Antipsicóticos atípicos no tratamento da irritabilidade severa em crianças e adolescentes com perturbação do espectro do autismo: Uma Revisão

A perturbação do espectro do autismo é uma perturbação do neurodesenvolvimento, com origem no sistema nervoso central, caracterizada por distúrbios na comunicação social e pela presença de padrões restritos e repetitivos de comportamento e de interesses. Tem início na infância e afeta significativamente a vida das crianças e das suas famílias. A irritabilidade e a agressão são alterações psiquiátricas comuns e coexistem na perturbação do espectro do autismo (25%), sendo que o uso de antipsicóticos atípicos deve ser considerado. O objetivo da presente revisão é analisar a eficácia e a segurança a curto e a longo prazo da risperidona, do aripiprazol e da paliperidona no tratamento da irritabilidade em crianças e adolescentes com perturbação do espectro do autismo. Foi realizada uma revisão da literatura, pesquisando a PubMed e a Cochrane Database of Systemic Reviews, utilizando os Medical Subject Headings. Os estudos considerados nesta revisão mostram a sua eficácia no tratamento a curto e a longo prazo. Embora os antipsicóticos atípicos tenham um perfil de segurança melhor que o dos antipsicóticos típicos, eles estão associados a um ganho ponderal significativo e a complicações metabólicas, que não devem ser negligenciadas. Durante o tratamento com antipsicóticos, seria prudente vigiar determinados parâmetros metabólicos e implementar medidas preventivas, nomeadamente uma dieta apropriada, caloricamente, e exercício físico, para reduzir o ganho de peso. Concluindo, o uso de antipsicóticos deve ser reservado para os casos graves e duradouros de irritabilidade, quando as intervenções comportamentais foram tentadas e falharam e quando o dano a si e a outros excede iminentemente o risco de danos causados pela medicação.Abstract Autism spectrum disorder is a brain-based neurodevelopmental disorder characterized by impairments in social communication and by the presence of restricted, repetitive patterns of behaviour and interests. It has its onset in early childhood and significantly impacts the children and the family lives. Irritability and aggression are common co-occurring psychiatric conditions in autism spectrum disorder (25%) and the usage of atypical antipsychotics might be considered. The goal of the present review is to analyse the short and long-term efficacy and safety of risperidone, aripiprazole and paliperidone in the treatment of irritability in children and adolescents with autism spectrum disorder. A literature review was performed, searching PubMed and Cochrane Database of Systemic Reviews, using the Medical Subject Headings. The studies considered in this review show their efficacy in the short and long-term treatment. Although atypical antipsychotics have a safer profile than typical antipsychotics, they are associated with a significant weight gain and metabolic complications that shouldn't be overlooked. During antipsychotic treatment, it would be prudent to conduct a metabolic screening and implement preventive measures such as a calorically appropriated diet and physical exercise to reduce weight gain. In conclusion, the use of antipsychotics should be reserved for severe and enduring cases of irritability, when behavioural interventions have been tried and failed and when harm to self and others imminently exceeds the risk of harm from medication

Palmitato de Paliperidona num Adulto com Síndrome de Asperger

Asperger’s syndrome is a disorder characterized by impaired social interaction and a pattern of stereotyped behaviors. These include repetitive behaviors, irritability, aggressiveness, hyperactivity and inattention. The treatment of behavioral symptoms is a challenge, with few studies on the effectiveness of different therapeutic approaches. This article is the first description of the successful use of monthly paliperidone palmitate in the treatment of behavioral symptoms in an adult with Asperger’s syndrome. A síndrome de Asperger éuma perturbação caraterizada pelo compromisso da interação social e um padrão de comportamentos estereotipados. Estes incluem comportamentos repetitivos, irritabilidade, agressividade, hiperatividade e desatenção. O tratamento dos sintomas comportamentais constitui um desafio, com escassos estudos acerca da eficácia das diferentes abordagens terapêuticas. Este artigo é a primeira descrição do uso bem‑sucedido de palmitato de paliperidona mensal no tratamento de sintomas comportamentais num adulto com síndrome de Asperger.&nbsp

Safety of Antipsychotic Medication in Individuals Diagnosed with Autism Spectrum Disorder (ASD)

