The effect of stimulants on irritability in autism comorbid with ADHD: a systematic review

Figures & data

Figure 1 PRISMA flow chart.

Table 1 The characteristics of excluded trials

Authors	Year	Methods	Reasons of exclusion and/or findings
McCracken et. al^Citation42	2014	Genotype data of 64 children with ASD and hyperactivity who were exposed to MPH were compared	Irritability was not reported as an outcome Excluded from review
Nickels et. al^Citation20	2008	Medical review of 124 children with “research-identified” autism among Olmsted County residents, ages 0–21 years, in the years 1976–1997	At least one side-effect in 66% of patients who received stimulants A trend for boys more than girls for a side-effect No association between the type of psychostimulant treatment (ie, dextroamphetamine or methylphenidate) and the occurrence of side-effects Ten episodes in nine different children who experienced irritability/anxiousness/worsening of behavior with methylphenidate Ten episodes in 10 different children who experienced irritability/anxiousness/worsening of behavior with dextroamphetamine Three episodes of irritability/anxiousness/worsening of behavior with mixed amphetamine salts
Poseny et al^Citation43	2007	Sixty-six children (mean age 7.5 years) with autistic disorder, Asperger’s disorder, and PDD not otherwise specified Randomized to varying sequences of placebo and three different doses of methylphenidate for a 4-week blinded, crossover study Methylphenidate doses used approximated 0.125, 0.25, and 0.5 mg/kg per dose, twice daily, with an additional half-dose in the late afternoon	It did not report if the effect of MPH on irritability was examined. Moreover, the adverse effects were not reported
Jahromi et al^Citation44	2009	33 children aged 5 to 13 years old A 4-week crossover trial of placebo and increasing doses of methylphenidate given in random order, each for 1 week	It did not report if the effect of MPH on irritability was examined. Moreover, the adverse effects were not reported
Birmaher et al^Citation45	1988	Case study	—
Di Martino et al^Citation46	2004	Open-label pilot trial including 13 children with PDD and moderate-to-severe hyperactivity/impulsivity Symptoms assessment using Clinical Global Impression (CGI), Childhood Autism, Child Psychiatric and Conners Parent and Teacher Rating Scales (CPRS) Assessment at baseline, and after 1 and 3 months of treatment	An hour after a single MPH dose (0.4 mg/kg), five children showed increased hyperactivity, stereotypes, dysphoria, or motor tics. There was a high rate of adverse effects Four of the remaining children were rated as improved, and four as unchanged There was no remarkable adverse effect in the remaining children

Abbreviations: ASD, Autism Spectrum Disorders; MPH, Methylphenidate: PDD, Pervasive developmental Disorders. 

Table 2 Trials examined the effect of stimulants on hyperactivity in autism and reported irritability

Authors	Year	Methods	Findings
Research Units on Pediatric Psychopharmacology Autism Network et al^Citation21	2005	Double-blind, placebo-controlled, crossover trial followed by open-label continuation 72 drug-free clinical sample children, aged 5–14 years, with pervasive developmental disorders accompanied by moderate-to-severe hyperactivity Increasing doses of methylphenidate (low, medium, and high doses) ranging from 7.5 mg/day to 50.0 mg/day in divided doses Subjects who tolerated the test dose (n=66) were assigned to receive placebo for 1 week and then three methylphenidate doses Children responding to methylphenidate then entered 8 weeks of open-label treatment at the individually determined best dose	Methylphenidate improved hyperactivity more than placebo Methylphenidate respondent rate was 49% for hyperactivity. Methylphenidate did not improved irritability 18% of subjects exited the study due to intolerable adverse effects and the rate for irritability was 8.3% The rates of irritability for low, medium, and high dosages was 7.6%, 12.1%, and 10.0%, respectively
Handen et al^Citation48	2000	Thirteen children aged 5.6–11.2 years with autism and ADHD symptoms Double-blind, placebo-controlled crossover study of methylphenidate (0.3 and 0.6 mg/kg per dose)	Eight subjects responded positively with a minimum 50% decrease in Hyperactivity Index Irritability was among significant adverse side-effects. However, its mean score was less than that of placebo. The percentage of irritability with higher doses was 70%, while in the placebo group it was 63.3%
Quintana et al^Citation49	1995	Methylphenidate (MPH) for the treatment of selected symptoms of autistic disorder double-blind crossover study using placebo and two MPH doses (10 mg or 20 mg bid) 10 children, ages 7–11, with a DSM-III-R diagnosis of autistic disorder	Statistically significant improvement on MPH over placebo for hyperactivity Irritability in 4% patients with high dose of MPH (20 mg) Lack of worsening or serious adverse effect including irritability The irritability score of ABC decreased from 11.8 to 4.0 (P<0.01).
Kim et al^Citation47	2017	27 children with autism and ADHD were randomized to different dose titration schedules of long-acting liquid methylphenidate (MPH) for 6 weeks Aberrant behavior checklist (ABC) was used to check irritability	Low-to-moderate doses of MPH was effective in reducing ADHD symptoms and it was tolerated well Low dose of MPH did not increase irritability score Moderate dose of MPH significantly decreased irritability score

Abbreviations: ADHD, Attention Deficit Hyperactivity Disorder; MPH, Methylphenidate.

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