Methylphenidate Treatment in Children with Borderline IQ and Mental Retardation: Analysis of Three Aggregated Studies

Objective: To determine response of low-IQ children with attention deficit hyperactivity disorder (ADHD) symptoms to methylphenidate (MPH). Methods: An aggregated analysis was conducted in 90 children with low IQ who received the same dose regimen of MPH in three independent, placebo-controlled studies. Active drug and placebo were given from 2 to 4 weeks each. Outcome measures included teacher and parent ratings on standardized behavior scales (mean n = 84), performance on computer-controlled cognitive-motor tests (n = 62), and measures of cardiovascular response (n = 85). Results: Both teachers and parents rated the children consistently as being improved on subscales assessing attention, overactivity, and conduct problems. Some 44% of the subjects showed at least a 30% reduction compared with placebo on teacher ratings. MPH improved accuracy on several cognitive tests, response speed was increased on some, and seat activity declined for one of three tests; heart rate was mildly increased (3.9 beats/minute) with MPH. Analyses of IQ and mental age as moderator variables suggested that lower functional level (especially lower IQ) may be associated with a less favorable response to MPH. Conclusions: Children with low IQ and ADHD clearly respond to MPH, but their rate of beneficial response appears to be well under that of normal-IQ children and more varied. Different attentional mechanisms may moderate response to psychostimulants

Cognitive Effects of Risperidone in Children with Autism and Irritable Behavior

Objective: The objective of this research was to explore the effects of risperidone on cognitive processes in children with autism and irritable behavior. Method: Thirty-eight children, ages 5-17 years with autism and severe behavioral disturbance, were randomly assigned to risperidone (0.5 to 3.5 mg/day) or placebo for 8 weeks. This sample of 38 was a subset of 101 subjects who participated in the clinical trial; 63 were unable to perform the cognitive tasks. A double-blind placebo-controlled parallel groups design was used. Dependent measures included tests of sustained attention, verbal learning, hand-eye coordination, and spatial memory assessed before, during, and after the 8-week treatment. Changes in performance were compared by repeated measures ANOVA. Results: Twenty-nine boys and 9 girls with autism and severe behavioral disturbance and a mental age ≥18 months completed the cognitive part of the study. No decline in performance occurred with risperidone. Performance on a cancellation task (number of correct detections) and a verbal learning task (word recognition) was better on risperidone than on placebo (without correction for multiplicity). Equivocal improvement also occurred on a spatial memory task. There were no significant differences between treatment conditions on the Purdue Pegboard (hand-eye coordination) task or the Analog Classroom Task (timed math test). Conclusion: Risperidone given to children with autism at doses up to 3.5 mg for up to 8 weeks appears to have no detrimental effect on cognitive performance

Therapeutic effects of methylphenidate for attention-deficit/hyperactivity disorder in children with borderline intellectual functioning or intellectual disability: A systematic review and meta-analysis

Attention-deficit/hyperactivity disorder (ADHD) frequently co-occurs with intellectual disability in children, and may further compromise learning. Methylphenidate is a first-line treatment for ADHD, however no previous meta-analysis has evaluated its overall efficacy for ADHD in children with comorbid intellectual disability (ID) or borderline intellectual functioning. The PubMed/MEDLINE, Cochrane CENTRAL and ScienceDirect databases were systematically searched from inception through 2018/7/15 for clinical studies that investigated the effects of methylphenidate in children with ADHD and ID. A random-effects model meta-analysis was used for data synthesis. Eight studies (average Jadad score = 2.5) enrolling 242 participants receiving methylphenidate and 181 participants receiving placebo were included. The meta-analysis showed that methylphenidate led to a significant improvement in ADHD symptoms relative to placebo (Hedges’ g = 0.878, p < 0.001). Meta-regression analysis pointed to an association between the dose of methylphenidate and overall improvement in ADHD severity (slope = 1.334, p < 0.001). Finally, there was no significant difference in drop-out rate [odds ratio (OR) = 1.679, p = 0.260] or rate of treatment discontinuation due to adverse events (OR = 4.815, p = 0.053) between subjects receiving methylphenidate and those taking placebos. Our study suggests that methylphenidate retains its efficacy in children with ADHD and borderline intellectual functioning or ID

Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.

Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event

Evaluating movement disorders in pediatric patients receiving risperidone: a comparison of spontaneous reports and research criteria for TD

<p>Abstract</p> <p>Background</p> <p>Movement disorders (MD) in children are relatively common and may be associated with medication use. Objective methods (ie rating scales) and specific research criteria may be helpful in identifying MD-related adverse events that would otherwise not be apparent from spontaneous reports. We assessed whether more stringent and rigorous criteria would provide MD rates similar to those derived subjectively from spontaneous reports.</p> <p>Methods</p> <p>MDs were assessed in children with disruptive behavior disorders (DBDs) and subaverage intelligence receiving risperidone. Data were from three 1-year, open-label studies in subjects 4–14 years old. Dyskinesia severity was rated by the Extrapyramidal Symptom Rating Scale (ESRS) dyskinesia subscale. Tardive dyskinesia (TD) was defined: mild dyskinesia (scores 2, 3) in two anatomical areas; or moderate dyskinesia (score ≥ 4) in one area for ≥ 4 weeks in subjects without dyskinesia at baseline (scores 0, 1).</p> <p>Results</p> <p>The mean (± SD) age of subjects was 9.4 ± 2.4 years, the mean (± SD) risperidone dose was 1.6 ± 0.7 mg/day, and the mean (± SD) exposure was 317.8 ± 104.5 days. ESRS data were available for 668 subjects. Mean ESRS scores were low throughout the study. At baseline, 655 subjects had no dyskinetic symptoms. One subject met predefined TD criteria after a risperidone dose reduction. Symptoms persisted for 4 weeks, resolving with continued treatment and no dosage change. Two different subjects had TD by spontaneous adverse-event reports, with dyskinetic symptoms at 1–2 visits, and symptoms that resolved after treatment discontinuation. Thirteen subjects had dyskinesia at baseline; their mean ESRS dyskinesia scores decreased at endpoint.</p> <p>Conclusion</p> <p>Using objective rating scales and research criteria, low-dose risperidone was associated with low risk of TD and other MDs in children with DBDs in three large 1-year studies. Careful, objective evaluation of emergent MDs during all stages of treatment is essential for identifying treatment-emergent TD.</p

Clinical guidance on pharmacotherapy for the treatment of attention-deficit hyperactivity disorder (ADHD) for people with intellectual disability.

INTRODUCTION: ADHD causes significant distress and functional impairment in multiple domains of daily life. Therefore, diagnosis and treatment are important to improve the quality of life of people. The pharmacotherapy for ADHD is well established but needs systematic evaluation in Intellectual Disability (ID) populations. AREAS COVERED: This paper reviews the ADHD pharmacological treatment in people with ID using the PRISMA guidance for scoping reviews to help identify the nature and strength of evidence. EXPERT OPINION: In the last 20 years, seven randomized controlled trials have evaluated pharmacotherapies for ADHD in people with ID; five looking at methylphenidate. Generally, studies were underpowered; all but two had less than 25 participants. Of the two larger trials one was single blinded and therefore open to bias. Only two used a parallel-group method, the remainder were mostly short crossover trials; not ideal when measuring behavioral and psychological parameters which are long standing. The remaining evidence is made up of observational studies. Methylphenidate and atomoxetine, particularly at higher doses, have shown clear benefits in people with ID. Most people with ID tolerated ADHD medications well. Benefits were seen in behavioral and/or cognitive domains. The evidence base is limited, though promising, for dexamfetamine, clonidine, and guanfacine

Moderators, Mediators, and Other Predictors of Risperidone Response in Children with Autistic Disorder and Irritability

Objective/Background: The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritabilityin autistic disorder. This paper explores moderators and mediators of this effect. Method: Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results. Results: Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: Those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5'-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo. Conclusion: The benefit–risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems non-specifically predict better outcome. Mineral interactions with risperidone deserve further study

Developing a utility index for the Aberrant Behavior Checklist (ABC-C) for fragile X syndrome

Purpose This study aimed to develop a utility index (the ABC-UI) from the Aberrant Behavior Checklist-Community (ABC-C), for use in quantifying the benefit of emerging treatments for fragile X syndrome (FXS). Methods The ABC-C is a proxy-completed assessment of behaviour and is a widely used measure in FXS. A subset of ABC-C items across seven dimensions was identified to include in health state descriptions. This item reduction process was based on item performance, factor analysis and Rasch analysis performed on an observational study dataset, and consultation with five clinical experts and a methodological expert. Dimensions were combined into health states using an orthogonal design and valued using time trade-off (TTO), with lead-time TTO methods used where TTO indicated a state valued as worse than dead. Preference weights were estimated using mean, individual level, ordinary least squares and random-effects maximum likelihood estimation [RE (MLE)] regression models. Results A representative sample of the UK general public (n = 349; mean age 35.8 years, 58.2 % female) each valued 12 health states. Mean observed values ranged from 0.92 to 0.16 for best to worst health states. The RE (MLE) model performed best based on number of significant coefficients and mean absolute error of 0.018. Mean utilities predicted by the model covered a similar range to that observed. Conclusions The ABC-UI estimates a wide range of utilities from patient-level FXS ABC-C data, allowing estimation of FXS health-related quality of life impact for economic evaluation from an established FXS clinical trial instrument