In adults with autism, an early case series and an open-label trial of clomipramine demonstrated effectiveness in the treatment of interfering repetitive thoughts and behaviors (Brodkin, McDougle, Naylor, Cohen, & Price, 1997; McDougle et al., 1992). Differences in global clinical improvement with clomipramine treatment were observed by diagnosis, with response noted in 63 % of those with autism, 33 % of those with Asperger’s disorder, and 55 % of those with pervasive developmental disorder not otherwise specified (PDD-NOS) (Brodkin et al., 1997).

There are two double-blind, placebo-controlled crossover trials of clomipramine that include combined cohorts of children, adolescents, and young adults (Gordon, State, Nelson, Hamburger, & Rapoport, 1993; Remington, Sloman, Konstantareas, Parker, & Gow, 2001). Mean ages were 16.3 and 10.4 years, respectively, so results may be more applicable to younger populations.

The Gordon et al. (1993) study compared treatment with clomipramine to desipramine, another TCA with more prominent noradrenergic activity, in 12 subjects, aged 6–23 years (mean age, 10.4 years). Clomipramine (mean dose, 152 mg/day) was found to be more effective than placebo and desipramine (mean dose, 127 mg/day) at decreasing stereotypies, anger, and compulsive, ritualized behavior. Both TCAs were superior to placebo at ameliorating hyperactivity. Adverse effects as a whole were minor, with no statistically significant differences between the drugs and placebo. However, clomipramine was associated with prolonged QTc interval in one subject and tachycardia in another. Dose reduction resolved these issues. Another subject experienced a grand mal seizure and was dropped from the study.

The Remington et al. (2001) study compared clomipramine to haloperidol, a typical antipsychotic, in the treatment of stereotypy in 36 subjects aged 10–36 years (mean age, 16.3 years). Clomipramine doses ranged from 100 to 150 mg/day (mean dose, 128.4 mg/day). Due to poor tolerance, only 37.5 % of the participants randomized to the clomipramine group were able to complete the trial, compared to 69.7 % in the haloperidol group and 65.5 % in the placebo group. Among those who completed trials of both drugs, clomipramine was comparable to haloperidol in terms of improvement from baseline. Clomipramine was effective on a measure of stereotypy, but it was not more effective than haloperidol. Identified adverse effects that limited trial completion in 12 (37.5 %) of the 32 clomipramine-treated subjects included fatigue or lethargy, tachycardia, insomnia, diaphoresis, nausea or vomiting, decreased appetite, and behavioral problems.

A case report of a 20-year-old female with autism showed that fluvoxamine (100 mg/day) led to improvements in repetitive behaviors, as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (Harvey & Cooray, 1995).

A 12-week, randomized, double-blind study examined fluvoxamine (276.7 mg/day) in 30 adults with autism, aged 18–53 years (mean age, 30 years), and found the drug superior to placebo for repetitive thoughts and behavior, maladaptive behavior, and aggression (McDougle et al., 1996). Eight (53 %) of 15 patients who received fluvoxamine were considered responders, compared to none in the placebo group. Language usage also improved as the result of decreased repetitive questioning. Fluvoxamine was well-tolerated with few adverse effects. Nausea and mild sedation occurred in a few patients.

In contrast to these studies of adults, controlled studies of fluvoxamine in children with autism have revealed poor efficacy and tolerability (McDougle, Kresch, & Posey, 2000; Sugie et al., 2005).

Case reports in adolescents and adults have shown both favorable and unfavorable responses to fluoxetine in the management of interfering repetitive behaviors.

One double-blind, placebo-controlled study of fluoxetine in adults with autism has been conducted to date. This 12-week trial of 37 subjects, aged 18–60 years (mean age, 34 years), revealed moderate efficacy of fluoxetine (mean dose, 64.8 mg/day) in the treatment of repetitive behaviors (Hollander et al., 2012). There was a 50 % response rate in the fluoxetine-treated group compared to 8 % in the placebo group. Adverse effects were mild to moderate and included bad or vivid dreams, insomnia, dry mouth, and headaches.

The results in adults are in contrast to a large, multi-site, randomized study of fluoxetine in children, where the drug was not effective in the management of repetitive behaviors (Autism Clinical Trials Network, Autism Speaks press release, 2009).

