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Psychopharmacological Interventions in Autism Spectrum Disorder

Politte, Laura C. MD; Henry, Charles A. MD; McDougle, Christopher J. MD

Author Information
doi: 10.1097/HRP.0000000000000030


Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders characterized by deficits in social communication and language, and by repetitive behaviors and restricted interests.1 ASDs were previously classified as pervasive developmental disorders (PDDs) in the revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). But the term ASD is more commonly used, and replaced PDD as a diagnostic category in DSM-5, published in May 2013. In DSM-IV-TR, distinct diagnoses within the category of PDDs included autistic disorder, Asperger’s disorder, pervasive developmental disorder not otherwise specified, childhood disintegrative disorder, and Rett’s disorder. In DSM-5, the last two disorders have been removed, with the remaining disorders now subsumed under the umbrella term ASD; rather than individual subdiagnoses, descriptive specifiers will now be used to characterize the profile of symptoms for individuals meeting ASD criteria. Of note, all studies described in this review were conducted using DSM-IV-TR criteria for PDDs; reflecting current practice of specialists in the field, however, the term ASD is used throughout this article.

In 2012, the Autism and Developmental Disabilities Monitoring Network of the U.S. Centers for Disease Control and Prevention estimated the prevalence of ASD as 1 in 88 children, an estimated increase of 78% from 2002 to 2008.2 More recently, a 2011–12 telephone survey by the center’s National Center for Health Statistics suggested that 1 in 50 U.S. school-aged children is now diagnosed with ASD.3 Though it remains uncertain whether the rising prevalence of ASD is driven primarily by increased awareness and higher detection rates or by a true rise in the prevalence of these disorders, there is no question that the burden on families, schools, health care systems, and individuals is significant and ongoing.4–6 As more children with ASD transition into adulthood, the need for comprehensive services for adults with autism will also increase.7,8

The treatment of individuals with ASD is complex and typically includes behavioral therapy, language and communication training, occupational therapy, special education, vocational training and support, and management of associated medical conditions, such as seizure disorders and gastrointestinal symptoms. While there is no single, definitive treatment for ASD, early intensive behavioral interventions can reduce core autistic symptoms and improve developmental outcomes.9 Psychiatric comorbidity is common in ASD,10 and the presence of additional diagnoses such as attention-deficit/hyperactivity disorder (ADHD) and intellectual disability substantially increases health care expenditures compared to children who have ASD without such comorbidities.6 Furthermore, psychiatric symptoms can impede progress in educational and therapeutic settings and cause significant distress for patients and their families.

When psychiatric symptoms or maladaptive behaviors lead to distress and impairment above and beyond core autistic symptoms, psychopharmacological treatment is often employed. In a database analysis of children with ASD aged 2–17 years, 27% of all participants took at least one psychotropic medication, with greatest rates of use (66%) in adolescents.11 Eighty percent of children diagnosed with a comorbid psychiatric disorder were taking at least one psychotropic medication. Common targets of medication management in ASD include anxiety, ADHD symptoms (inattention, impulsivity, and hyperactivity), compulsions and interfering repetitive behaviors, sleep disturbance, and irritability, which can include mood lability, severe tantrums, self-injurious behavior, and aggression. In higher-functioning children and adolescents with ASD, depression is also common.12–14 The thorough assessment of individuals with ASD should include an inventory of these symptom domains in addition to a detailed developmental and medical history. Physicians who evaluate patients with ASD should also be mindful that many patients and their families will choose to seek out natural remedies and treatments that may include vitamins, supplements, and oral chelating agents that have the potential to interact with prescribed medications; inquiry about complementary and alternative strategies should be included in every assessment. A review of supplemental treatment strategies is beyond the scope of this article, though there is substantial support for the efficacy of melatonin for sleep dysregulation in ASD, particularly delayed sleep onset.15–23

This article aims to review the literature pertaining to the use of psychotropic medications in treating the psychiatric symptoms in ASD. For most medications, limited data are available regarding efficacy in ASD populations, owing in part to small sample sizes, heterogeneity within the disorder, and methodological difficulties in organizing multicenter trials. Currently, only two medications—risperidone and aripiprazole—have U.S. Food and Drug Administration (FDA) indication for use in autism, specifically for the treatment of severe irritability. Many psychiatric medications are prescribed off-label, however, for interfering symptoms associated with ASD. Benzodiazepines are excluded from this review as no clinical trials of these medications in ASD have been published, and the existing literature is primarily limited to case reports of benzodiazepines used to treat catatonia occurring in the context of autism.

Novel medications that show promise in ASD but are still under development, particularly oxytocin and agents affecting glutamate transmission, are also reviewed. Translational research holds the promise of targeted, neurobiologically sound treatments for core symptoms of autism. Some researchers advocate early pharmacological intervention during critical windows of brain development to enhance plasticity and experience-dependent change, or to potentially correct derangements in neurotransmission.24 Pharmacological studies in very young children present ethical and practical challenges, however, and few studies have included participants younger than five years old, in whom brain plasticity is at its peak. Animal studies of novel treatments will be helpful in identifying potential critical windows for intervention and also in determining long-term side effects, which are largely unknown for commonly used medications.24

The authors have chosen to organize this review by classes of medication (e.g., atypical antipsychotics), as opposed to target symptom clusters (e.g., irritability) due to the broad range of measures frequently employed in the study of any particular medication in this population. Broad measures reflect an initially limited understanding of how individual medications will affect those with ASD, and results often cross categories of associated symptoms (e.g., an atypical antipsychotic may reduce both irritability and hyperactivity). Reporting the results of individual medication trials by category of medication is intended to reduce overlap in the description of results.


A literature search was conducted using the PubMed database for articles in English language pertaining to the use of psychiatric medications in ASD. In addition to “autism spectrum disorders,” search terms included general classes of medication (e.g., atypical antipsychotics) and individual medication names (e.g., risperidone). Particular weight was given to randomized, controlled trials, though due to limited publications for most medications, case reports and the results of open-label studies are also included. Reference sections of relevant articles were reviewed for additional pertinent publications.


Given the core compulsive and repetitive behaviors present in ASD and frequent comorbid anxiety symptoms,13,25 treatment with serotonin reuptake inhibitors and tricyclic antidepressants is an obvious option. Results from early case series and open trials with clomipramine have been mixed. Positive reports noted improvements in repetitive behaviors, aggression, social engagement, language, adventitious movements, and adaptive behavior.26–28 In the largest of the open studies (n = 35 adults), 13 participants experienced adverse effects, with 3 reporting seizures.27 Two of these participants had a preexisting seizure disorder that had been stabilized on anticonvulsants, and 1 experienced a new onset tonic-clonic seizures. Two of the open-label trials in children reported difficulties with agitation and aggression.29,30 Examining blinded controlled trials in clomipramine, two trials, each with 12 participants, reported improvement in overall autistic symptoms and also in compulsive behaviors and anger as compared to both placebo and desipramine.31,32 Clomipramine’s differential effect on these measures over desipramine seems to implicate clominpramine’s serotonergic action. Both clomipramine and desipramine were helpful in decreasing hyperactivity, an outcome that might be consistent with the common noradrenergic effect of both medications. Side effects in these studies were minimal, with clomipramine not differing from placebo, though in the second report, one participant had a prolonged QTc interval (0.45 seconds), and another became tachycardic (resting heart rate 160–170 beats per minute). These effects resolved after dose reduction. One individual treated with clomipramine suffered from a grand mal seizure.

Looking at selective serotonin reuptake inhibitors (SSRIs), open trials in children and adults with ASD have been mostly positive, with notable improvements in obsessive-compulsive symptoms, anxiety, depressive symptoms, aggression, and overall symptom severity.33–42 Difficulty with activation side effects and agitation were frequent in some reports.34,41,43,44 The two placebo-controlled trials in adults have shown efficacy in important outcome measures. A 12-week double-blind investigation of fluvoxamine in 30 adults with ASD noted improvement in repetitive thoughts and behaviors, aggression, language function, and maladaptive behavior.45 Treatment with the mean dose of 276.7 mg/day was overall well tolerated, with side effects mostly limited to nausea and sedation. A similarly designed, more recent study of 37 adults treated with fluoxetine also noted improvements, specifically with measures of repetitive behavior and overall global functioning.46 Again, side effects were minimal at a moderately high mean dose of 64.76 mg/day. Peak dosing was reached by week 8 of the study.

Placebo-controlled trials of SSRIs in children have been mostly discouraging. In the first investigation, only 1 of 18 children with ASD treated with fluvoxamine showed improvement in established target symptoms.47 Side effects were common, including trouble with agitation and aggression. Dosing was modest, with a mean dose of 106.9 mg/day. In a second study, 45 children with ASD randomized to an eight-week placebo-controlled, crossover study were treated with fluoxetine.48 Improvement was noted in repetitive behavior as measured by the Children’s Yale-Brown Obsessive Compulsive Scale, with a moderate to large effect size. The mean dose of 9.9 mg per day was low.

The two most recent placebo-controlled studies of SSRIs in children with ASD have been negative. Results from a 12-week National Institute of Mental Health–funded, multicenter, placebo-controlled study of citalopram (mean dose, 16.5 mg daily) in 149 children with ASD found no difference in repetitive behaviors or global improvement compared to placebo.49 Participants did demonstrate statistically significant improvement in irritability as measured by the Aberrant Behavior Checklist (ABC), though the improvement was modest and not thought to be clinically meaningful. Activation side effects were common in the treatment group, with significantly greater rates of impulsivity, hyperactivity, distractibility, stereotypy, and insomnia. Two children in the citalopram group had seizure episodes. Finally, an industry-sponsored, placebo-controlled trial of a fluoxetine preparation developed by Neuropharm was tested in 158 children with autism.50 Though details of the study have not been published, the released findings indicated no improvement in repetitive behaviors compared to placebo.

