Table 5.

Randomized, Controlled Trials of Treatments for Aggression in Adults with Autism Spectrum Disorder

Study	Diagnosis	Subjects (number, sex, mean age, FS IQ, verbal/nonverbal)	Intervention	Measure of aggression	Adverse effects	Outcome	Limitations
Elliott et al. (1994)120	Autistic disorder (DSM-III-R20) Profound ID	n = 6 total 2 adult females with ASD and aggression 32.5 years Unclear FS IQ, but both subjects had profound ID and mental age of 5.1	Vigorous, antecedent aerobic exercise (defined as exercise elevating heart rate to above 130 beats per minute after 20 minutes) via use of motorized treadmill at 4.0 miles per hour	Behavioral observation	None reported	Significant reduction in number and frequency of aggressive incidents (1 subject) and in frequency of property destruction (1 subject)	Small sample size Inadequate random sequence generation Unclear allocation concealment Possible concern for selective reporting
McDougle et al. (1996)121	Autistic disorder (DSM-III-R,20 ICD-10;23 corroborated with ADI-R24 and ADOS25)	n = 30 27 male, 3 female 30.1 years Mean FS IQ = 79.9 26 verbal, 4 nonverbal	Fluvoxamine 50–300 mg/day for 12 weeks	BAS34	Moderate sedation (2 subjects) Nausea (3 subjects)	Significant improvement in aggressive behavior as measured by changes in BAS34 scores compared to placebo group (F = 4.57; p < .03)	Inadequate random sequence generation Unclear allocation concealment Possible concern for selective reporting
McDougle et al. (1998)48	Autistic disorder (DSM-IV;21 17 subjects) PDD NOS (DSM-IV;21 14 subjects) Corroborated with ADI-R24 and ADOS25	n = 31 22 male, 9 female 28.1 years Mean FS IQ=54.6 15 verbal, 16 nonverbal	Risperidone up to 6 mg/day for 12 weeks	SIB-Q46	Sedation (8 subjects), weight gain (2 subjects), enuresis (2 subjects) were most common side effects in double-blind phase of study	Significant reduction in aggression compared to placebo, as measured by changes in total SIB-Q46 scores (F3,84 = 6.51; p < .001) Reduction in aggression (as reflected by changes in total SIB-Q46 scores) in 12-week open-label phase, in which 15 subjects from prior placebo group then received risperidone (F3,42 = 3.07; p < .05)	Possible concern for selective reporting
Hellings et al. (2006)122	Autistic disorder (DSM-IV;21 28 subjects) PDD NOS (DSM-IV;21 8 subjects) Unclear how many subjects diagnosed with ASD were adults	n = 40 total 19 adult subjects: 11 male, 8 female ID: 3 mild, 4 moderate, 6 severe, 6 profound Unclear how many adults were diagnosed with ASD	Risperidone low (2 mg/day) or high (4–5 mg/day) dose for 4 weeks in randomized, placebo-controlled, crossover design; followed by 24-week, open-label risperidone (dose adjusted as needed)	ABC-I30	Sedation and gastrointestinal disturbance (nausea and abdominal discomfort) in 13 subjects Akathisia in 2 adult subjects (leading to dropout from the study) Recurrent oculogyric crises in one adult subject (which resolved with dose reduction) Mean weight gain = 6.0 kg in adult subjects	Significant decrease in ABC-I30 scores at both doses compared to placebo (e.g., for adults, from 19.16 in first placebo phase to 11.15 in low-dose risperidone phase and to 13.31 in high-dose risperidone phase) 23 subjects (57.5%) showed 50% reduction in Irritability subscale score (full response) and 35 subjects (87.5%) showed 25% decrease Clinical gains (as measured by ABC-I30 scores) maintained during 24-week open-label maintenance phase	Heterogeneous sample, making predictors of response challenging to assess due to small subgroups Cannot exclude compromising of rater blinding with crossover design since subjects received study drug at predictable stages, and drug response and side effects may have been recognizable to a single rater Inadequate random sequence generation Unclear allocation concealment Possible concern for selective reporting