One open-label study of sertraline in 42 adults with ASDs, aged 18–39 years (mean age, 26 years) demonstrated moderate effectiveness and good tolerability in the treatment of repetitive behaviors (McDougle, Brodkin, et al., 1998). Notably, better treatment responses were observed in adults with autistic disorder and PDD-NOS compared to Asperger’s disorder.

There are currently no published double-blind, placebo-controlled studies of citalopram in the treatment of repetitive behaviors in adults with ASDs. In children and adolescents, King et al. (2009) conducted a large, multi-site, double-blind, placebo-controlled trial that found no significant difference between citalopram and placebo in the treatment of repetitive behaviors. There also was an increased likelihood of adverse events. This study demonstrates poor response and tolerability of the drug in children. Studies in adults are needed to better understand the efficacy and tolerability of citalopram in this population.

The only study of haloperidol that included adolescents and adults with autism was in the aforementioned study by Remington et al. (2001). Haloperidol was dosed from 1 to 1.5 mg/day (mean dose, 1.3 mg/day). In the treatment of stereotypy, haloperidol and clomipramine were comparable in terms of improvement from baseline. Adverse effects, such as fatigue or lethargy, dystonia, depression, and behavioral problems, led to discontinuation in 7 of 33 (21 %) subjects.

A 12-week, randomized, placebo-controlled trial that examined 31 adults with autism and PDD-NOS, aged 18–44 years (mean age, 28 years), found risperidone (mean dose, 2.9 mg/day) significantly more effective than placebo in reducing interfering repetitive behavior, as measured by the compulsion subscale of the Y-BOCS (McDougle, Holmes, et al., 1998). Aggression towards self and others was also significantly reduced. Risperidone was well-tolerated. Adverse effects included mild, transient sedation.

One small open-label study of olanzapine (mean dose, 7.8 mg/day) in 12 adults with ASDs, aged 5–42 years (mean age, 20.9 years), showed no statistically significant change in repetitive behaviors as measured by the Y-BOCS compulsion subscale (Potenza, Holmes, Kanes, & McDougle, 1999).

Quetiapine treatment (mean dose, 250 mg/day) of two adolescents with autism, aged 13 and 15 years, revealed no statistically significant improvements in repetitive behaviors based on the Aberrant Behavior Checklist (ABC) Stereotypy subscale and the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) compulsion subscale (Martin, Koenig, Scahill, & Bregman, 1999).

One open-label trial of ziprasidone (mean dose, 98.3 mg/day) in 12 adolescents with autism, aged 12–18 years (mean age, 14.5 years), did not reveal statistically significant decreases in repetitive behavior as measured by the ABC Stereotypy subscale (Malone, Delaney, Hyman, & Cater, 2007).

A case series examined this glutamate antagonist in the treatment of three individuals with autism and MR, aged 15–20 years (Wink, Erickson, Stigler, & McDougle, 2011). Dosages ranged from 100 to 200 mg/day. There were reductions in interfering repetitive behaviors in all three subjects. Adverse effects included mild anemia in one individual.

The only study of haloperidol that included adolescents and adults with autism was in the aforementioned study by Remington et al. (2001). Haloperidol (mean dose, 1.3 mg/day) was favored over clomipramine in the management of irritability, hyperactivity, and global symptom severity using the Childhood Autism Rating Scale (CARS) and the ABC as outcome measures. Adverse effects, such as fatigue or lethargy, dystonia, depression, and behavioral problems, led to discontinuation in 7 of 33 (21 %) subjects.

Clozapine is an atypical antipsychotic that is limited in use due to an increased risk of agranulocytosis and potential to lower the seizure threshold. A case series in three individuals with autism, aged 15-, 17-, and 27-years-old, highlighted successful treatment with clozapine for the management of recurrent aggression toward self and others (Chen, Bedair, McKay, Bowers, & Mazure, 2001; Gobbi & Pulvirenti, 2001; Lambrey et al., 2010). In all cases, prior antipsychotic medications were not efficacious or had caused EPS. Clozapine (275–400 mg/day), with treatment duration ranging from 15 days to 5 years, was well-tolerated and led to marked behavioral improvement and decreased aggression in all individuals. The Lambrey et al. (2010) report observed a 1-kg weight gain in one individual. Favorable results were also observed in a retrospective analysis of six adolescents and adults with ASDs, aged 14–34 years (mean age, 23 years), who were treated with clozapine (from 10 months to 7 years) for severe aggression, property destruction, and self-injurious behavior (SIB) (Beherec et al., 2011). Weight gain (mean 14.3 kg) was the only significant adverse event.