In summary, despite the positive placebo-controlled trials with SSRI treatment in adults with ASD, findings in children have been mostly negative. In particular, the negative results of two large placebo-controlled studies are difficult to ignore. Age-related differences in serotonin functioning in those with autism may be a factor in the limited efficacy of, and the vulnerability to side effects with, SSRI treatment in children.51 Unfortunately, alternative treatment options are not readily available for repetitive/compulsive symptoms in those with autism. Because of the limited alternatives and sometimes severe repetitive and compulsive behaviors that often impair functioning, a trial with an SSRI in children and adolescents might be considered. Low initial dosing with slow titration would be recommended, with close monitoring of activation side effects and treatment-emergent aggression.

Buspirone and mirtazapine are serotonergic agents with unique profiles that may also be useful alternatives to SSRIs for treating anxiety and irritable mood associated with ASD. Buspirone is a partial serotonin receptor type 1A agonist with anxiolytic and antidepressant effects that has been associated with improved anxiety, irritability, and hyperactivity in ASD in a few case reports and one open-label study with 22 participants.52–55 Buspirone has a relatively mild side-effect profile in comparison to SSRIs and neuroleptics, and the authors of this article often utilize buspirone to treat anxiety in patients who have tolerated SSRIs poorly. In a few reports, mirtazapine, a serotonin reuptake inhibitor at low doses with noradrenergic effects (α2 antagonism) at higher doses, has shown promise for treating problematic sexual behaviors associated with autism.56–59 An open-label study of mirtazapine for treating a variety of symptoms associated with ASD reported significant overall improvement in 34.6% but no improvement in core autistic features.60 As with buspirone, the authors have used mirtazapine in clinical practice for patients who have difficulty tolerating SSRIs, particularly those with prominent anxiety accompanied by sleep disturbance.


Although ADHD could not be co-diagnosed with a pervasive developmental disorder according to DSM-IV criteria, ADHD-related symptoms are common in ASD.25,61 This co-diagnosis is allowed in DSM-5. Treatment of such symptoms has been investigated with psychostimulants and other medications used for ADHD. Some initial reports suggested that the psychostimulants were ineffective for individuals with ASD, with common side effects including increased tics, stereotypies, and agitation.62–64 Other uncontrolled studies, however, reported improved attention, hyperactivity, impulsivity, and stereotypies, with minimal side effects.65–69 Initial small placebo-controlled, crossover studies with methylphenidate (n = 10 and n = 13) in children with autism noted improved hyperactivity.70,71 Side effects of social withdrawal and irritability were evident at higher doses in some children.70

In a large double-blind, placebo-controlled, crossover trial conducted by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, the effects of methylphenidate 0.125–0.5 mg/kg/day were investigated in 72 children with ASD over one-week periods.72 Improvement in the ABC-Hyperactivity subscale score was reported, with a small to medium effect size. Forty-nine percent of children were determined to be responders by a combined measure of improvement in hyperactivity and global severity, as determined by the Clinical Global Impressions–Improvement scale (CGI-I). Side effects of note included social withdrawal (particularly at higher doses) and irritability. The response rate was lower than the 70%–80% response observed in the Multisite Multimodal Treatment of Children with ADHD study, and side effects were more common.73 Eighteen percent of the participants discontinued the trial, most frequently due to irritability. Of note, a small placebo-controlled, crossover trial of 14 preschool-aged children with developmental delay or PDD reported a similar response rate and side-effect profile.74

Given the evidence from the controlled trials, psychostimulants are an option in treating ADHD symptoms in ASD. Caution should be advised for the well-known adverse events that are noted in non-autistic populations. For example, those with ASD are at risk for developing psychotic symptoms, and evidence of psychotic changes may be difficult to detect due to communication impairments, potentially presenting as irritability.75 In the reviewed trials, irritability is a particular vulnerability with psychostimulant use in ASD. Given the rapid onset of effect and side effects, short trials might be used to readily clarify potential treatment response. Such an approach was taken in the RUPP study, which used a closely monitored test-dose phase to screen for initial tolerance.

Alpha-2 agonists have demonstrated effectiveness in reducing ADHD symptoms and also oppositionality in children.76–81 An open-label trial with clonidine in 19 children with ASD noted improved sleep and, to a lesser extent, ADHD symptoms, aggression, and mood instability.82 Two small placebo-controlled studies (n = 8 and n = 9 participants) also reported positive findings, with improved irritability, hyperactivity, inappropriate speech, oppositionality, stereotypy, sensory reactivity, and global illness severity.83,84 In the smaller sample study, however, no benefit for clonidine over placebo was identified based on clinician ratings.84

A chart review of 80 youth with ASD treated with guanfacine demonstrated effectiveness in 24% of participants, with specific improvements in hyperactivity, inattention, insomnia, and tics.85 Many of the participants had been nonresponders to a prior trial of methylphenidate or had been unable to tolerate it. Those with Asperger’s disorder or PDD not otherwise specified and those without mental retardation showed a higher response rate. A prospective open study of 25 children with ASD also noted improvement in hyperactivity.86 Forty-eight percent were considered responders by improvement in global illness severity. Daytime sedation and mid-cycle awakenings were noted, along with irritability and constipation. A small placebo-controlled, crossover study of 11 children with developmental disorders (the majority of whom had ASD diagnoses) treated with guanfacine demonstrated improved hyperactivity, with 48% determined to be responders by a 50% reduction in hyperactivity symptoms.87 Drowsiness and irritability were noted. None of these investigations found significant changes in blood pressure or heart rate. A National Institute of Mental Health–funded, placebo-controlled trial of guanfacine extended-release (Intuniv) for treating hyperactivity in children aged 5–17 years with ASD is currently under way, though results are not yet available (

Atomoxetine has also been investigated in children with ASD. A retrospective study noted a 60% response rate as determined by a rating of “much improved” or “very much improved” on the CGI-I.88 Specific improvements were noted in conduct, hyperactivity, inattention, and learning. Three open-label studies of children with ASD noted a decrease in ADHD symptoms,89–91 with one of the studies reporting improved irritability, stereotypies, repetitive speech, and social withdrawal.89 By contrast, one open study of children with severe ASD was negative, showing no change in the primary outcome measure of hyperactivity.92 One large placebo-controlled trial of atomoxetine (dosed at 1.2 mg/kg/day) in 97 children with ASD found improved ADHD symptoms.93 Eighty-one percent versus 65% with placebo reported side effects, with nausea, decreased appetite, and mid-cycle awakenings reported at significantly higher rates in the atomoxetine group. No serious adverse events were noted. Finally, in a smaller placebo-controlled, crossover study of 16 children with ASD, a decrease in hyperactivity was noted, though the improvement in attention only approached statistical significance.94 One individual was hospitalized secondary to severe difficulty with aggression.

Finally, a placebo-controlled study of 39 children with autism investigated the effects of amantadine, dosed at 0.5 mg/kg/day.95 Improvements were noted in clinician-rated measures of hyperactivity and inappropriate speech, though the improvement in parent ratings did not reach statistical significance. Side effects were minimal.


Atypical antipsychotics are among the most extensively studied and widely used medications for treating severely disruptive behavior in individuals with ASD. To date, risperidone and aripiprazole are the only two medications with FDA indications specifically in autism; both are approved for managing irritability in children and adolescents.

Of the atypical antipsychotics, risperidone has been most thoroughly investigated, with evidence for its efficacy in treating severe irritability associated with ASD established in two large randomized, placebo-controlled trials, leading to FDA approval in 2006.96,97 In 2002, the RUPP Autism Network published results of a multisite, controlled trial of risperidone in children with autism and severe behavioral disturbance (n = 101; age range, 5–17 years) that included an eight-week active treatment phase followed by a four-month open-label continuation phase and two-month discontinuation phase.96 Sixty-nine percent of the participants in the risperidone group met responder status (25% reduction in ABC-Irritability [ABC-I] subscale score and CGI-I rating of “much improved” or “very much improved”) compared to 12% in the placebo group. Two-thirds of participants maintained this benefit at six months in the open-label phase, and a similar proportion number (62.5%) relapsed with placebo substitution during the blinded discontinuation phase, leading to elimination of this latter phase for ethical reasons. A subsequent eight-week controlled trial in a Canadian sample of youth with ASD97 generated a slightly lower response rate for risperidone (54%) and higher placebo response rate (18%) based on the same response criteria, though reductions in ABC-I subscale scores were similar across studies (−56.9% vs. −64%). Additional open-label and controlled trials of risperidone in children with ASD and severe irritability have generally supported short-term response rates in the range of 57% to 72%.98–101 Improvement has also been observed in secondary measures of restrictive, repetitive, and stereotyped behaviors; adaptive functioning; hyperactivity; social withdrawal; and communication.96–98,101 A follow-up study conducted by the RUPP Autism Network found that the addition of manualized parent training to risperidone resulted in improved outcome scores and lower risperidone doses during combination treatment than with risperidone alone.102

Common side effects observed across studies of risperidone included sedation, increased appetite, weight gain, and elevated prolactin levels. Sedation was reported at a rate of 37% and 72% in the two largest controlled trials, though this side effect had abated for most participants by eight weeks.97,103,104 In both treatment groups, participants gained an average of 2.7 kg in eight weeks, substantially more than their placebo-group counterparts.97,105 At six months, participants had gained an average of 5.6 kg, representing an average 16.7% absolute weight increase and 10.6% BMI increase.105 Hyperprolactinemia tends to peak during acute treatment and decline with chronic treatment, though remained double the baseline level at two years in the RUPP study;106 the clinical significance of asymptomatic elevation in prolactin levels has yet to be determined. No significant differences in extrapyramidal symptoms (EPS) were reported between treatment arms in the largest studies.96,97 The authors of those studies did not include reports of blood sugar levels or lipid levels, though hyperglycemia and hyperlipidemia have been associated with the use of antipsychotics in other clinical populations.

