetivo: Tratar conductas desadaptativas o síntomas diana que: Síntomas severos y deterioro funcional no cedan con int. conductuales/ ambientales Comorbilidad psiquiátrica Fundamental: Medir síntomas en el tiempo a través de escalas de evaluación para supervisar la eficacia (ABC, CGI, CARS) Considerar que Responden ≠ a niños sin TEA: Más sensibles a RAM Dificultad en identificar síntomas diana Fact. Médicos que pueden contribuir (dolor, menstruación, alt. Sueño, infección) Los niños con ASD pueden ser más sensibles a la farmacoterapia y tienen más efectos secundarios (Towbin, 2003; Aman, 2008) * Puede ser difícil establecer claramente los síntomas de destino porque los niños con TEA tienen problemas en la comunicación y en la identificación de su emociones (por ejemplo, ¿Es la ansiedad? Anger? Impulsividad?) * Factores médicos contribuir? (El dolor, la menstruación, la incautación, el sueño problemas, infección Medicines should be used for clearly defined maladaptive behaviors or target symptoms * Measure these symptoms over time using rating scales to monitor efficacy (ABC, CGI, CARS) Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - K Stigler- Child Adolesc Psychiatric Clin N Am 23 (2014)–82 Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187

Estudio de pacientes en la Red de Tratamiento TEA 3-56 a (prom. 16 a) con n= 2.853: 53% tomaba fármacos: 45% psicotrópicos antidepresivos, psicoestimulantes, Antipsicóticos 12% anticonvulsivantes 6% vitaminas/ suplementos Toma de uno o más psicotrópicos: 44% 6-11 años; 64% 12-17años A pesar de que la ½ de los n y a con TEA toman psicotrópicos, estos no son efectivos para tratar los sínt. Centrales del TEA 2014 This is exemplified by a recent study that examined rates of medication use in 2853 individuals with ASD enrolled in the Autism Treatment Network registry.6 Among those in the registry, 44% of subjects aged 6 to 11 years and 64% of subjects aged 12 to 17 years, were receiving one or more psychotropic medications J Child Adolesc Psychopharmacol Winter;12(4): Prevalence and patterns of use of psychoactive medicines in individuals with autism in the Autism Society of North Carolina. Langworthy-Lam KS1, Aman MG, Van Bourgondien ME. Author information Abstract The aim of this study was to assess the prevalence and patterns of psychoactive and over-the-counter medicines in a large cohort of individuals with autism. We conducted a mail survey of 3,228 families that are members of the Autism Society of North Carolina. This is one of the largest chapters of the Autism Society of America. The survey form addressed current medicines used, side effects, demographic characteristics, and medical conditions. Some 1,538 member families within the society (48%) responded to the survey. In all, 703 (45.7%) individuals with autism were taking psychotropic drugs, 191 (12.4%) antiepileptic drugs (AEDs), and 86 (5.7%) supplements for autism. The total number taking psychotropic, antiepileptic, or vitamin treatments was 816 (53.1%). Antidepressants (taken by 21.7% of the sample), antipsychotics (16.8%), and stimulants (13.9%) were the most commonly prescribed agents. Univariate and multivariate analyses were conducted to examine factors associated with treatment. Greater age, more severe autism and mental retardation, and more restricted housing were often associated with greater use of psychoactive agents. These findings suggest that individuals with autism are a frequently medicated group, although the empirical research support for most agents being used is still very limited.

Irritabilidad/ Agresividad hiperactividad, impulsividad, inatención Conductas disruptivas Conductas repetitivas, estereotipias Ansiedad (rigidez, TOC ) Alt. del sueño Depresión T. Del ánimo Identificar conductas objetivo de tto: (por ejemplo, la agresión, la explosiva estallidos, rabietas, autolesiones)

Irritabilidad/ Agresividad hiperactividad, impulsividad, inatención Conductas disruptivas Conductas repetitivas, estereotipias Ansiedad (rigidez, TOC ) Alt. del sueño Depresión T. Del ánimo (por ejemplo, la agresión, la explosiva estallidos, rabietas, autolesiones)

Epidemiología de la agresividad en N y A con TEA:
Prevalencia alta (n=1380) : 68% agresión al cuidador Otros estudios: 50%  Irritabilidad, ansiedad, hiperactividad 30% mod-severa irritabilidad, si no es tratada, dificulta intervenciones. Se req. Frecuentemente uso de fcos EPIDEMIOLOGY OF ASD Interfering behavioral problems including irritability, anxiety, and hyperactivity are commonly observed in ASD, with reported prevalence rates of approximately 50% in this population.5 Furthermore, approximately 30% of individuals with ASD have been shown to exhibit moderate to severe irritability, which left untreated, can significantly impede meaningful participation in behavioral and educational interventions. The management of such behavioral problems frequently necessitates the use of psychotropic medications. In general, pharmacologic agents have been increasingly prescribed for a variety of symptoms in this diagnostic group.6.

Agresividad EN tea Otros estudiados:
Haloperidol: RCT contra placebo con entrenamiento lenguaje, de niños 2.6 to Dosis de 1.7 mg/d en estereotipias en niños > de 4 a, seguimiento con CPRS. Efectos beneficiosos en el aprendizaje cuando se combina con tto conductual Mejoría en el afecto (irritabilidad, labilidad, negativismo) RAM son frecuentes: sedación, SEP, 1/3 sufre de distonia/ diskinesia tardia (por eso, preferidos AA) aggression, repetitive behaviors, hyperactivity, depression and anxiety, and sleep disorders TREATMENT OF ASD-ASSOCIATED/COMORBID SYMPTOMS Aggression, Irritability, and Self-Injury Aggression and related symptoms are the associated problems that often elicit the most concern in ASD. Although behavioral and environmental approaches are recommended as the initial treatment, more severe or even dangerous behaviors usually result in requests for urgent pharmacologic intervention. Such behaviors can lead to injury, removal from less-restrictive classrooms or placements, and hospitalization. Patients can present with a variety of aggressive acts directed to self, others, and property. The prevalence of such acts is high. For instance, in a study of 1380 subjects with ASD, 68% demonstrated aggression to a caregiver and 49% to noncaregivers.10 The following classes of medications are used to treat aggressive behaviors. Antipsychotics The efficacy of these agents was first documented in the 1970s by Magda Campbell at NY Bellevue Hospital. In her now classic studies,11 Campbell pioneered the use of RCTs in child psychopharmacology, a field that had been largely dominated up to that point by case reports and naturalistic studies. Antipsychotics have now become commonly used agents in ASD,12 perhaps influenced by observations of possible benefits on a variety of commonly associated behaviors and the fact that the only two FDA-approved agents for the condition are aripiprazole and risperidone. Haloperidol Campbell and colleagues11 studied ASD children with severe aggression aged 2.6 to 7.2 years and randomized them to haloperidol or placebo in combination with language training. Haloperidol at an average dose of 1.7 mg/d resulted in significant improvement in withdrawal and stereotypy in children 4.5 years and older, as assessed by the CPRS. In addition, there were beneficial effects on learning when the antipsychotic was combined with behavioral treatment. Later studies13 confirmed the initial beneficial findings, including an improvement in aggression, as haloperidol was shown to be more effective than placebo for negativism, angry affect, and lability of affect. However, sedation was common, and about one-third of children developed motor symptoms such as dystonias and withdrawal dyskinesias. As a result, concern over the possible high risk of tardive dyskinesia emerged,14 and the potential for these side effects made haloperidol a less favored option once atypical antipsychotics became available.15 Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken Pediatr Clin N Am 59 (2012) 175–187

Agresividad en TEA: Risperidona:
2 meses se tratan 101 N y A prom. 9 años agresivos e irrritables con Risperidona prom 1,8 mg /d vs placebo 4 meses estudio abierto de respondedores con dosis estable 2 meses RCT con sustitución por placebo RUPP Red de autismo: RCT n=101 de 6-12 años (prom 9a) agresivos, irritables Risperidona en 1,8 mg/d 2014 Risperidone Risperidone has been investigated for the treatment of irritability in ASD via case series, open-label trials, and double-blind, placebo-controlled studies.12–15 An 8-week, double-blind, placebo-controlled study of risperidone (mean dosage, 1.8 mg/d;range, 0.5–3.5 mg/d) was conducted in 101 children and adolescents (mean age, 8.8 years) with autism and associated irritability.15 In this multisite trial, risperidone treatment led to a 57% decrease on the Aberrant Behavior Checklist (ABC) Irritability subscale score versus a 14% reduction with placebo. Furthermore, 69% in the risperidone group, versus 12% in the placebo group, were responders as determined by a rating of “much improved” or “very much improved” on the Clinical Global Impressions-Improvement (CGI-I) scale and a 25% or greater improvement on the ABC Irritability subscale score. Increased appetite, weight gain (risperidone, mean 2.7 kg; placebo, 0.8 kg), dizziness, sedation, and sialorrhea were among the adverse effects reported. Subjects who responded to risperidone (N 5 63) subsequently entered a 16-week, open-label trial.16 The mean dose of risperidone remained stable during this extension phase. The study participants continued to gain weight, with a mean increase of 5.1 kg over the 24 weeks. After the 16-week phase, 32 subjects considered responders were randomized to either continue risperidone or undergo gradual placebo substitution over 4 weeks. Only 2 (12.5%) of 16 subjects who continued on risperidone were found to relapse. In contrast, 10 (63.5%) of 16 subjects who un derwent placebo substitution relapsed, suggesting the need for longer-term treatment. An 8-week, multisite, double-blind, placebo-controlled study of risperidone (mean dose, 1.2 mg/d) was completed in 79 children and adolescents (mean age, 7.5 years) with ASD.17 The authors recorded a 64% decrease on the ABC Irritability subscale score with risperidone treatment versus a 31% reduction with placebo. In addition, 53% of subjects in the risperidone group were deemed responders in comparison to 18% of those in the placebo group. Adverse effects included sedation, tachycardia, extrapyramidal symptoms (EPS), increased appetite, and weight gain (risperidone, 2.7 kg; placebo, 1 kg), among others. in BOSTIC The results of the RUPP risperidone trial were published in 2002 and may ultimately contribute to risperidone getting a specific indication for the treatment of behavioral disturbance in autism. The network enrolled 101 subjects aged 8.8 F 2.7 years and, using the Aberrant Behavior Checklist irritability subscale as a primary outcome measure, found that behavioral symptoms including aggression, hyperactivity, and irritability all improved significantly on risperidone dosed from 0.5 mg/day to 2.5 or 3.5 mg/day (for children weighing above 45 kg) over a period of 8 weeks [29] . Treatment responders, as defined by at least a 25% decrease in the irritability score and a rating of much improved or very much improved on the Clinical Global Impressions improvement scale, was 69% in the risperidone group and 12% in the placebo group. In 23 of the 34 responders, these improvements remained during an extension phase of 6 months. With respect to side effects, receipt of risperidone was associated with a statistically significant average weight gain of 2.7 F 2.9 kg, compared with 0.8 F 2.2 kg in the placebo controls. Increased appetite, fatigue, drowsiness, dizziness, and drooling were also statistically more common in the risperidone-treated subjects than in those who received placebo. Risperidone Dissatisfaction with conventional antipsychotics, due to extrapyramidal side effects and lack of efficacy in negative symptoms of schizophrenia, led to intense efforts to find alternatives. Risperidone, the first in a new class of agents termed atypical antipsychotics, was approved for schizophrenia in adults by the FDA in 1993. Given the expectation of improved efficacy and lower rates of adverse effects, atypicals became first-line agents for many conditions requiring neuroleptics, including ASD. Following the Campbell tradition, risperidone was rigorously studied by the NIMH Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. RUPP conducted a multiphase trial comparing the effects of risperidone in comparison with placebo for the treatment of aggressive behaviors in patients aged 5 to 17 years with ASD. There was an initial double-blind, 8-week RCT study16 with 101 participants, followed by a 4-month open-label trial ending in an 8-week randomized, double-blind, placebo-substitution study of risperidone withdrawal.17 The studies found that risperidone, in mean doses of 2.08 mg/d, was effective for reducing moderate to severe tantrums, aggression, and self-injurious behavior in children with autism. Outcomes were assessed by the ABC-I and CGI-I. These gains were stable over time and did not necessitate dose increases, but relapse was seen in the majority if the medication was withdrawn at 6 months. The investigators found no evidence of dyskinesia or dystonia. However, the observed weight gain of 5.6 kg for the risperidone group was more than twice the expected weight gain over a 6-month period. The FDA approved risperidone in 2006 for the treatment of irritability associated with autistic disorder, including symptoms of aggression, deliberate selfinjury, temper tantrums, and quickly changing moods, in children and adolescents aged 5 to 16 years, with a maximum recommended dose of 3 mg/d. A metaanalysis that reviewed all risperidone RCT studies for subjects with ASD published after 2000 found that the agent yielded a large mean effect size of Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187 Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - Stigler - Child Adolesc Psychiatric Clin N Am 23 (2014) 73–82