Risperidone is an atypical antipsychotic that is FDA-approved for the treatment of irritability associated with autism in children and adolescents aged 5–16 years. As such, multiple controlled studies have been conducted of risperidone in youth, supporting its efficacy for this target symptom domain in autism (Desousa, 2010; McCracken et al., 2002; McDougle et al., 2005; Shea et al., 2004).

A 4-week, open-label study of risperidone (modal dose, 0.5 mg twice/day) in 11 individuals with autism, aged 6–34 years (mean age, 18 years), showed improvement in explosive aggression, SIB, and poor sleep hygiene (Horrigan & Barnhill, 1997).

Risperidone was efficacious in a 12-week, double-blind, placebo-controlled trial that examined 31 adults with ASDs, aged 18–44 years (mean age, 28 years) (McDougle, Holmes, et al., 1998). Risperidone was dosed between 1 and 10 mg/day (mean dose, 2.9 mg/day). Eight (57 %) of 14 risperidone-treated participants were deemed responders compared with none in the placebo group. Risperidone was superior to placebo in reducing aggression, irritability, and the overall behavioral symptoms of autism, as well as repetitive behavior, anxiety or nervousness, and depression. Of the 15 patients in the placebo group who received open-label risperidone following the double-blind phase, nine (60 %) were judged to be responders after 12 weeks. Risperidone was well-tolerated. Adverse effects were mild and included mild, transient sedation, and there was no evidence of EPS, cardiac events, or seizures.

The adverse effect of weight gain has also been assessed in adolescents and adults with ASDs, with significant weight gain observed over 1 year of treatment. A double-blind, placebo-controlled crossover study of risperidone in 19 children, adolescents, and adults with autism and MR, aged 6–65 years (mean age, 21 years), for the management of aggression and SIB was conducted (Hellings, Zarcone, Crandall, Wallace, & Schroeder, 2001). Adolescents aged 13–16 years (n = 6) gained a mean of 8.4 kg (range 3.6–15.5 kg), and adults aged 21–51 (n = 8) gained a mean of 5.4 kg (range 0–9.5 kg). Tapering and discontinuation of the drug resulted in diminished weight gain.

Long-term risperidone treatment has also been assessed in adolescents and adults with ASDs. A double-blind, placebo-controlled crossover study examined 40 children, adolescents, and adults with MR, 36 of whom had ASDs, aged 8–56 years (mean age, 22 years) (Hellings et al., 2006). Twenty-four (57.5 %) of 40 subjects were considered responders according to a 50 % decrease in the Aberrant Behavior Checklist-Irritability (ABC-I) subscale score, while 35 of 40 (87.5 %) subjects showed a 25 % decrease. Gender, autism diagnosis, mood disorder diagnosis, or concomitant seizure medications did not affect the response. Dosages ranged from 1.2 to 2.9 mg/day for children and adolescents and 2.4–5.2 mg/day for adults. Common adverse effects included increased appetite and weight gain, with mean weight gain equalling 8.3 kg for adolescents and 6.0 kg for adults.

A 12-week, open-label study of olanzapine (mean 7.8 mg/day) in eight individuals with ASDs, aged 5–42 years (mean age, 21 years), found significant improvements in irritability (and other symptoms) among 75 % of participants (Potenza et al., 1999). Olanzapine was well-tolerated but adverse effects included increased appetite, weight gain, and sedation. Neither EPS nor changes in liver function tests were observed.

Two open-label studies (12- and 8-weeks, respectively) that have examined quetiapine for adolescents with ASDs (mean ages, 14 years) revealed minimal global treatment response despite significant improvements in irritability (Findling et al., 2004; Golubchik, Sever, & Weizman, 2011). Mean doses were 291.7 and 122.7 mg/day, respectively.