Background: Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition which presents in childhood. In the UK, risperidone is the only antipsychotic drug approved for the management of behavioural disturbance in children and adolescents with ASD. Aim: To explore the safety of antipsychotic medication use in people with ASD. Method: Four observational studies using a UK primary care database as a data source. The first study was a descriptive study to provide up-to-date information on the prevalence of ASD and psychotropic medication prescribing. Next, two analytical studies, of different designs, to investigate the risk of incident seizure associated with antipsychotic use, were conducted. A cohort study comparing the risk of incident seizure in people using antipsychotics with the users of other psychotropics; followed by a selfcontrolled case series analysis on the risk of incident seizure associated with antipsychotic use. Lastly, a cohort study to investigate the relationship between the risk of cardiac events and antipsychotic exposure, compared to other psychotropics, was conducted. Results: There has been a noticeable increase (3.3-fold) in the prevalence of ASD over the period from 2009 to 2016. Over this period, 12.4% of the treated ASD patients had been prescribed antipsychotics; 50.7% of antipsychotic prescriptions was for risperidone and 49.3% was for other antipsychotics. The hazard ratios of the risk of incident seizure and cardiac events associated with antipsychotic use were 1.28 (95% CI: 0.74-2.19) and 1.27 (95% CI: 0.62-2.62), respectively. During the first month of other psychotropic medication treatment, the incidence rate ratio of seizure was 1.57, 95% CI:1.03-2.38. Conclusion: This research found no evidence of an increased risk of incident seizure or cardiac outcomes associated with antipsychotic use compared to other psychotropics ASD patients. A short term increase in the risk of incident seizure was noted with the use of psychotropics other than antipsychotics

The challenge of detecting adverse events in adults with autism spectrum disorder who have intellectual disability

Adults with autism spectrum disorder (ASD) and associated intellectual disability (ID) take a high number of different psychotropic drugs simultaneously. Nowadays, little is known about this multidrug pattern efficacy and safety. The present study has endeavored to fill this gap creating a local pharmacovigilance system. A 36-month, retrospective and prospective, observational, and multicenter pharmacovigilance study was carried out in adults with ASD and ID (n = 83). Information regarding ongoing medications (polypharmacy: taking simultaneously >4 drugs; safety profile: adverse events' number, adverse drug reactions' number, and affected system; and observed-to-expected [O/E] ratio using the summary of product characteristics), and current diagnoses were recorded. A median of four ongoing medications per participant was registered, half of the sample was under polypharmacy regimen. Regarding all ongoing medications, 50% were antipsychotic drugs, and 47% of participants had >1 antipsychotic prescribed. In contrast, only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related either to nervous or metabolic systems, and almost a third were not previously described in the corresponding drug summary of products characteristics. Extrapyramidalism, gynecomastia, hypercholesterolemia, and urinary retention were some AEs that occurred more frequently than expected (O/E ratio > 6 times) according to our data. The highest O/E ratio scores (>120 times) were for hypercholesterolemia and rhabdomyolysis caused by valproic acid. According to the number of adverse events and adverse drug reactions reported in electronic health records locally and nationally by clinicians, we need to increase awareness about medications safety. LAY SUMMARY: A 36-month study in adults with autism, ID, and polypharmacy (>4 drugs) was done to investigate drug safety on everyone. A median of four medications per person was registered, half were antipsychotic drugs, and 47% of participants had >1 antipsychotic medication simultaneously. Only 64 adverse events were identified from electronic health records, mostly due to risperidone. Half of them were related to nervous or metabolic systems and a third were not previously described in the drug information sheet

Aggression in autism spectrum disorder: presentation and treatment options

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent difficulties in social communication and social interaction, coupled with restricted, repetitive patterns of behavior or interest. Research indicates that aggression rates may be higher in individuals with ASD compared to those with other developmental disabilities. Aggression is associated with negative outcomes for children with ASD and their caregivers, including decreased quality of life, increased stress levels, and reduced availability of educational and social support. Therapeutic strategies including functional behavioral assessment, reinforcement strategies, and functional communication training may have a significant impact in reducing the frequency and intensity of aggressive behavior in individuals with ASD. Pharmacologic treatments, particularly the use of second-generation antipsychotics, may also be of some benefit in reducing aggression in individuals with ASD. With the ever-increasing rate of ASD diagnosis, development of effective therapeutic and pharmacologic methods for preventing and treating aggression are essential to improving outcomes in this disorder

A multi-national comparison of antipsychotic drug use in children and adolescents, 2005-2012