In 2009, aripiprazole became the second agent approved by the FDA for managing irritability in children 6–17 years old with autism—a decision based on positive results from two multisite, industry-sponsored, randomized, double-blind, placebo-controlled trials.107,108 In the first trial, 218 youth with ASD and significant irritability were treated for eight weeks with fixed doses of aripiprazole 5, 10, or 15 mg daily.107 All groups demonstrated significant improvement on primary outcome measures (ABC-I and CGI-I scores), though response rate (defined as ABC-I reduction ≥25% and CGI-I of “much improved” or “very much improved,” as in the RUPP risperidone trial) separated from placebo only for the 5 mg treatment arm. Response rate for the 5 mg group was 55.8%, compared to an unusually large placebo response rate of 34.7%. In the second controlled trial—of 98 youth with autism—aripiprazole was flexibly dosed up to 15 mg/day for eight weeks, with most participants (74%) ultimately taking 5–10 mg/day at study endpoint.108 The overall treatment response rate of 52.2% mirrors the response rate found for the 5 mg treatment group in its companion study, and placebo response was lower at 14.3%. ABC-I subscale scores declined by a mean of 12.9 points for all treatment groups compared to 5 points for placebo, for an effect size of 0.87. Clinically significant residual symptoms presumably persisted for many individuals, however, as the mean endpoint ABC-I subscale score was only slightly lower than the minimum entrance-criterion score of 18 (indicating irritability of at least moderate severity).

In both studies, sedation and somnolence were the most commonly reported adverse effects, resolving in a median of 19 and 23 days, respectively.109 Discontinuation due to any adverse effect ranged from 7.4% to 10.6% across treatment arms (compared to 7.7% and 5.9% for the studies’ respective placebo groups). Aripiprazole was associated with significantly more weight gain at eight weeks compared to placebo (1.3–2 kg vs. 0.3–0.8 kg for placebo; p < .05),107,108 though not as great as that observed in the risperidone studies. Treatment-emergent EPS occurred at rates of 14.9%–23% in treatment groups compared to 8%–11.8% in placebo groups. Vomiting was twice as common with active treatment (13.7%) as with placebo in pooled data (6.9%).109 In a 52-week open-label extension study in 330 individuals, mean weight increase was 6.3 kg, corresponding to a change in BMI z-score of 0.31; weight gain tended to plateau over time.110 High-density lipoprotein levels declined in 30% of individuals, though clinically significant elevations of total cholesterol (5.2%), low-density lipoproteins (6.5%), triglycerides (4.6%), and serum glucose (1.9%) were less common. Mean serum prolactin levels declined from baseline to endpoint. EPS-related events were reported in 14.5% of subjects, leading to drug discontinuation in half of this group. Aripiprazole has not been associated with significant QTc interval prolongation or other abnormal ECG findings in children with ASD.111

Other atypical antipsychotics have not been as thoroughly investigated in children with autism, and the studies have typically yielded mixed results. Two small open-label trials of olanzapine reported high response rates (6/7 and 5/6 participants),112,113 though results from an additional two studies were less robust (3/25 participants and 12/40 participants were responders).114,115 A small randomized, controlled trial of 11 patients found a treatment response rate of 50% (3 of 6).116 Weight gain was substantial across studies and greater than observed with risperidone and aripiprazole; in one study, participants gained an average of 4 kg in six weeks of treatment.112 Mild, transient sedation was also common in all studies.

Open-label studies of quetiapine have generally found minimal efficacy and poor tolerability due to excessive sedation, weight gain, and increased aggression or agitation,117,118 though one study suggested quetiapine may be helpful for sleep disturbance and aggression (possibly reduced secondary to sedation).119 By contrast, two chart reviews employing retrospective assignment of CGI-I scores found response rates of 40%–60%, though susceptibility to bias with this study design limits conclusions.120,121

Ziprasidone has shown promise in the treatment of irritability, aggression, hyperactivity, and impulsivity in autism, though published data are limited to one open-label study, one case series, and two case reports.122–125 Significant overall improvement, defined as a CGI-I rating of “much improved” or “very much improved,” was reported in 50% and 75% of participants in the case series and open-label study, respectively (each consisting of 12 participants).124,125 An advantage included weight neutrality or weight loss for those patients discontinuing an alternative antipsychotic.124,126,127 Initial sedation was common,124,125 and in two patients with comorbid bipolar disorder, symptoms were rated as “much worse” with ziprasidone.125 QTc intervals were found to increase by 14.7 milliseconds from baseline;124 ECG monitoring during ziprasidone treatment is recommended.

Information regarding the efficacy of paliperidone, the extended-release active metabolite of risperidone, in patients with ASD is limited to one open-label study and three case reports.128–130 Results from a study of 25 adolescents with autism and severe irritability are encouraging, with 84% of participants showing significant improvement in irritability.130 Weight gain and increased serum prolactin were common, and mild to moderate EPS were reported in 4 individuals.

As in other disorders, clozapine is not considered a first-line agent for severe irritability, given its potentially serious side effects of agranulocytosis, seizures, and cardiomyopathy. The need for frequent blood draws is a major limiting factor for many individuals with autism, some of whom experience intense anxiety with needlesticks. Case reports indicate that clozapine may be useful in cases of severe aggression and self-injury that have not responded to other antipsychotic and mood-stabilizing agents.131–134

Recently approved second-generation antipsychotics, including asenapine, iloperidone, and lurasidone, have not been studied in autism or pediatric populations, though further investigation may be warranted, given their potentially more favorable metabolic profiles.135

In summary, atypical antipsychotics, particularly risperidone and aripiprazole, are considered first-line agents for treating severe irritability and aggression in children and adults with ASD. Clinicians must carefully weigh the risks and benefits of those agents, however, as they carry a significant potential side-effect burden. Weight gain is more common than not with all atypical antipsychotics except ziprasidone, and while metabolic derangements such as dyslipidemia and hyperglycemia have not been well established in clinical trials with ASD populations, they are known risks from studies of other neuropsychiatric disorders. Furthermore, caregivers may find that aggression is more difficult to contain and safely manage in a heavier child. Hyperprolactinemia is common with all agents except aripiprazole, and the long-term effects of elevated prolactin in the absence of clinical stigmata are largely unknown.


Anticonvulsants with mood-stabilizing properties have been investigated as potential treatments for core symptoms of autism and for affective dysregulation, aggression, and impulsivity in ASD, with mixed results.

Divalproex sodium has been the most extensively studied medication in this class. It gained early attention from case reports of substantial improvement in language and maladaptive behaviors in children with autism and with clinical seizures or abnormal EEGs.136–138 However, small sample sizes, heterogeneity within samples, and, in one study, a large placebo response limit the ability to draw definitive conclusions about the efficacy of divalproex sodium for this population. In a pilot study of 14 children and adults with ASD treated with divalproex sodium (mean dose, 768 582 mg/day; mean peak valproate level, 75.8 12.6 μg/mL), 10 (71%) showed substantial improvement in retrospectively assigned CGI-I scores.139 Areas of subjective improvement included autistic symptoms, aggression, impulsivity, and mood lability. In two subsequent randomized, double-blind, placebo-controlled trials of divalproex sodium in relatively small samples of children and adolescents with ASD (n = 30; n = 27), one study reported significant improvement in irritability (62.5% responder status in active treatment group vs. 9% in placebo group), whereas the other did not find between-group differences for aggression and irritability.140,141 Both trials used CGI-I, ABC-I, and Overt Aggression Scale scores as outcome measures and reported similar valproate blood levels, though full-scale intelligence quotient scores were somewhat higher in the study with positive findings (means: 63.3 vs. 54). Divalproex sodium was associated with improved repetitive behaviors as measured by the Children’s Yale-Brown Obsessive Compulsive Scale in a randomized, placebo-controlled trial of 13 individuals with autism.142 Another small study suggested that divalproex sodium may be effective in preventing irritability associated with fluoxetine treatment in children with ASD.136 Though divaloproex sodium is generally well tolerated, side effects of behavioral activation, rash, sedation, nausea and vomiting, and weight gain may be limiting factors for some. Divalproex should not be considered a first-line medication for young women of child-bearing potential, given the increased risks of fetal malformations in the event of pregnancy and of developing polycystic ovarian syndrome. Monitoring valproate blood levels and administering liver function tests periodically can also present a challenge in children with ASD.

Lamotrigine was studied in a randomized, double-blind, placebo-controlled trial for treating core autistic symptoms and associated aberrant behaviors in 28 children (aged 3–11 years) with autistic disorder, titrated to 5 mg/kg/day over eight weeks and maintained for four weeks.143 The group receiving lamotrigine did not differ from placebo on any ABC subscales, Vineland Adaptive Behavior Scales, or measures of autistic behaviors, and outcome assessors were unable to predict who was assigned to which group. The researchers conducted the study based on previous clinical observation of benefit for inattention, hyperactivity, and stereotypy in six children with autism and epilepsy, and while this study suggests that lamotrigine is not effective for children with ASD who do not have seizures, a subset of children with ASD and comorbid seizure disorder may show behavioral improvement with treatment.