A case report described a 15-year-old male with autism and moderate MR who had poor responses to previous psychotropic medications but responded well to ziprasidone dosed 60 mg, twice daily, combined with methylphenidate (MPH) dosed 60 mg/day in divided doses (Duggal, 2007). He demonstrated improved maladaptive behaviors, attention to tasks, hyperactivity, impulsivity, and listening.

A retrospective chart review examined ten adults with autism (mean age, 43 years) who were switched to ziprasidone (mean dose, 128 mg/day) from another atypical antipsychotic to target maladaptive behaviors (Cohen, Fitzgerald, Khan, & Khan, 2004). Sixty percent showed improved behavior, while 10 % had no change and 30 % showed decompensated behavior.

A 6-week, open-label study of adolescents (mean age, 14.5 years) treated with ziprasidone (mean dose, 98.3 mg/day) found 75 % to be treatment responders (Malone et al., 2007). Cardiac QTc interval increased by a mean of 14.7 ms, which was a statistically, but not clinically, significant increase.

A case series that examined children, adolescents, and young adults treated with ziprasidone (mean dose, 59.23 mg/day) for at least 6 weeks found 50 % to be responders (McDougle, Kem, & Posey, 2002). No cardiovascular side effects were reported.

Aripiprazole is an atypical antipsychotic that is FDA-approved for the treatment of irritability associated with autism in children and adolescents aged 6–17 years. Thus, several controlled studies have demonstrated its efficacy for irritability in youth with ASDs (Marcus et al., 2009, 2011; Owen et al., 2009; Stigler et al., 2009).

In adults, a case report of a 38-year-old Afro-Caribbean man with autism and MR found that aripiprazole treatment resulted in decreased aggression, weight loss, and improved mobility and alertness (Shastri, Alla, & Sabaratnam, 2006).

Two multicenter, 8-week, double-blind, placebo-controlled studies demonstrated the efficacy, safety, and tolerability of aripiprazole in children and adolescents with autism, aged 6–17 years (mean ages, 9.7 and 9.3 years, respectively), in the treatment of irritability (Marcus et al., 2009; Owen et al., 2009). Dosages were fixed at 5, 10, and 15 mg/day, and all treatment arms produced significantly greater improvement from baseline than placebo in the Marcus et al. (2009) study. The Owen et al. (2009) study utilized a flexible dose design.

Case reports of a 16-year-old female and 20-year-old male with autism and comorbid MR found significant improvements in irritability after treatment with paliperidone (Stigler, Erickson, Mullett, Posey, & McDougle, 2010).

An 8-week, open-label study of paliperidone (mean dose, 7.1 mg/day) in adolescents and young adults with autism, aged 12–21 years (mean age, 15.3 years), showed significant improvement in the treatment of irritability, as evidenced by an 84 % response rate (Stigler, Mullett, Erickson, Posey, & McDougle, 2012).

A case series that examined five individuals with autism, aged 13–33 years, revealed reduced aggressive and impulsive behavior in three of the subjects after treatment with clomipramine (McDougle et al., 1992). An open-label trial of clomipramine (mean dose, 139 mg/day) in 35 adults with ASDs, aged 18–44 years (mean age, 30 years) showed improvement in aggression, among other symptoms (Brodkin et al., 1997).

In the aforementioned study by Remington et al. (2001), which compared clomipramine (mean dose, 128.4 mg/day) to haloperidol in 36 subjects with ASD, aged 10–36 years (mean age, 16.3 years), the two drugs were found to be equally effective for the treatment of irritability, although clomipramine was significantly limited in use due to adverse effects (Remington et al., 2001).

A case report of a 30-year-old male with autism and comorbid OCD exhibited decreased temper tantrums with fluvoxamine 150 mg/day (McDougle, Price, & Goodman, 1990).

A double-blind, placebo-controlled study in 30 adults with autism, aged 18–53 years (mean age, 30 years), found fluvoxamine (mean dose, 276.7 mg/day) superior to placebo for reducing maladaptive behavior and aggression, in addition to repetitive thoughts and behavior (McDougle et al., 1996).

