Pharmacologic treatment options for children and adolescents with autism spectrum disorder

Abstract: Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition that is often associated with severe behavioural challenges that can be as diverse in response to treatment as they are in presentation. While environmental, behavioural, communicative, therapeutic and supportive interventions are critical considerations for any individual with ASD, pharmacologic interventions are often helpful and can be necessary for improving level of functioning and quality of life. Medication treatment targets largely include frequently associated symptoms, such as irritability, or common comorbidities, such as attention deficit hyperactivity disorder (ADHD) and anxiety disorders. There is also some emerging evidence for improvement in core social impairment of ASD and some novel treatments are available, although more evidence is needed before widespread use for this indication can be recommended. In cases with symptoms refractory to first-line treatments, medications with a significant although lesser evidence base are worth consideration. It is helpful to be aware of the ever-changing treatment landscape and its potential risks and benefits when reviewing and monitoring pharmacologic options with patients and families. The goal of this review is to provide an overview of the evidence base to date for medication management of common symptom clusters in ASD, with a focus on the United States.
Keywords: A ntipsychotics, autism, autism spectrum disorder, behaviour, psychopharmacology
Original submitted:  09 February 2017; Revised submitted: 07 June 2017; Accepted for publication:  08 August 2017.

Key points

  • For children with autism who suffer from impairing psychiatric symptoms, it is important to weigh up the risks and benefits of medication options as well as to optimise non-pharmacologic interventions.
  • Awareness of the varied strengths and limitations of the current evidence base optimally informs a discussion of medication risks and benefits.
  • Irritability, aggression, and self-injurious behaviour represent the most well defined symptom cluster in ASD, with risperidone and aripiprazole carrying the strongest pharmacologic evidence for this indication.
  • Promising preliminary studies are not yet at the point of supporting routine medication use for the core social impairment symptom cluster of autism.
  • Children with comorbid ASD and ADHD generally respond well to ADHD medications, though not quite as well and with higher rates of side effects than non-autistic children with ADHD; nonetheless, these classes of medications are still reasonably effective and well tolerated, and routine use in children with comorbid autism and ADHD is justified. 

Introduction

Autism spectrum disorder (ASD), as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), is a neurodevelopmental disorder characterised by persistent difficulties in social communication and social interaction, coupled with restricted, repetitive patterns of behaviour or interest[1]
. The Centers for Disease Control and Prevention (CDC) estimate of prevalence in the United States (US) has risen to nearly 1 in 68, with the rate varying widely depending on the community studied[2]
. Additional behaviours frequently associated with ASD include aggression, self-injury and severe tantrums, which often cause families greater stress than the core features of ASD[3],[4]
. Additionally, attention deficit hyperactivity disorder (ADHD) and anxiety disorders are frequently co-morbid with ASD, which can present unique challenges for diagnosis and treatment in this population[5]
. The American Academy of Child and Adolescent Psychiatry recommends multidisciplinary assessment and treatment for individuals with ASD, including educational interventions, communication interventions, intensive and individualised behavioural interventions, and pharmacologic treatment for specific target symptoms or comorbidities when appropriate[6]
.

Challenges to pharmacologic management of behavioural symptoms in ASD include heterogeneity of presentation; high rates of psychiatric comorbidity; higher rates of adverse effects from selective serotonin reuptake inhibitors (SSRIs) and stimulants than neurotypical populations; paucity of US Food and Drug Administration (FDA) indications for medications in ASD; and difficulty in gauging treatment response and adverse effects in the context of limited communication skills, multiple informants and potential placebo-by-proxy effects[7],[8],[9],[10],[11]
. Additionally, treatment-resistant aggression and irritability in individuals with ASD is relatively common, and may require referral to a tertiary care centre and treatment with multiple medications[12]
, including multiple antipsychotics in some cases[13]
.

Pharmacists can be particularly helpful to individuals with ASD, their families and their medical providers in the following ways: education of other healthcare professionals; raising awareness of drug–drug interactions, including concurrent herbal or over-the-counter medications; ensuring appropriate dosing and administration; reporting adverse drug reactions; educating on non-tablet administration options that can be critical for compliance for many patients, including patches, liquids and chewable forms; medication monitoring including reminders of when to check laboratory test results and electrocardiograms; and ensuring adherence to the clozapine Risk Evaluation and Mitigation Strategies (REMS) programme.

This article aims to briefly review the current evidence base for common medications prescribed or indicated for treatment of symptom clusters and common comorbidities of ASD with a focus on the US. Some medications that show promise for future use are also included. A comprehensive review of all medications that have been studied in autism or that have preliminary evidence for use for symptom clusters associated with autism is outside the scope of this article, and may be found in more comprehensive reviews[6],[7],[14]
.

Sources and selection criteria

The primary scope of this article includes randomised controlled trials (RCTs) of pharmacologic interventions for key symptom clusters in children and adolescents with ASD, focusing particularly on placebo-controlled trials in children and adolescents (Table 1). If RCTs were lacking for a medication that otherwise appears in mainstream use in treatment of patients with ASD, open-label studies were sometimes included and noted as such in the text. An initial PubMed search was conducted for RCTs in ASDs in humans written in English, using various combinations of the following search terms: ASD, autism, treatment, placebo. No age-related restriction was used in the search as the majority of the evidence was already in children and adolescents, and studies conducted in adults would still be considered for inclusion with a specifier if the general body of evidence was otherwise lacking.

Medications whose primary aim was treatment of side effects of another medication and not a key symptom cluster, such as metformin for prevention of antipsychotic-induced weight gain, were considered outside the scope of this review. Also generally excluded were studies that addressed treatment of a comorbidity in patients with ASD, such as treatment of bipolar disorder or schizophrenia in patients with ASD, as addressing all potential psychiatric comorbidities that could occur was outside the scope of the article. ADHD was an exception and was given its own section given the high rate of comorbidity, as well as some overlap in diagnostic criteria with ASD. The same rationale was used for the inclusion of anxiety disorders.

Once a particular medication was identified as appropriate for inclusion in the paper, PubMed was searched again with the initial criteria, as well as the generic name of that medication, to identify placebo-controlled RCTs pertaining to that medication that may have been missed by the original search.

