Psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorders

Figures & data

Figure 1. Preferred reporting items for systematic reviews and meta-analysis flowchart reporting the search strategy and retrieved studies.

Table 1. Characteristics of included studies.

Study (year)	Age range/mean age (SD) in years	Patients (n)	M/F	Design	Type(s) of ASD	Assessment of ADHD symptoms	Stimulant(s) type and formulation	Stimulant(s) dose	Key findings^†	Ref.
Controlled studies
Quintana et al. (1995)	7–11/8.5 (1.3)	10	6/4	Double-blind, placebo-controlled, crossover trial	AD: 10	ABC; CAPQ; hyperactivity factor of the CTQ	MPH immediate release	10–20 mg b.i.d.	Significant improvement of ADHD symptoms on the hyperactivity subscale of the CTQ and ABC-hyperactivity factor	[27]
Handen et al. (2000)	5.6–11.2/7.4 (1.7)	13	10/3	Double-blind, placebo-controlled, crossover trial	AD: 9; PDD-NOS: 4	CTQ (Hyperactivity Index); ABC	MPH immediate release	Two doses (0.3 mg/kg and 0.6 mg/kg) b.i.d. or t.i.d.	62% (8 out of 13) of participants were considered responders based on a 50% decrease of the Conners’ Hyperactivity Index. The most common adverse events included irritability, sadness, decreased appetite and social withdrawal	[22]
RUPP Network (2005)	5–13.7/7.5 (2.2)	72 in the inclusion phase; six participants excluded after the test-dose phase	59/7	Randomized, double-blind, placebo-controlled, crossover trial followed by open-label continuation	AD: 47; AS: 5; PDD-NOS: 14	ABC	MPH immediate release	0.125, 0.250 and 0.500 mg/kg t.i.d.	MPH > placebo (ES: 0.20–0.54); 49% (35 out of 72) were responders; magnitude of response was less than in typically developing children with ADHD. Adverse effects were more frequent than in typically developing children with ADHD (discontinuation in 18% of participants)	[18]
Posey et al. (2007)	5–13.7	66	59/7	Randomized, double-blind, placebo-controlled, crossover trial followed by open-label continuation	AD: 47; AS: 5; PDD-NOS: 14	Swanson, Nolan and Pelham Questionnaire (revised for DSM-IV)	MPH immediate release	0.14 (low dose), 0.27 (medium dose) and 0.48 (high dose) mg/kg per dose b.i.d. + half dose at 4 PM	MPH > placebo on the SNAP-IV ADHD, inattention and hyperactivity/impulsivity subscales (ES: 0.06–0.77)	[26]
Ghuman et al. (2009)	3–5.9/4.8 (1.0)	14	13/1	Randomized, double-blind, placebo-controlled, crossover trial	AD: 5; PPD-NOS: 7 (ID: 2)	Conners’ Parent and Teacher Rating Scales (ADHD subscale) Nisonger Child Behavior Rating Form (hyperactivity subscale)	MPH immediate release	2.5–10 mg/kg b.i.d.	MPH > placebo (ES on the primary outcome: 0.97). 50% considered to be MPH responders. 50% of the participants experienced one or more adverse events	[21]
Uncontrolled studies
Hoshino et al. (1977)	2–13/7 (3.4)	15	11/4	Uncontrolled open-label trial: 2-week to 14-month MPH treatment	Autism: 15	Werry–Weiss–Peters Activity Scale	MPH immediate release	5–10 mg (0.3–1.0 mg/kg/day) administered before breakfast	Global improvement of 9 out of 15 children (60%). Improvement in ‘hyperactivity’, ‘impulsiveness’ and ‘inability to concentrate’ in 84, 79 and 47% of patients, respectively. Most common adverse events (temporary): decreased appetite (47%), irritability (40%), insomnia (33%) and self-mutilative behavior (27%)	[23]
Birmaher et al. (1988)	4–16/7.4 (1.7)	9	8/1	Uncontrolled open-label trial: 1-week baseline, 2-week MPH treatment	Autism: 9	CPQ; CTQ	MPH immediate release	10–50 mg/day (divided in two doses/day)	Significant improvement of 8 out of 9 children (89%) in CTQ and CPQ scores. No major adverse effects. Mild insomnia lasting for a few days. No worsening of stereotypies	[19]