A 26-year-old female demonstrated reduced temper outbursts at home and at school when treated with fluoxetine 20 mg/day, in addition to improved repetitive, stereotypical behavior (Mehlinger, Scheftner, & Poznanski, 1990). A case series that examined patients with autism between 13 and 21 years of age found improvements in irritability during treatment with fluoxetine (20 mg/day for at least 6 weeks), although this symptom was often thought to be part of the patients’ depressive illnesses (Ghaziuddin, Tsai, & Ghaziuddin, 1991). A retrospective chart review of seven subjects with autism, aged 9–20 years (mean age, 16 years), treated with fluoxetine (mean dose, 37.14 mg/day) for 1.3–32 months found improvement in the ABC-I subscale by 21 %, as well as other domains (Fatemi, Realmuto, Khan, & Thuras, 1998).

An open-label study of nine adults with MR, five of whom had autism, aged 20–47 years (mean age, 31 years), found that sertraline (mean duration, 110 days) resulted in improved self-injury and/or aggression in 89 % of participants (Hellings, Kelley, Gabrielli, Kilgore, & Shah, 1996). A 12-week, open-label study in 42 adults with ASDs, aged 18–39 years (mean age, 26 years), found a 57 % response rate to sertraline (mean dose, 122 mg/day), mostly in the areas of aggressive and repetitive symptoms (McDougle, Brodkin, et al., 1998). An enhanced clinical response was observed in individuals with autism and PDD-NOS as opposed to Asperger’s disorder.

One case study highlighted successful treatment of violent aggression with transdermal clonidine in a 26-year-old female with autism and intermittent explosive disorder (Koshes & Rock, 1994). The subject’s regimen of thioridazine, carbamazepine, and clonazepam was augmented with two 0.3-mg transdermal clonidine patches per week (total 0.6 mg/day), with significant improvement in behavior.

Double-blind, placebo-controlled trials of naltrexone in adults with autism have generally demonstrated poor efficacy in managing SIB (Willemsen-Swinkels, Buitelaar, Nijhof, & van England, 1995; Zingarelli et al., 1992). In one study, only one subject in eight (age range, 19–39 years; mean age, 29 years) showed a partial decrease in maladaptive behaviors (Zingarelli et al., 1992). No adverse effects were observed. Another study found naltrexone to have no therapeutic effect on the management of self-injury among 33 adults with MR, 16 of whom had autism (age range, 18–46 years; mean age, 29 years), and it was poorly tolerated (Willemsen-Swinkels et al., 1995).

Buspirone has shown favorable results in case reports of adults with ASDs treated for severe aggression and self-injury. One case of a 41-year-old male with autism and mild MR showed decreased frequency and severity of aggression over 2 years after buspirone (80 mg/day) was added to a regimen of phenytoin, haloperidol, phenobarbital, and imipramine (for enuresis) (Hillbrand & Scott, 1995). Another case of a 33-year-old female with autism and profound MR showed positive response to buspirone (90 mg/day) in the management of self-injury, property destruction, and physical aggression over 1.5 years (Brahm, Fast, & Brown, 2008). Buspirone was well-tolerated with no adverse effects observed in these patients.

A retrospective pilot study that examined 14 individuals with ASDs, aged 5–40 years (mean age, 18 years), found improved aggression, irritability, and affective instability in 71 % of subjects treated with divalproex sodium (mean dose, 768 mg/day), although many had comorbid Axis I psychiatric diagnoses (Hollander, Dolgoff-Kaspar, Cartwright, Rawitt, & Novotny, 2001). Subjects were treated for 0.5–43 months (mean duration, 10.7 months). Adverse effects were mild to moderate and included fatigue/sedation, behavioral activation, digestive disturbance, and weight gain, among others.

Double-blind, placebo-controlled studies in children and adolescents have revealed mixed results. One study (mean age, 11 years) found no differences between valproate and placebo groups in the management of severe aggression (Hellings et al., 2005), although the other (mean age, 9.5 years) found statistically significant improvement in irritability compared to placebo (Hollander et al., 2010).

There are no published reports of lamotrigine treatment for irritability in adolescents or adults with ASDs. A 12-week, double-blind, placebo-controlled study in children with ASDs (aged 3–11 years) revealed unfavorable results, finding no differences between drug and placebo for the treatment of irritability, hyperactivity, stereotypies, lethargy, and emotional reciprocity (Belsito, Law, Kirk, Landa, & Zimmerman, 2001). Parent rating scales showed marked improvement, which was thought to be due to expectations of benefits.