Table 1: The major randomised, placebo-controlled trials (RCTs) reviewed in this article
Placebo-controlled RCT name Target symptom cluster Medication name Medication class Dose n Study duration Age range Primary endpoint measure Statistically significant treatment response — primary endpoint measure Common adverse effects (study medication > placebo) Severe adverse effects (study medication > placebo)
McCracken et al. 2002Irritability and aggressionRisperidoneAtypical antipsychotic0.5–3.5mg/day (mean dose 1.8 +/- 0.7mg/day), two divided doses1018 weeks5–17 yearsABC-I; at least 25% improvement in 69% risperidone group vs 12% placebo group; 56.9% decrease in main irritability score vs 14.1% in placebo groupYes — both primary measure aimed at irritability, as well as multiple secondary outcome measures of repetitive behaviourIncreased appetite (73%: 24% mild, 12% moderate), fatigue (59%: 47% mild, 12% moderate, subsided by week 6 in most cases), drowsiness (49%), dizziness (16%), drooling (27%), weight gain (2.7 +/- 2.9kg vs 0.8 +/- 2.2kg in placebo group)None
Shea et al. 2004Irritability and aggressionRisperidoneAtypical antipsychoticMean dose 1.17mg/day798 weeks5–12 ABC-I; 64% improvement from baseline score vs 31% in placeboYes100% experienced at least one adverse effect: somnolence (72.5%, resolved in 86.2% of cases, primarily due to changes in dose timing), upper respiratory tract infection (37.5%), rhinitis (27.5%), increased appetite (22.5%), abdominal pain (20%), weight gain (10%; average weight gain 2.7kg vs 1.0kg in placebo), tremor (10%), tachycardia (12.5%), increased average pulse rate by 8.9bpm, increased average systolic blood pressure by 4mmHg, none of cases of increased blood pressure considered clinically significantNone
Marcus et al. 2009Irritability and aggressionAripiprazoleAtypical antipsychotic5–15mg2188 weeks6–17 yearsABC-I, 12.4–14.4% reduction in ABC-I (depending on dose) vs 8.4% reduction placebo group; CGI-IYes88% on study medication experienced at least one adverse effect; sedation (24%), fatigue (15%), vomiting (13%) increased appetite (12%), tremors (10%), drooling (9%), EPS (7%), weight gain (4%)10% aripiprazole (vs 7.7% placebo) terminated treatment due to adverse effects: sedation, drooling, tremor
Owen et al. 2009Irritability and aggressionAripiprazoleAtypical antipsychotic2–15mg/day988 weeks6–17 yearsABC-I; 12.9% reduction vs 5% reduction in placebo groupNo Weight gain (29%), fatigue (21%), somnolence (17%), vomiting (15%), EPS (15%), increased appetite (15%), sedation (11%), drooling (9%), diarrhoea (9%), pyrexia (9%)10.6% aripiprazole group (vs 6% placebo) terminated treatment due to adverse events; fatigue, vomiting, weight and appetite increase
Hollander et al. 2006Irritability and aggressionOlanzapineAtypical antipsychotic7.5–12.5mg/day118 weeks6–14 yearsCGI-INo — insignificant linear trend toward improvement in CGI-I. Small, low-powered studyIncreased appetite, sedation, weight gain (7.5 +/- 4.8lbs vs 1.5 +/- 1.5lbs placebo)Two cases of severe weight gain vs zero cases with placebo
Loebel et al. 2016Irritability and aggressionLurasidoneAtypical antipsychotic20 or 60mg/day1506 weeks6–17 yearsABC-INo71% 20mg, 75% 60mg, 57% placebo group; vomiting, somnolence, nasopharyngitis, akathisia, nausea12.2% 20mg group, 2.0% 60mg group, 10.2% placebo group 
Campbell et al. 1978Behavioural problems (including restrictive/repetitive behaviour)Haloperidol (haloperidol plus behavioural therapy vs placebo plus behavioural therapy)First-generation antipsychotic1.65mg/day (0.5–4mg/day)4010 weeks2.6–7.2 yearsCPRSYes — significant improvement in stereotypy on CPRS, but only for the older subset (ages 4.5–7.2 years)Mainly excessive sedation (n=12); overall adverse effects 16 on haloperidol and 5 on placeboNot mentioned 
Anderson et al. 1984Various behavioural problems (withdrawal, stereotypes, relatedness, hyperactivity, temper tantrums)Haloperidol  (haloperidol and language training vs language training alone vs haloperidol alone)First-generation antipsychotic0.5–3.0mg/day40Alternating each 4 weeks haloperidol-placebo-haloperidol or placebo-haloperidol-placebo2.3–6.9 yearsCPRS, CGI-S, CGI-I, Conners parent-teacher questionnaireYes — haloperidol and language training superior to either language training alone or haloperidol aloneSedation (78%), irritability(28%), EPS (>25%)None
Anderson et al. 1989Various behavioural problems (withdrawal, stereotypes, relatedness, hyperactivity, temper tantrums)HaloperidolFirst-generation antipsychotic0.8 +/- 0.6mg/day (0.25–4.0mg/day)454 weeks (on study medication)2.02–7.58 yearsCPRS, CGI-S, Conners parent-teacher questionnaireYes — CPRS, CGI-S, only the temper outbursts scale of Conners parent-teacher questionnaireSedation, EPSNone
Jaselkis et al. 1992HyperactivityClonidineAlpha2 agonist0.15–0.20mg/day in 3 divided doses86 weeks5–10 yearsCPRS, ABCNo — any clinician-rated scale.  Yes — CPRS, teacher-rated ABC irritability, hyperactivity, stereotypy, inappropriate speech subscalesHypotension (25%), drowsiness (38%)None
Rezaei et al. 2010Disruptive behaviourTopiramate add-on (risperidone + topiramate vs risperidone + placebo)AntiepilepticUp to 200mg/day408 weeks3–12 yearsABC-C (community)Yes — subscale scores for irritability, stereotypic behaviour, hyperactivity/noncomplianceSomnolence (35% vs 5% control group P =0.04), decreased appetite (35% vs 5% control group, P =0.04)Not mentioned
Hellings et alIrritability and aggressionValproateAntiepileptic/ mood stabiliserVPA blood level range 58.6–101.1mcg/dL308 weeks6–20 yearsABC-C irritability subscaleNoIncreased appetite (P =0.03), skin rash (P =0.06); mean weight gain 1.98 =/- 1.88kg VPA vs 1.1 +/- 1.1kg for placeboSevere skin rash (n=1)
Hollander et al. 2010Irritability and aggressionValproateAntiepileptic/ mood stabiliserMinimum VPA trough level 50 μ/ml, maximum 110μ/ml; responder mean trough level 89.77 (31.7) higher than nonresponder mean trough level 64.33 (59.3)2712 weeksMean age 9.46 +/- 2.46 yearsABC-I, CGI-IYes Comparable to placeboIrritability (n=1), severe insomnia (n=1)
Hollander et al. 2006Repetitive behavioursValproateAntiepileptic/ mood stabiliserMean trough serum level at endpoint: 58.23 +/- 21.63μ/ml; mean dose at endpoint 822.92 +/- 326.21mg/d13 8 weeksTwelve aged 5–17 years, one aged 40CY-BOCSYes, also a large effect size (d=1.616) Any adverse event 77% divalproex vs 50% placebo, no statistically significant specific adverse eventsNone
Hardanet al. 2012Irritability and aggressionn-acetylcysteine (NAC)OTC supplement/ antioxidant900mg TID2912 weeks3–10 yearsABC-IYes (P <0.001), also notable effect size (d=.96)GI adverse events (diarrhoea, constipation, nausea and vomiting) 79% in NAC vs 47% in placeboNone
Ghanizadeh et al. 2013Irritability and aggressionn-acetylcysteine (NAC)OTC supplement/ antioxidant600mg BID318 weeks8.8 +/- 3.1 yearsABC-IYesConstipation (16.1% NAC vs 3.2% placebo); increased appetite (16.1% NAC vs 9.7% placebo); nervousness (12.9% NAC vs 0% placebo); fatigue (12.9% NAC vs 3.2% placebo); daytime drowsiness (12.9% NAC vs 6.5% placebo)None
Nikooet al. 2015Irritability and aggressionn-acetylcysteine (NAC)OTC supplement/ antioxidant600–900mg/day40 10 weeks4–12 yearsABC-C irritability subscaleYes — irritability subscale and hyperactivity/noncompliance subscalesMild and transient with no significant difference between NAC and placeboNone
Dean et al. 2016Social responsiveness and repetitive behaviourn-acetylcysteine (NAC)OTC supplement/ antioxidant500mg/day986 months3.1–9.9 yearsSocial Responsiveness Scale (SRS), Children’s Communication Checklist, Repetitive Behavior Scale-RevisedNo — not for any primary or secondary endpointNo difference between NAC and placeboNo difference between NAC and placebo
RUPP 2005ADHDMethylphenidateStimulant7.5–50mg/day, weight-based724 weeks  5–14 yearsABC-hyperactivity; CGI-IYes — also, effect size 0.20–0.54Appetite decrease (18%), difficulty falling asleep (15%), emotional outbursts (10%), irritability (10%)18% discontinued due to any adverse event, notably irritability (8%)
Handen et al. 2000ADHDMethylphenidateStimulant0.3 and 0.6mg/kg/dose, 2–3 times per day137–14 days (crossover every 7 days between low dose, high dose and placebo)5.6–11.2 years50% decrease on Conners Hyperactivity IndexYes — Conners Hyperactivity Index (61% responded) (P =0.000), Iowa (P =0.004), ABC (irritability P =0.032, stereotypy P =0.006, hyperactivity P =0.003, inappropriate speech P =0.001). No — Child Autism Rating Scale, ABC lethargy subscale (P =0.239)38% any side effect, mainly drowsiness, appearing depressed or sad; irritability at higher dose23% discontinued for severe side effects; social withdrawal, dullness, sadness, irritability, one case of skin picking; severe side effects occurred within 24 hours of a new dose
Scahill et al. 2015ADHDGuanfacineAlpha2 agonist1–4mg/day, modal dose 3mg628 weeks8.5 +/- 2.25 yearsABC-hyperactivity subscaleYes — parent-rated ABC-hyperactivity subscale (P <0.001, effect size=1.67); clinician-rated ADHD rating scale (P <0.001 all three measures)Statistically significant adverse events included slightly lower blood pressure and pulse rate; drowsiness (86.7%), fatigue (63.3%), decreased appetite (43.3%), emotional/tearful (40%), dry mouth (40%), irritability (36.7%), anxiety (30%), mid-sleep awakening (30%)One case of sudden severe aggression
Harfterkamp et al. 2012ADHDAtomoxetineNorepinephrine reuptake inhibitor1.2mg/kg/day in 2 divided doses978 weeks6–17 yearsADHD-RSYes — ADHD-RS — overall (P <0.001), inattention (P =0.003), hyperactivity–impulsivity (P <0.001), CTRS-R:S teacher-rated hyperactivity (P =0.024). No — CTRS-R:S teacher-assessed cognitive problems/inattention, oppositional problems, and ADHD symptoms; clinical global improvement — ADHD81% any adverse effect vs 65.3% in placebo group (P =0.11); nausea/vomiting (29%), decreased appetite (27%), fatigue (23%), early morning awakening (10%)None
Arnold et al. 2006ADHDAtomoxetineNorepinephrine reuptake inhibitorMean highest dose 44.2 +/- 21.9mg/day; maximum 1.4mg/kg/day, or 1.2mg/kg/day if taking a significant CYP2D6 inhibitor166 weeks5–15 yearsABC-hyperactivity subscaleYes — ABC-hyperactivity subscale (P =0.043, effect size d=0.90)Mild stomach upset or nausea/vomiting (100% vs 31% placebo, P =0.006); fatigue (75% vs 44% placebo, P =0.004); racing heart (25% vs 0% placebo, P =0.048); significantly higher pulse in atomoxetine group (6–8bpm)One patient (7%) disontinued due to intolerable side effects. This patient was rehospitalised for recurrent violence after ziprasidone, a concurrent medication on which aggression had previously been stable following a previous history of hospitalisation for aggression, was decreased (connection to study medication not clear)
Handenet al. 2015ADHDAtomoxetine, parent training and their combination (ATX, ATX + PT, placebo + PT, or placebo)Norepinephrine reuptake inhibitorMaximum dose 1.8mg/kg/day.  Mean final dose in ATX arm = 1.38 +/- 0.47mg/kg/day; mean final dose in ATX+PT arm = 1.35 +/- 0.45mg/kg/day12810 weeks5.0–14.11 yearsParent-rated SNAP, CGI-IYes — SNAP (ATX, ATX + PT, placebo + PT > placebo); CGI-I noncompliance and CGI-I ADHD; HSQ score (ATX alone, ATX+PT > placebo); ABC hyperactivity/noncompliance (ATX > placebo, ATX + PT > placebo, PT > placebo); other scales (irritability, parent and teacher inappropriate speech, SSQ) PT >placeboSignificantly greater decreased appetite and abdominal pain in ATX arms than placebo armsDropout rate due to adverse effects (non-significantly) twice as large in placebo arms than ATX arms, suggesting a low likelihood of intolerable side effects. One seizure on ATX with another known cause, clinically felt to be unrelated to ATX
Erickson et al. 2014Social withdrawalAcamprosateNMDA receptor partial agonistMean final dose 1,073mg/day (range 666–1,998mg/day), or 27.9 +/- 11.3mg/kg/day (range 10.7-44.2mg/kg/day)1210 weeks (following 2 weeks placebo lead-in)5–15 yearsCGI-I, ABC-SWYes — mean ABC-SW score; SRS total raw score; ABC hyperactivity; ADHD rating scale; CGI-S75% (n=8) with mild adverse eventsNone
Aman et al. 2016Social responsiveness  MemantineNMDA receptor antagonist3–15mg/day, based on weight12112 weeks6–12 yearsCaregiver ratings on SRSNo — no significant difference in primary or secondary endpoints, except one communication measure with significant worsening in memantine vs placebo85% memantine vs 77% placebo. Notable side effects irritability (6.7% vs 3.3% placebo) and aggression (6.7% vs 4.9% placebo)One mood disorder, considered unrelated to treatment
Ghaleiha et al. 2013Irritability and aggressionMemantine add-on to risperidone (risperidone plus memantine vs risperidone plus placebo)NMDA receptor antagonistUp to 20mg/day if >40kg, up to 15mg/day if 10–40kg (memantine)4010 weeks4–12 yearsIrritability subscale of ABC-CYes — ABC-C subscale scores for irritability, stereotypic behaviour, hyperactivityNo significant difference in adverse effects between groupsNone
Minshawi et al. 2016Social skillsd-cycloserine add-on to social skills trainingNMDA receptor partial agonist50mg vs placebo 30 minutes prior to weekly social skills training sessions6710  weeks (10 doses – one dose/week prior to social skills training)5–11 years, mean age 8.56 yearsSocial Responsiveness Scale (SRS) No — difference between d-cycloserine and placebo in any primary or secondary outcome; however, as published elsewhere (Wink et al. 2017), the post-treatment observation phase of the study did demonstrate significantly more gains in the DCS group than placebo group at week 22  
Frye et al. 2016Verbal impairmentFolinic acidVitamer for folic acid2mg/kg/day4812 weeks3 years 4 months — 13 years 4 monthsAge-appropriate version of CELF (clinical evaluation of language fundamentals, PLS-5 (preschool language scales)Yes for FRAA-positive patients (P =0.02, effect size 0.91) but not FRAA-negative patients (P =0.58, effect size 0.30)None with or approaching significanceNone
Chugani et al. 2016Restricted and repetitive behaviourBuspirone5HT1A serotonin partial agonist2.5 or 5.0mg BID16624 weeks2–6 yearsADOS composite total scoreNo for primary outcome.  Yes for time-by-treatment effect of ADOS restricted and repetitive behaviour score for 2.5mg dose but not placebo or 5.0mg dosesNo significant difference in adverse effects between groupsNone