2 meses se tratan 101 N y A prom. 9 años agresivos e irrritables con Risperidona prom 1,8 mg /d vs placebo 4 meses estudio abierto de respondedores con dosis estable 2 meses RCT con sustitución por placebo RUPP Red de autismo: 69% de N y A: mejoría significativa en: Agresividad / Irritabilidad / Pataletas Hiperactividad Resp. A placebo: 12% RAM: sedación, mareo, sialorrea, aumento 2,7 kg RCT n=101 de 6-12 años (prom 9a) agresivos, irritables Risperidona en 1,8 mg/d 2014 Risperidone Risperidone has been investigated for the treatment of irritability in ASD via case series, open-label trials, and double-blind, placebo-controlled studies.12–15 An 8-week, double-blind, placebo-controlled study of risperidone (mean dosage, 1.8 mg/d;range, 0.5–3.5 mg/d) was conducted in 101 children and adolescents (mean age, 8.8 years) with autism and associated irritability.15 In this multisite trial, risperidone treatment led to a 57% decrease on the Aberrant Behavior Checklist (ABC) Irritability subscale score versus a 14% reduction with placebo. Furthermore, 69% in the risperidone group, versus 12% in the placebo group, were responders as determined by a rating of “much improved” or “very much improved” on the Clinical Global Impressions-Improvement (CGI-I) scale and a 25% or greater improvement on the ABC Irritability subscale score. Increased appetite, weight gain (risperidone, mean 2.7 kg; placebo, 0.8 kg), dizziness, sedation, and sialorrhea were among the adverse effects reported. Subjects who responded to risperidone (N 5 63) subsequently entered a 16-week, open-label trial.16 The mean dose of risperidone remained stable during this extension phase. The study participants continued to gain weight, with a mean increase of 5.1 kg over the 24 weeks. After the 16-week phase, 32 subjects considered responders were randomized to either continue risperidone or undergo gradual placebo substitution over 4 weeks. Only 2 (12.5%) of 16 subjects who continued on risperidone were found to relapse. In contrast, 10 (63.5%) of 16 subjects who un derwent placebo substitution relapsed, suggesting the need for longer-term treatment. An 8-week, multisite, double-blind, placebo-controlled study of risperidone (mean dose, 1.2 mg/d) was completed in 79 children and adolescents (mean age, 7.5 years) with ASD.17 The authors recorded a 64% decrease on the ABC Irritability subscale score with risperidone treatment versus a 31% reduction with placebo. In addition, 53% of subjects in the risperidone group were deemed responders in comparison to 18% of those in the placebo group. Adverse effects included sedation, tachycardia, extrapyramidal symptoms (EPS), increased appetite, and weight gain (risperidone, 2.7 kg; placebo, 1 kg), among others. in BOSTIC The results of the RUPP risperidone trial were published in 2002 and may ultimately contribute to risperidone getting a specific indication for the treatment of behavioral disturbance in autism. The network enrolled 101 subjects aged 8.8 F 2.7 years and, using the Aberrant Behavior Checklist irritability subscale as a primary outcome measure, found that behavioral symptoms including aggression, hyperactivity, and irritability all improved significantly on risperidone dosed from 0.5 mg/day to 2.5 or 3.5 mg/day (for children weighing above 45 kg) over a period of 8 weeks [29] . Treatment responders, as defined by at least a 25% decrease in the irritability score and a rating of much improved or very much improved on the Clinical Global Impressions improvement scale, was 69% in the risperidone group and 12% in the placebo group. In 23 of the 34 responders, these improvements remained during an extension phase of 6 months. With respect to side effects, receipt of risperidone was associated with a statistically significant average weight gain of 2.7 F 2.9 kg, compared with 0.8 F 2.2 kg in the placebo controls. Increased appetite, fatigue, drowsiness, dizziness, and drooling were also statistically more common in the risperidone-treated subjects than in those who received placebo. Risperidone Dissatisfaction with conventional antipsychotics, due to extrapyramidal side effects and lack of efficacy in negative symptoms of schizophrenia, led to intense efforts to find alternatives. Risperidone, the first in a new class of agents termed atypical antipsychotics, was approved for schizophrenia in adults by the FDA in 1993. Given the expectation of improved efficacy and lower rates of adverse effects, atypicals became first-line agents for many conditions requiring neuroleptics, including ASD. Following the Campbell tradition, risperidone was rigorously studied by the NIMH Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. RUPP conducted a multiphase trial comparing the effects of risperidone in comparison with placebo for the treatment of aggressive behaviors in patients aged 5 to 17 years with ASD. There was an initial double-blind, 8-week RCT study16 with 101 participants, followed by a 4-month open-label trial ending in an 8-week randomized, double-blind, placebo-substitution study of risperidone withdrawal.17 The studies found that risperidone, in mean doses of 2.08 mg/d, was effective for reducing moderate to severe tantrums, aggression, and self-injurious behavior in children with autism. Outcomes were assessed by the ABC-I and CGI-I. These gains were stable over time and did not necessitate dose increases, but relapse was seen in the majority if the medication was withdrawn at 6 months. The investigators found no evidence of dyskinesia or dystonia. However, the observed weight gain of 5.6 kg for the risperidone group was more than twice the expected weight gain over a 6-month period. The FDA approved risperidone in 2006 for the treatment of irritability associated with autistic disorder, including symptoms of aggression, deliberate selfinjury, temper tantrums, and quickly changing moods, in children and adolescents aged 5 to 16 years, with a maximum recommended dose of 3 mg/d. A metaanalysis that reviewed all risperidone RCT studies for subjects with ASD published after 2000 found that the agent yielded a large mean effect size of Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187 Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - Stigler - Child Adolesc Psychiatric Clin N Am 23 (2014) 73–82

2 meses se tratan 101 N y A prom. 9 años agresivos e irrritables con Risperidona prom 1,8 mg /d vs placebo 4 meses estudio abierto de respondedores con dosis estable 2 meses RCT con sustitución por placebo RUPP Red de autismo: 2/3 de respondedores mantienen efecto por 6 m 64% de los pacientes con sustitución a placebo recaen (vs 13% de los que continuan) Aumento de 6 kg (> x2 que placebo) en 6 m RCT n=101 de 6-12 años (prom 9a) agresivos, irritables Risperidona en 1,8 mg/d 2014 Risperidone Risperidone has been investigated for the treatment of irritability in ASD via case series, open-label trials, and double-blind, placebo-controlled studies.12–15 An 8-week, double-blind, placebo-controlled study of risperidone (mean dosage, 1.8 mg/d;range, 0.5–3.5 mg/d) was conducted in 101 children and adolescents (mean age, 8.8 years) with autism and associated irritability.15 In this multisite trial, risperidone treatment led to a 57% decrease on the Aberrant Behavior Checklist (ABC) Irritability subscale score versus a 14% reduction with placebo. Furthermore, 69% in the risperidone group, versus 12% in the placebo group, were responders as determined by a rating of “much improved” or “very much improved” on the Clinical Global Impressions-Improvement (CGI-I) scale and a 25% or greater improvement on the ABC Irritability subscale score. Increased appetite, weight gain (risperidone, mean 2.7 kg; placebo, 0.8 kg), dizziness, sedation, and sialorrhea were among the adverse effects reported. Subjects who responded to risperidone (N 5 63) subsequently entered a 16-week, open-label trial.16 The mean dose of risperidone remained stable during this extension phase. The study participants continued to gain weight, with a mean increase of 5.1 kg over the 24 weeks. After the 16-week phase, 32 subjects considered responders were randomized to either continue risperidone or undergo gradual placebo substitution over 4 weeks. Only 2 (12.5%) of 16 subjects who continued on risperidone were found to relapse. In contrast, 10 (63.5%) of 16 subjects who un derwent placebo substitution relapsed, suggesting the need for longer-term treatment. An 8-week, multisite, double-blind, placebo-controlled study of risperidone (mean dose, 1.2 mg/d) was completed in 79 children and adolescents (mean age, 7.5 years) with ASD.17 The authors recorded a 64% decrease on the ABC Irritability subscale score with risperidone treatment versus a 31% reduction with placebo. In addition, 53% of subjects in the risperidone group were deemed responders in comparison to 18% of those in the placebo group. Adverse effects included sedation, tachycardia, extrapyramidal symptoms (EPS), increased appetite, and weight gain (risperidone, 2.7 kg; placebo, 1 kg), among others. in BOSTIC The results of the RUPP risperidone trial were published in 2002 and may ultimately contribute to risperidone getting a specific indication for the treatment of behavioral disturbance in autism. The network enrolled 101 subjects aged 8.8 F 2.7 years and, using the Aberrant Behavior Checklist irritability subscale as a primary outcome measure, found that behavioral symptoms including aggression, hyperactivity, and irritability all improved significantly on risperidone dosed from 0.5 mg/day to 2.5 or 3.5 mg/day (for children weighing above 45 kg) over a period of 8 weeks [29] . Treatment responders, as defined by at least a 25% decrease in the irritability score and a rating of much improved or very much improved on the Clinical Global Impressions improvement scale, was 69% in the risperidone group and 12% in the placebo group. In 23 of the 34 responders, these improvements remained during an extension phase of 6 months. With respect to side effects, receipt of risperidone was associated with a statistically significant average weight gain of 2.7 F 2.9 kg, compared with 0.8 F 2.2 kg in the placebo controls. Increased appetite, fatigue, drowsiness, dizziness, and drooling were also statistically more common in the risperidone-treated subjects than in those who received placebo. Risperidone Dissatisfaction with conventional antipsychotics, due to extrapyramidal side effects and lack of efficacy in negative symptoms of schizophrenia, led to intense efforts to find alternatives. Risperidone, the first in a new class of agents termed atypical antipsychotics, was approved for schizophrenia in adults by the FDA in 1993. Given the expectation of improved efficacy and lower rates of adverse effects, atypicals became first-line agents for many conditions requiring neuroleptics, including ASD. Following the Campbell tradition, risperidone was rigorously studied by the NIMH Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. RUPP conducted a multiphase trial comparing the effects of risperidone in comparison with placebo for the treatment of aggressive behaviors in patients aged 5 to 17 years with ASD. There was an initial double-blind, 8-week RCT study16 with 101 participants, followed by a 4-month open-label trial ending in an 8-week randomized, double-blind, placebo-substitution study of risperidone withdrawal.17 The studies found that risperidone, in mean doses of 2.08 mg/d, was effective for reducing moderate to severe tantrums, aggression, and self-injurious behavior in children with autism. Outcomes were assessed by the ABC-I and CGI-I. These gains were stable over time and did not necessitate dose increases, but relapse was seen in the majority if the medication was withdrawn at 6 months. The investigators found no evidence of dyskinesia or dystonia. However, the observed weight gain of 5.6 kg for the risperidone group was more than twice the expected weight gain over a 6-month period. The FDA approved risperidone in 2006 for the treatment of irritability associated with autistic disorder, including symptoms of aggression, deliberate selfinjury, temper tantrums, and quickly changing moods, in children and adolescents aged 5 to 16 years, with a maximum recommended dose of 3 mg/d. A metaanalysis that reviewed all risperidone RCT studies for subjects with ASD published after 2000 found that the agent yielded a large mean effect size of Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187 Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - Stigler - Child Adolesc Psychiatric Clin N Am 23 (2014) 73–82

Aprobada por la FDA (2006) para la irritabilidad , agresividad, cambios anímicos en N y A 5-16 a con dosis máx. 3 mg/d (tamaño efecto 1.21) Al aplicar otras escalas (R-F RLRS y CYBOCS) mejoraron las conductas sensoriales y motoras, las reacciones afectivas y la respuesta sensoriales Otros estudios revelan mejoría en el retraimiento social (63% vs 40% pbo)… asociado a disminución irritabilidad? CORE SOCIAL y COMUNICACIÓN The logical next step was to study risperidone in children with autism. The RUPP Autism Network randomized 101 children (mean age, 8.8 years) to 8 weeks of risperidone or placebo. 25 At baseline, all patients had significant irritability, aggression, or self-injury as rated by the Aberrant Behavior Checklist (ABC).26 Risperidone led to significant reduction on all of the ABC subscales compared to placebo, but the reductions in social withdrawal and inappropriate speech were only significant at the p=0.03 level (insignificant following Bonferroni correction for multiple analyses). To further analyze the efficacy of risperidone on the core symptoms of autism in this group of highly irritable patients, McDougle et al.27 examined secondary outcome measures that included a modified Ritvo-Freeman Real Life Rating Scale (R-F RLRS) 28 and modified Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS).29 On the R-F RLRS, significant improvement was seen on the following subscales: sensory motor behaviors, affectual reactions, and sensory responses. However, there was no significant change on the social relationship to people or language subscales. A second multicenter, placebo-controlled study of risperidone in children with PDD was conducted in Canada.30 Seventy-nine children (mean age 7.5 years) were randomized to either risperidone (mean dose 1.2 mg/day) or placebo for 8 weeks. Significant improvement (p<0.05) was seen on all subscales of the ABC, but were of greatest magnitude for irritability and hyperactivity. Social withdrawal decreased by 63% in the risperidone group compared to 40% for placebo (p<.01). Studies have also examined risperidone in even younger children. Risperidone is occasionally needed in very young children due to the severity of the irritability and agitation, which can be extreme.31 Nagaraj et al.32 randomized 39 children (ages 2− 9 years; mean age 5 years) to risperidone 1 mg/day or placebo and examined ratings on the Childhood Autism Rating Scale (CARS).33 The children had variable presenting symptoms, but 36/39 (92%) were considered having problems with irritability. At 6 months, 12 of 19 (63%) children treated with risperidone showed a 20% improvement in CARS score compared to none of 20 (0%) treated with placebo. In a study by Luby et al.34, 23 children (ages 2− 6 years; mean age 4 years) also received risperidone (0.5− 1.5mg/day) or placebo for 6 months. However, these investigators found risperidone only minimally efficacious compared to placebo at 6 months possibly owing to group differences at baseline or small sample size. In contrast to the study by Nagaraj et al. 32, high degrees of irritability were not required for study entry. These studies suggest that risperidone may have modest benefit for reducing social withdrawal, repetitive language, and/or core symptoms of autism (as rated by CARS) in children with PDD exhibiting high levels of baseline irritability. It is unclear whether risperidone improves these symptoms in the absence of irritability.