Lundqvist et al. (2009)123	Autistic disorder (DSM-IV;21 10 subjects) ID (DSM-IV;21 20 subjects)	n = 20 13 male, 7 female 37 years ID: 7 mild, 5 moderate, 8 severe 5 verbal, 15 nonverbal Unclear sex ratio, ID distribution, and verbal/nonverbal ratio among the 10 subjects with ASD	10–20 minute sessions of vibroacoustic music twice weekly for 5 weeks (music therapy involving vibrations, delivered through specially designed speakers built into a chair, bed, or other equipment in order to administer low-frequency sound vibrations enabling listener to hear and physically feel the music)	Behavior Problems Inventory31 Behavior observation analysis (in which video recordings of vibroacoustic music treatment sessions analyzed minute by minute with regard to type of behavior problem and frequency of behaviors)	None	Within ASD group, significant reduction in frequency and severity of self-injurious behavior ([F(1,18) = 5.02; p = .038], and [F(1,18) = 7.13; p = .016], respectively) Reduction in stereotypical and aggressive behavior in non-ASD group but not in ASD group	Small sample size Heterogeneity of problematic behaviors among subjects limited study power and raised error variance Inadequate random sequence generation Unclear allocation concealment Possible concern for selective reporting
Lewis et al. (2018)124	ASD (DSM-5;1 unclear number of subjects) Autistic disorder (DSM-IV;21 unclear number of subjects) Asperger’s syndrome (DSM-IV;21 unclear number of subjects) PDD NOS (DSM-IV;21 unclear number of subjects)	n = 8 7 male, 1 female 24 years Mean FS IQ unclear Verbal/nonverbal status of subjects unclear	Transdermal nicotine 7 mg daily or placebo for 1 week, followed by 1-week washout period, during which all subjects received transdermal placebo, followed by 1 week of transdermal nicotine 7 mg daily or placebo, whichever was not received during first week	ABC-I30	Well tolerated, with no subjects dropping out of study due to side effects	In 5 subjects with available primary outcome data, mean ABC-I30 scores decreased from baseline compared to placebo group, but difference was not significant (effect size = 0.49; p = .44) Significant correlation between improvement in ABC-I30 and sleep with nicotine compared to placebo (r2 = 0.89; p = .016)	Small sample size Short treatment period Questionable degree to which 7 mg dose of transdermal nicotine engaged α7 nAChR Cannot exclude compromising of rater blinding with crossover design since subjects received study drug at predictable stages, and drug response and side effects may have been recognizable to a single rater Inadequate random sequence generation Unclear allocation concealment Possible concern for selective reporting
Chez et al. (2018)125	Autistic disorder (DSM-IV-TR;22 corroborated with ADOS25)	n = 14 11 male, 3 female 21.92 years Mean FS IQ = 56.70 Unclear verbal/nonverbal ratio	DM/Q or placebo for 8 weeks, then 4-week washout period, then opposite treatment for another 8 weeks, then another 4-week washout period	ABC-I30	No reported serious adverse effects	In the 12 subjects who completed the study, DM/Q associated with significant reduction in irritability and aggression as measured by changes in ABC-I,30 with nearly 4-point difference in change scores between DM/Q and placebo (F1,10 = 7.42; p = .021)	Relatively small sample size Possible bias due to missing outcome data (2 randomized subjects withdrew from study as result of behavioral deterioration and were not included in analysis) Cannot exclude compromising of rater blinding with crossover design since subjects received study drug at predictable stages, and drug response and side effects may have been recognizable to a single rater Inadequate random sequence generation Unclear allocation concealment Possible concern for selective reporting

ABC-I, Aberrant Behavior Checklist–Irritability subscale; ADI, Autism Diagnostic Interview; ADOS, Autism Diagnostic Observation Schedule; ASD, autism spectrum disorder; BAS, Brown Aggression Scale; DM/Q, dextromethorphan/quinidine; DSM, Diagnostic and Statistical Manual of Mental Disorders; FS IQ, Full Scale Intelligence Quotient; ICD-10, International Statistical Classification of Diseases and Related Health Problems, 10th revision; ID, intellectual disability; IQ, intelligence quotient; α7 nAChR, alpha-7 nicotinic acetylcholine receptor; PDD NOS, pervasive developmental disorder not otherwise specified; SIB-Q, Self-Injurious Behavior Questionnaire.