Over the last decades, an increase in antipsychotic (AP) prescribing and a shift from first-generation antipsychotics (FGA) to second-generation antipsychotics (SGA) among youth have been reported. However, most AP prescriptions for youth are off-label, and there are worrying long-term safety data in youth. The objective of this study was to assess multinational trends in AP use among children and adolescents. A repeated cross-sectional design was applied to cohorts from varied sources from Denmark, Germany, the Netherlands, the United Kingdom (UK) and the United States (US) for calendar years 2005/2006–2012. The annual prevalence of AP use was assessed, stratified by age group, sex and subclass (FGA/SGA). The prevalence of AP use increased from 0.78 to 1.03% in the Netherlands’ data, from 0.26 to 0.48% in the Danish cohort, from 0.23 to 0.32% in the German cohort, and from 0.1 to 0.14% in the UK cohort. In the US cohort, AP use decreased from 0.94 to 0.79%. In the US cohort, nearly all ATP dispensings were for SGA, while among the European cohorts the proportion of SGA dispensings grew to nearly 75% of all AP dispensings. With the exception of the Netherlands, AP use prevalence was highest in 15–19 year-olds. So, from 2005/6 to 2012, AP use prevalence increased in all youth cohorts from European countries and decreased in the US cohort. SGA were favoured in all countries’ cohorts

Akathisia and Newer Second‐Generation Antipsychotic Drugs: A Review of Current Evidence

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155998/1/phar2404_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155998/2/phar2404.pd

The frequency of epileptic seizures during therapy with antipsychotics and placebo within randomized-controlled trials

Die vorliegende Arbeit untersucht die Auftretenshäufigkeit epileptischer Anfälle als schwere unerwünschte Wirkung („serious adverse events“) während der Therapie mit Antipsychotika der zweiten Generation im Rahmen randomisierter placebo-kontrollierter Studien. Anhand vordefinierter Ein- und Ausschlusskriterien wurden verschiedene Literaturdatenbanken systematisch nach Medikamentenstudien durchsucht. In der Auswertung wurden die Häufigkeiten in der Gesamtgruppe sowie in verschiedenen Subgruppen bestimmt sowie metaanalytisch verglichen. Es wurden 314 Studien mit 67.642 Patienten eingeschlossen. Insgesamt zeigte sich kein Hinweis auf ein erhöhtes Krampfanfallrisiko unter Antipsychotika im Vergleich zu Placebo.This doctoral thesis is investigating the frequency of epileptic seizures described as serious adverse events during therapy with second-generation antipsychotics in placebo-controlled randomized trials. There was a systematic search in different databases for trials according to predefined in- and exclusion criteria. The frequencies of the total population and of various subgroups were determined and meta-analytically compared. 314 Studies with 67.642 Patients could be included. Altogether there was no evidence for increased seizure risk during therapy with antipsychotics compared to placebo

Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism

BACKGROUND: Dysregulation of extracellular signal-related kinase (ERK) activity has been potentially implicated in the pathophysiology of autistic disorder (autism). ERK is part of a central intracellular signaling cascade responsible for a myriad of cellular functions. ERK is expressed in peripheral blood lymphocytes, and measurement of activated (phosphorylated) lymphocytic ERK is commonly executed in many areas of medicine. We sought to conduct the first study of ERK activation in humans with autism by utilizing a lymphocytic ERK activation assay. We hypothesized that ERK activation would be enhanced in peripheral blood lymphocytes from persons with autism compared to those of neurotypical control subjects. METHOD: We conducted an initial study of peripheral lymphocyte ERK activation in 45 subjects with autism and 26 age- and gender-matched control subjects (total n = 71). ERK activation was measured using a lymphocyte counting method (primary outcome expressed as lymphocytes staining positive for cytosolic phosphorylated ERK divided by total cells counted) and additional Western blot analysis of whole cell phosphorylated ERK adjusted for total ERK present in the lymphocyte lysate sample. RESULTS: Cytosolic/nuclear localization of pERK activated cells were increased by almost two-fold in the autism subject group compared to matched neurotypical control subjects (cell count ratio of 0.064 ± 0.044 versus 0.034 ± 0.031; p = 0.002). Elevated phosphorylated ERK levels in whole cell lysates also showed increased activated ERK in the autism group compared to controls (n = 54 total) in Western blot analysis. CONCLUSIONS: The results of this first in human ERK activation study are consistent with enhanced peripheral lymphocytic ERK activation in autism, as well as suggesting that cellular compartmentalization of activated ERK may be altered in this disorder. Future work will be required to explore the impact of concomitant medication use and other subject characteristics such as level of cognitive functioning on ERK activation