Agresividad: Risperidona:
RCT 6m en niños 2-9 años n=40, dosis 1mg/d eficaz para disminuir la hiperactividad y agresividad. RAM: Sedación, diskinesia transitoria, aumento apetito y peso (con risp. 2,8 kg vs placebo 1,7) 2014 An 8-week, multisite, double-blind, placebo-controlled study of risperidone (mean Randomized controlled trials of risperidone have also been conducted in young children with ASD. A double-blind, placebo-controlled trial of risperidone was completed in 40 children (age range, 2–9 years) over a duration of 6 months.18 Risperidone at a total daily dose of 1 mg/d was considered efficacious for symptoms of hyperactivity and aggression. Adverse effects included sedation, transient dyskinesia, increased appetite, and weight gain (risperidone, 2.8 kg; placebo, 1.7 kg). Another placebo-controlled study of risperidone (mean dose, 1.1 mg/d; range, 0.5–1.5 mg/d) in 24 children (age range, 2–6 years) with ASD found the drug minimally efficacious in comparison to placebo; possibly because study participation did not require high levels of baseline irritability.19 Transient sedation, sialorrhea, and weight gain (risperidone, 3 kg; placebo, 0.6 kg) were among the adverse effects reported Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187 Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - K. Stigler, MD - Child Adolesc Psychiatric Clin N Am 23 (2014) An Update on Pharmacologic Treatments for Autism Spectrum Disorders B. King, MDa, J. Bostic, MDChild Adolesc Psychiatric Clin N Am 15 (2006)

Agresividad: Risperidona:
Estudio similar n=79 de 5-12 aRisperidona 1mg/d prom (dosis máx: mg/kg/d) Efectivo en 87% de pacientes vs 40% placebo en mejorar auto - heteroagresión y pataletas RAM principal  somnolencia 77% (vs 7% placebo); otros: aumento de FC y PAS Aprobada por la FDA (2006) para la irritabilidad , agresividad, cambios anímicos en N y A 5-16 a con dosis máx. 3 mg/d (tamaño efecto 1.21) FCOS risperidone for irritability, aggression, self-injury, impulsivity, and restricted, repetitive, and stereotyped patterns of behavior both in adults and children with autism. In a multicenter, placebo-controlled study of risperidone in 79 children with autism and other PDDs, the greatest magnitude of improvement was observed for irritability and hyperactivity (risperidone was associated with a 64% reduction in ABC Irritability subscale scores versus 31% with placebo), and with a decrease of social withdrawal by 63% in the risperidone group compared with 40% decrease in the placebo group (Shea at al., 2004). Risperidone showed sustained efficacy and good tolerability during an intermediate length of treatment in children with autism characterized by tantrums, aggression and/or self-injurious behavior in some studies. Discontinuation after six months was associated with a rapid return of disruptive and aggressive behavior in most subjects. The most significant side effects with risperidone are increase in weight and appetite. Mild transient sedation, tremor and hypersalivation have also been reported in several studies BOSTIC The results of the RUPP risperidone trial were published in 2002 and may ultimately contribute to risperidone getting a specific indication for the treatment of behavioral disturbance in autism. The network enrolled 101 subjects aged 8.8 F 2.7 years and, using the Aberrant Behavior Checklist irritability subscale as a primary outcome measure, found that behavioral symptoms including aggression, hyperactivity, and irritability all improved significantly on risperidone dosed from 0.5 mg/day to 2.5 or 3.5 mg/day (for children weighing above 45 kg) over a period of 8 weeks [29] . Treatment responders, as defined by at least a 25% decrease in the irritability score and a rating of much improved or very much improved on the Clinical Global Impressions improvement scale, was 69% in the risperidone group and 12% in the placebo group. In 23 of the 34 responders, these improvements remained during an extension phase of 6 months. With respect to side effects, receipt of risperidone was associated with a statistically significant average weight gain of 2.7 F 2.9 kg, compared with 0.8 F 2.2 kg in the placebo controls. Increased appetite, fatigue, drowsiness, dizziness, and drooling were also statistically more common in the risperidone-treated subjects than in those who received placebo. Risperidone Dissatisfaction with conventional antipsychotics, due to extrapyramidal side effects and lack of efficacy in negative symptoms of schizophrenia, led to intense efforts to find alternatives. Risperidone, the first in a new class of agents termed atypical antipsychotics, was approved for schizophrenia in adults by the FDA in 1993. Given the expectation of improved efficacy and lower rates of adverse effects, atypicals became first-line agents for many conditions requiring neuroleptics, including ASD. Following the Campbell tradition, risperidone was rigorously studied by the NIMH Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. RUPP conducted a multiphase trial comparing the effects of risperidone in comparison with placebo for the treatment of aggressive behaviors in patients aged 5 to 17 years with ASD. There was an initial double-blind, 8-week RCT study16 with 101 participants, followed by a 4-month open-label trial ending in an 8-week randomized, double-blind, placebo-substitution study of risperidone withdrawal.17 The studies found that risperidone, in mean doses of 2.08 mg/d, was effective for reducing moderate to severe tantrums, aggression, and self-injurious behavior in children with autism. Outcomes were assessed by the ABC-I and CGI-I. These gains were stable over time and did not necessitate dose increases, but relapse was seen in the majority if the medication was withdrawn at 6 months. The investigators found no evidence of dyskinesia or dystonia. However, the observed weight gain of 5.6 kg for the risperidone group was more than twice the expected weight gain over a 6-month period. The FDA approved risperidone in 2006 for the treatment of irritability associated with autistic disorder, including symptoms of aggression, deliberate selfinjury, temper tantrums, and quickly changing moods, in children and adolescents aged 5 to 16 years, with a maximum recommended dose of 3 mg/d. A metaanalysis that reviewed all risperidone RCT studies for subjects with ASD published after 2000 found that the agent yielded a large mean effect size of Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187

Agresividad en TEA: Aripiprazol
RCT de 2 meses de 231 N y A de a  Eficacia para agresividad, dosis mg/d (prom 9mg d) RAM: sedación, aumento de peso, SEP en dosis fija. Estudio abierto de un año de seguimiento (n=300) en dosis 2-15 mg/d: Efectivo, seguro y bien tolerado, disminuyendo la irritabilidad por 1 año. Aprobado por la FDA el 2009 para agresividad en N y A de 6-17 a TEA. Respuesta variable s/ dosis. Dosis mantención recomendad 5-15 mg/d 2014 Aripiprazole Case series, open-label studies, and double-blind, placebo-controlled trials have found aripiprazole effective for the treatment of irritability in ASD.29–31 An 8-week, double-blind, placebo-controlled, fixed-dose study of aripiprazole was conducted in 231 children and adolescents (age range, 6–17 years) with autism.30 In this study, participants received placebo or aripiprazole (5, 10, or 15 mg/d). Significant improvement in symptoms of irritability was found at all doses of the drug, as measured by the ABC Irritability subscale score. However, only the 5 mg/d treatment group responded to aripiprazole, based on a CGI-I scale score of “much improved” or “very much improved” and a 25% or greater improvement on the ABC Irritability subscale score. Sedation, EPS, and weight gain were among the adverse effects reported. Serious adverse events included presyncope (N 5 1) and increased aggression (N 5 1). Another 8-week, double-blind, placebo-controlled trial of aripiprazole in 98 youth (age range, 6–17 years) with autism used a flexible dosing schedule (2–15 mg/d).31 Significant improvement in irritability was recorded, as determined by the ABC Irritability subscale score. In addition, significantly more subjects in the aripiprazole group, versus the placebo group, were considered responders, as measured by a rating of “much improved” or “very much improved” on the CGI-I scale and a 25% or greater improvement on the ABC Irritability subscale score. Adverse effects included sedation, vomiting, drooling, tremor, and weight gain, among others. A subsequent 52-week, open-label study of aripiprazole (dose range, 2–15 mg/d) investigated the drug’s long-term safety and tolerability in 300 subjects aged 6 to 17 years with autism.32 The study included de novo subjects as well as participants of the aforementioned double-blind studies.30,31 Concomitant psychotropic medications (except alpha-2 agonists, carbamazepine, oxcarbazepine, and other antipsychotics) were allowed during the trial. A total of 199 (60%) of 300 subjects completed the trial, with the authors concluding that aripiprazole was generally safe and well tolerated. Increased appetite, weight gain, vomiting, and insomnia were among the more commonly reported adverse effects. A secondary paper that evaluated the drug’s effectiveness found most subjects “much” or “very much” improved on the CGI-I at study endpoint.33 Overall, the study concluded that aripiprazole decreased irritability for up to a year in children and adolescents with autism. PEDIATRICS Aripiprazole Two large controlled studies documented the short-term efficacy of aripiprazole for severe aggression and irritability in subjects 6 to 17 years old with autistic disorder. A fixed-dose 8-week study19 found that the agent at 5, 10, or 15 mg/d was superior to placebo. The second RCT20 was also 8 weeks long but used flexible doses reaching a mean of 8.6 mg/d by the end of the study. Symptoms in both studies were rated with the ABC-I and the CGI-I. The most commonly reported adverse events associated with aripiprazole treatment were sedation and weight gain in both studies, and extrapyramidal symptoms mostly in the fixeddose study, but these events rarely led to treatment discontinuation. was approved by the FDA for the treatment of irritability associated with autistic disorder in patients aged 6 to 17 years in Aripiprazole dosing and response can vary considerably; the usual recommended clinical dose for maintenance is between 5 and 15 mg/d. Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187 Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - K. Stigler, MD - Child Adolesc Psychiatric Clin N Am 23 (2014) An Update on Pharmacologic Treatments for Autism Spectrum Disorders B. King, MDa, J. Bostic, MDChild Adolesc Psychiatric Clin N Am 15 (2006)