Medications (organised by targeted symptom cluster)

Irritability, aggression and self-injurious behaviour

The irritability symptom cluster includes aggression, self-injurious behaviour and severe tantrums, which are common targets for pharmacologic management for children with ASD[15]
and are often greater sources of concern than the core features of ASD[3],[4]
. Behavioural interventions can help with understanding and modifying environmental triggers for such behaviour, but aggressive behaviour can also be a major safety concern that impedes participation in needed therapeutic interventions and other meaningful activities[16]
. Reduction of severe irritability through pharmacologic management can be a major way to improve functioning and quality of life for a child with autism.

Second-generation antipsychotics

Risperidone and aripiprazole are the only medications currently FDA-approved for the treatment of irritability associated with ASD. Second-generation antipsychotics have a lower risk of dyskinesias than first-generation antipsychotics, and are currently considered first-line treatment for irritability and aggression in autism[17]
. It should be noted that controlled studies in children are largely short-term, but that longer-term side effects of antipsychotic use can include weight gain, associated metabolic risk and extrapyramidal symptoms.

Risperidone: Risperidone is FDA-approved for the treatment of irritability in ASD. Multiple large, double-blind, placebo-controlled trials have demonstrated improvements in irritability with risperidone treatment[18],[19]
, including a pivotal study by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. In this 8-week, multisite, randomised, double-blind, placebo-controlled trial in 101 children, aged 5–17 years, risperidone resulted in a large and statistically significant decrease in irritability on the Aberrant Behavior Checklist — Irritability subscale (ABC-I) compared with placebo (56.9% reduction in ABC-I with risperidone versus 14.1% reduction in ABC-I with placebo), as well as a clinical response rate of 69% with risperidone treatment versus 12% in the placebo group. Adverse effects included increased appetite, weight gain, fatigue, drowsiness, dizziness and drooling[18]
.

In an uncontrolled follow-up study of this pivotal RUPP trial, risperidone continued to be beneficial for treatment of irritability and other maladaptive behaviour when participants were assessed an average of 21 months after entry into the original study[20]
. Weight gain, increased appetite and enuresis were also associated with longer-term use[20]
.

Aripiprazole: Aripiprazole is FDA-approved for treatment of irritability in youths with ASD, with two large, placebo-controlled clinical trials in children with ASD supporting its use. One trial (n=218) saw a significant reduction in ABC-I of 12.4–14.4% (depending on dose) versus an 8.4% reduction in the placebo group. The second trial (n=98) saw a significant reduction in the ABC-I of 12.9% with aripiprazole versus 5% with the placebo group. Both trials lasted 8 weeks and were in children aged 6–17 years. Sedation, weight gain and extrapyramidal symptoms were common adverse effects in both trials[21],[22]
. Clinically significant prolactin elevation, a common concern with other antipsychotics, was less likely for aripiprazole than placebo in both Owen et al. and Marcus et al. (1 patient versus 3 patients and 0 patients versus 2 patients, respectively). In addition, aripiprazole was associated with a significant decrease in serum prolactin levels compared with placebo in Owen et al. (–6.3 aripiprazole versus 1.6ng/mL placebo) and Marcus et al. (–5.2–5.8ng/mL depending on dose, versus +0.9ng/mL placebo)[21],[22]
.

In a 52-week open-label long-term follow-up of one of these studies (n=199, youths with ASD aged 6–17 years), reductions in irritability as measured by average ABC-I scores were maintained unchanged throughout this follow-up study[23]
. Aripiprazole was generally well tolerated, although weight gain, dyslipidaemia and extrapyramidal symptoms were significant concerns with long-term use[24]
.

In a comparison trial of aripiprazole and risperidone (n=59) in which children aged 4–18 years were randomised to either medication for 2 months of treatment, a similar reduction in the ABC-I was seen with both medications, suggesting that they are similarly effective for treatment of irritability and aggression in youth with ASD. Similar rates of adverse effects were also seen, including increased appetite, drooling and drowsiness[25]
. Rates of weight gain with aripiprazole and risperidone treatment appear similar in children with ASD[26]
.

Paliperidone: Paliperidone is not FDA-approved to treat irritability in ASD, and placebo-controlled data are still needed, but preliminary open-label evidence is promising. In one small (n=25), 8-week open-label trial, 84% of participants clinically responded, having demonstrated improvement noted on both the Clinical Global Impression–Improvement scale (CGI-I) and the ABC-I. Paliperidone was well tolerated[27]
. Weight gain and prolactin elevation was substantial, but comparable to other atypical antipsychotics[27]
. In a case report, a five-year-old with ASD and severe aggression treated with paliperidone palmitate demonstrated significant improvement in aggressive behaviour with improvements noted on the ABC irritability, lethargy, stereotypy and hyperactivity subscales. The patient also had substantial weight gain, but no other notable side effects[28]
.

