Table 3.

Prospective Open Trials of Treatments for Aggression in Adults with Autism Spectrum Disorder

Study	Diagnosis	Subjects (number, sex, mean age)	Nature of aggression	Intervention	Measure of aggression	Adverse effects	Outcome
Ratey et al. (1987)100	Autistic disorder (DSM-III19)	n = 8 7 male, 1 female 32 years	Assaults on staff (not specified, except biting in 1 female subject)	Propranolol at average dose of 225 mg/day for 4 weeks	Staff report	Low HR and low BP at doses higher than 420 mg/day (1 subject) Unspecified adverse effects in another subject eventually necessitating discontinuation of medication	Substantial reduction in aggressive and impulsive behavior in all 8 subjects as reported by hospital staff Improvements in repetitive behavior, attention span, social skills over 4–5 months
Kuperman & Stewart (1987)101	Infantile autism (DSM-III19)	n = 3 Unclear sex ratio of subjects with ASD Unclear mean age	Physically aggressive behavior (not specified)	Propranolol at mean dose of 166 mg/day	Parent, teacher, and physician report	No serious adverse effects reported A few subjects reported tiredness that resolved within few weeks	Reduction in aggressive incidents as observed and reported by parents, teachers, and treating physicians in 10 of 16 subjects However, unclear how many of responders were those with ASD
King & Davanzo (1996)102	Pervasive developmental disorder (DSM-III-R20) ID (severe in 2 subjects, profound in 5 subjects)	n = 7 adults with ASD and aggression as target symptom 3 male, 4 female 44.86 years	Aggression (not specified)	Buspirone at doses ranging from 30 to 60 mg/day for periods ranging from 58 to 289 days	Residential staff recording of frequency and severity of aggressive incidents	Unclear	Buspirone associated with worsening of frequency and severity of aggression in subjects with ASD compared to those without ASD
Hellings et al. (1996)103	Autistic disorder (DSM-III-R20) ID (borderline in 1, mild in 3, moderate in 3, severe in 2)	n = 9 total (5 adults with ASD) Unclear sex distribution among subjects with ASD Unclear mean age of subjects with ASD	Aggressive and self-injurious behavior (not specified)	Sertraline 25–150 mg/day for average of 109 days	CGI-S35	Agitation and skin picking in 1 subject at 50 mg/day who dropped out after 18 weeks	Substantial improvement in CGI-S35 ratings in 8 of 9 subjects (mean improvement = 2.44) However, unclear how many of the 5 patients with ASD benefited from sertraline in terms of improvement in aggressive behavior
Brodkin et al. (1997)104	Autistic disorder (DSM-IV;21 18 subjects) Asperger disorder (DSM-IV;21 6 subjects) PDD NOS (DSM-IV;21 11 subjects)	n = 35 24 male, 11 female 30.2 years	Aggression (including destruction of property) and self-injurious behavior (not specified)	Clomipramine at average dose of 131 mg/day for 12 weeks	Brown Aggression Scale34	Seizures (3 subjects, 2 of whom had preexisting seizure disorder being treated with carbamazepine)	Significant reduction in subjects’ scores on Brown Aggression Scale34 (from average = 10.6 pretreatment to average = 3.7 posttreatment), including self-injurious behavior and destruction of property
Connor et al. (1997)41	Autistic disorder (DSM-III-R20) ID (profound)	n = 12 total (1 adult with ASD) 1 male with ASD 24 years	Physical assaults, verbal threats of violence, self-injurious behavior, explosive property destruction among sample as a whole; unclear whether the 1 adult with ASD was being treated for aggression or for inattention/overactivity	Nadolol at mean dose of 109 mg/day for average of 11 weeks	Overt Aggression Scale40	Insomnia, sedation, nausea, and nightmares were the most commonly reported side effects among all 12 subjects	Significant reduction in Overt Aggression Scale40 scores for the 10 subjects with aggression (F[2,18] = 5.43; p < .05) However, unclear from study whether the 1 adult with ASD was among the subjects with aggressive behavior or among those with inattention/overactivity as target behavior
Horrigan & Barnhill (1997)105	Autistic disorder (DSM-III-R20) ID (borderline in 1, moderate in 1, severe in 3)	n = 5 5 male 27.8 years	Aggression (including hitting, kicking, biting) and self-injurious behavior (head banging, self-biting)	Risperidone at mean dose of 1 mg/day for 4 weeks	Conners APTQ36	Mild, initial sedation (2 subjects) Weight gain (from 1.27 to 3.64 kg) in all 5 subjects	Significant improvement (reduction) in aggression as reflected by improved Conners APTQ36 scores (with changes ranging from −8 to −17 points) in all 5 adult subjects