Levetiracetam has been studied in two small samples of children with autism, with conflicting results.144,145 In an open-label study of ten young boys with autism and no seizure history, levetiracetam was associated with significant improvement in measures of ADHD symptoms, emotional lability, and aggression, though individuals who had been weaned from medications prescribed for aggression upon study entry (risperidone, carbamazepine, desipramine) demonstrated worsened aggression during the course of the study.145 A double-blind, placebo-controlled trial in 20 children failed to support these earlier, positive findings; individuals treated with levetiracetam did not show significant improvement in global scores of autism, aggression, affective instability, repetitive behaviors, hyperactivity, or impulsivity.144 Both studies were limited by the small sample size and lack of selection for patients with high scores on measures of target symptoms.

Reports of oxcarbazepine use for irritability in ASD populations are limited to a retrospective case series of 30 youth and a case report of 3 patients.146,147 Subjective improvement in maladaptive behaviors was reported in the 3 patients.146 In the case series, 14 patients (47%) were retrospectively rated as “much improved” on the CGI-I (mean CGI-I response, 2.9), though 7 patients (23%) terminated treatment due to significant adverse events, including hyponatremia, seizures, allergy, and, most commonly (n = 4), worsened irritability.147 In the absence of controlled trials, the efficacy of oxcarbazepine for irritability in ASD cannot be determined, and caution is recommended because of the risk of adverse events.

Topiramate has not been evaluated in controlled trials as a behavioral treatment in individuals with ASD. A small case series (n = 5) and retrospective chart review (n = 15) reported response rates for overall improvement (CGI-I rating of 1 or 2) of 40% and 53%, respectively; side effects in a minority included mild sedation (n = 2), cognitive difficulties (n = 2), and rash (n = 1).148,149 In a study of ten youth with ASD treated with topiramate for weight reduction in conjunction with atypical antipsychotic use, weight loss was inconsistent, and four patients discontinued due to adverse behavioral side effects.150

To date, beyond individual case reports, no studies have been published concerning the traditional mood stabilizer lithium in individuals with ASD.

In general, response rates for improved maladaptive behaviors with anticonvulsants are lower than with the atypical antipsychotics risperidone and aripiprazole. Anticonvulsants should be considered, however, in certain subsets of ASD populations, including those with poor response or tolerability to treatment with atypical antipsychotics or with concurrent seizure disorders. Controlled trials would be necessary to draw stronger conclusions regarding their effectiveness.


Oxytocin (OT), a nine-amino-acid neuropeptide synthesized in the hypothalamus and widely circulated systemically and in the central nervous system, is involved in mammalian social behavior, including affiliation, attachment, and social cognition.151 Below-average plasma OT levels have been associated with autism,152 and in a subset of individuals with autism, social impairment may be related to dysfunction of the OT system, likely due to genetic variation in system components.153 In healthy adult volunteers, intranasal OT administered in a single dose improved the ability to infer the affective mental state of others (theory of mind) on the most difficult items of the Reading the Mind in the Eyes (RMET) task.154

OT has been investigated in a number of small samples as a possible therapeutic agent for treating core social deficits in autism, with encouraging results.155–158 In a randomized, placebo-controlled, within-subject study, 15 adults with autism or Asperger’s disorder received single intravenous infusions of either OT or placebo, followed by infusions of the other a week later.157 In post-infusion testing, participants who received OT during the first condition showed superior retention of affective speech comprehension compared to those receiving placebo first. A subsequent controlled trial in 19 adults with ASD found that OT 24 IU administered intranasally twice a day for six weeks led to significant improvements in social cognition on the RMET task and in overall quality of life, though with no significant change, compared to placebo, on primary outcome measures of social ability (Diagnostic Analysis of Nonverbal Accuracy) and repetitive behaviors (Repetitive Behavior Scale Revised).155 In a sample of adolescent boys (12–19 years old), a single dose of intranasal OT (18 or 24 IU) improved emotion recognition on the RMET task,156 and OT intranasal administration for two months to a 16-year-old girl with autism improved social communication and irritability.158

In a randomized, double-blind study, based on findings from animal studies showing a link between OT dysregulation and repetitive behaviors, Hollander and colleagues159 administered a four-hour intravenous infusion of synthetic OT (Pitocin) to 15 male adults with ASD, with each participant receiving both placebo and OT. During the OT infusion, 86.7% (n = 13/15) of participants showed a decline in repetitive behaviors from beginning to endpoint, compared to 40% (n = 6/13) during the placebo phase. No serious adverse effects were reported in these studies.

Limitations of published reports include small sample sizes, which limit the power to detect anything but large effects, and exclusion of individuals with intellectual disability, a common comorbid condition in ASD. Lower-functioning individuals have largely been excluded from OT trials due to difficulty in administering social-cognition tasks in this group, as the measures typically require language-based responses. The effects of long-term administration of OT remain unknown. Numerous clinical trials are currently under way to further characterize the efficacy of OT in treating core social impairment in autism, including three placebo-controlled trials in children and two controlled trials in adults with ASD.160 One trial of note will include children as young as three years old, including those with comorbid intellectual disability, with plans for data collection on potential biomarkers: OXT mRNA expression, OXTR methylation, and OXTR mRNA expression (NCT01308749). OT is not currently commercially available for the treatment of ASD. The therapeutic potential of OT may be limited in part by its short half-life and low ability to penetrate the blood-brain barrier; non-peptide oxytocin receptor agonists, currently under investigation in animal models, may be a promising alternative in the future.161


Given that glutamate is the major excitatory neurotransmitter in the central nervous system, dysregulation within the glutamate system has been proposed as a possible neurobiological mechanism of disease in autism.162 Several medications modulating glutamate neurotransmission are under investigation for treating core autistic features and also related behavioral symptoms.

Memantine is a noncompetitive antagonist of the N-methyl-D-aspartate receptor (NMDAR; an ionotropic glutamate receptor), marketed for the treatment of cognitive impairment associated with Alzheimer’s dementia. Data from mouse models of fragile X syndrome, a single-gene disorder with associated symptoms of autism, suggests that memantine may exert its effect by correcting abnormal synaptic formation and growth of dendritic spines.163 Open-label use of memantine in 151 pediatric and young adult patients with ASD (mean age, 9 years; range, 2.5–26 years) to treat core autistic symptoms led to overall improvement (as determined by clinician-rated CGI-I scores) in language in 70% of participants, social functioning in 70.7% of participants, and repetitive behaviors in 12.1% of participants.164 The mean daily dose was 12.67 mg and ranged from 2.5 to 30 mg/day. Side effects included increased irritability, hyperactivity, and “manic-type behaviors.” A retrospective review of 18 children with ASD (mean age, 11.4 years; range, 6–19 years) treated with open-label memantine (mean dose, 10.1 mg/day; range, 2.5–20 mg/day) for social communication impairment and inattention yielded similar results, with 61% rated as “much improved” or “very much improved” on the CGI-I.165 Adverse effects occurred in 39%, most commonly irritability (n = 4/18), though irritability improved in a comparable number of children (n = 4/18) during the course of treatment. Memantine was reported to significantly reduce disruptive behavior and social withdrawal in the single case of a 23-year-old man with autism.166 Multisite, placebo-controlled trials are currently under way to determine the efficacy of memantine for social communication deficits in children with autism.160

Riluzole is a glutamate-modulating agent approved by the FDA for treating amyotrophic lateral sclerosis, with preliminary evidence suggesting a benefit for psychiatric disorders with presumed glutamatergic dysfunction, including obsessive-compulsive disorder, treatment-resistant depression, and fragile X syndrome.167–172 Though the exact mechanism of action is unknown, riluzole is thought to reduce glutmate-induced excitotoxicity by enhancing glutamate reuptake into presynaptic cells and inhibiting presynaptic glutamate release.161 Limited case reports of individuals with autism treated with riluzole for severe repetitive or compulsive behaviors suggest a benefit for this particular symptom cluster.173,174 Notable side effects have included anemia, pancreatitis, and elevation in live function tests.168,174,175

D-cycloserine, an NMDAR partial agonist that binds to the regulatory glycine binding site on NMDARs, has been shown to normalize aberrant NMDAR function in a mouse model of autism and to improve social interaction.176 In a prospective, single-blind study of ten individuals with autism (mean age, 10 years; range, 5.1–27.6 years) treated with ascending doses of D-cycloserine for eight weeks, 40% showed significant overall improvement, notably in severity of social withdrawal.177 D-cycloserine has been investigated in other neuropsychiatric disorders with proposed glutamatergic dysfunction, including schizophrenia, but with less promising results, possibly due to the agent’s relatively low affinity for the glycine binding site.178 The related compound D-serine is a full agonist at the glycine site and may exert a more therapeutic effect, though no results from studies of D-serine in humans have yet been reported. A preclinical trial of a newly developed NMDAR glycine-site partial agonist, GLYX-13, has also suggested improvement in autistic-like social communication deficits in mice179 and is being investigated as an augmentative treatment in major depressive disorder.160

N-acetylcysteine (NAC), a glutamate transmission modulator and antioxidant-promoting agent, is a prodrug of cysteine primarily used to minimize liver damage in the setting of acetaminophen overdose and as a mucolytic in cystic fibrosis. Recent trials suggest that NAC may also reduce symptom burden as an augmenting agent in various neuropsychiatric disorders, including bipolar disorder, schizophrenia, and disorders of impulse control such as obsessive-compulsive disorder, trichotillomania, and pathological gambling.180–185 Hardan and colleagues186 conducted a 12-week randomized, placebo-controlled trial of NAC in 33 children with autism, finding significant reduction on the ABC-Irritability subscale for NAC compared to placebo. Nonsignificant improvement in repetitive behaviors and stereotypy was also observed, though social communication symptoms as measured by the Social Responsiveness Scale did not change. NAC was well tolerated, with few side effects, primarily gastrointestinal upset. These findings have not yet been replicated in larger controlled trials.