Quetiapine: There are no placebo-controlled trials of quetiapine for treatment of irritability in children with ASD, and there are minimal open-label data to support its use. In a small (n=9), 12-week open-label trial of quetiapine in boys aged 10–17 years with ASD, only two children responded with CGI scores of 1 (very much improved) or 2 (much improved), one child dropped out of the study due to worsened irritability, and another dropped out due to sedation[29]
. In another small (n=11), 8-week open-label trial of quetiapine in children aged 13–17 years with ASD, aggressive behaviour significantly decreased in severity and sleep disturbances significantly improved from baseline to end point. Quetiapine was well tolerated in this trial[30]
.

Olanzapine: There are minimal and equivocal data to support olanzapine as a treatment option for irritability in children with ASD. A small (n=11), double-blind, placebo-controlled pilot study of olanzapine in children aged 6–14 years with ASD demonstrated a linear trend, although insignificant, toward clinical improvement on the CGI-I. Substantial weight gain was a significant adverse effect in this study. Increased appetite and sedation were also common[31]
. There is also open-label evidence for improvement in irritability in a comparative effectiveness trial of olanzapine versus haloperidol in 12 youths (mean age 7.8 +/- 2.1 years) with ASD. In this trial, improvement on the CGI-I was seen in five out of six children in the olanzapine group and three out of six children in the haloperidol group[32]
.

Ziprasidone: Ziprasidone shows potential as a weight-neutral option for treating irritability in youths with ASD based on a small amount of open-label and retrospective evidence of effectiveness. Nine out of 12 adolescents with ASD showed clinical improvement on the CGI-I in one 6-week open-label, pilot study[33]
. Significant side effects included sedation, QTc elevation and dystonic reactions. Ziprasidone did not affect weight or prolactin levels, and total cholesterol of participants decreased. QTc interval increased by a mean of 14.7ms[33]
. In a retrospective, naturalistic review of 42 youths (mean age 11.8 years) with ASD and irritability who were treated with ziprasidone, the clinical response rate (based on CGI-I) was around 40%. Ziprasidone did not result in weight gain in this study either[34]
.

Clozapine: Prescribing and dispensing clozapine must be done through the FDA-mandated Clozapine Risk Evaluation and Mitigation Strategy (Clozapine REMS) because of the need for close monitoring for agranulocytosis. As a result of this risk, as well as other severe adverse effects such as lowered seizure threshold, cardiomyopathy and weight gain, clozapine is often reserved as a “last resort” medication. Although clozapine has excellent evidence for treatment-resistant schizophrenia[35]
, evidence for treatment of aggression in ASD, however promising and well tolerated, is limited to a six-patient chart review[36]
and case reports/case series[37],[38],[39],[40]
.

Lurasidone: Lurasidone is the only atypical antipsychotic with a negative placebo-controlled trial targeting irritability in ASD. Lurasidone has been demonstrated through a 6-week, 150-patient, multi-centre, double-blind, placebo-controlled trial to not improve irritability in children and adolescents with ASD, arguing against its use for this indication[41]
.

First-generation antipsychotics

Haloperidol: The short-term safety and efficacy of haloperidol in youths with ASD for behavioural symptom reduction and general clinical improvement has been demonstrated in multiple placebo-controlled studies[42],[43],[44],[45]
, an open-label study[46]
and a significant comparative effectiveness trial versus olanzapine (described above)[32]
. In a notable double-blind, placebo-controlled trial of haloperidol in children aged 2.3–6.9 years with ASD (n=40), CGI-I scores were superior in haloperidol and language training versus language training alone[44]
. Sedation[32],[43],[44],[45],[46]
and weight gain[32]
were common adverse effects, however, in general, haloperidol tended to be well tolerated overall in short-term studies. Extrapyramidal symptoms were observed as an adverse effect in two short-term studies[43],[44]
. Dyskinesias and withdrawal dyskinesias have been reported with longer-term haloperidol use in children with ASD[47]
.

Non-antipsychotic medications

Alpha-2 agonists: Alpha-2 agonists are currently primarily used to treat hyperactivity and impulsivity in the setting of ADHD, including ADHD that is comorbid with autism; however, clonidine may play a role in treatment of irritability in some individuals with ASD[16]
. In a 6-week placebo-controlled trial of clonidine in eight children (aged 5–10 years) with ASD, teacher-rated (but not clinician-rated) improvement in hyperactivity, irritability and stereotypy was noted[48]
. Clonidine also correlated with small improvements in aggression in an open-label, retrospective review of 19 children with ASD[49]
.

Lithium: Lithium is not considered first-line treatment for ASD-associated irritability[7]
, but there is some evidence to support its use, particularly in the case of comorbid mood symptoms. In a retrospective chart review of youths with ASD treated as inpatients, 43% of the 30 patients studied showed significant clinical improvement. The response rate was higher (71%) for children with significant mood disorder symptoms prior to treatment, especially those more specific for bipolar disorder (mania, euphoria). Regarding tolerability, 47% of youths with ASD taking lithium reported at least one side effect[50]
.

There are additionally two case reports of dramatic response to lithium in adolescents with ASD and a deletion in SHANK3 on chromosome 22q13.3, associated with Phelan-McDermid Syndrome. Both patients presented with regression and catatonia-like symptoms unresponsive to benzodiazepines and returned to baseline functioning with lithium treatment[51]
. Despite its promise, lithium treatment in youths is limited by the required close monitoring of therapeutic drug levels, as well as the associated risks of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism and weight gain, particularly with longer-term treatment[52]
.

Antiepileptics: Epilepsy is commonly comorbid in ASD and the question often arises as to whether antiepileptics may have a role in treatment of behavioural symptoms associated with the condition. A meta-analysis of seven double-blind, randomised, placebo-controlled studies of antiepileptic medications in ASD (four valproate, one lamotrigine, one levetiracetam and one topiramate) targeting irritability/aggression or global improvement demonstrated no difference between medication and placebo groups for treatment of irritability/aggression or global improvement, although it was noted that medications with diverse actions were pooled in the meta-analysis and that studies were low-powered[53]
. However, the authors also note that the sparsity and small size of the anti-epileptic studies in ASD must be considered when interpreting the results of the meta-analysis[53]
.

Within the individual studies used in the meta-analysis, lamotrigine and levetiracetam did not separate from placebo, valproic acid yielded mixed results, and the topiramate study, an 8-week, double-blind combination study of topiramate and risperidone versus placebo and risperidone in children with autism (DSM-IV) aged 3–12 years, showed significant improvement in the topiramate combination group in several subscales of the ABC-C (community), including irritability, stereotypic behaviour and hyperactivity/noncompliance versus the control group. Somnolence and decreased appetite were more common in the topiramate group, with no significant difference in weight between the two groups at the end of the study. Topiramate had been slowly titrated with the intention of minimising the risk of cognitive side effects[54]
.

Valproic acid: As noted above, studies of valproate targeting irritability in ASD have produced mixed results. Valproate did not separate from a large placebo response in a randomised, double-blind, placebo-controlled trial in 30 youths (aged 6–20 years) with ASD[55]
. In another randomised, double-blind, placebo-controlled trial of valproate in 27 youths (mean age 9.46 +/- 2.46, mean nonverbal IQ 63.3 +/- 23.9) with ASD with severe irritability at baseline, valproate resulted in a statistically significant improvement in irritability global clinical response. Individuals in this study were more likely to be judged valproate responders when they were found to have higher valproate blood levels: a mean of 89.77 (31.7) in responders versus 64.33 (59.3) in non-responders. Adverse events were comparable to placebo in this trial[56]
. Valproate requires close monitoring for potentially severe and fatal adverse effects, including liver toxicity, hyperammonemia independent of liver function tests and pancreatitis. Generally, valproic acid is not considered a first- or second-line agent targeting irritability in persons with ASD.

N-Acetylcysteine (NAC): NAC is an antioxidant that helps glutathione formation and regulation of extracellular glutamate levels. Given mounting evidence of a possible role of glutathione deficiency and oxidative stress in ASD, there has been investigation into whether NAC may be helpful for treatment of irritability in youths with ASD. A pilot placebo-controlled trial of NAC in 29 autistic children, aged 3–10 years, showed improvement on the ABC-I. In this study, NAC was well tolerated, with only minor gastrointestinal adverse effects[57]
.

NAC treatment also appeared to reduce irritability as measured by the ABC-I in 2 small, double-blind, placebo-controlled trials of children with autism (aged 3.5–16 years and 4–12 years) who were already being treated with risperidone. NAC was again well tolerated in these studies[58],[59]
. A recent randomised, placebo-controlled clinical trial of NAC 500g/day for 6 months in 98 children with autism did not demonstrate any difference between NAC and placebo in social responsiveness, communication or repetitive behaviour, and also no difference between NAC and placebo in adverse effects[60]
. NAC has some promising evidence for improving irritability and likely does not improve social responsiveness or repetitive behaviour. Despite these findings, NAC is not considered a first- or second-agent for the treatment of ASD-associated irritability.

Naltrexone: Naltrexone is an opioid antagonist used in addictive disorders that has been studied as a potential treatment for self-injury in ASD. A systematic review of naltrexone treatment (n=127) versus placebo (n=27) in children with ASD across 10 different studies reviewed both published and unpublished clinical trials. The authors concluded that, overall, naltrexone appears to possibly improve irritability and hyperactivity in some children with ASD but does not improve the core features of the disorder. Sedation and weight loss were fairly common adverse effects, but naltrexone was well tolerated overall[61]
. Generally, naltrexone is of limited potential use targeting interfering behaviour associated with ASD.

