Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1: a study protocol for a randomised placebo-controlled crossover trial

Abstract

IntroductionDopamine dysregulation has been identified as a key modulator of behavioural impairment in neurofibromatosis type 1 (NF1) and a potential therapeutic target. Preclinical research demonstrates reduced dopamine in the brains of genetically engineered NF1 mouse strains is associated with reduced spatial-learning and attentional dysfunction. Methylphenidate, a stimulant medication that increases dopaminergic and noradrenergic neurotransmission, rescued the behavioural and dopamine abnormalities. Although preliminary clinical trials have demonstrated that methylphenidate is effective in treating attention deficit hyperactivity disorder (ADHD) symptoms in children with NF1, its therapeutic effect on cognitive performance is unclear. The primary aim of this clinical trial is to assess the efficacy of methylphenidate for reducing attention deficits, spatial working memory impairments and ADHD symptoms in children with NF1.Methods and analysisA randomised, double-blind, placebo-controlled trial of methylphenidate with a two period crossover design. Thirty-six participants with NF1 aged 7–16 years will be randomised to one of two treatment sequences: 6 weeks of methylphenidate followed by 6 weeks of placebo or; 6 weeks of placebo followed by 6 weeks of methylphenidate. Neurocognitive and behavioural outcomes as well as neuroimaging measures will be completed at baseline and repeated at the end of each treatment condition (week 6, week 12). Primary outcome measures are omission errors on the Conners Continuous Performance Test-II (attention), between-search errors on the Spatial Working Memory task from the Cambridge Neuropsychological Test Automated Battery (spatial working memory) and the Inattentive and Hyperactivity/Impulsivity Symptom Scales on the Conners 3-Parent. Secondary outcomes will examine the effect of methylphenidate on executive functions, attention, visuospatial skills, behaviour, fine-motor skills, language, social skills and quality of life.Ethics and disseminationThis trial has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.Trial registration numberACTRN12611000765921.

Assessing Psychiatric Comorbidity and Pharmacologic Treatment Patterns Among Patients With Neurofibromatosis Type 1

“…A year-long clinical study of children with NF1 found that the administration of the stimulant medication methylphenidate significantly improved cognitive and academic performance as well as social deficits [17]. Double-blind placebo-controlled crossover trials have demonstrated the efficacy of methylphenidate in reducing ADHD symptoms at four weeks [45] and cognitive symptoms at six weeks [46]. The efficacy of stimulants in patients with NF1 and ADHD has been theorized to relate to the predominance of the combined subtype in this population [47].…”

Neurofibromin Structure, Functions and Regulation

“…The molecular mechanisms responsible for such regulation are still unknown. Clinical trials conducted with methylphenidate showed an effect in the reduction of attention deficits, spatial working memory impairments, and ADHD symptoms in children with NF1 [121].…”

Psychiatric disorders in patients with neurofibromatosis

“…Although preliminary clinical trials have demonstrated that methylphenidate is eff ective in treating ADHD symptoms in children with NF1, its therapeutic eff ect on cognitive performance is unclear. Currently an ongoing randomised, doubleblind, placebo-controlled trial to assess the effi cacy of methylphenidate for reducing att ention deficits, spatial working memory impairments and ADHD symptoms in children with NF1 is being conducted (44). The results of this trial will be published in the near future.…”