Arbaclofen (also known as STX209; developed by Seaside Therapeutics) is a GABAB receptor agonist that inhibits presynaptic release of glutamate and thereby reduces glutamate transmission postsynaptically. A recently published randomized, controlled trial of arbaclofen in individuals with fragile X syndrome reported improved social withdrawal and irritability, most significantly in those most severely affected by the disorder.187 Headaches and sedation were the most commonly reported side effects. Seaside Therapeutics has preliminarily reported improved irritability, social withdrawal, and overall symptom severity in an open-label, Phase II study of arbaclofen in 32 children with ASD, though full results have not yet been published.188 At a May 2013 conference, the company also reported preliminary results from a Phase 2 placebo-controlled trial of arbaclofen in 150 children aged 5–21 years with ASD. While no improvement was seen in the primary outcome measure of social withdrawal, arbaclofen-treated participants showed significant overall improvement, as measured by CGI-Severity scores.189


ASD requires comprehensive care across the lifespan and frequently includes pharmacotherapy for associated emotional problems and maladaptive behaviors, symptoms that may appear different at different developmental stages. Screening for these symptom clusters—particularly sleep disturbance, anxiety, ADHD symptoms, irritability, repetitive behaviors, and compulsions—may reveal significant distress and impairment that could be amenable to improvement with thoughtful medication management. Pharmacological interventions have the potential, when effective, to enhance individuals’ participation in behavioral and educational therapies, leading to better outcomes and overall quality of life.

In general, however, response rates to traditional psychotropic medications in ASD populations have been lower than those observed in studies of disorders with some shared clinical features, such as ADHD and obsessive-compulsive disorder. Methylphenidate, for example, may be effective for some children with ASD and symptoms of ADHD, though not as many respond positively as in ADHD without ASD. Similarly, improvement in repetitive behaviors and compulsions with SSRIs has been modest in comparison to improvements seen in obsessive-compulsive disorder. This variability likely reflects a different underlying neurobiology in autism that has yet to be fully understood, and highlights the complexity of constructs such as attention and repetitive behavior. Medications may also be more efficacious and better tolerated at different points in development, perhaps indicating that changing neurotransmission patterns influence response. SSRIs, including fluoxetine and fluvoxamine, are generally associated with greater efficacy and lower side-effect burden in adults than in children with ASD, possibly due to differential serotonergic activity observed during these stages.190 Atypical antipsychotics, particularly risperidone and aripiprazole, stand out as well-characterized treatments with large effect sizes for managing irritability in ASD. Metabolic side effects are common, however, and pose a risk to overall health, generally limiting their use to those with the most severe symptoms. Table 1 summarizes findings from the largest available randomized, controlled trials for medications studied in ASD populations. It is noteworthy that well-designed, placebo-controlled studies of behavioral medications in ASD are scarce; more rigorous, multisite trials are needed to guide sound, evidence-based care. Clinicians treating individuals with ASD should keep in mind that families are often wary of the allopathic medical approach to the treatment of autism; increasing the body of evidence to support these interventions will lead to better care and increased credibility with the general public.

Table 1:
Randomized, Controlled Trials of Medications in Autism Spectrum Disorder with Minimum Sample Size of 30 Subjects

Given the frequently poorer tolerability and lower response rates of many psychotropic medications in ASD populations, medications with novel mechanisms of action need to be more actively investigated—both medications in development and those already in use for related disorders. As with other neuropsychiatric disorders, the future of care for individuals with autism lies in better understanding its neurobiological underpinnings, allowing for the development of targeted interventions. Currently, oxytocin and agents that modulate glutamate transmission show promise, but further study is needed to determine their utility. Genetic and neuroimaging studies comparing individuals with ASD who respond positively to particular medications with those who do not could help determine endophenotypes within the autism spectrum and aid in developing more tailored interventions in the future.

More controlled trials in ASD populations are needed to determine parameters and guidelines for using all classes of psychotropic medications. In the meantime, distress and impairment from associated symptoms can be profound, and trials of psychotropic medications are often undertaken in clinical practice when symptom burden is determined to outweigh the risk of potential side effects. A cautious approach is recommended, starting at low doses and increasing slowly according to tolerability. Though much remains unknown about the etiology of autism, emerging rational approaches to pharmacotherapy hold promise for the future.

Declaration of interest: Dr. Henry is a consultant to Beacon Health Strategies. The authors have disclosed that the U.S. Food and Drug Administration has not approved the use of any medication, except aripiprazole and risperidone, for the treatment of autism spectrum disorder as discussed in this article. Please consult the product’s labeling for approved information.