Attention-deficit hyperactivity disorder (ADHD)

ADHD is commonly comorbid with ASD and can contribute to functional impairment[5]
. The two disorders have both distinct and overlapping clinical criteria and neurobiological features [62]
. Targeted treatment for comorbid ADHD is often warranted, and treatment options are similar in children with and without autism. Key points of what is known of pharmacologic treatment specific to comorbid ADHD and ASD are detailed below.

Stimulants

Only the methylphenidate (MPH) class of psychostimulant medications has been well studied for treatment of ADHD symptoms in youths with ASD. Review of the placebo-controlled trials, as well as a meta-analysis, suggest that methylphenidate may be effective for treatment of ADHD symptoms in youths with comorbid ASD in nearly 50% of cases[8],[9],[63],[64]
. Adverse effects in the studies included insomnia, appetite loss, irritability and social withdrawal[8],[9]
.

In the RUPP trial of MPH in children with autism, six of the original 72 participants discontinued the trial in the initial phase due to intolerable irritability, and 13/72 (18%) discontinued at any point for any adverse event. Irritability was a common adverse event noted in 5/66 with low dose, 8/66 with medium dose and 5/50 with high dose, versus 2/66 with placebo. Of those who completed the trial, parent-rated irritability scores did not differ between MPH and placebo[8]
. Overall, response rates were lower in the RUPP trial (49% versus 77%) and adverse event discontinuation rates much higher (13% versus 1.4%) than those noted in the Multimodal Treatment Study of Children with ADHD (MTA), a major MPH trial in children with ADHD[8],[65]
.

Additional evidence suggests that preschoolers with ASD or intellectual disability appear to have more difficulty tolerating methylphenidate, with adverse effect rates of about 50%[66]
. In children with both ASD and hyperactivity, there is some evidence for methylphenidate improving social functioning, including joint attention[67]
. In a retrospective chart review, MPH appeared significantly more helpful for comorbid ADHD in children with Asperger’s syndrome (DSM-IV) than those with pervasive developmental disorder-not otherwise specified (PDD-NOS) or autistic disorder[68]
. Results of stimulant trials in ASD warrant additional study to define who with ASD may best respond to this drug class, given the clearly reduced tolerability of stimulants in the ASD population compared with use in neurotypical youths.

Alpha-2-agonists

Guanfacine and clonidine are two alpha-2-agonists commonly used in the US to treat symptoms of ADHD. Although less studied in youths with ASD than methylphenidate, there is evidence supporting this class of medications for treatment of this target symptoms cluster.

Guanfacine: In a 62-patient, double-blind, multisite, placebo-controlled trial, guanfacine ER significantly improved hyperactivity in children (mean age 8.5 +/- 2.25) with ASD and corresponded with greater clinical global improvement[69]
. Adverse effects included sedation and decreased appetite. Blood pressure and heart rate decreased slightly in the first four weeks of treatment and returned toward baseline by eight weeks. In a smaller double-blind, crossover study of guanfacine in 11 youths (aged 5–9 years) with comorbid ASD and ADHD, treatment resulted in significant general clinical improvement and reduction in teacher-rated hyperactivity. Drowsiness/lethargy was the most prominent adverse effect[70]
. Generally, both guanfacine and guanfacine ER are commonly used agents in the treatment of ADHD in persons with ASD.

Clonidine: Evidence of clonidine’s effectiveness in youths with ASD includes an 8-patient (aged 5–10 years), placebo-controlled trial with teacher-rated (but not clinician-rated) improvement in hyperactivity, irritability and stereotypy[48]
. Hypotension was the most significant reported adverse effect[48]
. A retrospective review of clonidine use for treatment of sleep or behavioural problems in ASD indicated small behavioural improvement, decreased sleep initiation time and decreased frequency of nighttime awakening, according to parental report[49]
.

Atomoxetine: Atomoxetine has been studied for treatment of co-morbid ADHD in individuals with ASD, and appears to potentially be an effective treatment option for some individuals[64]
. Three RCTs of atomoxetine in children with ASD and comorbid ADHD showed significant improvement in hyperactive symptoms, although not inattentive symptoms[71],[72],[73]
. In one of these major trials (n=97, aged 6–17 years), the rates of general clinical improvement were quite low in the atomoxetine group (20.9%) and not statistically significantly greater than placebo (8.7%)[71]
. Response rates were more encouraging in another trial (n=128, aged 5–14 years), with a 46.9% response rate from atomoxetine versus 16.1% from placebo[73]
. Significant side effects in these studies included nausea and fatigue[71],[72],[73]
and decreased appetite and delayed sleep onset[73]
. In a 28-week, open-label, follow-up study (n=88, aged 6–17 years), ADHD symptoms continued to improve and adverse effects abated[74]
.

Repetitive behaviours

Restrictive and repetitive behaviours, interests and activities are a core symptom cluster of ASD, and can contribute to behaviour problems, difficulty with transitions and impairment of overall functioning. Few medications have shown a significant impact on this behavioural symptom cluster, although risperidone, haloperidol and atomoxetine may be helpful for some individuals. In an 8-week, double-blind, placebo-controlled trial (n=101) of risperidone targeting irritability in youths (aged 5–17 years) with ASD, significant improvement was seen in multiple secondary outcome measures of maladaptive repetitive behaviour, such as improvement in a modified Ritvo-Freeman Real Life Rating Scale subscale that focused on sensory motor behaviours (effect size 0.45), and improvement in the maladaptive behaviour domain of the Vineland Adaptive Behavior Scales (effect size 1.03)[75]
.

Additionally, haloperidol treatment coincided with a significant reduction in stereotypic movements in an older subset of children (aged 4.5–7.2 years) in a small, placebo-controlled trial (n=18)[45]
. A placebo-controlled trial of atomoxetine for children with comorbid ASD and ADHD demonstrated improvement in the ABC stereotypic behaviour subscale[76]
. A small (n=13), 8-week, double-blind, placebo-controlled trial of divalproex sodium targeting repetitive behaviours in children and one adult with autism spectrum disorders (aged 5–17 and one 40-year-old participant) demonstrated significant improvement on the CY-BOCS with a large effect size (d=1.616)[77]
.

SSRIs and tricyclic antidepressants appear to not have a role in addressing this symptoms cluster in youth. Cochrane reviews of randomised, placebo-controlled trials of these medication classes in ASD demonstrate that these medication classes do not improve the core features including repetitive behaviours[10],[78]
. In fact, the Cochrane review of SSRIs for core features of ASD concluded that there was no clear evidence of benefit for the above indications in children, although there was some limited evidence in adults. There was emerging evidence of harm with use of SSRIs in children with ASD for these indications, as adverse effects were commonly greater than placebo despite no evidence of benefit[10]
. The authors concluded that, while SSRIs do not appear to be a treatment for core features of autism, whether or not to carefully treat a co-occurring condition such as obsessive-compulsive disorder, a mood disorder or an anxiety disorder in a person with ASD could still reasonably be made on a case-by-case basis.

Valproic acid has had mixed results regarding effect on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) in the placebo-controlled trials available to date. In one 8-week study of 13 individuals with autism (12 were ages 5–17, one was age 40; average IQ 60, range 30–104), subjects were randomised to valproic acid or placebo. Mean trough at end point was 58.23–21.63mg/ml. The study demonstrated a significant improvement in the CY-BOCS at end point, and with a large effect size of 1.616[77]
. In a later, larger study in youth with ASD with severe irritability at baseline (described in the valproic acid section above), no difference in CY-BOCS scores at end point was observed between valproic acid and placebo[56]
.

Core social impairment

Impairment in social communication and social interaction is the major core diagnostic feature of autism, resulting in impairment of functioning and quality of life. Identifying pharmacologic interventions for core social impairment has remained a challenge, despite tremendous work done in the past decade. Recent investigations have focused on glutamatergic agents such as acamprosate (see below), memantine (see below), riluzole[79]
and amantadine[80],[81]
, as well as GABA modulators such as arbaclofen[82],[83]
and bumetanide[84]
as potential treatments for ASD core social impairment via helping to restore the potential imbalance in excitatory and inhibitory neurotransmission reported in ASD. Sulforaphane, a dietary phytochemical derived from broccoli, also has some promising preliminary evidence for improving social responsiveness[85]
. Further studies are needed, but preliminary studies are promising.

Acamprosate: In an open-label pilot study in six children with ASD (aged 6–12.5 years), acamprosate corresponded with large effect sizes (1.4, 1.5 and 1.8, respectively) on the ABC social withdrawal (SW) subscale, the ABC hyperactivity subscale and the clinical global impressions-severity scale (CGI-S)[86]
. In a 12-week, single-blind, placebo lead-in pilot study, acamprosate resulted in statistically significant improvements in social withdrawal (improvement in mean ABC-SW subscale score, effect size 1.0, improvement in SRS total raw score, effect size 1.5), hyperactivity (ABC hyperactivity subscale, effect size 1.3; ADHD Rating Scale, effect size 1.7), and clinical severity (CGI-S, effect size 1.2) in 12 children (aged 5–15 years)[87]
. Acamprosate was well tolerated in both studies.