Cohen et al. (1998)106	Autistic disorder (DSM-IV;21 2 subjects) PDD NOS (DSM-IV;21 1 subject)	n = 3 2 male, 1 female 38 years	Physical assaults, self-injurious behavior	Risperidone 3–6 mg daily for 3 months	Aggression monitored by direct care staff who “remained relatively consistent,” although no interrater reliability established, and no specific instruments/scales used to measure aggression	Sedation (2 subjects) Akathisia (2 subjects) Pedal edema (1 subject, though this subject was also taking divalproex, which could have accounted for edema)	Substantial decrease in aggressive behavior in 2 of 3 subjects
McDougle et al. (1998)46	Autistic disorder (DSM-IV;21 22 subjects) Asperger’s disorder (DSM-IV;21 6 subjects) PDD NOS (DSM-IV;21 14 subjects) All diagnoses aided by ADI-R24 and ADOS25	n = 42 27 male, 15 female 26.1 years	Aggression, self-injurious behavior, and property destruction (not specified)	Sertraline 50–200 mg (mean = 122 mg) daily for 9 weeks	SIB-Q46 CGI-I35	Weight gain (3 subjects) and anxiety/agitation (2 subjects) were the most commonly reported side effects	57% response rate (24 of 42 subjects) in terms of aggression, with response defined by CGI-I35 posttreatment rating of “much improved” or “very much improved” Within DSM-IV21 diagnostic subtypes, 68% (15 of 22) subjects with autistic disorder, 0% (0 of 6) subjects with Asperger’s disorder, and 64% (9 of 14) subjects with PDD NOS were responders; lack of apparent response in subjects with Asperger’s disorder possibly due to lower baseline severity of difficulties in this subgroup
Dartnall et al. (1999)107	Autistic disorder (DSM-IV;21 2 subjects) ID (both subjects profound)	n = 2 1 male, 1 female (separately studied) 30 years and 24 years, respectively	Subject 1: Aggression toward others and the environment (e.g., head-butting others, suddenly and violently clearing items off tables)	Risperidone up to 3 mg/day (unspecified time interval)	Aggression recorded by residential staff with half-hour interval “spoilage” or sampling technique in which waking hours divided into half-hour intervals, with interval marked “spoiled” if target behavior occurred one or more times during interval	No major adverse effects	Dramatic improvement in aggressive and self-injurious behaviors, with maintenance of gains for 24 months
			Subject 2: Grabbing others	Risperidone up to 4 mg/day for 2 months	Aggression recorded by residential staff with half-hour interval “spoilage” or sampling technique in which waking hours divided into half-hour intervals, with interval marked “spoiled” if target behavior occurred one or more times during interval	40-pound weight gain over first year and unilateral gynecomastia	Virtual elimination of aggression and other target behaviors, with maintenance of gains over 34 months
Potenza et al. (1999)47	Autistic disorder (DSM-IV;21 5 subjects) PDD NOS (DSM-IV;21 3 subjects) All diagnoses aided by ADI-R24 and ADOS25	n = 8 (4 adults with ASD) 3 male, 1 female 20.9 years	Aggressive behavior (unspecified)	Olanzapine 5–20 mg daily (mean = 7.8 mg daily) for 10 weeks (with a 2-week introductory period of 2.5 mg daily for all subjects)	SIB-Q46 Visual Analog Scale51	Weight gain (6 subjects) Sedation (3 subjects)	Significant reduction in aggressive behavior in 6 of 7 subjects who completed study, as measured by changes in SIB-Q46 scores (mean = 55.38 pretreatment to mean = 19.75 posttreatment) and by reductions in clinician ratings of “aggressive” on the Visual Analog Scale51 over time (mean = 46.25 pretreatment to mean = 7.50 posttreatment) Positive effects first observable at end of 4th week of treatment However, unclear how many of 6 responders were adults
Rossi et al. (1999)108	Autistic disorder (DSM-IV21)	n = 25 23 male, 2 female 9 years (range = 2 to 20); unclear how many adults)	Aggression toward others (not specified)	Niaprazine 1 mg/kg/day for 60 days	Behavioral Summarized Scale for Autistic Disorder33	Moderate daytime drowsiness in a few subjects	Significant reduction in Behavioral Summarized Scale for Autistic Disorder33 scores in 52% of subjects (p < .05) after 60 days on number of dimensions, including aggression toward others However, unclear how many responders were adults
