Growing evidence of pharmacotherapy effectiveness in managing attention-deficit/hyperactivity disorder in young children with or without autism spectrum disorder: a minireview.

Many children with autism spectrum disorder (ASD) also have attention-deficit/hyperactivity disorder (ADHD). ADHD in children is associated with increased risk of negative outcomes, and early intervention is critical. Current guidelines recommend psychosocial interventions such as behavioral training as the first line of therapy in managing ADHD symptoms in children with or without ASD. Where symptoms are refractory to these interventions, medications such as stimulants, α2-adrenergic agonist inhibitors, selective norepinephrine reuptake inhibitors, and second-generation antipsychotics are recommended. However, these pharmacotherapies do not have regulatory approval for use in children of preschool age, and evidence on their safety and efficacy in this population has historically been very limited. Since publication of the current guidelines in 2020, several new randomized controlled trials and real-world studies have been published that have investigated the efficacy and tolerability of these medications in preschool children with ADHD, with or without comorbid ASD. Here, we provide a review of the key findings of these studies, which suggest that there is growing evidence to support the use of pharmacological interventions in the management of ADHD in preschool children with comorbid ASD.

Atomoxetine Treatment of Attention Deficit/Hyperactivity Disorder Symptoms in 3-6-Year-Old Children with Autism Spectrum Disorder: A Retrospective Cohort Study.

Atomoxetine is indicated for the management of attention deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6 to 18 years. Few studies have assessed the safety and tolerability of atomoxetine in younger patients. This retrospective cohort study included 133 children aged 3-6 years who were diagnosed with ADHD comorbid with autism spectrum disorder (ASD). The primary endpoint was the evaluation of the safety profile of atomoxetine. In total, 50 patients (37.6%) experienced adverse events (AEs), which led to treatment discontinuation in 23 patients (17.3%). The most common AEs were gastrointestinal (24.1%), aggression or hostility (12.8%), and increased hyperactivity (9.0%). In the 23 patients who discontinued treatment, all the AEs resolved after treatment ceased. Among the 110 patients who completed at least 6 months' treatment, atomoxetine titrated to a dose of 1.2-1.8 mg/kg/day appeared to be well tolerated and effective. The Clinical Global Impression-Improvement score improved to 1 ("very much improved") and 2 ("much improved") in 62.4% and 20.3% of children, respectively, at their last visit. Overall, atomoxetine appeared to be well tolerated in younger children with comorbid ADHD and ASD. Nevertheless, close patient monitoring remains essential, and the study limitations necessitate caution in generalizing these findings to broader populations. Long-term prospective studies are required.

Apparent germline mosaicism for a novel 19p13.13 deletion disrupting NFIX and CACNA1A.

We report on a case of apparent germline mosaicism in a family of two sisters carrying a novel 19p13.13 deletion. The 11-year-old proposita was referred for evaluation of macrocephaly, moderate intellectual disability (ID), and episodic ataxia. Array comparative genomic hybridization (CGH) detected a 399 kb microdeletion with breakpoints within genes NFIX and CACNA1A. A similar deletion was also seen in the elder sibling who presented with macrocephaly, ID, and strabismus. The deletions were confirmed to be de novo after the parental aCGH analysis suggesting that this is an example of germinal mosaicism. This study contributes additional information for the newly identified 19p13 deletion syndrome and clarifies the clinical roles of genes in the involved region. This case of apparent germline mosaicism represents the only known family in the cohort of 1,800 patients analyzed by our group.

Core Signs and Symptoms in Children with Autism Spectrum Disorder Improved after Starting Risperidone and Aripiprazole in Combination with Standard Supportive Therapies: A Large, Single-Center, Retrospective Case Series.

Background: There are a number of medications prescribed to address comorbid challenging behaviors in children with autism spectrum disorder (ASD), including risperidone and aripiprazole. This retrospective case series reports the use of these drugs in children aged 2 to 13 years. Methodology: A total of 82 children (mean age, 5 years; 79% male) with ASD treated at the Kids Neuro Clinic and Rehab Center in Dubai between January 2020 and September 2021 were included in this retrospective case series. All patients had comorbid challenging behaviors that were resistant to standard supportive therapies alone and warranted pharmacological intervention. The Childhood Autism Rating Scale­2nd Edition Standard form (CARS2-ST) and the Clinical Global Impression (CGI)­Severity (CGI-S) and CGI­Improvement (CGI-I) scales were used to assess the severity of ASD at baseline and to monitor response to treatment with risperidone or aripiprazole. Results: Besides the expected improvement in comorbid challenging behaviors, 79/82 patients (96%) attained a CGI-I score of 2 or 1 following treatment, and 35/82 patients (43%) achieved both a CGI-I score of 1 and minimal-to-no symptoms as per the CARS2-ST test, with complete resolution of their ASD signs and symptoms. The differences in the overall mean CARS2-ST and CGI-S scores pre- and post-treatment were statistically significant (Z = −7.86, p < 0.0001 for both), with pre- and post-treatment mean values of 42 and 23 for CARS2-ST, respectively, and 6 and 2 for CGI-S, respectively. The main side effects were asymptomatic elevated prolactin (n = 12) and excessive weight gain (n = 2). Conclusions: ASD core symptoms and comorbid behaviors in young children improved following chronic treatment with antipsychotic medications, either with or without medications for attention deficit hyperactivity disorder, when combined with standard supportive therapies. Double-blind, placebo-controlled clinical trials are needed to verify these findings.