Memantine: Memantine may be an emerging treatment targeting social withdrawal[88]
, inattention[88],[89]
and anxiety[88]
in ASD, although results have been mixed overall[90]
. In a 12-week RCT of memantine in 121 children with ASD (aged 6–12 years) with a 48-week open-label extension phase, memantine was not superior to placebo regarding improvement in social responsiveness and was actually significantly inferior to placebo in a secondary communication measure[91]
. In a randomised, double-blind, placebo-controlled trial of memantine as add-on therapy to risperidone in children aged 4–12 years with ASD, treatment with memantine did not result in a significant improvement in social withdrawal or inappropriate speech, but did result in significant improvement in irritability, stereotypic behaviour and hyperactivity in the risperidone plus memantine group. Memantine was generally well tolerated in both studies[91],[92]
.

Oxytocin: The oxytocin system plays a role in human social cognition and attachment, making it a substance of great interest as potential treatment of ASD-associated core social impairment[93],[94]
. Intranasal oxytocin significantly improved caregiver-rated social responsiveness (SRS-P) in 31 children with ASD (aged 3.0–8.9 years) in a placebo-controlled, randomised, clinical crossover trial[95]
. Oxytocin influenced activity in brain regions implicated in social-emotional processing on neuroimaging of 16 children with ASD (mean age 13 years)[96]
. Oxytocin improved performance on the Reading-the-mind-in-the-eyes test and quality of life in adults with ASD, although significant improvement was not found in primary measures of social impairment[97]
. Oxytocin was well tolerated in the treatment studies[95],[97]
.

D-cycloserine: D-cycloserine is a partial NMDA agonist hypothesised as a potential autism treatment through regulation of glutamate neurotransmission. A small, single-blind pilot study of D-cycloserine suggested dose-related improvements in social withdrawal in 10 individuals (mean age 10 years, SD 7) with ASD[98]
. A subsequent 20-patient randomised, double-blind, non-placebo-controlled trial of daily versus weekly dosing of D-cycloserine in adolescents and young adults with ASD demonstrated an average 37% reduction over time in the pooled group in the ABC subscale 3, for stereotypies and repetitive movements[99]
. However, two larger randomised, double-blind, placebo-controlled trials of D-cycloserine in children with ASD failed to show any difference from placebo in any primary or secondary outcome measures of social impairment[100],[101]
.

A recent 10-week placebo-controlled trial of weekly social skills training immediately following a weekly D-cycloserine dose in 67 children with ASD (mean age 8.56 years, IQ>70 given the demands of social skills training) demonstrated no significant impact of D-cycloserine on social skills or any primary or secondary outcome at study conclusion; however, in this study, the Social Responsiveness Scale (SRS) raw score greatly improved in both groups, laying the groundwork for future D-cycloserine combination studies in ASD[100]
. In addition, published more recently, post-treatment 22-week follow-up assessments did demonstrate more sustained social skills gains in the D-cycloserine group in follow-up on the SRS with a moderate to large effect size (P =0.003, d=0.82). Participants, caregivers and investigators had remained blinded to treatment assignment until after the 22-week assessment. A pilot eye-tracking measure was also completed at weeks 11 and 22, and demonstrated increased percent time looking at the face as a whole in the DCS group at week 22 follow-up (P <0.0001)[102]
.

Verbal communication

Verbal communication impairment in ASD is primarily addressed through speech therapy, alternative communication modalities and other therapeutic interventions[6]
; however, impaired verbal communication may emerge as a target for pharmacologic management as well. Recent research has explored folinic acid as a potential treatment in ASD, given that cerebral folate deficiency appears relatively common in autism, and positive folate receptor-(alpha) autoantibody status may be dramatically more common in the ASD than non-ASD population[103]
. In a recent randomised, double-blind, placebo-controlled trial, folinic acid supplementation was shown to significantly improve verbal communication in 48 children, aged from 3 years 4 months to 13 years 4 months, with idiopathic ASD, language impairment and positive folate receptor-(alpha) autoantibody status[103]
. This work is preliminary, but future investigation of folic acid coupled with speech therapy interventions is warranted in youths with ASD and positive receptor-(alpha) autoantibody status.

Anxiety

Anxiety is a common comorbidity in ASD that can dramatically impact quality of life and overall functioning[5],[104]
. A recent review of treatment of anxiety in youths with ASD notes that, to date, there are very few studies specific to treatment of anxiety in youths with ASD, and those that have been published are short-term uncontrolled studies. In two retrospective, uncontrolled, chart-review citalopram studies focusing on anxiety in ASD (n=17, aged 4–15; n=15, aged 6–16) CGI improved over time in most patients (59%; 66%), but strength of evidence was low[105],[106]
. Fluvoxamine targeting various anxiety diagnoses in children with ASD did not correlate with improvement on CGI in the group as a whole in one open-label trial (n=18, aged 7–18), although it was noted that all four females in the trial were at least partial responders. Behavioural activation was common and resulted in discontinuation for three participants[107]
.

In an open-label study of buspirone for anxiety or irritability in children with ASD (n=22, aged 6–17), buspirone was well tolerated and benefit was unclear — 41% had a marked response and 32% had a moderate response in the CGI, with no control[108]
. Buspirone was also well tolerated in a large (n=166), 24-week, placebo-controlled trial in children aged 2–6 with ASD targeting various outcome measures, with no difference in adverse effects between buspirone and placebo[109]
. There remains no rigorous evidence base supporting buspirone use in ASD. In contrast to pharmacologic management, psychotherapy for anxiety appears to be about equally effective in individuals with higher-functioning ASD as those without ASD[104]
.

Sleep disorders

Sleep complaints are commonplace in children with ASD and appear to persist through adolescence[110]
. Children with ASD also demonstrate notable differences in sleep architecture[111]
. Parent training and behavioural approaches to promoting quality sleep are essential and considered first line in treatment of sleep disorders in children with ASD[112]
. In conjunction with behavioural approaches, melatonin may be particularly helpful as a pharmacologic approach for insomnia in ASD[113]
. Benzodiazepines and diphenhydramine can have a paradoxical effect in children with autism and worsen sleep problems[111]
. Clonidine reduced parent-reported night-time awakenings and sleep initiation time in a small retrospective review in children with ASD that has been described in greater detail above[49]
.

Discussion

While the evidence base supporting pharmacotherapy decision-making in ASD has extensively grown in recent years, several questions remain unanswered. Among target symptoms of treatment, irritability is clearly the best defined in the field. Adequate trials of risperidone and aripiprazole are the clear first steps for treating this symptom cluster in ASD. Despite clarity regarding initial approaches to irritability treatment, the field remains unclear on best evidence-based approaches to treatment-resistant irritability. Trials of third- and fourth-line second generation antipsychotics (SGAs), use of typical antipsychotics and combination antipsychotic therapy are likely next steps in irritability treatment algorithms. The field will need to continue to explore novel pharmacotherapy approaches to irritability when first-line agents fail.

In ADHD associated with autism, it is clear that stimulants have reduced tolerability in the ASD population, yet many persons with ASD will adequately respond to this drug class. However, the field remains clearly uncertain about best-practice pharmacotherapy approaches to treating the core social impairment and repetitive behaviour associated with autism. Ongoing work to parse the heterogeneity of ASD using various means, including neuroimaging, peripheral molecular study, genetic analyses and electrophysiology, among other techniques, will be necessary in the future to define subgroups within ASD that will best respond to a particular targeted treatment that may address core ASD domains.

While a common target of treatment, anxiety remains a poorly understood ASD comorbidity without a solid evidence base for prescribing. This background likely contributes to what may be overuse of agents typically used to treat anxiety in other conditions, such as SSRIs, that have demonstrated reduced tolerability and effectiveness in persons with autism. Hopefully, significant future work will continue to better characterise ASD-associated anxiety, thus leading to rigorous clinical trials focused on this important symptom cluster.

The generally off-label nature of ASD pharmacotherapy combined with drug tolerability challenges within this population renders this area of practice challenging. In the end, all pharmacotherapy in ASD must balance medication-associated risks versus the often real and significant risks of associated interfering behaviours that commonly co-occur with the disorder.

In many cases medication management is helpful or even critical when interfering symptoms are severe or resistant to behavioural intervention in persons with ASD. Many available pharmacologic treatments for symptoms associated with ASD are currently off-label. The evolving evidence base for potential risks and benefits needs to be carefully weighed for each child’s situation. In addition, given the heterogeneity of autism, more targeted interventions are needed and may be on the horizon.