1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed., text rev. Washington, DC: American Psychiatric Press, 2000.
2. Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Prinicipal Investigators; Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ 2012; 61: 1–19.
3. Blumberg SJ, Kogan MD, Schieve LA, Jones JR, Lu MC. Changes in prevalence of parent-reported autism spectrum disorder in school-aged U.S. children: 2007 to 2011–2012. Natl Health Stat Report 2013; (65): 1–28.
4. Cadman T, Eklund H, Howley D, et al. Caregiver burden as people with autism spectrum disorder and attention-deficit/hyperactivity disorder transition into adolescence and adulthood in the United Kingdom. J Am Acad Child Adolesc Psychiatry 2012; 51: 879–88.
5. Cidav Z, Marcus SC, Mandell DS. Implications of childhood autism for parental employment and earnings. Pediatrics 2012; 129: 617–23.
6. Peacock G, Amendah D, Ouyang L, Grosse SD. Autism spectrum disorders and health care expenditures: the effects of co-occurring conditions. J Dev Behav Pediatr 2012; 33: 2–8.
7. Cimera RE, Cowan RJ. The costs of services and employment outcomes achieved by adults with autism in the US. Autism 2009; 13: 285–302.
8. Shattuck PT, Roux AM, Hudson LE, Taylor JL, Maenner MJ, Trani JF. Services for adults with an autism spectrum disorder. Can J Psychiatry 2012; 57: 284–91.
9. Reichow B, Barton EE, Boyd BA, Hume K. Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev 2012; 10: CD009260.
10. Joshi G, Petty C, Wozniak J, et al. The heavy burden of psychiatric comorbidity in youth with autism spectrum disorders: a large comparative study of a psychiatrically referred population. J Autism Dev Disord 2010; 40: 1361–70.
11. Coury DL, Anagnostou E, Manning-Courtney P, et al. Use of psychotropic medication in children and adolescents with autism spectrum disorders. Pediatrics 2012; 130 suppl 2: S69–76.
12. Mazefsky CA, Conner CM, Oswald DP. Association between depression and anxiety in high-functioning children with autism spectrum disorders and maternal mood symptoms. Autism Res 2010; 3: 120–7.
13. Mazefsky CA, Folstein SE, Lainhart JE. Overrepresentation of mood and anxiety disorders in adults with autism and their first-degree relatives: what does it mean? Autism Res 2008; 1: 193–7.
14. Strang JF, Kenworthy L, Daniolos P, et al. Depression and anxiety symptoms in children and adolescents with autism spectrum disorders without intellectual disability. Res Autism Spectr Disord 2012; 6: 406–12.
15. Andersen IM, Kaczmarska J, McGrew SG, Malow BA. Melatonin for insomnia in children with autism spectrum disorders. J Child Neurol 2008; 23: 482–5.
16. Cortesi F, Giannotti F, Sebastiani T, Panunzi S, Valente D. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. J Sleep Res 2012; 21: 700–9.
17. Garstang J, Wallis M. Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child Care Health Dev 2006; 32: 585–9.
18. Giannotti F, Cortesi F, Cerquiglini A, Bernabei P. An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord 2006; 36: 741–52.
19. Guenole F, Godbout R, Nicolas A, Franco P, Claustrat B, Baleyte JM. Melatonin for disordered sleep in individuals with autism spectrum disorders: systematic review and discussion. Sleep Med Rev 2011; 15: 379–87.
20. Malow B, Adkins KW, McGrew SG, et al. Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. J Autism Dev Disord 2012; 42: 1729–37; author reply 1738.
21. Wasdell MB, Jan JE, Bomben MM, et al. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res 2008; 44: 57–64.
22. Wirojanan J, Jacquemont S, Diaz R, et al. The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome. J Clin Sleep Med 2009; 5: 145–50.
23. Wright B, Sims D, Smart S, et al. Melatonin versus placebo in children with autism spectrum conditions and severe sleep problems not amenable to behaviour management strategies: a randomised controlled crossover trial. J Autism Dev Disord 2011; 41: 175–84.
24. Bethea TC, Sikich L. Early pharmacological treatment of autism: a rationale for developmental treatment. Biol Psychiatry 2007; 61: 521–37.
25. Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 2008; 47: 921–9.
26. Brasic JR, Barnett JY, Kaplan D, et al. Clomipramine ameliorates adventitious movements and compulsions in prepubertal boys with autistic disorder and severe mental retardation. Neurology 1994; 44: 1309–12.
27. Brodkin ES, McDougle CJ, Naylor ST, Cohen DJ, Price LH. Clomipramine in adults with pervasive developmental disorders: a prospective open-label investigation. J Child Adolesc Psychopharmacol 1997; 7: 109–21.
28. McDougle CJ, Price LH, Volkmar FR, et al. Clomipramine in autism: preliminary evidence of efficacy. J Am Acad Child Adolesc Psychiatry 1992; 31: 746–50.
29. Brasic JR, Barnett JY, Sheitman BB, Tsaltas MO. Adverse effects of clomipramine. J Am Acad Child Adolesc Psychiatry 1997; 36: 1165–6.
30. Sanchez LE, Campbell M, Small AM, Cueva JE, Armenteros JL, Adams PB. A pilot study of clomipramine in young autistic children. J Am Acad Child Adolesc Psychiatry 1996; 35: 537–44.
31. Gordon CT, Rapoport JL, Hamburger SD, State RC, Mannheim GB. Differential response of seven subjects with autistic disorder to clomipramine and desipramine. Am J Psychiatry 1992; 149: 363–6.
32. Gordon CT, State RC, Nelson JE, Hamburger SD, Rapoport JL. A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Arch Gen Psychiatry 1993; 50: 441–7.
33. Ghaziuddin M, Tsai L, Ghaziuddin N. Fluoxetine in autism with depression. J Am Acad Child Adolesc Psychiatry 1991; 30: 508–9.
34. Alcami Pertejo M, Peral Guerra M, Gilaberte I. [Open study of fluoxetine in children with autism]. Actas Espanolas de Psiquiatria 2000; 28: 353–6.
35. Buchsbaum MS, Hollander E, Haznedar MM, et al. Effect of fluoxetine on regional cerebral metabolism in autistic spectrum disorders: a pilot study. Int J Neuropsychopharmacol 2001; 4: 119–25.
36. DeLong GR, Ritch CR, Burch S. Fluoxetine response in children with autistic spectrum disorders: correlation with familial major affective disorder and intellectual achievement. Dev Med Child Neurol 2002; 44: 652–9. Comment: Bates G, Willson SW. Use of selective serotonin reuptake inhibitors in children with pervasive developmental disorder: risk of treatment emergent mania. Dev Med Child Neurol 2003;45:359; author reply 360.
37. DeLong GR, Teague LA, McSwain Kamran M. Effects of fluoxetine treatment in young children with idiopathic autism. Dev Med Child Neurol 1998; 40: 551–62. Comment: Bax M. A treatment that works. Dev Med Child Neurol 1998;40:507.
38. Hellings JA, Kelley LA, Gabrielli WF, Kilgore E, Shah P. Sertraline response in adults with mental retardation and autistic disorder. J Clin Psychiatry 1996; 57: 333–6.
39. McDougle CJ, Brodkin ES, Naylor ST, Carlson DC, Cohen DJ, Price LH. Sertraline in adults with pervasive developmental disorders: a prospective open-label investigation. J Clin Psychopharmacol 1998; 18: 62–6.
40. Namerow LB, Thomas P, Bostic JQ, Prince J, Monuteaux MC. Use of citalopram in pervasive developmental disorders. J Dev Behav Pediatr 2003; 24: 104–8.
41. Owley T, Walton L, Salt J, et al. An open-label trial of escitalopram in pervasive developmental disorders. J Am Acad Child Adolesc Psychiatry 2005; 44: 343–8.
42. Desousa A. An open-label trial of risperidone and fluoxetine in children with autistic disorder. Indian J Psychol Med 2010; 32: 17–21.
43. Henry CA, Steingard R, Venter J, Guptill J, Halpern EF, Bauman M. Treatment outcome and outcome associations in children with pervasive developmental disorders treated with selective serotonin reuptake inhibitors: a chart review. J Child Adolesc Psychopharmacol 2006; 16: 187–95.
44. Steingard RJ, Zimnitzky B, DeMaso DR, Bauman ML, Bucci JP. Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder. J Child Adolesc Psychopharmacol 1997; 7: 9–15.
45. McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH. A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996; 53: 1001–8.
46. Hollander E, Soorya L, Chaplin W, et al. A double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders. Am J Psychiatry 2012; 169: 292–9.
47. McDougle CJ, Kresch LE, Posey DJ. Repetitive thoughts and behavior in pervasive developmental disorders: treatment with serotonin reuptake inhibitors. J Autism Dev Disord 2000; 30: 427–35.
48. Hollander E, Phillips A, Chaplin W, et al. A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology 2005; 30: 582–9.
49. King BH, Hollander E, Sikich L, et al. Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism. Arch Gen Psychiatry 2009; 66: 583–90.
50. Autism Speaks. Autism Speaks announces results reported for the Study of Fluoxetine in Autism (SOFIA): first industry-sponsored trial for the Autism Clinical Trials Network (ACTN) [Press release]. 18 Feb 2009.
51. McDougle CJ, Posey D. Genetics of childhood disorders: XLIV. Autism, part 3: psychopharmacology of autism. J Am Acad Child Adolesc Psychiatry 2002; 41: 1380–3.
52. Brahm NC, Fast GA, Brown RC. Buspirone for autistic disorder in a woman with an intellectual disability. Ann Pharmacother 2008; 42: 131–7.
53. Buitelaar JK, van der Gaag RJ, van der Hoeven J. Buspirone in the management of anxiety and irritability in children with pervasive developmental disorders: results of an open-label study. J Clin Psychiatry 1998; 59: 56–9.
54. McCormick LH. Treatment with buspirone in a patient with autism. Arch Fam Med 1997; 6: 368–70.
55. Realmuto GM, August GJ, Garfinkel BD. Clinical effect of buspirone in autistic children. J Clin Psychopharmacol 1989; 9: 122–5.
56. Albertini G, Polito E, Sara M, Di Gennaro G, Onorati P. Compulsive masturbation in infantile autism treated by mirtazapine. Pediatr Neurol 2006; 34: 417–8.
57. Coskun M, Karakoc S, Kircelli F, Mukaddes NM. Effectiveness of mirtazapine in the treatment of inappropriate sexual behaviors in individuals with autistic disorder. J Child Adolesc Psychopharmacol 2009; 19: 203–6.
58. Coskun M, Mukaddes NM. Mirtazapine treatment in a subject with autistic disorder and fetishism. J Child Adolesc Psychopharmacol 2008; 18: 206–9.
59. Nguyen M, Murphy T. Mirtazapine for excessive masturbation in an adolescent with autism. J Am Acad Child Adolesc Psychiatry 2001; 40: 868–9.
60. Posey DJ, Guenin KD, Kohn AE, Swiezy NB, McDougle CJ. A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders. J Child Adolesc Psychopharmacol 2001; 11: 267–77.
61. Leyfer OT, Folstein SE, Bacalman S, et al. Comorbid psychiatric disorders in children with autism: interview development and rates of disorders. J Autism Dev Disord 2006; 36: 849–61.