Agresividad en TEA: Series pequeñas, limitaciones metodológicas y resultados mixtos para Metilfenidato, Ac. Valproico, Lamotrigina Olanzapina: Dosis 8mg/d Buena respuesta (Sup. A haldol) < irritabilidad, HA y alt. lenguaje, pero RAM importantes Quetiapina: estudios peq- con resultados mixtos. Dosis media= mg/d, respuesta de %. RAM. Otros: escasa y contradictoria evidencia con Guanfasina, clonidina, naltrexona, litio, levetirazetam, clozapina Alpha2 Adrenergic Agonists Clonidine A small 6-week, double-blind, placebo-controlled, crossover study of clonidine (4–10 mg/kg/d) in eight youth with autism (mean age, 8.1 years; range, 5–13 years) found disparate results.35 Although parent and teacher ratings noted significant improvement in irritability, hyperactivity, and oppositionality with clonidine versus placebo, investigator ratings found no significant difference between treatment groups. Sedation, hypotension, and decreased activity were among the adverse effects recorded. A 4-week, double-blind, placebo-controlled, crossover study of transdermal clonidine (mean dosage, 3.6 mg/kg/d; range, 0.16–0.48 mg/d) was conducted in nine subjects with autism (mean age, 12.9 years; range, 5–33 years).36 Symptoms of impulsivity and hyperactivity were noted to improve with clonidine. Sedation and fatigue were among the adverse effects reported. Guanfacine An 8-week, prospective, open-label trial of guanfacine (dose range, 1–3 mg/d) recorded improvement in hyperactivity in 12 (48%) of 25 subjects with ASD.37 Parent ratings also noted a significant reduction in symptoms of irritability. The study participants (mean age, 9 years; range, 5–14 years) were previous nonresponders to methylphenidate. Adverse effects included irritability, sedation, and sleep disturbance. Three subjects discontinued study participation due to decreased frustration tolerance and tearfulness. A 6-week, double-blind, placebo-controlled, crossover study of guanfacine (dose range, 1–3 mg/d) was conducted in 11 children (mean age, 7.3 years; range, 5–9 years) with intellectual disability and/or an ASD.38 A significant reduction in hyperactivity was found in 45% of the subjects. However, no significant improvement was observed in symptoms of irritability. Sedation and increased irritability were among the adverse effects recorded. Antipsychotics/neuroleptics Other atypical neuroleptics may hold some promise for this population based on non–placebo-controlled trials. Olanzapine was superior to haloperidol in one small, open trial [49], and olanzapine significantly improved irritability, hyperactivity, and inappropriate speech in another open trial with 25 juveniles. Significant improvements based on the Clinical Global Impressions scale occurred in only 3 of 23 patients completing the trial, however [50]. In two open trials, quetiapine was effective in fewer than one third of juveniles after up to 12 weeks of treatment [51,52]. More recently, Corson and colleagues [53] found quetiapine to be modestly effective when used openly in patients who had PDD and severe behavioral disturbance. Ziprasidone seems to b promising based on a case series of only 12 patients [54] and may be less likely to induce weight gain than risperidone, olanzapine, and quetiapine. An open switch study of adults (mean age, 43 years) who had ASD and who converted from another antipsychotic because of side effects such as weight gain or hyperprolactinemia, provided preliminary support for this strategy [55]. A recent study reporting the effects of aripiprazole in five children who had PDD noted that all of these subjects responded well and that aripiprazole may be less likely to cause substantial weight gain [56,57]. Despite some potential important differences among the antipsychotic agents, weight gain remains a troubling concern for patients who have ASD and who are treated with antipsychotics. In an open trial, the anticonvulsant topiramate was titrated up to 0.6 to 2.9 mg/kg/day in 10 patients aged 8 to 19 years who had ASD of whom 8 were receiving risperidone. Only six patients were able to sustain treatment with this agent; four of those had variable weight loss, and two gained weight [58] . Side effects of prolactinemia have emerged in juvenile patients who have ASD treated with atypical antipsychotics, most notably risperidone [59] . Over 12 weeks, patients experienced significant increases in serum prolactin, from 166 to 504 ng/mL, at doses of 0.75 to 2 mg/day. PEDIATRICS Other antipsychotics Other agents in this class lack large-scale controlled studies. Small open-label reports suggest variable benefits of olanzapine21 and ziprasidone,22 which have possible support, versus quetiapine,23 which has not appeared to be Beneficial Adverse effects All antipsychotics in children carry the risk of potentially serious side effects such as neuroleptic malignant syndrome, galactorrhea, dyskinesias, cardiovascular changes, and allergic reactions. Fortunately, these serious adverse events are estimated to be rare or uncommon; a large review estimated the annualized risk for tardive dyskinesia to be less than 0.5%, and remission of the disorder after drug discontinuation is a common observation.24 Nevertheless, it is of obvious importance to systematically monitor for the appearance of such untoward effects and develop strategies to minimize them. Although a comprehensive discussion of this topic is beyond the scope of this article, an excellent review is available elsewhere.25 Box 1 lists common adverse effects and suggestions for monitoring adverse effects including observation, laboratory tests, and specific rating scales such as the Abnormal Involuntary Movement Scale (AIMS).26 2014 Quetiapine Retrospective and open-label studies of quetiapine have been published in ASD, with mixed findings. A retrospective medical record review of quetiapine (mean dose, 249 mg/d; range, 25–600 mg/d) found that 8 (40%) of 20 patients with ASD (mean age, 12.1 years; range, 5–28 years) responded to the drug over a mean duration of 60 weeks (range, 4–180 weeks).23 Adverse effects were recorded in half of the patients and resulted in drug discontinuation in 15%. Another retrospective review of quetiapine (mean dose, 477 mg/d) was conducted in 10 subjects (age range, 5–19 years) with ASD over a mean duration of 22 weeks (range, 10–48 weeks).24 The authors reported that 6 (60%) of 10 patients responded to the drug, with improvement noted in symptoms of hyperactivity and inattention. Mild sedation, weight gain, and sialorrhea were among the adverse effects recorded. A small 16-week, open-label study of quetiapine (mean dose, 225 mg/d) in six subjects (mean age, 10.9 years; range, 6–15 years) with autism found that only two (33%) youth responded to the drug.25 Of the other four subjects, three withdrew because of sedation or lack of effectiveness, and one withdrew due to a possible seizure. Behavioral activation, increased appetite, and weight gain (range, 0.9–8.2 kg) were also noted. Another small open-label study of quetiapine (mean dose, 292 mg/d; range, 100–450 mg/d) was completed in nine subjects with autism aged 10 to 17 years (mean age, 14.6 years).26 In this 12-week study, two participants (22%) were considered responders. Two subjects withdrew from the study due to sedation or agitation and aggression. Commonly reported adverse effects included sedation, weight gain, and increased agitation. Ziprasidone Ziprasidone (mean dose, 59.2 mg/d; range, 20–120 mg/d) was investigated in 12 youth (mean age, 11.6 years; range, 8–20 years) with autism or pervasive developmental disorder not otherwise specified.27 This case series found 6 (50%) of 12 subjects responded to the drug over a mean treatment duration of 14.2 weeks (range, 6–30 weeks). Improvement was observed in symptoms of aggression, agitation, and irritability. Transient sedation was the most commonly reported adverse effect. There were no reported cardiovascular adverse effects. A mean change in weight of 2.6 kg (range, 16 to 12.7 kg) was recorded. A 6-week, open-label study of ziprasidone was completed in 12 adolescents, aged 12 to 18 years (range, 14.5 years), with autism and associated irritability.28 The study found that 9 (75%) of 12 subjects responded to the drug at a mean dosage of 98.3 mg/d (range, 20–160 mg/d). Sedation was a commonly reported adverse effect. Dystonic reactions developed in two study participants. Ziprasidone treatment was weight neutral and led to decreased measures of total cholesterol. The mean QTc at study endpoint increased by 14.7 ms. The association of ziprasidone with QTc prolongation on electrocardiography resulted in an FDA warning. Individuals with known cardiac disease (eg, cardiac arrhythmias, long QT syndrome) or those taking other drugs that can prolong the QTc interval should not be prescribed ziprasidone without careful monitoring and consultation with a cardiologist. Paliperidone Paliperidone was investigated in an 8-week, open-label study of 25 adolescents and young adults (mean age, 15.3 years; range, 12–21 years) with autism.34 The investigators found that 21 (84%) of the subjects responded to paliperidone at a mean dose of 7.1 mg/d (range, 3–12 mg/d), as determined by a CGI-I scale score of “much improved” or “very much improved” and a 25% or greater improvement on the ABC Irritability subscale score. Participants, on average, gained 2.2 kg (range, 3.6 to 17.9 kg) during the trial. Although mean serum prolactin increased over the 8 weeks [5.3 ng/mL (baseline); 41.4 (endpoint)], no signs or symptoms of hyperprolactinemia were recorded. Other adverse effects included sedation, EPS, and increased appetite. Clozapine reportes de caso/ evidencia retrospectiva de 10 casos de N/A/Adultos podría ser beneficosa en la irritab. Y agresividad. Bien tolerada en gral. Sin RAM graves To date, 4 small case reports have found clozapine beneficial for symptoms of irritability in children and adults with autism.7–10 Enuresis, transient sedation, constipation, and sialorrhea were among the adverse effects noted in these reports. Recently, a retrospective medical record review of clozapine was conducted in six patients aged 14 to 34 years with ASD.11 Significant improvement in aggressive behavior was reported. The drug was considered generally well tolerated. No agranulocytosis was recorded. Constipation, tachycardia, metabolic syndrome, and weight gain (mean weight gain, kg) were reported adverse effects. Limited research has been conducted on clozapine in ASD for reasons that may include its potential to lower the seizure threshold and its association with agranulocytosis necessitating frequent hematological monitoring. Olanzapine A 12-week, open-label study of olanzapine (mean dose, 7.8 mg/d) in ASD found six (86%) of seven study completers (mean age, 20.9 years; range, 5–42 years) responded to the drug.20 Although symptoms such as irritability and hyperactivity improved, subjects experienced adverse effects including sedation, increased appetite, and weight gain (mean, 8.4 kg). A 6-week, open-label study of olanzapine (mean dose, 7.9 mg/d) was completed in 12 children with autism (mean age, 7.8 years), using haloperidol (mean dose, 1.4 mg/d) as a standard comparator.21 Five (83%) of six subjects were considered responders in the olanzapine group and three (50%) of six subjects were deemed responders in the haloperidol group. On average, olanzapine treatment (mean, 4.1 kg; range, 2.7–7.2 kg) was associated with greater weight gain versus haloperidol treatment (mean, 1.4 kg; range, 2.5 to 14 kg). A small 8-week, double-blind, placebo-controlled trial of olanzapine (mean dose, 10 mg/d; range, 7.5–12.5 mg/d) was conducted in 11 youth with ASD (age range, 6–14 years).22 Three (50%) of six subjects in the olanzapine group were judged responders, compared with one (20%) of five subjects in the placebo group. Adverse effects included sedation, increased appetite, and weight gain (olanzapine, 3.4 kg; placebo, 0.68 kg ). FCOS Following publication of several case reports and open-label case series of its effectiveness for behavioral symptoms in autism and other PDDs, including motor restlessness, hyperactivity, selfinjurious behavior, aggression, irritability and anger (Potenza et al., 1999), an open-label comparison with haloperidol described reductions in aggression in patients with autism (Malone et al., 2001). Improvement was also seen in some aspects of social behavior, in hyperactivity, self-harm, irritability, anxiety and depression in this study. Olanzapine was associated with a positive response in children with PDDs in one placebo-controlled study, but it was rather difficult to interpret the results due to a small size of the sample (Hollander, Wasserman et al., 2006). Increased appetite, weight gain, and sedation were reported as notable side effects in the majority of studies There have been four published studies with quetiapine targeting disruptive behavior in autism so far (Corson et al., 2004; Findling et al., 2004; Hardan et al., 2005; Martin et al., 1999). However, the sample size in all the studies was rather small, and the data suggests that quetiapine may not be a particularly effective agent in the treatment of children and adolescents with PDDs. Overall, quetiapine was poorly tolerated, which led to drug discontinuation in several subjects. Common side effects included sedation, increased appetite, weight gain, agitation, and a possible seizure induction in one case. Patients with autism often don’t tolerate blood draws required weekly to biweekly to monitor white blood cell counts. In addition, these patients are more vulnerable to develop seizures on clozapine than the general population, therefore the drug is rarely used clinically. Three case reports showed a marked reduction in aggressiveness, hyperactivity, and repetitive motions and no side effects were reported (Chen et al., 2001; Gobbi & Pulvirenti, 2001; Zuddas et al., 1996). Aripiprazole Preliminary data from one prospective, open-label study suggest that aripiprazole may be effective for severe irritability in pediatric patients with PDDs and, except for mild extrapyramidal symptoms, is well tolerated (Stigler et al., 2009). However, the results from a recent retrospective study on aripiprazole monotherapy in children and adolescents with PDDs with severe behavioral disorders were rather inconclusive, and aripiprazole was discontinued because of lack of efficacy or presence of adverse effects (agitation, self-injurious behaviors, insomnia) in more than one-third of the patients (Masi et al., 2009). Lithium A case report described lithium (900 mg/d) augmentation of fluvoxamine treatment in an adult with autism.39 The authors noted improvement in aggression and impulsivity after 2 weeks of treatment. DIVALPROATO Divalproex sodium Open-label and double-blind, placebo-controlled studies have investigated divalproex sodium in ASD.40–42 An 8-week, double-blind, placebo-controlled trial of divalproex sodium (mean endpoint blood level, 77.8 mg/mL) for irritability was completed in 30 subjects (age range, 6–20 years) with ASD.42 The authors found no significant difference between drug and placebo, as determined by the ABC Irritability subscale. Increased appetite, hyperammonemia, and skin rash requiring study discontinuation were among the adverse effects recorded. Divalproex sodium was also investigated in a 12-week, double-blind, placebo-controlled study of 27 children and adolescents (age range, 5–15 years) with ASD and irritability.41 In this study, 62.5% of subjects in the divalproex sodium group [mean blood level, 89.8 mg/mL (responders); 64.3 mg/mL (nonresponders)], compared with 9% in the placebo group, were considered responders. Adverse effects included weight gain, headache, and insomnia, among others. Lamotrigine A 12-week, double-blind, placebo-controlled trial of lamotrigine (5 mg/kg/d) was conducted in 28 children (mean age, 5.8 years; range, 3–11 years) with autism.43 No significant difference was found between the drug and placebo groups as based on several rating scales, including the ABC Irritability subscale score. The most frequently reported adverse effects were insomnia and hyperactivity. Methylphenidate The role of methylphenidate (MPH) in treating attentional problems in typically developing children is well documented.27 Two RCTs examined MPH’s potential benefit for the treatment of aggression in ASD28,29 in subjects 5 to 11 years old. Although the results showed superiority over placebo on the ABC-I, the trials were small and of short duration, and one study28 had a high percentage of children with intolerable side effects, often including agitation, mood changes, and abnormal movements. Overall, MPH is less commonly used for the treatment of aggression. A 12-week randomized double-blind, placebo-controlled study30 evaluated the use of divalproex sodium for aggression in 55 children aged 5 to 17 years, in which the agent demonstrated modest superiority to placebo. The primary outcome measures were the ABC-I and CGI. There was a trend for responders to have higher valproate blood levels compared with nonresponders. Adverse effects reported in the study were minimal. Other agents Naltrexone, an opioid receptor antagonist, and clonidine, an a2-adrenergic agonist, were studied in RCTs and showed superiority to placebo.31 However, small samples and other study limitations made the findings difficult to generalize, so these agents are not considered a first choice for treating aggression. Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187 Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - K. Stigler, MD - Child Adolesc Psychiatric Clin N Am 23 (2014) An Update on Pharmacologic Treatments for Autism Spectrum Disorders B. King, MDa, J. Bostic, MDChild Adolesc Psychiatric Clin N Am 15 (2006)