Author disclosures and conflicts of interest:

The authors report no direct conflicts of interest with this report. Logan K Wink’s current research is supported by the Simons Research Foundation, Autism Speaks, Roivant Sciences Ltd and Cures Within Reach. Wink has served as a past consultant for Otsuka. Craig A Erickson is a consultant to and holds equity in Confluence Pharmaceuticals and is a consultant to Neurotrope and Fulcrum. Erickson is a past consultant to Alcobra Pharmaceuticals, the Roche Group and Novartis. He holds non-related IP held by CCHMC and Indiana University, and receives or has received research grant support from the John Merck Fund, Indiana University School of Medicine, Cincinnati Children’s Hospital Medical Center, Autism Speaks, the United States Department of Defense, the Simons Foundation, the United States Centers for Disease Control, the National Fragile X Foundation, The Roche Group, Neuren Pharmaceuticals, the National Institutes of Health and Roivant Sciences Ltd. Kelli C Dominick, Cara M Fosdick, Lynn McClellan and Ernest V Pedapati have no conflicts to report.

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References

[1] American Psychiatric Association: diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA, American Psychiatric Publishing; 2013. 

[2] Centers for Disease Control and Prevention. Autism spectrum disorder, data and statistics. Available at: http://www.cdc.gov/ncbddd/autism/data.html (accessed October 2017) 

[3] Hastings RP, Kovshoff H, Ward NJ et al. Systems analysis of stress and positive perceptions in mothers and fathers of pre-school children with autism. J Autism Dev Disord 2005;35:635–644. doi: 10.1007/s10803-005-0007-8

[4] Lecavalier L, Leone S & Wiltz J. The impact of behaviour problems on caregiver stress in young people with autism spectrum disorders. J Intellect Disabil Res 2006;50:172–183. doi: 10.1111/j.1365-2788.2005.00732.x

[5] 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;36:849–861. doi: 10.1007/s10803-006-0123-0

[6] Volkmar F, Siegel M, Woodbury-Smith M et al. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 2014;53:237–257. doi: 10.1016/j.jaac.2013.10.013

[7] Accordino RE, Kidd C, Politte LC et al. Psychopharmacological interventions in autism spectrum disorder. Expert Opin Pharmacother 2016;17:937–952. doi: 10.1517/14656566.2016.1154536

[8] Research Units on Pediatric Psychopharmacology Autism N. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 2005;62:1266–1274. doi: 10.1001/archpsyc.62.11.1266

[9] 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;30:245–255. doi: 10.1023/a:1005548619694

[10] Williams K, Brignell A, Randall M et al. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev 2013:Cd004677. doi: 10.1002/14651858.CD004677.pub3

[11] Grelotti DJ & Kaptchuk TJ. Placebo by proxy. BMJ 2011;343:d4345. doi: 10.1136/bmj.d4345

[12] Adler BA, Wink LK, Early M et al. Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: a chart review study. Autism Int J Res Pract 2015;19:102–106. doi: 10.1177/1362361314524641

[13] Wink LK, Pedapati EV, Horn PS et al. Multiple antipsychotic medication use in autism spectrum disorder. J Child Adolesc Psychopharmacol 2017;27(1):91–94. doi: 10.1089/cap.2015.0123

[14] Sung M, Chin CH, Lim CG et al. What’s in the pipeline? Drugs in development for autism spectrum disorder. Neuropsychiatr Dis Treat 2014;10:371–381. doi: 10.2147/ndt.s39516

[15] Posey DJ, Stigler KA, Erickson CA et al. Antipsychotics in the treatment of autism. J Clin Invest 2008;118:6–14. doi: 10.1172/jci32483

[16] Stigler KA & McDougle CJ. Pharmacotherapy of irritability in pervasive developmental disorders. Child Adolesc Psychiatr Clin N Am 2008;17:739–752, vii-viii. doi: 10.1016/j.chc.2008.06.002

[17] Erickson CA, Posey DJ, Stigler KA et al. Pharmacologic treatment of autism and related disorders. Pediatr Ann 2007;36:575–585. doi: 10.3928/0090-4481-20070901-09

[18] McCracken JT, McGough J, Shah B et al. Risperidone in children with autism and serious behavioral problems. New Eng J Med. 2002;347:314–321. doi: 10.1056/NEJMoa013171

[19] 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:e634–641. doi: 10.1542/peds.2003-0264-F

[20] Aman M, Rettiganti M, Nagaraja HN et al. Tolerability, safety, and benefits of risperidone in children and adolescents with autism: 21-month follow-up after 8-week placebo-controlled trial. J Child Adolesc Psychopharmacol 2015;25:482–493. doi: 10.1089/cap.2015.0005

[21] 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;48:1110–1119. doi: 10.1097/CHI.0b013e3181b76658

[22] Owen R, Sikich L, Marcus RN et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 2009;124:1533–1540. doi: 10.1542/peds.2008-3782

[23] Marcus RN, Owen R, Manos G et al. Aripiprazole in the treatment of irritability in pediatric patients (aged 6–17 years) with autistic disorder: results from a 52-week, open-label study. J Child Adolesc Psychopharmacol 2011;21:229–236. doi: 10.1089/cap.2009.0121

[24] 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;72:1270–1276. doi: 10.4088/JCP.09m05933

[25] Ghanizadeh A, Sahraeizadeh A & Berk M. A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial. Child Psychiatry Hum Dev 2014;45:185–192. doi: 10.1007/s10578-013-0390-x

[26] Wink LK, Early M, Schaefer T et al. Body mass index change in autism spectrum disorders: comparison of treatment with risperidone and aripiprazole. J Child Adolesc Psychopharmacol 2014;24:78–82. doi: 10.1089/cap.2013.0099

[27] Stigler KA, Mullett JE, Erickson CA et al. Paliperidone for irritability in adolescents and young adults with autistic disorder. Psychopharmacol 2012;223:237–245. doi: 10.1007/s00213-012-2711-3

[28] Kowalski JL, Wink LK, Blankenship K et al. Paliperidone palmitate in a child with autistic disorder. J Child Adolesc Psychopharmacol 2011;21:491–493. doi: 10.1089/cap.2011.0035

[29] Findling RL, McNamara NK, Gracious BL et al. Quetiapine in nine youths with autistic disorder. J Child Adolesc Psychopharmacol 2004;14:287–294. doi: 10.1089/1044546041649129

[30] Golubchik P, Sever J & Weizman A. Low-dose quetiapine for adolescents with autistic spectrum disorder and aggressive behavior: open-label trial. Clin Neuropharmacol 2011;34:216–219. doi: 10.1097/WNF.0b013e31823349ac

[31] 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;16:541–548. doi: 10.1089/cap.2006.16.541

[32] Malone RP, Cater J, Sheikh RM et al. Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J Am Acad Child Adolesc Psychiatry 2001;40:887–894. doi: 10.1097/00004583-200108000-00009

[33] Malone RP, Delaney MA, Hyman SB et al. Ziprasidone in adolescents with autism: an open-label pilot study. J Child Adolesc Psychopharmacol 2007;17:779–790. doi: 10.1089/cap.2006.0126

[34] Dominick K, Wink LK, McDougle CJ et al. A retrospective naturalistic study of ziprasidone for irritability in youth with autism spectrum disorder. J Child Adolesc Psychopharmacol 2015;25:397–401. doi: 10.1089/cap.2014.0111

[35] Lally J & MacCabe JH. Antipsychotic medication in schizophrenia: a review. Br Med Bull 2015;114:169–179. doi: 10.1093/bmb/ldv017

[36] Beherec L, Lambrey S, Quilici G et al. Retrospective review of clozapine in the treatment of patients with autism spectrum disorder and severe disruptive behaviors. J Clin Psychopharmacol 2011;31:341–344. doi: 10.1097/JCP.0b013e318218f4a1

[37] Wink LK, Badran I, Pedapati EV et al. Clozapine for drug-refractory irritability in individuals with developmental disability. J Child Adolesc Psychopharmacol 2016;26:843–846. doi: 10.1089/cap.2015.0216

[38] 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. doi: 10.1089/cap.2009.0057

[39] Gobbi G & Pulvirenti L. Long-term treatment with clozapine in an adult with autistic disorder accompanied by aggressive behaviour. J Psychiatry Neurosci 2001;26:340–341. PMID: 11590976

[40] Chen NC, Bedair HS, McKay B et al. Clozapine in the treatment of aggression in an adolescent with autistic disorder. J Clin Psychiatry 2001;62:479–480. PMID: 11465533

[41] Loebel A, Brams M, Goldman RS et al. Lurasidone for the treatment of irritability associated with autistic disorder. J Autism Dev Disord 2016;46:1153–1163. doi: 10.1007/s10803-015-2628-x

[42] Campbell M, Anderson LT & Meier M. A comparison of haloperidol, behavior therapy, and their interaction in autistic children [proceedings]. Psychopharmacol Bull 1979;15:84–86. PMID: 373009

[43] Anderson LT, Campbell M, Adams P et al. The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children. J Autism Dev Disord 1989;19:227–239. PMID: 2663834

[44] Anderson LT, Campbell M, Grega DM et al. Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms. Am J Psychiatry 1984;141:1195–1202. doi: 10.1176/ajp.141.10.1195

[45] Campbell M, Anderson LT, Meier M et al. A comparison of haloperidol and behavior therapy and their interaction in autistic children. J Am Acad Child Psychiatry 1978;17:640–655. PMID: 370186