There are no published reports of levetiracetam treatment for irritability in adolescents or adults with ASDs. A 10-week, double-blind, placebo-controlled study of levetiracetam (mean dose, 862.50 mg/day) in children and adolescents with ASDs (mean age, 8.72 years) revealed no significant difference between drug and placebo for the management of aggression and affective instability (Wasserman et al., 2006).

There are no published studies of topiramate for irritability in adults with ASDs. However, an open-label retrospective study of topiramate (mean dose, 235 mg/day) in adolescents with ASDs (mean age, 14.7 years) found 53 % to be clinical responders with improvement in conduct, hyperactivity, and inattention (Hardan, Jou, & Handen, 2004).

In children with autism, a double-blind, placebo-controlled study of topiramate combined with risperidone found that, compared to risperidone monotherapy, combination treatment led to a greater reduction in hyperactivity/noncompliance, irritability, and stereotypic behavior (Rezaei et al., 2010).

A case report describes treatment with MPH (dosed 40 mg/day in divided doses) in a 26-year-old male with Asperger’s disorder (Roy, Dillo, Bessling, Emrich, & Ohlmeier, 2009). MPH resulted in improved attention, aggression, impatience, and social behavior.

The remaining available research has been focused on children with ASDs (Birmaher, Quintana, & Greenhill, 1988; Di Martino, Melis, Cianchetti, & Zuddas, 2004; Ghuman et al., 2009; Handen, Johnson, & Lubetsky, 2000; Jahromi et al., 2009; Nickels et al., 2008; Posey et al., 2007; Quintana et al., 1995; RUPP, 2005; Santosh, Baird, Pityaratstian, Tavare, & Gringras, 2006; Schmidt, 1982; Strayhorn, Rapp, Donina, & Strain, 1988). Controlled research, such as the large, multi-site study conducted by the Research Units on Pediatric Psychopharmacology Autism Network (2005), suggests that children with ASDs are less likely to respond to psychostimulants and more likely to experience adverse effects compared to typically-developing children with attention-deficit/hyperactivity disorder (ADHD).

A case report of atomoxetine (ATX) in a 22-year-old adult with autism found improvement in hyperactivity on the ABC Hyperactivity subscale (Niederhofer, Damodharan, Joji, & Corfield, 2006). Other symptoms such as irritability, inadequate eye contact, and inappropriate speech were also noted to decrease. However, clinician ratings did not show any improvement. Adverse effects included increased drowsiness.

ATX appears safe and effective for treating hyperactivity in some children with ASDs, with fewer intolerable adverse effects than MPH (Arnold et al., 2006). An open-label study of ATX (mean dose 1.2 mg/kg/day) in children and adolescents with ASDs aged 6–14 years (mean age, 7.7 years) found a 75 % response rate with significant improvement in ADHD symptoms (Posey et al., 2006). Other improvements were noted in irritability, social withdrawal, stereotypy, and repetitive speech. The drug was overall well-tolerated.

There is one double-blind, placebo-controlled, crossover study of clonidine involving adolescents and adults in the treatment of “hyperarousal behaviors” associated with autism (Fankhauser, Karumanchi, German, Yates, & Karumanchi, 1992). These behaviors were defined in terms of affectual and sensory responses, and did not refer specifically to the symptoms of ADHD. This study examined nine males with autism, aged 5–33 years (mean age, 13 years), who were treated with transdermal clonidine patches dosed 0.005 mg/kg/day (mean dose, 0.16 mg/day). Transdermal clonidine resulted in significant clinical improvement on the Clinical Global Impression-Improvement (CGI-I) scale.

In some children with ASDs, clonidine has been moderately effective in the treatment of hyperactivity and irritability (Jaselskis, Cook, Fletcher, & Leventhal, 1992).

There are no published studies of guanfacine in adults with ASDs. In children (aged 5–9 years), a double-blind, placebo-controlled study of guanfacine (dosed between 1 and 3 mg/day) revealed significant benefits in the ABC Hyperactivity subscale (Handen, Sahl, & Hardan, 2008). Adverse effects of drowsiness and irritability were observed.

There are no published studies of buspirone for ADHD symptoms in adolescents or adults with ASDs. In children, a case report (using a double-blind, placebo-controlled approach) found buspirone to be efficacious in decreasing hyperactivity (McCormick, 1997).