Fava & Strauss (2009)109	ASD (unclear which criteria used, but subjects had been diagnosed with autism per authors) ID (all subjects profound)	n = 27 (9 adults with ASD) Unclear sex distribution 37.8 years	Aggressive behavior (hitting, overturning furniture, spitting, threatening others)	2 different multisensory rooms (Snoezelen and stimulus preference rooms) for 25 minutes 3 times a week for 7 weeks	Target behaviors recorded by 3 “blind” observers (who did not know purpose of study and were not familiar with subjects) consisting of 2 occupational therapists and 1 behavioral psychologist	None reported	Frequency of aggressive behaviors decreased significantly (F = 35.361; p = .00014) after treatment only for individuals with ASD who attended Snoezelen condition, whereas stimulus preference condition effective in reducing disruptive behaviors only in individuals with profound ID without ASD
Miyaoka et al. (2011)110	Asperger’s disorder (DSM-IV;2 number of adult subjects unclear) PDD NOS (DSM-IV;21 number of adult subjects unclear)	n = 40 subjects (unclear how many adults) Unclear sex ratio 15.6 years (range = 12 to 22 years)	Aggression, self-injurious behavior, tantrums (not specified)	Yokukansan (TJ-54) at dose of 2.5–7.5 grams daily (mean = 6.2 grams daily) for 14 weeks	CGI-I35 ABC30 (30% reduction in score)	Well tolerated; no subjects exited study due to adverse events	Response (as measured by ratings of “much improved” or “very much improved” on CGI-I35 and 30% reduction in ABC30 score) in 36 of 40 subjects (90%) in terms of aggression, self-injury, and tantrums However, unclear how many of 40 subjects were adults, and how many adults were considered responders
Miyaoka et al. (2012)58	Aspergers disorder (DSM-IV;21 number of adult subjects unclear) PDD NOS (DSM-IV;21 number of adult subjects unclear)	n = 40 subjects (unclear how many adults) 22 male, 18 female 22.7 years (range = 8 to 40 years)	Aggression, self-injurious behavior, tantrums (not specified)	Yokukansan (TJ-54) at dose of 2.5–7.5 grams daily (mean = 6.4 grams daily) for 14 weeks	CGI-S35 (final score of 1 or 2) ABC-I30 (80% or greater improvement)	Well tolerated; no subjects exited study due to adverse events	Response (as measured by final score of 1 [normal, not at all ill] or 2 [borderline mentally ill] on CGI-S35 and 80% reduction in ABC-I30 score) in 36 of 40 subjects (90%) in terms of aggression, self-injury, and tantrums However, unclear how many of 40 subjects were adults, and how many adults were considered responders
Stigler et al. (2012)111	Autistic disorder (DSM-IV-TR;22 25 adolescent and young adult subjects; number of adult subjects unclear)	n = 25 subjects (unclear how many adults) 21 male, 4 female 15.3 years (range = 12 to 21 years)	Severe tantrums, aggression, self-injury (not specified)	Paliperidone 3–12 mg daily (average = 7.1 mg daily) for 8 weeks	CGI-S35 ABC-I30 VABS Maladaptive Behavior Subscales49 (secondary measure of irritability/aggression)	Increased appetite, weight gain (average = 2.2 kg), sedation, and rhinitis	Significant treatment response in 21 of 25 subjects (84%) as measured by CGI-I35 score of “much improved” or “very much improved” and ≥25% improvement on ABC-I30 subscale score (mean = 30.3 pretreatment to mean = 12.6 posttreatment), with specific improvements in realms of severe tantrums, aggression, and self-injury Significant improvement also noted on VABS Maladaptive Behavior Subscales,49 with mean total scores decreasing from 37.4 to 25.1 (p ≤ .001); all subjects with prior ineffective response to risperidone for irritability/aggression responded to paliperidone However, unclear how many adults in study, and of these, how many were responders

ABC, Aberrant Behavior Checklist; ABC-I, Aberrant Behavior Checklist–Irritability Subscale; ADI-R, Autism Diagnostic Interview–Revised; ADOS, Autism Diagnostic Observation Schedule; ASD, autism spectrum disorder; BP, blood pressure; CGI-I/S, Clinical Global Impression Scale–Improvement/Severity; Conners APTQ, Conners Abbreviated Parent-Teacher Questionnaire; DSM, Diagnostic and Statistical Manual of Mental Disorders; HR, heart rate; ID, intellectual disability; PDD NOS, pervasive developmental disorder not otherwise specified; PANSS, Positive and Negative Symptom Scale; SIB-Q, Self-Injurious Behavior Questionnaire; VABS, Vineland Adaptive Behavior Scale.