Conclusiones sobre Tto Agresividad en TEA:
Agresividad limita terapias e inclusión Risperidona y aripiprazol son los fcos aprobados por FDA RAM limitan uso de AT (SEP) y AA (metabólicos)  monitorización Efectos beneficiosos por 6-12 meses Estudios pequeños de Anticonvulsivantes, estabilizadores ánimo (-). Proyección + prometedora: alfa 2 adrenérgicos, Modulador glutamatérgico y antioxidante N-acetylcysteine para manejo irritabilidad y agresividad en TEA 2014 CONCLUSION AND FUTURE DIRECTIONS Research into the pharmacotherapy of severe behavioral disturbance in ASD has primarily focused on the atypical antipsychotics. Although these studies have significantly contributed to the pharmacologic management of this symptom domain in ASD, there remains an ongoing need to identify more effective and better tolerated treatments in this population. Compounds with different mechanisms of action will continue to be explored. As such, one recent study investigated the use of the glutamatergic modulator and antioxidant N-acetylcysteine for irritability in 33 children (age range, 3–10 years) with autism.45 In this 12-week, double-blind, placebo-controlled trial, the drug dosage was increased by 900 mg/d every 4 weeks to reach a final target dose of 900 mg three times daily. Subjects in the N-acetylcysteine group, compared to the placebo group, demonstrated significant improvement in irritability as measured by the ABC Irritability subscale. The drug was generally well tolerated. Although these findings are encouraging, the severity of irritability at baseline (mean ABC Irritability subscale score 5 17) was notably lower than that of studies of risperidone and aripiprazole (mean ABC Irritability subscale score 5 26 and 28, respectively).15,30 Additional research is needed to better understand the potential role of N-acetylcysteine, as well as other novel compounds, in the treatment of irritability in ASD. Biol Psychiatry Jun 1;71(11): doi: /j.biopsych Epub 2012 Feb 18. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Hardan AY1, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, Frazier TW, Tirouvanziam R. Author information Abstract BACKGROUND: An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism. METHODS: This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale. RESULTS: Thirty-three subjects (31 male subjects, 2 female subjects; aged years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96). CONCLUSIONS: Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted. N y A con TEA presentan frecuentemente irritabilidad que genera pataletas y agresividad Se requiere un enfoque multimodal Risperidona y aripiprazol son los únicos aprobados por la FDA DISCUSSION Most evidence to date supports the use of atypical antipsychotics as first-line pharmacotherapeutic agents for targeting irritability in ASD. As such, risperidone and aripiprazole are the only drugs currently approved for this target symptom domain in children and adolescents with autism. Relatively small controlled studies of the anticonvulsants and mood stabilizers for irritability in youth with ASD have generally demonstrated negative results. Ongoing large-scale controlled studies of medications such as guanfacine may shed light on the usefulness of alpha2 adrenergic agonists for symptoms of milder irritability in this population. Estudios pequeños de Anticonvulsivantes y estabilizadores ánimo, result. (-) Estudios más extensos de agonistas alfa 2 adrenérgicos (guanfasina) podría ser prometedor Clinical implications Aggressive behaviors toward self and others displayed by some ASD children result in grave concern, possibly more restrictive placements, and are significant predictors of inpatient treatment.32 Consequently, many of the pharmacologic investigations in this population are geared toward addressing this potentially dangerous set of behaviors. The atypical antipsychotics risperidone and aripiprazole are the most studied agents in ASD, are approved by the FDA for treating irritability (not ASD per se), and have shown solid evidence of effectiveness. Older haloperidol studies also provide favorable evidence for its off-label use. However, the level of evidence is also high for the risk of developing clinically limiting side effects for all antipsychotics, such as the extrapyramidal effects of conventional agents or the metabolic changes of atypical neuroleptics. 11,16,20 Close monitoring of patients using these agents is essential. Divalproex and MPH are off-label options with modest evidence of effectiveness. The decision to initiate pharmacologic treatment should be based on severity of symptomatology, degree of impairment, risk to self or others, and prevention of hospitalization. While no widely endorsed clinical algorithms for treatment of aggression exist, clinicians generally attempt initial treatment with lower-risk alternatives to antipsychotics. However, in the context of poor response or tolerability, or severe and dangerous symptoms, such agents are often replaced by one of the two FDA-approved antipsychotics for rapid management and stabilization. Length of recommended treatment is difficult to derive from published evidence, but treatment benefits appear to be durable for up to 6 to 12 months. Efforts to reduce and possibly discontinue such treatment at the end of this period should be strongly considered.

Conductas Repetitivas en TEA:
Patrones conductuales, intereses o actividades repetitivos y estereotipados 1era línea: Terapia conductual, pero muchas veces insuficiente Uso de IRSS surge de que TEA presenta disfunción 5HT y sínt. Repetitivos tipo O-C IRSS son fármacos más usados en TEA. Cuentan con varios estudios, pero no RCT. A pesar de su frec. Uso, la evidencia es mixta. Evidencia mixta para trastornos ansiedad y depresión EN tea. Indicación: tto para CR severas, T. Ansiedad o distress asociado conductas motoras repetitivas de bajo nivel (mecerse y movimientos de las EE) y de más alto nivel (rutinas y rituales ) Prsentes en otros trastornos del neurodesarrollo Repetitive Behaviors Restricted repetitive and stereotyped patterns of behavior, interests, and activities (RRBs) have been described since the work of Kanner33 as core features of ASD, and their presence is also currently necessary to meet DSM-IV-TR1 diagnostic criteria. RRBs can be classified into lower-level repetitive motor behaviors such as rocking and limb movements, and higher-level routines and rituals such as the classically described insistence on sameness. RRBs and stereotypies are not unique to ASD and can be found in many other developmental disorders, although researchers agree that these tend to be more frequent in ASD.34 Behavioral therapies are the first line for RRBs but the behaviors can be quite difficult to manage; because of the major challenges that uncontrolled RRBs can pose to educational and social performance, and risks of danger and actual harm to self or others, pharmacologic treatment is often considered. The following agents have been evaluated and are often prescribed for the target of RRBs. Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187 Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - K. Stigler, MD - Child Adolesc Psychiatric Clin N Am 23 (2014) An Update on Pharmacologic Treatments for Autism Spectrum Disorders B. King, MDa, J. Bostic, MDChild Adolesc Psychiatric Clin N Am 15 (2006)

RCT fluoxetina de 5 meses, n=39, edad 5-16 años, con incremento gradual de 2,5 mg/d hasta promedio 10 mg/ d . Disminución significativa de conductas repetitivas (CYBOCS) RAM no significativos. Sin mejora en la interacción social ni en el lenguaje. Otros posibles efectos: mejoras cognitiva y agresividad. Se observó mayor beneficio en familias con T. Depresivo CORE COMUNICACIÓN Y LENGUAJE Hollander et al. administered fluoxetine to 39 children (ages 5− 16 years, mean age 8.2 years) during a 20-week (8 weeks on drug) placebo-controlled crossover study.21 Liquid fluoxetine was dosed starting at 2.5 mg/day and increased on a weekly basis to reach a maximal target dose of 0.8 mg/kg/day by week 4, if needed. The mean final dose was 0.4 mg/kg/day (mean dose 9.9 mg/day, range 2.4− 20 mg/day). Fluoxetine was significantly better than placebo for reducing repetitive behaviors on the Children's Yale-Brown Obsessive-Compulsive Scale (CYBOCS) (Scahill et al., 1997). There was no improvement on measures of speech or social interaction. Side-effects were not significantly different between fluoxetine and placebo. Thus, fluoxetine may lead to a reduction in repetitive behavior or stereotypy in children with PDD. Placebo-controlled trials support the use of fluvoxamine in adults with autism and fluoxetine in children with PDD for select symptoms, but to date these drugs have not been shown to significantly improve core social and language impairment in controlled studies. Additional uncontrolled reports have reported benefits from other SSRIs including sertraline, paroxetine, citalopram, and escitalopram.22 Overall, improvements have been most commonly reported in symptoms of anxiety, mood disturbance, aggression, and repetitive behavior. A more optimistic view of the effectiveness of SSRIs has been put forth by De Long et al.23 In their clinical treatment of 129 young children (ages 2− 8 years) with autism, fluoxetine treatment (4 − 40 mg/day over 5− 76 months) was associated with a positive response in 89 of 129 children (69 %). Their report is intriguing in that improvements in a number of core autistic symptoms were reported. However, the data is difficult to interpret in comparison to controlled studies given the lack of standardized outcome measures and placebo control. FCOS Fluoxetine In a double-blind, placebo controlled crossover trial children and adolescents with autism spectrum disorders showed a significant reduction in repetitive behaviors, and there were no significant differences in side effect profiles between placebo and fluoxetine (Hollander et al., 2005). Several open-label trials have also demonstrated alleviation of some autistic symptoms with fluoxetine for both adults and children, and improvement was seen in behavioral (repetitive rituals, aggression, selfharm), cognitive, affective, and social areas (Buchsbaum et al., 2001; DeLong et al., 1998; Fatemi at al., 1998). The response to fluoxetine strongly correlated with a family history of major affective disorder in two studies (DeLong et al., 2002; DeLong et al., 1998). Drug induced insomnia, hyperactivity, increased agitation, aggression and manic symptoms were reported as notable side effects most of the studies. Sertraline Sertraline was effective in improving aggression and interfering repetitive behavior, in an open label study of adults with PDDs. Interestingly, subjects with PDD-NOS showed significantly greater improvement than those with Asperger Disorder. Side effects included agitation and worsening of anxiety (McDougle et al., 1998). In another open-label study, sertraline was administered for the treatment of transition-associated anxiety and agitation in children with autism, and eight of nine subjects showed some degree of response to treatment. Adverse effects were described as minimal. However, two subjects showed significant worsening of their behavior when their doses were raised to 75 mg (Steingard et al., 1997). Paroxetine Only a few case reports (Posey et al., 1999; Snead et al., 1994) and one open label study in 15 adults with severe and profound mental retardation (including seven patients with PDDs) (Davanzo et al., 1998) have been published, and paroxetine is currently less frequently used in children due to concern about agitation, aggression, self-harm and suicidality. The limited data are suggestive of paroxetine being effective on a broad range of symptoms including aggression, irritability, tantrums, and interfering preoccupations. However, a decreased response to the treatment was reported in the open label study at the 4-month follow up. Insomnia and increased agitation were reported as side effects. Selective serotonin reuptake inhibitors Researchers reasoned that selective serotonin reuptake inhibitors (SSRIs) could be effective for RRBs, because of the consistent reports of serotoninergic dysfunction in ASD and because such symptoms share aspects of the phenomenology of obsessions and compulsions known to respond to SSRIs. Antidepressants are the most common class of psychotropics prescribed for individuals with ASD,12 and although their benefits have been described in many case reports and uncontrolled studies,35 such benefits have not been confirmed in large RCTs. Rigorous studies were conducted in youth with ASD only for fluoxetine and citalopram. Fluoxetine at a mean dose of 9.9 mg/d was better than placebo for RRBs according to the CY-BOCS in a study of 39 children aged 5 to 16 years.36 On the other hand, a later study of 158 subjects with autism 5 to 17 years old37 compared fluoxetine with placebo; using the CY-BOCSPDD measure of repetitive behaviors during a 14-week treatment period, no fluoxetine benefit was observed. In addition, a 12-week RCT of citalopram studied 149 children aged 5 to 17 years with ASD and high levels of RRBs, who were begun on 2.5 mg of citalopram daily with weekly increases up to a maximum dose of 20 mg/d (mean dose 16 mg/d). The outcome was evaluated by CY-BOCS and again, no significant differences were found between the placebo and citalopram groups.38 One-third of children in these studies were reported to experience serotoninergic activation type side effects, specifically increased activity, mood changes, and insomnia. On the other hand, open label studies of escitalopram have been more positive on benefits for irritability. 39 Therefore, taken together, the literature on the benefits and safety in ASD is quite mixed, despite the high frequency of their community use. Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187 Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - K. Stigler, MD - Child Adolesc Psychiatric Clin N Am 23 (2014) An Update on Pharmacologic Treatments for Autism Spectrum Disorders B. King, MDa, J. Bostic, MDChild Adolesc Psychiatric Clin N Am 15 (2006)