Risperidone or Aripiprazole Can Resolve Autism Core Signs and Symptoms in Young Children: Case Study.

Risperidone and aripiprazole are approved by the USA Food and Drug Administration for the treatment of irritability and aggression in children from the ages of 5 and 6 years, respectively. However, there are no approved medications for the treatment of autism spectrum disorder (ASD) core signs and symptoms. Nevertheless, early intervention is recognized as key to improving long-term outcomes. This retrospective case study included 10 children (mean age, 2 years 10 months) with ASD who presented with persistent irritability and aggression before 4 years of age that was unresponsive to behavioral interventions and sufficiently severe to consider pharmacological intervention with risperidone or aripiprazole combined with standard supportive therapies. Besides ameliorating comorbid behaviors, improvement was observed in ASD core signs and symptoms for all patients, with minimal-to-no symptoms observed in 60% of patients according to the Childhood Autism Rating Scale 2-Standard Test and Clinical Global Impression scales. Excessive weight gain in two patients was the only adverse effect observed that required intervention. This is the first study to suggest that ASD can potentially be treated in very young children (<4 years). Clinical trials are urgently required to validate these findings among this pediatric population.

Pharmacological Intervention in Children with Autism Spectrum Disorder with Standard Supportive Therapies Significantly Improves Core Signs and Symptoms: A Single-Center, Retrospective Case Series.

PURPOSE: Autism spectrum disorder (ASD) is a debilitating neurodevelopmental disorder with high heterogeneity and no clear common cause. Several drugs, in particular risperidone and aripiprazole, are used to treat comorbid challenging behaviors in children with ASD. Treatment with risperidone and aripiprazole is currently recommended by the Food and Drug Administration (FDA) in the USA for children aged 5 and 6 years and older, respectively. Here, we investigated the use of these medications in younger patients aged 4 years and older. PATIENTS AND METHODS: This retrospective case series included 18 children (mean age, 5.7 years) with ASD treated at the Kids Neuro Clinic and Rehab Center in Dubai. These patients began treatment with risperidone or aripiprazole at the age of 4 years and older, and all patients presented with comorbid challenging behaviors that warranted pharmacological intervention with either risperidone or aripiprazole. RESULTS: All 18 children showed objective improvement in their ASD core signs and symptoms. Significant improvement was observed in 44% of the cases, and complete resolution (minimal-to-no-symptoms) was observed in 56% of the cases as per the Childhood Autism Rating Scale 2-Standard Test (CARS2-ST) and the Clinical Global Impression (CGI) scales. CONCLUSION: Our findings indicate that the chronic administration of antipsychotic medications with or without ADHD medications is well tolerated and efficacious in the treatment of ASD core and comorbid symptoms in younger children when combined with standard supportive therapies. This is the first report to suggest a treatment approach that may completely resolve the core signs and symptoms of ASD. While the reported outcomes indicate significant improvement to complete resolution of ASD, pharmacological intervention should continue to be considered as part of a multi-component intervention in combination with standard supportive therapies. Furthermore, the findings support the critical need for double-blind, placebo-controlled studies to validate the outcomes.

Role of methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism in pediatric cerebrovascular disorders.

Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation (MTHFR TT) has been linked to an increased risk for stroke, coronary artery disease, and migraine headaches. The authors analyzed the potential link between MTHFR 677C>T homozygosity and childhood stroke. A true association might facilitate screening, recurrence risk stratification, and treatment in patients with cerebrovascular disease. They performed a retrospective chart review of children tested for the MTHFR 677C>/T mutation; 533 patients underwent MTHFR testing, and 8% were homozygous for the MTHFR 677C>T mutation. There was no difference in the cohort compared with the prevalence in the general population. This suggests that the MTHFR 677 C>T polymorphism played a minimal role or no role in stroke risk. However, the data suggest that the MTHFR TT genotype may influence migraine susceptibility in children because there was a higher proportion of migraine patients (28.6%) with the MTHFR TT homozygous genotype.