62. Aman MG. Stimulant drugs in the developmental disabilities revisited. J Dev Phys Disabil 1996; 4: 347–66.
63. Campbell M, Small AM, Hollander CS, et al. A controlled crossover study of triiodothyronine in autistic children. J Autism Child Schizophr 1978; 8: 371–81.
64. Stigler KA, Desmond LA, Posey DJ, Wiegand RE, McDougle CJ. A naturalistic retrospective analysis of psychostimulants in pervasive developmental disorders. J Child Adolesc Psychopharmacol 2004; 14: 49–56.
65. Birmaher B, Quintana H, Greenhill LL. Methylphenidate treatment of hyperactive autistic children. J Am Acad Child Adolesc Psychiatry 1988; 27: 248–51.
66. Geller B, Guttmacher LB, Bleeg M. Coexistence of childhood onset pervasive developmental disorder and attention deficit disorder with hyperactivity. Am J Psychiatry 1981; 138: 388–9.
67. Hoshino Y, Kumashiro H, Kaneko M, Takahashi Y. The effects of methylphenidate on early infantile autism and its relation to serum serotonin levels. Folia Psychiatr Neurol Jpn 1977; 31: 605–14.
68. Strayhorn JM Jr, Rapp N, Donina W, Strain PS. Randomized trial of methylphenidate for an autistic child. J Am Acad Child Adolesc Psychiatry 1988; 27: 244–7.
69. Vitriol C, Farber B. Stimulant medication in certain childhood disorders. Am J Psychiatry 1981; 138: 1517–8.
70. Handen BL, Johnson CR, Lubetsky M. Efficacy of methylphenidate among children with autism and symptoms of attention-deficit hyperactivity disorder. J Autism Dev Disord 2000; 30: 245–55.
71. Quintana H, Birmaher B, Stedge D, et al. Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 1995; 25: 283–94.
72. Research Units on Pediatric Psychopharmacology Autism Network. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 2005; 62: 1266–74.
73. Greenhill LL, Swanson JM, Vitiello B, et al. Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial. J Am Acad Child Adolesc Psychiatry 2001; 40: 180–7.
74. Ghuman JK, Aman MG, Lecavalier L, et al. Randomized, placebo-controlled, crossover study of methylphenidate for attention-deficit/hyperactivity disorder symptoms in preschoolers with developmental disorders. J Child Adolesc Psychopharmacol 2009; 19: 329–39.
75. King BH, Lord C. Is schizophrenia on the autism spectrum? Brain Res 2011; 1380: 34–41.
76. Biederman J, Melmed RD, Patel A, et al. A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics 2008; 121: e73–84.
77. Connor DF, Findling RL, Kollins SH, et al. Effects of guanfacine extended release on oppositional symptoms in children aged 6–12 years with attention-deficit hyperactivity disorder and oppositional symptoms: a randomized, double-blind, placebo-controlled trial. CNS Drugs 2010; 24: 755–68.
78. Sallee FR, McGough J, Wigal T, Donahue J, Lyne A, Biederman J. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2009; 48: 155–65.
79. Connor DF, Barkley RA, Davis HT. A pilot study of methylphenidate, clonidine, or the combination in ADHD comorbid with aggressive oppositional defiant or conduct disorder. Clin Pediatr (Phila) 2000; 39: 15–25.
80. Jain R, Segal S, Kollins SH, Khayrallah M. Clonidine extended-release tablets for pediatric patients with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2011; 50: 171–9.
81. Kollins SH, Jain R, Brams M, et al. Clonidine extended-release tablets as add-on therapy to psychostimulants in children and adolescents with ADHD. Pediatrics 2011; 127: e1406–13.
82. Ming X, Gordon E, Kang N, Wagner GC. Use of clonidine in children with autism spectrum disorders. Brain Dev 2008; 30: 454–60.
83. Fankhauser MP, Karumanchi VC, German ML, Yates A, Karumanchi SD. A double-blind, placebo-controlled study of the efficacy of transdermal clonidine in autism. J Clin Psychiatry 1992; 53: 77–82.
84. Jaselskis CA, Cook EH Jr, Fletcher KE, Leventhal BL. Clonidine treatment of hyperactive and impulsive children with autistic disorder. J Clin Psychopharmacol 1992; 12: 322–7.
85. Posey DJ, Puntney JI, Sasher TM, Kem DL, McDougle CJ. Guanfacine treatment of hyperactivity and inattention in pervasive developmental disorders: a retrospective analysis of 80 cases. J Child Adolesc Psychopharmacol 2004; 14: 233–41.
86. Scahill L, Aman MG, McDougle CJ, et al. A prospective open trial of guanfacine in children with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2006; 16: 589–98.
87. Handen BL, Sahl R, Hardan AY. Guanfacine in children with autism and/or intellectual disabilities. J Dev Behav Pediatr 2008; 29: 303–8.
88. Jou RJ, Handen BL, Hardan AY. Retrospective assessment of atomoxetine in children and adolescents with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2005; 15: 325–30.
89. Posey DJ, Wiegand RE, Wilkerson J, Maynard M, Stigler KA, McDougle CJ. Open-label atomoxetine for attention-deficit/hyperactivity disorder symptoms associated with high-functioning pervasive developmental disorders. J Child Adolesc Psychopharmacol 2006; 16: 599–610.
90. Troost PW, Steenhuis MP, Tuynman-Qua HG, et al. Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study. J Child Adolesc Psychopharmacol 2006; 16: 611–9.
91. Zeiner P, Gjevik E, Weidle B. Response to atomoxetine in boys with high-functioning autism spectrum disorders and attention deficit/hyperactivity disorder. Acta Paediatr 2011; 100: 1258–61.
92. Charnsil C. Efficacy of atomoxetine in children with severe autistic disorders and symptoms of ADHD: an open-label study. J Atten Disord 2011; 15: 684–9.
93. Harfterkamp M, van de Loo-Neus G, Minderaa RB, et al. A randomized double-blind study of atomoxetine versus placebo for attention-deficit/hyperactivity disorder symptoms in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 2012; 51: 733–41.
94. Arnold LE, Aman MG, Cook AM, et al. Atomoxetine for hyperactivity in autism spectrum disorders: placebo-controlled crossover pilot trial. J Am Acad Child Adolesc Psychiatry 2006; 45: 1196–205.
95. King BH, Wright DM, Handen BL, et al. Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. J Am Acad Child Adolesc Psychiatry 2001; 40: 658–65.
96. McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002; 347: 314–21.
97. Shea S, Turgay A, Carroll A, et al. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics 2004; 114: e634–41.
98. McDougle CJ, Holmes JP, Carlson DC, Pelton GH, Cohen DJ, Price LH. A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry 1998; 55: 633–41.
99. Malone RP, Maislin G, Choudhury MS, Gifford C, Delaney MA. Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness. J Am Acad Child Adolesc Psychiatry 2002; 41: 140–7.
100. Nagaraj R, Singhi P, Malhi P. Risperidone in children with autism: randomized, placebo-controlled, double-blind study. J Child Neurol 2006; 21: 450–5.
101. Troost PW, Lahuis BE, Steenhuis MP, et al. Long-term effects of risperidone in children with autism spectrum disorders: a placebo discontinuation study. J Am Acad Child Adolesc Psychiatry 2005; 44: 1137–44.
102. Aman MG, McDougle CJ, Scahill L, et al. Medication and parent training in children with pervasive developmental disorders and serious behavior problems: results from a randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2009; 48: 1143–54.
103. Aman MG, Arnold LE, McDougle CJ, et al. Acute and long-term safety and tolerability of risperidone in children with autism. J Child Adolesc Psychopharmacol 2005; 15: 869–84.
104. Pandina GJ, Bossie CA, Youssef E, Zhu Y, Dunbar F. Risperidone improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord 2007; 37: 367–73.
105. Martin A, Scahill L, Anderson GM, et al. Weight and leptin changes among risperidone-treated youths with autism: 6-month prospective data. Am J Psychiatry 2004; 161: 1125–7.
106. Anderson GM, Scahill L, McCracken JT, et al. Effects of short- and long-term risperidone treatment on prolactin levels in children with autism. Biol Psychiatry 2007; 61: 545–50.
107. Marcus RN, Owen R, Kamen L, et al. A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry 2009; 48: 1110–9.
108. Owen R, Sikich L, Marcus RN, et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 2009; 124: 1533–40.
109. Aman MG, Kasper W, Manos G, et al. Line-item analysis of the Aberrant Behavior Checklist: results from two studies of aripiprazole in the treatment of irritability associated with autistic disorder. J Child Adolesc Psychopharmacol 2010; 20: 415–22.
110. Marcus RN, Owen R, Manos G, et al. Safety and tolerability of aripiprazole for irritability in pediatric patients with autistic disorder: a 52-week, open-label, multicenter study. J Clin Psychiatry 2011; 72: 1270–6.
111. Ho JG, Caldwell RL, McDougle CJ, et al. The effects of aripiprazole on electrocardiography in children with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2012; 22: 277–83.
112. Malone RP, Cater J, Sheikh RM, Choudhury MS, Delaney MA. Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J Am Acad Child Adolesc Psychiatry 2001; 40: 887–94.
113. Potenza MN, Holmes JP, Kanes SJ, McDougle CJ. Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study. J Clin Psychopharmacol 1999; 19: 37–44.
114. Fido A, Al-Saad S. Olanzapine in the treatment of behavioral problems associated with autism: an open-label trial in Kuwait. Med Princ Pract 2008; 17: 415–8.
115. Kemner C, Willemsen-Swinkels SH, de Jonge M, Tuynman-Qua H, van Engeland H. Open-label study of olanzapine in children with pervasive developmental disorder. J Clin Psychopharmacol 2002; 22: 455–60.
116. Hollander E, Wasserman S, Swanson EN, et al. A double-blind placebo-controlled pilot study of olanzapine in childhood/adolescent pervasive developmental disorder. J Child Adolesc Psychopharmacol 2006; 16: 541–8.
117. Findling RL, McNamara NK, Gracious BL, et al. Quetiapine in nine youths with autistic disorder. J Child Adolesc Psychopharmacol 2004; 14: 287–94.
118. Martin A, Koenig K, Scahill L, Bregman J. Open-label quetiapine in the treatment of children and adolescents with autistic disorder. J Child Adolesc Psychopharmacol 1999; 9: 99–107.
119. Golubchik P, Sever J, Weizman A. Low-dose quetiapine for adolescents with autistic spectrum disorder and aggressive behavior: open-label trial. Clin Neuropharmacol 2011; 34: 216–9.
120. Corson AH, Barkenbus JE, Posey DJ, Stigler KA, McDougle CJ. A retrospective analysis of quetiapine in the treatment of pervasive developmental disorders. J Clin Psychiatry 2004; 65: 1531–6.
121. Hardan AY, Jou RJ, Handen BL. Retrospective study of quetiapine in children and adolescents with pervasive developmental disorders. J Autism Dev Disord 2005; 35: 387–91.