RUPP: Risperidona: disminuye compulsiones de 35 a 15% las a través de CYBOCS; aripiprazol también RCT citalopram, resultados mixtos Otros estudios abiertos: Escitalopram: más beneficios en irritabilidad Sertralina: Podria mejorar tolerancia a cambios en rutinas, en bajas dosis. Otros Reporte de casos: paroxetina, mirtazapina (RAM) 1/3 de los pacientes presentaron activación, cambios de ánimo, insomnio. Otros: agitación, irritabilidad, viraje Dados resultados mixtos, titular dosis lentamente y discutirlo con la familia. PEDIATRICS Depression and Anxiety The literature on effects of psychotropics for the treatment of depression and anxiety is sorely limited, despite the frequent description of dysphoria and apparent anxious behaviors in individuals with ASD. Although there is strong empirical support for the SSRIs as treatment for children with anxiety disorders, it is uncertain if benefits seen in typical children translate to children with ASD. It is interesting that some positive support exists for use of these medicines in adults with ASD,51,52 but the high rate of significant adverse reactions to SSRIs in children, such as disinhibition, hyperactivity, and somatic complaints, greatly temper any enthusiasm for their common usage in youth with ASD J Child Adolesc Psychopharmacol Spring;7(1):9-15. Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder. Steingard RJ1, Zimnitzky B, DeMaso DR, Bauman ML, Bucci JP. Sertraline has open-trial support now in both adults [37] and juveniles [38] . The intolerance of children with autistic disorder to changes in their routine or environment is well known, typically presenting with acute symptoms of anxiety, panic, irritability, or agitation. In a clinical sample of children (6-12 years old) with autistic disorder and transition-induced behavioral deterioration, 8 of 9 patients showed a clinically significant improvement in response to sertraline treatment. Only one child was taking concurrent psychotropic medication. Therapeutic doses were surprisingly low in all cases (25-50 mg daily), with a clinical response appearing generally in 2-8 weeks. Adverse effects were minimal (one child developed stomachaches), except for apparent sertraline-induced behavioral worsening in 2 children when their doses were raised to 75 mg daily. In 3 children, an initial satisfactory clinical response appeared to diminish after 3-7 months of treatment, despite steady or increased doses. In 6 patients, the beneficial effects persisted throughout the several-month follow-up period. Only four of the children's families were identified as having mood and/or anxiety disorders. This open-label study suggests that short-term sertraline treatment may reduce the behavioral reactions seen in association with situational transitions or environmental changes in children with autistic disorder, though the beneficial effect may be only temporary in some children. Our experience suggests that small doses of sertraline may be effective and that some children may require divided doses of sertraline during the day. Controlled studies are needed to determine the efficacy, safety, and pharmacokinetics of sertraline in treating this "need for sameness," both in short-term and long-term studies of children with autistic disorder. Paroxetine has positive case reports in juveniles [39] , and citalopram [40,41] and escitalopram [42] have open trials reporting benefit for anxiety, aggression, stereotypy, and preoccupation symptoms for juveniles who have PDD. X All of the SSRI antidepressants have been explored for patients who have ASD. Liquid formulations, allowing the administration of very low doses, are now available for fluoxetine, sertraline, fluvoxamine, paroxetine, citalopram, and escitalopram. At least some of these antidepressants seem to improve repetitive thoughts and behaviors. Controlled trials with fluoxetine [32] and fluvoxamine [33] in adults who have PDD showed significant benefits over placebo, and findings from a controlled trial in children and adolescents support the effectiveness of fluoxetine in reducing repetitive behaviors in children who have PDD [34] . On the other hand, a controlled trial of fluvoxamine in juveniles who have PDD revealed a much less robust response that perhaps was eclipsed by the emergence of significant side effects including behavioral activation [35] . A recent open-label study with low-dose fluvoxamine found a significant response in only 17% of treated children [36] . Sertraline has open-trial support now in both adults [37] and juveniles [38] . Paroxetine has positive case reports in juveniles [39] , and citalopram [40,41] and escitalopram [42] have open trials reporting benefit for anxiety, aggression, stereotypy, and preoccupation symptoms for juveniles Mirtazapine was examined in 26 juveniles and young adults who have PDD who experienced improvement on target symptoms of aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia [43] . Dosing parameters may differ for patients who have ASD. Hollander and colleagues [34] found liquid fluoxetine at low doses (9.9 mg/day F mg) FINDLING 2009 Pharmacotherapy for Severe Repetitive Behaviors, Anxiety and Affective Instability Antidepressants In the past, tricyclic antidepressants, clomipramine and imipramine in particular, were commonly used to treat several symptoms in individuals with autism, but produced severe adverse effects and risks, for example, cardiotoxicity, that outweighed any potential benefits. Therefore, Selective Serotonin Reuptake Inhibitors (SSRIs) have received more attention as a potential treatment for repetitive behaviors, anxiety, irritability, depression, self-injurious behavior, and aggression associated with autism and other PDDs (Kolevzon et al., 2006; Soorya et al., 2008). However, the safety of SSRIs has been questioned because of their potential to cause or exacerbate agitation and aggression, and perhaps selfharm and suicidality in the pediatric population (Gould et al., 2003). Therefore, if SSRIs are used in children and adolescents, treatment should include prior discussion with the patient (and family if appropriate) of foreseeable side effects such as anxiety, agitation, irritability, hostility, impulsivity, hypomania and activation syndrome that may affect aggression, self-injurious behavior and suicidality. Treatment should be started at a low dose, the dosage titrated based on response and toleration, and close monitoring should be provided for agitation, aggression, self-harm Psychopharmacology of Autism Spectrum Disorders - G. Kaplan, J. McCracken / Pediatr Clin N Am 59 (2012) 175–187 Psychopharmacologic Management of Serious Behavioral Disturbance in ASD - K. Stigler, MD - Child Adolesc Psychiatric Clin N Am 23 (2014) An Update on Pharmacologic Treatments for Autism Spectrum Disorders B. King, MDa, J. Bostic, MDChild Adolesc Psychiatric Clin N Am 15 (2006)

Hiperactividad en TEA:
Comorbilidad de TEA que tienen TDA: 30 y 80% Psicoestimulantes son 3er fármaco más indicado en TEA TEA / TDAH comórbidos (dsm5) presentan > dificultades Estudio NIMH RUPP Autism Network: RCT n=72 , 5-13 a, Metilfenidato dosis menores y estándar. disminuye hiperactividad e impulsividad, pero < respuesta y > RAM que TDAH solo. RAM: H-A, irritabilidad, disforia, tics, estereotipias  > abandono tto. Se sugieren < dosis. Atomoxetina: estudio pequeño con buena respuesta y <RAM. Otros que < H-A: Risperidona y aripiprazol BOSTIC The RUPP network has recently completed a second large, randomized, controlled trial of methylphenidate in children who have both PDD and ADHD. Preliminary results indicate that methylphenidate may be helpful for some children but that the percentage of responders is less than that reported for children who have ADHD alone. Because of concerns about the possibility of exacerbation of behavioral problems associated with stimulant use in this population, the investigators enrolled only subjects who tolerated the drug in a preliminary exposure. Because of this precaution, the reported rate of response may slightly overestimate the rate of response that might be expected for the general population that has PDD PEDIATRICS Hyperactivity Clinicians have long noted the high prevalence of inattentive and hyperactive symptoms in children with ASD, and research has found that 28% to 78% of children with ASD meet diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD).42,43 Furthermore, children who meet both diagnostic criteria have more severe clinical difficulties than children with ASD alone.44 Although current DSM-IV criteria do not allow the comorbid coding of both diagnoses,1 it seems that DSM-V, scheduled to appear in 2013, will resolve this dilemma.45 Multiple agents have been investigated to treat hyperactivity. Stimulants Amphetamines and MPH are the options of choice to treat attentional hyperactive problems in typically developing children.27 Stimulants are the third most common class of drug prescribed in ASD.12 MPH has been used preferentially in this population. A retrospective chart review of 195 subjects aged 2 to 19 years found that stimulants appeared to be ineffective and poorly tolerated for the majority of patients with ASD. There is only one published large MPH RCT study, which was conducted by the NIMH RUPP Autism Network.46 The study of 72 children aged 5 to 13 years was designed to evaluate the efficacy and safety of multiple daily doses of immediate release MPH. Three strengths were used of about 0.15 mg/kg, 0.25 mg/kg, and 0.5 mg/kg. These doses, lower than those recommended for typically developing children, were used to minimize the possibility of side effects. All doses were superior to placebo in reducing hyperactivity and impulsiveness as measured by the ABC hyperactivity subscale, the primary outcome measure. However, even the highest effect size of 0.54 in this study was much lower than that usually achieved in typically developing children.47 Irritability was a common complaint and overall, 18% of subjects discontinued the trial because of adverse effects, at least double the intolerance seen in typically developing children with ADHD. Stimulant medications remain the most effective agents in the treatment of inattention and hyperactivity and have been used increasingly in patients who have ASD. Because stimulants can exacerbate ticlike behaviors or stereotypies, the risk–benefit ratio of stimulants in these patients must always be carefully examined and discussed with families. Indeed, Di Martino and colleagues [75] found that, with a single test dose of methylphenidate (0.4 mg/kg), approximately one third of patients experienced increased hyperactivity, stereotypies, dysphoria, or motor tics, so titration was not attempted. In low doses (0.3–0.6 mg/kg/day), many patients show improvement in hyperactivity but not in any of the core symptoms of ASD Atomoxetine Atomoxetine is a selective norepinephrine reuptake inhibitor, approved by the FDA for treatment of ADHD symptoms in typically developing children and adults. Atomoxetine was examined in a small placebo-controlled, crossover pilot trial48 for the treatment of hyperactivity of children with ASD. In this study, there were 16 children aged 5 to 15 years treated for 6 weeks at doses of 1.2 to 1.4 mg/kg per day, not exceeding a total dose of 100 mg/d. For the ABC-H, the primary outcome measure, improvement significantly favored atomoxetine. Adverse events were described as tolerable, with no tendency to increase stereotypy. Atomoxetine had an effect size similar to that shown in the MPH trial by the RUPP,46 with effects mainly seen on hyperactiveimpulsive behaviors. However, this study was small and allowed concomitant administration of other psychotropics, placing further limitations on generalizability. Atypical antipsychotics Secondary analyses of the ABC-H scale from large RCTs demonstrated that risperidone16 and aripiprazole20 are associated with large reductions of hyperactivity in children with ASD Other agents Clonidine, an a2-agonist, was associated with a superior reduction in disruptive behaviors over placebo in a small, controlled trial.49 Guanfacine, an a2A-adrenergic agonist, has been reported to demonstrate modest improvement in a retrospective study, in particular in irritability and explosive behavior. An additional open-label study of 25 children with ASD and high levels of ADHD symptoms suggested moderate benefit over 8 weeks.50 However, no RCTs have been conducted for this class of agent. Clinical implications Hyperactivity is a frequent symptom that, when severe, interferes with educational and social interventions. As such, it is often the subject of requests for pharmacologic treatment. Unfortunately, none of the highly effective treatments for typically developing children have the same robust response in ASD, and the rate of side effects even at low doses is remarkably high. MPH is the best studied agent and although its use is off-label, it has the strongest evidence for modest effectiveness. MPH requires starting at doses roughly half that of usual doses in typically developing patients with ADHD and close monitoring of side effects, particularly irritability. a-Agonists deserve more research exploration, and often form a solid second-line treatment choice. While antipsychotics have also shown effectiveness for marked hyperactivity, their off-label use for this indication and potential significant toxicity make them a less favored choice. Psychopharmacology of Autism Spectrum Disorders - G. KaplanPediatr Clin N Am 59 (2012) 175–187 Bostic

Terapias no farmacológicas:
Tratamiento conductual + Entrenamiento habilidades verbales y sociales Terapia ocupacional y física promueven mayor progreso (dif. Coordinación y sensoriales) Objetivo: Rehabilitación de aspectos que interfieren con logros evolutivos Autonomía y autocuidado Lenguaje Integración sensorial Psicomotricidad Regulación emocional Atención Función ejecutiva Aprendizaje Destrezas desarrollo habilidades comunicacionales (pragmática) y sociales Entrenamiento verbales estrategias solución de problemas decodificación verbal /no Verbal Mentalización y apoyo educacional/laboral/ vocacional Other treatments such as occupational therapy and physical therapy may promote progress because they address possible comorbid difficulties of motor coordination and sensory deficits. Progress may be slow, in part, owing to the pervasive nature of the core deficits and comorbid features.