Ishizaki et al. (2001)	NS	141 patients with ADHD or PDD with ADHD symptoms	NS	Follow-up open-label study	PDD	NS	MPH immediate release	0.3 mg/kg once in the morning	MPH effective in 83 out of 141 individuals. Efficacy of MPH did not differ between patients with PDD and those without PDD. Excitability, nausea, anorexia and/or insomnia reported in 23% of patients	[24]
Di Martino et al. (2004)	NA/7.9 (2.1)	13	12/1	Uncontrolled open-label trial. First phase: single dose of MPH. Second phase: 12-week MPH treatment	AD: 7; AS: 3; PDD-NOS: 3	CPQ; CTQ; CPRS (hyperactivity factor)	MPH immediate release	Mean dose: 0.5 ± 0.2 mg/kg/day in single dose or b.i.d.	Adverse effects after the first phase in 38% of children. Responders after the second phase: 75%. After 1 week of open-label treatment there was significant improvement in the hyperactivity factor score of the CPRS. After 12 weeks there was significant improvement in the CPQ and CTQ-long version-revised. No clinically significant adverse events were reported	[20]
Stigler et al. (2004)	2–19/7.26 (3.45)	195	174/21	Retrospective study	AD: 104; AS: 34; PDD-NOS: 57	NA	MPH, AMP, DEX, pemoline	Mean dose (mg/day): MPH: 12.9; AMP: 10.4; DEX: 5.8; pemoline: 33.3	24.6, 23.2 and 11.1% of patients with one, two and three stimulants trials responded to the first trial, respectively. 43% responded to a second trial. Adverse events were observed in 57.5% of trials. Agitation was more common in children with AD or PDD-NOS than AS	[29]
Santosh et al. (2006)	ASD: 13.1 (3.2) ADHD: 12.4 (3.0)	61 ASD; 113 ADHD	141/33	Retrospective study	AD + ADHD: 7; AS + ADHD: 13; PDD-NOS + ADHD: 41; ADHD only: 113	Clinical assessment of symptom profile (hyperactivity, impulsivity, inattention)	MPH; DEX	MPH: 10–50 mg/day or dexamphetamine: 5–30 mg/day	Significant improvement of ADHD symptoms in both children with ASD with ADHD and ADHD only	[28]
	ASD: 11.6 (2.7) ADHD: 11.6 (2.5)	27 ASD; 25 ADHD	44/8	Prospective study 1–6 month stimulant treatment (quasi-experimental)	ASD with ADHD: 27; ADHD only: 25	Clinician-completed profile of neuropsychiatric symptoms	MPH	Mean MPH dose: ∼30 mg/day	Significant improvement of ADHD symptoms was seen in both children with ADHD and ADHD with ASD
Nickels et al. (2008)	<21/7.6	124; 65 treated	95/29	Retrospective study	Autism: 124	NA	MPH, DEX, mixed AMP salts, pemoline, methamphetamine	Average daily dose in MPH equivalent units: 23.4	Favorable response to treatment in 69.4% of episodes of treatment. At least one side effect for 66% of the children	[25]

^†Of relevance for the present review.

ABC: Aberrant Behavior Checklist; AD: Autistic disorder; AMP: Amphetamine; AS: Asperger’s syndrome; ASD: Autism spectrum disorder; b.i.d.: Twice daily; CAPQ: Conners’ Abbreviated Parent Questionnaire; CPQ: Conners’ Parent Questionnaire; CPRS: Child Psychiatric Rating Scale; CTQ: Conners’ Teacher Questionnaire; DEX: Dexamphetamine; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, fourth edition; ES: Effect size; F: Female; ID: Intellectual disability; M: Male; MPH: Methylphenidate; NA: Not applicable; NS: Not specified; PDD: Pervasive developmental disorder; PDD-NOS: Pervasive developmental disorder not otherwise specified; RUPP: Research Unit on Pediatric Psychopharmacology; SD: Standard deviation; SNAP-IV: Swanson, Nolan and Pelham Questionnaire revised for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition; t.i.d.: Three-times daily.

Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

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