122. Duggal HS. Ziprasidone for maladaptive behavior and attention-deficit/hyperactivity disorder symptoms in autistic disorder. J Child Adolesc Psychopharmacol 2007; 17: 261–3.
123. Goforth HW, Rao MS. Improvement in behaviour and attention in an autistic patient treated with ziprasidone. Aust N Z J Psychiatry 2003; 37: 775–6.
124. Malone RP, Delaney MA, Hyman SB, Cater JR. Ziprasidone in adolescents with autism: an open-label pilot study. J Child Adolesc Psychopharmacol 2007; 17: 779–90.
125. McDougle CJ, Kem DL, Posey DJ. Case series: use of ziprasidone for maladaptive symptoms in youths with autism. J Am Acad Child Adolesc Psychiatry 2002; 41: 921–7.
126. Cohen SA, Fitzgerald BJ, Khan SR, Khan A. The effect of a switch to ziprasidone in an adult population with autistic disorder: chart review of naturalistic, open-label treatment. J Clin Psychiatry 2004; 65: 110–3.
127. McDougle CJ, Stigler KA, Erickson CA, Posey DJ. Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry 2008; 69 suppl 4: 15–20.
128. Roser P, Haussleiter IS, Juckel G, Brune M. Paliperidone in an adult patient with Asperger syndrome: case report. Pharmacopsychiatry 2009; 42: 78–9.
129. Stigler KA, Erickson CA, Mullett JE, Posey DJ, McDougle CJ. Paliperidone for irritability in autistic disorder. J Child Adolesc Psychopharmacol 2010; 20: 75–8.
130. Stigler KA, Mullett JE, Erickson CA, Posey DJ, McDougle CJ. Paliperidone for irritability in adolescents and young adults with autistic disorder. Psychopharmacology (Berl) 2012; 223: 237–45.
131. Chen NC, Bedair HS, McKay B, Bowers MB Jr, Mazure C. Clozapine in the treatment of aggression in an adolescent with autistic disorder. J Clin Psychiatry 2001; 62: 479–80.
132. Gobbi G, Pulvirenti L. Long-term treatment with clozapine in an adult with autistic disorder accompanied by aggressive behaviour. J Psychiatry Neurosci 2001; 26: 340–1.
133. Lambrey S, Falissard B, Martin-Barrero M, et al. Effectiveness of clozapine for the treatment of aggression in an adolescent with autistic disorder. J Child Adolesc Psychopharmacol 2010; 20: 79–80.
134. Zuddas A, Ledda MG, Fratta A, Muglia P, Cianchetti C. Clinical effects of clozapine on autistic disorder. Am J Psychiatry 1996; 153: 738.
135. De Hert M, Yu W, Detraux J, Sweers K, van Winkel R, Correll CU. Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder: a systematic review and exploratory meta-analysis. CNS Drugs 2012; 26: 733–59.
136. Anagnostou E, Esposito K, Soorya L, Chaplin W, Wasserman S, Hollander E. Divalproex versus placebo for the prevention of irritability associated with fluoxetine treatment in autism spectrum disorder. J Clin Psychopharmacol 2006; 26: 444–6.
137. Childs JA, Blair JL. Valproic acid treatment of epilepsy in autistic twins. J Neurosci Nurs 1997; 29: 244–8.
138. Plioplys AV. Autism: electroencephalogram abnormalities and clinical improvement with valproic acid. Arch Pediatr Adolesc Med 1994; 148: 220–2.
139. Hollander E, Dolgoff-Kaspar R, Cartwright C, Rawitt R, Novotny S. An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry 2001; 62: 530–4.
140. Hellings JA, Weckbaugh M, Nickel EJ, et al. A double-blind, placebo-controlled study of valproate for aggression in youth with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2005; 15: 682–92.
141. Hollander E, Chaplin W, Soorya L, et al. Divalproex sodium vs placebo for the treatment of irritability in children and adolescents with autism spectrum disorders. Neuropsychopharmacology 2010; 35: 990–8.
142. Hollander E, Soorya L, Wasserman S, Esposito K, Chaplin W, Anagnostou E. Divalproex sodium vs. placebo in the treatment of repetitive behaviours in autism spectrum disorder. Int J Neuropsychopharmacol 2006; 9: 209–13.
143. Belsito KM, Law PA, Kirk KS, Landa RJ, Zimmerman AW. Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord 2001; 31: 175–81.
144. Wasserman S, Iyengar R, Chaplin WF, et al. Levetiracetam versus placebo in childhood and adolescent autism: a double-blind placebo-controlled study. Int Clin Psychopharmacol 2006; 21: 363–7.
145. Rugino TA, Samsock TC. Levetiracetam in autistic children: an open-label study. J Dev Behav Pediatr 2002; 23: 225–30.
146. Kapetanovic S. Oxcarbazepine in youths with autistic disorder and significant disruptive behaviors. Am J Psychiatry 2007; 164: 832–3.
147. Douglas JF, Sanders KB, Benneyworth MH, et al. Brief report: retrospective case series of oxcarbazepine for irritability/agitation symptoms in autism spectrum disorder. J Autism Dev Disord 2013; 43: 1243–7.
148. Hardan AY, Jou RJ, Handen BL. A retrospective assessment of topiramate in children and adolescents with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2004; 14: 426–32.
149. Mazzone L, Ruta L. Topiramate in children with autistic spectrum disorders. Brain Dev 2006; 28: 668.
150. Canitano R. Clinical experience with topiramate to counteract neuroleptic induced weight gain in 10 individuals with autistic spectrum disorders. Brain Dev 2005; 27: 228–32.
151. Lukas M, Neumann ID. Oxytocin and vasopressin in rodent behaviors related to social dysfunctions in autism spectrum disorders. Behav Brain Res 2013; 251: 85–94.
152. Modahl C, Green L, Fein D, et al. Plasma oxytocin levels in autistic children. Biol Psychiatry 1998; 43: 270–7.
153. Sauer C, Montag C, Worner C, Kirsch P, Reuter M. Effects of a common variant in the CD38 gene on social processing in an oxytocin challenge study: possible links to autism. Neuropsychopharmacology 2012; 37: 1474–82.
154. Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC. Oxytocin improves “mind-reading” in humans. Biol Psychiatry 2007; 61: 731–3.
155. Anagnostou E, Soorya L, Chaplin W, et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 2012; 3: 16.
156. Guastella AJ, Einfeld SL, Gray KM, et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010; 67: 692–4.
157. Hollander E, Bartz J, Chaplin W, et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry 2007; 61: 498–503.
158. Kosaka H, Munesue T, Ishitobi M, et al. Long-term oxytocin administration improves social behaviors in a girl with autistic disorder. BMC Psychiatry 2012; 12: 110.
159. Hollander E, Novotny S, Hanratty M, et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 2003; 28: 193–8.
160. http://
161. Ring RH, Schechter LE, Leonard SK, et al. Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist. Neuropharmacology 2010; 58: 69–77.
162. Carlson GC. Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders. Pharmacol Biochem Behav 2012; 100: 850–4.
163. Wei H, Dobkin C, Sheikh AM, Malik M, Brown WT, Li X. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome. PLoS One 2012; 7: e36981.
164. Chez MG, Burton Q, Dowling T, Chang M, Khanna P, Kramer C. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol 2007; 22: 574–9.
165. Erickson CA, Posey DJ, Stigler KA, Mullett J, Katschke AR, McDougle CJ. A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl) 2007; 191: 141–7.
166. Erickson CA, Chambers JE. Memantine for disruptive behavior in autistic disorder. J Clin Psychiatry 2006; 67: 1000.
167. Coric V, Taskiran S, Pittenger C, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry 2005; 58: 424–8.
168. Erickson CA, Weng N, Weiler IJ, et al. Open-label riluzole in fragile X syndrome. Brain Res 2011; 1380: 264–70.
169. Grant P, Lougee L, Hirschtritt M, Swedo SE. An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. J Child Adolesc Psychopharmacol 2007; 17: 761–7.
170. Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry 2007; 61: 822–5.
171. Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 2004; 161: 171–4.
172. Zarate CA Jr, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 2005; 57: 430–2.
173. Veenstra-VanderWeele J. Increase in valproic acid levels during riluzole treatment in an adolescent with autism. J Child Adolesc Psychopharmacol 2010; 20: 163–5.
174. Wink LK, Erickson CA, Stigler KA, McDougle CJ. Riluzole in autistic disorder. J Child Adolesc Psychopharmacol 2011; 21: 375–9.
175. Grant P, Song JY, Swedo SE. Review of the use of the glutamate antagonist riluzole in psychiatric disorders and a description of recent use in childhood obsessive-compulsive disorder. J Child Adolesc Psychopharmacol 2010; 20: 309–15.
176. Won H, Lee HR, Gee HY, et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 2012; 486: 261–5.
177. Posey DJ, Kem DL, Swiezy NB, Sweeten TL, Wiegand RE, McDougle CJ. A pilot study of D-cycloserine in subjects with autistic disorder. Am J Psychiatry 2004; 161: 2115–7.
178. Goff DC, Herz L, Posever T, et al. A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Berl) 2005; 179: 144–50.
179. Moskal JR, Burgdorf J, Kroes RA, Brudzynski SM, Panksepp J. A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism. Neurosci Biobehav Rev 2011; 35: 1982–8.
180. Berk M, Copolov D, Dean O, et al. N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 2008; 64: 361–8.
181. Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry 2008; 64: 468–75.
182. Berk M, Dean O, Cotton SM, et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord 2011; 135: 389–94.
183. Grant JE, Kim SW, Odlaug BL. N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry 2007; 62: 652–7.
184. Lafleur DL, Pittenger C, Kelmendi B, et al. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl) 2006; 184: 254–6.
185. Magalhaes PV, Dean OM, Bush AI, et al. N-acetylcysteine for major depressive episodes in bipolar disorder. Rev Bras Psiquiatr 2011; 33: 374–8.
186. Hardan AY, Fung LK, Libove RA, et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry 2012; 71: 956–61.
187. Berry-Kravis EM, Hessl D, Rathmell B, et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med 2012; 4: 152ra27.
188. Seaside Therapeutics. Seaside Therapeutics reports positive data from phase 2 study of STX209 in autism spectrum disorders [Press release]. 9 Sep 2010.
189. Seaside Therapeutics. Seaside Therapeutics to announce results from a phase 2b clinical trial of arbaclofen in autism spectrum disorder at the International Meeting for Autism Research (IMFAR) 2013 conference [Press release]. 1 May 2013.
190. Scott MM, Deneris ES. Making and breaking serotonin neurons and autism. Int J Dev Neurosci 2005; 23: 277–85.

anticonvulsants; antidepressants; atypical antipsychotics; autism; autism spectrum disorders; mood stabilizers; oxytocin; pervasive developmental disorders; psychopharmacology; stimulants

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