Programas de tratamiento psicosocial:
Sistema TEACCH Tto y educación para niños con autismo y probl. De la comunicación Programa educacional estructurado a partir del niño y sus capacidades de aprendizaje Herramientas para entender su ambiente, siendo + predecible Herramientas comunicacionales que les expresar sus nec. apoyo escolar, familiar e inserción laboral Aumenta el aprendizaje en Niños con TEA no verbal y mejora calidad de vida El mayor recurso de una intervención eficaz son los padres y el sistema educacional Abordar stress parental

PECS (Sistema de comunicación basado en intercambio de imágenes) Se centra en la adquisición de habilidades comunicacionales básicas, desarrollar un lenguaje y entregar una forma de comunicación a los que no desarrollan lenguaje Es iniciada por el niño Intercambian imágenes por cosas o actividades deseadas El mayor recurso de una intervención eficaz son los padres y el sistema educacional Abordar stress parental

Método LOVAAS o Intervención conductual basada en el hogar Implementación de un ambiente intenso de estímulos y aprendizajes guiados por un terapeuta centrados en el lenguaje,juego, hab. Social, autonomía, académico. Floortime: Terapia del suelo de Greenspan: Centrado en el aspecto emocional y en la oportunidad de transformar un juego estereotipado en juego con sentido y que lo ayude a relacionarse. Técnicas de historias sociales de Carol Gray Objetivo es que mejoren capac. De mentalización incrementar el entendimiento de las situaciones sociales, sentirse cómodo y dar respuestas adecuadas ABA Método LOVAAS o Intervención conductual basada en el hogar: Niños con autismo no aprenden del ambiente. Implementación de un ambiente intenso de estímulos y aprendizajes guiados por un terapeuta, centrados en el lenguaje,juego, hab. Social, autonomía, académico. Esto les permitiría insertarse en la ed. Básica convencional. Terapia del suelo de Greenspan: Centrado en el aspecto emocional y en la oportunidad de transformar un juego estereotipado en juego con sentido y que lo ayude a relacionarse. Acercamiento –tono emocional – niño dirige y adulto lo sigue – adulto expande sin ser intrusivo – niño construye – cierre círculo comunicación Técnicas de historias sociales de Carol Gray: Objetivo es que m,ejoren capac. De mentalización; incrementar el entendimiento de las situaciones sociales, sentirse cómodo y dar respuestas adecuadas Intervenciones basadas en el desarrollo de relaciones sociales: las relaciones son automotivadas a partir del goce y satisfacción de experiencias previas. Si aprende a ser un ‘buen amigo’ en un setting terapeutico, lo podrá extrapolar

Terapias complementarias (CAM): ¿Por qué son usadas?
Causa y mecanismos TEA poco claros Características centrales son crónicas Síntomas son heterogéneos y fluctuantes Reacciones adversas de los fármacos CAM percibidos como naturales promoción salud rol más activo sobre la salud énfasis en los síntomas que la familia problematiza deseo de terapia con múltiples enfoques. 50-75% N y A con autismo son tratados con CAM, sobretodo cuando tienen def. intelectual. 30% con dieta. Although existing scientific data suggest the etiology is largely genetic with the plausibility of environmental factors, the specific causes are often not known. In addition, the symptoms are behaviorally defined, heterogeneous, and change with the acquisition of developmental skills. For these reasons, families of children with autism and related disorders may turn to therapies that are not based in the realm of conventional medical or psychologic practice. Treatments for children with autism spectrum disorders Research has shown that the most effective treatment is a combination of specialized and supportive educational programming, communication training (such as speech/language therapy), social skills support, and behavioral intervention [5,6]. Other treatments such as occupational therapy and physical therapy may promote progress because they address possible comorbid difficulties of motor coordination and sensory deficits. Progress may be slow, in part, owing to the pervasive nature of the core deficits and comorbid features. Children with chronic illness such as cancer, asthma, rheumatoid arthritis, and neurodevelopmental disorders such as autism are treated with CAM therapies at even higher rates. As many as 50% to 75% of children with autism may be treated with CAM [8,9] . CAM use may be even more likely in children with comorbid intellectual disability. Levy and colleagues [10] reported that almost one third of young children referred for evaluation of ASD were being treated with dietary therapies by their parents even before confirmation of the diagnosis. Who uses complementary and alternative medicine therapies and why Conventional medicine has been directed at the goals of diagnosis, treatment, and, when possible, cure of disease states. CAM practices add promotion of health and involvement of the patient in a process of healing that must ultimately address the underlying cause of illness as interpreted by the practitioner [11] . CAM is often perceived as ‘‘natural,’’ without the side effects of conventional medical treatments. The reasons why families use CAM have been studied in other chronic disorders of childhood. Adverse effects from conventional medication were the only significant predictors for CAM use in children with inflammatory bowel disease [12] . Similarly, for children with asthma, CAM use was predicted by older age, worse control of symptoms, more medications, more medical visits, and more side effects [13] . A survey in Italy identified the fear of side effects as the most common reason for parents to choose a CAM therapy for routine illness. Satisfaction was reported by 81% and successful symptom resolution attributed to the CAM therapy [11] . Adults who use CAM believe that a combined approach of CAM and conventional therapy is more likely to be successful than either treatment alone, and that nutritional support is an important part of health maintenance, preferring not to take prescription medications [14] . Among families of children with ASD surveyed by Hanson and colleagues [8] , over 75% chose therapies based on their perception of safety, the absence of side effects, or prior experience with side effects. Despite the common use of CAM, two third of families report that they base their therapeutic choices on the recommendation of their health care provider or scientific support. Approximately 50% of families report that they desire more control over the therapies elected and that they choose CAM because of a hope for a cure or because of recommendations by friends or families of other children with ASD. Only 39% elect CAM because they prefer ‘‘natural’’ therapies, and 25% report choices based on media. CAM therapies are pursued to treat core symptoms of ASD, as well as to increase attention, to enhance relaxation, to decrease gastrointestinal symptoms, to regulate sleep, and to promote general health, in that order [9] . Patients who seek out CAM providers may be seeking the longer visits typically offered pays more attention to the symptoms of concern to the family. Parents who use CAM for their children tend to use CAM for their own health and are better educated. It is not dissatisfaction with conventional care that leads families to employ CAM. The most commonly reported reasons are concern regarding side effects, the desire to include multiple approaches to address symptoms, and personal beliefs about health. With changes in society such as self-determination in health care, greater accessibility to information on the Internet, and a decline in faith in science and technology, people are seeking more control over their own medical decision making [14,15] .

Terapias complementarias (CAM) en N y A TEA:
Terapias de cuerpo y mente 30% Musicoterapia (B): comunicación y comp. sociales Yoga (C): sensación de bienestar, prevenir la ansiedad. Sin estudios en TEA. Terapias biológicas 50% Terapias corporales 25% Medicina energética A wide range of CAM therapies are used in children. The NCCAM groups CA Mind-body medicine Yoga–grade C Decreasing anxiety through nonpharmacologic techniques has great attraction to both families and clinicians. Yoga is a mind-body approach that enjoys popular practice for increasing the sense of well-being and control with the potential to decrease anxiety. A trial of yoga for symptoms of attention-deficit hyperactivity disorder (ADHD) was underpowered to demonstrate effect but suggested some benefit in children on medication [19]. Relaxation therapy decreased symptoms of anxiety in inpatients with anxiety in a child psychiatry service [20] and in children with mental retardation [21] . No studies have been published related to symptoms of autism and the response to yoga techniques. Music therapy–grade B The use of music to reinforce communication is frequently applied in the context of educational interventions. The use of music in a discrete therapeutic format to enhance social skill and communication development in children with autism has been examined in small trials, with the potential for positive effects on spoken and gestural communication [22]. No effect on overall behavior was reported. Clinical practice often pairs music with other interventions with subjective benefit [23]. Further study of the neurobiology of music processing in persons with autism may provide additional rationale for music therapy as a discrete treatment or a part of other educational interventions [24,25]. M therapies into four domains: (1) mind-body medicine, (2) biologically based practices, (3) manipulative and body-based practices, and (4) energy medicine. The most commonly used CAM treatments for ASD fall into the categories of biologically based practice and manipulative and body-based practices. Approximately half of families of children with ASD use a biologically based therapy, 30% a mind-body therapy, and 25% a manipulation or body-based method [8] . The range of reported response about usage is dependent upon the population queried and how the question is asked. Hanson [8] reported that 41% of respondents endorsed benefit with dietary and nutritional treatments, whereas Wong and Smith [9] found that 75% of respondents thought their treatments were helpful. 75% Creen que su terapia es efectiva

Terapias biológicas: Melatonina (B) Tr. Del sueño
dosis 0,75-6mg antes de dormir Vitamina B6 y Mg (B) Vitamina C (B) Aminoácidos () y carnosina Dieta libre de gluten (B) Omega 3 (B) Secretina (A) Frecuente y multifactorial, deterioro calidad de vida del paciente y familia Insomnio: RCT melatonina en dosis >6mg/d, s efectivo y sin RAM Risperidona y aripiprazol Melatonin–grade B. Some nutritional supplements have known pharmacologic properties. Melatonin is a hormone produced by the pineal gland that regulates sleep. Clinical studies have demonstrated abnormalities in melatonin production or release in individuals with ASD [34]. Clinical benefit in sleep onset and maintenance has been demonstrated in at least one large case series at doses ranging from 0.75 to 6 mg before bedtime [35]. This result would be predicted by the large effect size in small randomized trials [36]. Few side effects were reported. Andersen and colleagues [35] treated 107 children with autism with melatonin, many of whom were also being treated with psychotropic medications. Side effects of early morning sleepiness or enuresis were reported in three cases. No effect on seizures was noted. Dietary supplements Vitamin B6 /Mg2. –grade B. Vitamin supplements to improve symptoms of mental health disorders have been in use for over 50 years, with vitamin B6 and magnesium a popular treatment for autism over the past 20 years. This treatment has been the subject of reviews by several investigators [26–28]. Due to the small number of studies, methodologic deficits, and small sample sizes, meta-analysis could not be done, and the evidence was not adequate to support the use of these supplements. The most recent Cochrane Review [26] identified three studies completed between 1993 and 2002 that compared outcomes to the findings in a placebo or nontreated group. A total of 28 subjects were treated in these trials. Findling and colleagues [29] studied 12 participants using a randomized, double-blind, placebo-controlled trial following a 2-week pre-randomization placebo lead-in period. No effects of treatment were seen in the 10 subjects who completed the study. More recently, Kuriyama and colleagues [30] reported improvement in IQ and social quotient scores in eight children treated with vitamin B6 and Mg2.. Despite the fact that these studies met criteria for Cochrane Review, they all suffered from significant methodologic weaknesses, including an inadequate description of the diagnosis, selection criteria, and outcome measures. One additional study with similar methodologic issues has been published since this review, describing an open study of 33 children with ASD who were reported to improve in symptoms after magnesium and vitamin B6 treatment [31] Main results We included two trials with a total of 37 children diagnosed with ASD who were randomised into groups that received either omega- 3 fatty acids supplementation or a placebo. We excluded six trials because they were either non-randomised controlled trials, did not contain a control group, or the control group did not receive a placebo. Overall, there was no evidence that omega-3 supplements had Omega-3 fatty acids supplementation for autism spectrum disorders (ASD) (Review) Copyright © 2011 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd. an effect on social interaction (mean difference (MD) 0.82, 95% confidence interval (CI) to 4.48, I2 = 0%), communication (MD 0.62, 95% CI to 2.14, I2 = 0%), stereotypy (MD 0.77, 95% CI to 2.22, I2 = 8%), or hyperactivity (MD 3.46, 95% CI to 7.70, I2 = 0%). Authors’ conclusions To date there is no high quality evidence that omega-3 fatty acids supplementation is effective for improving core and associated symptoms of ASD. Given the paucity of rigorous studies in this area, there is a need for large well-conducted randomised controlled trials that examine both high and low functioning individuals with ASD, and that have longer follow-up periods. Dimethylglycine–grade B. Dimethylglycine and a related compound, trimethylglycine, are commonly used nutritional supplements. An older case series suggested improvement in language and attention in a group of children with intellectual disability treated with dimethylglycine. Two small, double-blind studies of dimethylglycine have not demonstrated positive effects on symptoms of autism in a comparison with placebo [32,33] . Vitamin C–grade B. Vitamin C is not commonly used as an isolated treatment but is frequently added to vitamin mixtures used by children with ASD. Dolske and colleagues [37] reported positive results of decreased stereotyped behavior in a 30-week, double-blind, placebo-controlled trial in 18 children with ASD. To date, this study has not been replicated. Other reports have implicated vitamin C in its role with oxidative stress. Amino acids–grade C and carnosine–grade B. Amino acids are precursors to neurotransmitters and act as neurotransmitters themselves [38]. As such, it is not surprising that some complementary approaches attempt to manipulate neurochemical actions by nutritional supplementation. The abnormalities in peripheral serotonin levels in persons with autism and their family members was one of the first biologic findings in autism [39]. Supplemental tryptophan might increase brain production of serotonin because the uptake across the blood-brain barrier is sensitive to the concentration in the bloodstream; however, no trials have examined the clinical effect of tryptophan supplementation on symptoms of autism. In adults with autism, tryptophan depletion exacerbated symptoms [40]. There are no peer-reviewed studies to date examining the effects of supplementation with other amino acids such as taurine, lysine, or GABA in children with autism, although they are often part of a CAM nutritional supplementation strategy. Taurine is a semiessential sulfur-containing amino acid derived from methionine and cystine. It has antioxidant properties and has been associated with improved visual learning in rodents. L-carnosine is a dipeptide that was demonstrated in one double-blind, placebo-controlled trial in 31 children with autism to improve expressive and receptive vocabulary, with subjective improvement on the Gilliam Autism Rating Scale over an 8-week trial at 800 mg/d [41]. Lysine is an amino acid exogenously obtained from meat and milk products. With methionine, it can be endogenously made into carnitine [42]. Carnitine is involved in intracellular transport of long chain fatty acids and is important in energy generation. Although carnitine has documented usefulness in specific deficiency states and in the presence of certain medications such as valproic acid, it has never been evaluated as a treatment for motor or behavioral symptoms of autism. One case series of children with autism with elevated alanine and low carnitine suggests that some children with autism may have mitochondrial disease [43] . Omega 3 fatty acids–grade B. Polyunsaturated fatty acids, in particular omega 3 fatty acids, are crucial for brain development and cannot be manufactured in the body. Dietary consumption occurs through the ingestion of fish or fish oils. Oral supplementation with essential fatty acids has become popular for children with developmental differences including autism and ADHD [44] . Studies have examined differences in plasma levels of children with autism, which are decreased when compared with that in typical volunteers [45,46] without clinical correlations. Recently, Amminger and colleagues [47] reported improvement in behavior following a randomized double-blind, placebo-controlled, 6-week pilot trial of oral supplementation in 13 children with ASD with severe behavior difficulties. No side effects were noted beyond gastrointestinal symptoms. Folate and oxidative stress–grade C. It has been hypothesized that exposure to toxic agents or endogenous abnormalities that lead to oxidative stress may cause neuronal insult and lead to the regression seen in as many as one third of children with autism [48] . Neuroanatomic differences in white and gray matter, cerebellar pathology (eg, Purkinje cell loss), and other evidence of cellular disruption [49] as well as functional abnormalities [50] led to the search for potential environmental causes of atypical brain development. Abnormal levels of antioxidants, transferrin, lipid peroxidases, methionine, and other biochemical intermediates have been reported in children with autism [51] without clinical correlation. James and colleagues [52] have described abnormal metabolic profiles in 20 children with autism compared with 33 controls, consistent with a presumed impaired methylation capacity. Laboratory findings normalized following a trial of folinic acid, betaine, and methylcobalamin; however, no clinical outcome data were reported. James and colleagues [53] also reported decreased measured indicators of methylation capacity in a larger population (80 with autism and 73 controls), also without clinical correlation. At present, there are no randomized controlled treatment trials reported in the scientific literature. These hypotheses require further study. Gluten-free/casein-free diet–grade B In addition to supplementation with vitamins or other nutritional supplements to address hypothetical deficiencies or to provide pharmacologic effect, modification of dietary intake has been a popular intervention for behavioral modification in children with ASD. It has been suggested that the elimination of the proteins gluten (found in barley, wheat, and rye) and casein (found in milk products), which either cause or aggravate symptoms of ASD after absorption across a damaged (‘‘leaky’’) intestinal lining by acting as false opiate neuropeptides, will improve the behavior of children with ASD. The significance of reports of increased levels of metabolites of casein and gluten in the urine of persons with autism remains unclear [54] . Urinary peptides are not used in conventional practice to prescribe or monitor dietary restriction. Anecdotal reports and case series of dietary restriction leading to subjective improvement in the symptoms of autism have resulted in a report of a small single-blind trial that suggested some improvement [55] and a double-blind trial that did not identify objective improvement in language or behavior, although some parents reported subjective differences [56] . It is not yet clear whether some of the perceived improvements are due to elimination of lactose in children who are lactose intolerant or to other changes related to the alteration in protein source and food composition. Families who desire to try the gluten-free/casein-free diet must be counseled that adequate calcium and vitamin D intake must be maintained with supplements or supplemented foods. Attention to protein intake is also important because many young children obtain much of their protein through dairy products. Vegetable-based beverages including rice, potato, and almond ‘‘milk’’ do not contribute to protein sufficiency as soy-based products do. Consultation with a registered dietitian should be recommended. Common dietary approaches to symptoms of inattention in children with ADHD are also often considered for children with ASD with hyperkinesis. Double-blind, placebo-controlled methods have consistently demonstrated no relationship of sugar to attention or related behaviors [57] . Although not specific for symptoms of ASD, there may be subgroups of children who do have a behavioral response to elimination of chemicals used as food colors [58] . Secretin–grade A Secretin, a gastrointestinal hormone, has the distinction of being one of the most extensively studied pharmacotherapeutic agent for autism. It came to light as a potential treatment after a lay television show highlighted a report of a case series by Horvath [63] describing improvement in symptoms of autism after administration during endoscopy to examine pancreatic secretions. More than a dozen well-designed, well-executed studies have been published, failing to demonstrate the efficacy of secretin for symptoms of autism [44] . A recent Cochrane Review reported 14 randomized controlled trials with a total of 618 children. Nine studies used a crossover treatment design. It was concluded that there is no evidence that single- or multiple-dose intravenous secretin is effective for the treatment of ASD [64] .

Conclusiones: Uso en el contexto de Tto multimodal para mejorar el manejo de la comorbilidad Elegir fco s/ Priorización síntomas objetivos Evaluar costo beneficio: expectativas realistas Riesgo de RAM: Indicación, titulación adecuada; psicoeducación y monitorización; suspensión Mayor comprensión fisiopatol. Apuntara a nuevos ttos Antipsicóticos atípicos: Agresividad, irritabilidad, hiperactividad, comp. Repetitivos Farmacoterapia. Elección según necesidades y ciclo evolutivo Terapias psicosociales RAM: alergia, contaminantes, interacciones Desde el area salud falta de apertura en el diálogo y estudios de estas terapias Terapias complementarias ABA PSICOPEDAGOGO Identifying effective drugs to treat core social and communication impairment in autism repetitive speech when prescribed risperidone. However, it is not clear whether this is an effect exhibiting high levels of irritability may receive benefit in certain aspects of socialization and presents many challenges. Currently, no drug has been consistently proven to be effective for the core social and communication impairment so central to the PDDs. Patients with autism are promising and deserve further study. Most promising among these are the glutamatergic unique to risperidone or simply secondary to a reduction in irritability. A number of other drugs challenging, but significant progress toward the goal of identifying treatments for autism, widely recommending these drugs for core symptom treatment. Conducting these trials is drugs and oxytocin. However, additional placebo-controlled trials are sorely needed before increase given the increased interest by society in studying the causes and treatments of autism. particularly irritability, has been made over the past quarter century. The rate of progress should The decision to use any medication Conclusion FCOS the patient. The majority of commonly must balance the benefits versus risks to many of these have proven to be ineffective studied in individuals with autism, and prescribed psychotropics have been or to cause serious adverse effects; Therefore, larger placebo-controlled studied, particularly in children. several others have not yet been rigorously needed before definitive statements regarding studies in individuals with autism are disorders like autism always made. The treatment of complex, polymorphous their safety and efficacy can be and setting out realistic brings a particular challenge to pharmacotherapy, symptoms should be tracked carefully medication efficacy is necessary. Target expectations about the benefits and is based on the risks and disability they and placed into a priority system that symptoms provides a crucial framework has been made, focusing on target create for the patient. Once an assessment for care (Table 1). and for subsequent medication adjustments with autism for possible medication use In practice, an assessment of a patient and needs to differentially consider factors needs to be quite comprehensive for example a careful observation shows mood or anxiety symptoms. If that contribute to disruptive, selfharming becomes aggressive, how is that that a patient, during periods of transition, plan? It could be that teaching of interpretation, what is the best treatment to be interpreted, and, based on that is effective enough to prevent serious coping strategies for certain transitions disabling that the individual cannot anxiety in the face of a transition is so aggression. It could be that mounting learn new skills and, at least for a while, during transition periods but is actually could be that aggression is not only present needs medication to lower anxiety. It care providers that a combined so pervasive and so harmful to exhausted initial way to go. And so on. Once improvement starting anti-psychotic drugs is the best approach of reducing demands and use of medication should be questioned has occurred the continued with highly disruptive and very be considered. Despite that, many individuals and additional or replacement strategies medication with the proviso that monitoring, disabling symptoms may need to stay on making adjustments, avoiding long-term medication management. or managing side effects is important to PEDIATRICS evaluate the use of psychopharmacologic agents in ASD. While core features of As reviewed in this article, clear progress has been made in defining approaches to SUMMARY several high-quality studies have shown success using various drug classes for the ASD have shown limited improvement from treatment with well-known psychotropics, psychopharmacologic approaches should always be viewed as one component of also carry a high risk of untoward effects that limit their widespread use. Therefore, management of commonly associated behaviors. Although effective, these medicines social functioning with multimodal interventions. Within this framework, pediatricians a broader, comprehensive treatment that addresses educational, behavioral, and atypical antipsychotics, in the treatment of the following targeted symptom domains: At present, evidence-based support exists for the role of psychotropics, particularly can play an important role in the oversight of ASD treatment benefit and safety. broad benefits in behavior observed in antipsychotic studies make these agents (1) aggression and severe irritability; (2) hyperactivity; and (3) repetitive behaviors. The interventions targeting mood and anxiety symptoms and severe, persistent insomnia. of other agents with lesser side-effect burdens. Substantial unmet need exists for a common treatment choice, especially in the face of severe symptoms and failure commonplace in community treatment of individuals with ASD, even though these Therefore, polypharmacy, as well as the use of complementary medicine agents, are when treatment goals are achieved. Given the increased psychotropic use in lowering dosing and evaluating appropriateness for discontinuation should be considered practices have not been thoroughly tested. Reducing medication exposure by dosing, types of side effects, and suggested monitoring in order to render the ASD, primary care pediatricians can benefit from greater familiarity with recommended interventions. molecular pathophysiology in ASD will point to new and more effective medical safest care possible. It is hoped that in the near future, emerging knowledge of underlying Individuals with autism spectrum disorder (ASD) frequently exhibit serious behavioral 2014 CONDUCTA Individuals with mild irritability may benefit from treatment with an alpha2 adrenergic A multimodal approach is used in the management of irritability in ASD. disturbance (irritability) involving severe tantrums, aggression, and self-injury. The atypical antipsychotics are often prescribed for the management of serious behavioral agonist. medications for irritability in children and adolescents with autism. Risperidone and aripiprazole are the only two Food and Drug Administration–approved disturbance. agents for irritability in ASD. Evidence to date has been mixed regarding the effectiveness of other pharmacologic develop more effective and better tolerated treatments Research into the pharmacotherapy of serious behavioral disturbance is needed to Pharmacologic treatment of patients who have ASD still relies on careful Pharmacotherapy practice in patients who have autism spectrum disorders BOSTIC such as venlafaxine or mirtazapine) seem to be most helpful for patients who existing agents. At this point, antidepressants (SSRIs and atypical antidepressants detection of symptoms most impairing to the patient and most likely to respond to or compulsions, and perhaps social avoidance/withdrawal. Neuroleptics have anxiety symptoms, repetitive behaviors as seen in patients who have obsessions d -cycloserine, an NMDA partial agonist, shows some potential to improve antagonists such as amantadine and perhaps memantine may be useful in some cases of social withdrawal, hyperactivity, and inappropriate speech, and seem to be most useful for irritability, hyperactivity, and aggression. NMDA behaviors, but accumulating research has highlighted the problems social responsiveness. The opioidergic agents may have a role revealed for selfinjurious have significant irritability. Stimulant medications may improve inattention and Cholinergic drugs similarly may emerge an alternative treatment for patients who with treating such a complex and heterogeneous problem with a single agent. hyperactivity symptoms in patients who have ASD, albeit at lower doses and with collaborate and invest in the pharmacotherapy process. Indeed, pill taking itself Regardless of the agent selected, patients who have ASD often cannot directly careful monitoring. Mood stabilizers are currently being investigated as well. who have ASD. Behavioral treatments to accomplish pill swallowing have been or the taste of liquid formulations constrains pharmacotherapy in many patients reported effective [78] , but clinicians should inquire about the strategies that others and to ensure that the medication is being administered safely and reliably. families use for administering medication, both to be able to pass ideas along to ASD has become more commonly recognized, but causative mechanisms CONCLUSIONES BOSTIC constellation of symptoms is matched with agents likely to improve those specific functioning among patients who have ASD, particularly when the patient’s remain elusive. Psychopharmacologic treatments can improve symptoms and addition, the sometimes exquisite sensitivity of patients who have ASD requires population, given an increased risk for seizures and other untoward effects. In symptoms. Consideration of the benefit–risk ratio remains a high priority in this careful initiation, titration, and monitoring of any psychopharmacologic regimen.

Tratamiento farmacológico y no farmacológico en el T. Espectro Autista
Dra Carolina Garcés Q Psiquiatra Infanto Juvenil UV Unidad de neuropsiquiatría Hospital Gustavo Fricke

Tratamiento farmacológico y no farmacológico en el T. Espectro Autista

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