[46] Hoshino Y, Yashima Y, Ishige K et al. Effects of small doses of haloperidol on autistic children. Fukushima J Med Sci 1979;26:43–54. PMID: 521004

[47] Campbell M, Armenteros JL, Malone RP et al. Neuroleptic-related dyskinesias in autistic children: a prospective, longitudinal study. J Am Acad Child Adolesc Psychiatry 1997;36:835–843. doi: 10.1097/00004583-199706000-00022

[48] Jaselskis CA, Cook EH, Jr., Fletcher KE et al. Clonidine treatment of hyperactive and impulsive children with autistic disorder. J Clin Psychopharmacol 1992;12:322–327. PMID: 1479049

[49] Ming X, Gordon E, Kang N et al. Use of clonidine in children with autism spectrum disorders. Brain Dev 2008;30:454-460. doi: 10.1016/j.braindev.2007.12.007

[50] Siegel M, Beresford CA, Bunker M et al. Preliminary investigation of lithium for mood disorder symptoms in children and adolescents with autism spectrum disorder. J Child Adolesc Psychopharmacol 2014;24:399–402. doi: 10.1089/cap.2014.0019

[51] Serret S, Thummler S, Dor E et al. Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports. BMC Psychiatry 2015;15:107. doi: 10.1186/s12888-015-0490-1

[52] McKnight RF, Adida M, Budge K et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012;379:721–728. doi: 10.1016/s0140-6736(11)61516-x

[53] Hirota T, Veenstra-Vanderweele J, Hollander E et al. Antiepileptic medications in autism spectrum disorder: a systematic review and meta-analysis. J Autism Dev Disord 2014;44:948–957. doi: 10.1007/s10803-013-1952-2

[54] Rezaei V, Mohammadi MR, Ghanizadeh A et al. Double-blind, placebo-controlled trial of risperidone plus topiramate in children with autistic disorder. Prog Neuro-psychopharmacol Biol Psychiatry 2010;34:1269–1272. doi: 10.1016/j.pnpbp.2010.07.005

[55] 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;15:682–692. doi: 10.1089/cap.2005.15.682

[56] 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;35:990–998. doi: 10.1038/npp.2009.202

[57] Hardan AY, Fung LK, Libove RA et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry 2012;71:956–961. doi: 10.1016/j.biopsych.2012.01.014

[58] Ghanizadeh A & Moghimi-Sarani E. A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders. BMC Psychiatry 2013;13:196. doi: 10.1186/1471-244x-13-196

[59] Nikoo M, Radnia H, Farokhnia M et al. N-acetylcysteine as an adjunctive therapy to risperidone for treatment of irritability in autism: a randomized, double-blind, placebo-controlled clinical trial of efficacy and safety. Clin Neuropharmacol 2015;38:11–17. doi: 10.1097/wnf.0000000000000063

[60] Dean OM, Gray KM, Villagonzalo KA et al. A randomised, double blind, placebo-controlled trial of a fixed dose of N-acetyl cysteine in children with autistic disorder. Aust NZ J Psychiatry 2016;51(3):241–249. doi: 10.1177/0004867416652735

[61] Roy A, Roy M, Deb S et al. Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review. J Intellect Disabil Res 2015;59:293–306. doi: 10.1111/jir.12122

[62] Di Martino A, Zuo XN, Kelly C et al. Shared and distinct intrinsic functional network centrality in autism and attention-deficit/hyperactivity disorder. Biol Psychiatry 2013;74:623–632. doi: 10.1016/j.biopsych.2013.02.011

[63] Quintana H, Birmaher B, Stedge D et al. Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord 1995;25:283–294. PMID: 7559293

[64] Reichow B, Volkmar FR & Bloch MH. Systematic review and meta-analysis of pharmacological treatment of the symptoms of attention-deficit/hyperactivity disorder in children with pervasive developmental disorders. J Autism Dev Disord 2013;43:2435–2441. doi: 10.1007/s10803-013-1793-z

[65] 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;40:180–187. doi: 10.1097/00004583-200102000-00012

[66] 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;19:329–339. doi: 10.1089/cap.2008.0137

[67] Jahromi LB, Kasari CL, McCracken JT et al. Positive effects of methylphenidate on social communication and self-regulation in children with pervasive developmental disorders and hyperactivity. J Autism Dev Disord 2009;39:395–404. doi: 10.1007/s10803-008-0636-9

[68] Stigler KA, Desmond LA, Posey DJ et al. A naturalistic retrospective analysis of psychostimulants in pervasive developmental disorders. J Child Adolesc Psychopharmacol 2004;14:49–56. doi: 10.1089/104454604773840481

[69] Scahill L, McCracken JT, King BH et al.; Research Units on Pediatric Psychopharmacology Autism. Extended-release guanfacine for hyperactivity in children with autism spectrum disorder. Am J Psychiatry 2015;172:1197–1206. doi: 10.1176/appi.ajp.2015.15010055

[70] Handen BL, Sahl R & Hardan AY. Guanfacine in children with autism and/or intellectual disabilities. J Dev Behav Pediatr 2008;29:303–308. doi: 10.1097/DBP.0b013e3181739b9d

[71] 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;51:733–741. doi: 10.1016/j.jaac.2012.04.011

[72] 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;45:1196–1205. doi: 10.1097/01.chi.0000231976.28719.2a

[73] Handen BL, Aman MG, Arnold LE et al. Atomoxetine, parent training, and their combination in children with autism spectrum disorder and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2015;54:905–915. doi: 10.1016/j.jaac.2015.08.013

[74] Harfterkamp M, Buitelaar JK, Minderaa RB et al. Long-term treatment with atomoxetine for attention-deficit/hyperactivity disorder symptoms in children and adolescents with autism spectrum disorder: an open-label extension study. J Child Adolesc Psychopharmacol 2013;23:194–199. doi: 10.1089/cap.2012.0012

[75] McDougle CJ, Scahill L, Aman MG et al. Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry 2005;162:1142–1148. doi: 10.1176/appi.ajp.162.6.1142

[76] Harfterkamp M, Buitelaar JK, Minderaa RB et al. Atomoxetine in autism spectrum disorder: no effects on social functioning; some beneficial effects on stereotyped behaviors, inappropriate speech, and fear of change. J Child Adolesc Psychopharmacol 2014;24:481–485. doi: 10.1089/cap.2014.0026

[77] Hollander E, Soorya L, Wasserman S et al. Divalproex sodium vs placebo in the treatment of repetitive behaviours in autism spectrum disorder. Int J Neuropsychopharmacol 2006;9:209–213. doi: 10.1017/s1461145705005791

[78] Hurwitz R, Blackmore R, Hazell Pet al. Tricyclic antidepressants for autism spectrum disorders (ASD) in children and adolescents. Cochrane Database Syst Rev 2012:Cd008372. doi: 10.1002/14651858.CD008372.pub2

[79] Ghaleiha A, Mohammadi E, Mohammadi MR et al. Riluzole as an adjunctive therapy to risperidone for the treatment of irritability in children with autistic disorder: a double-blind, placebo-controlled, randomized trial. Paediatr Drugs 2013;15:505–514. doi: 10.1007/s40272-013-0036-2

[80] 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;40:658–665. doi: 10.1097/00004583-200106000-00010

[81] Mohammadi MR, Yadegari N, Hassanzadeh E et al. Double-blind, placebo-controlled trial of risperidone plus amantadine in children with autism: a 10-week randomized study. Clin Neuropharmacol 2013;36:179–184. doi: 10.1097/WNF.0b013e3182a9339d

[82] Veenstra-VanderWeele J, Cook EH, King BH et al. Arbaclofen in children and adolescents with autism spectrum disorder: a randomized, controlled, Phase 2 trial. Neuropsychopharmacology 2016. doi: 10.1038/npp.2016.237

[83] Erickson CA, Veenstra-Vanderweele JM, Melmed RD et al. STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study. J Autism Dev Disord 2014;44:958–964. doi: 10.1007/s10803-013-1963-z

[84] Lemonnier E, Degrez C, Phelep M et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry 2012;2:e202. doi: 10.1038/tp.2012.124

[85] Singh K, Connors SL, Macklin EA et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci USA 2014;111:15550–15555. doi: 10.1073/pnas.1416940111

[86] Erickson CA, Early M, Stigler KA et al. An open-label naturalistic pilot study of acamprosate in youth with autistic disorder. J Child Adolesc Psychopharmacol 2011;21:565–569. doi: 10.1089/cap.2011.0034

[87] Erickson CA, Wink LK, Early MC et al. Brief report: pilot single-blind placebo lead-in study of acamprosate in youth with autistic disorder. J Autism Dev Disord 2014;44:981–987. doi: 10.1007/s10803-013-1943-3

[88] Joshi G, Wozniak J, Faraone SV et al. A Prospective open-label trial of memantine hydrochloride for the treatment of social deficits in intellectually capable adults with autism spectrum disorder. J Clin Psychopharmacol 2016;36:262–271. doi: 10.1097/jcp.0000000000000499

[89] Erickson CA, Posey DJ, Stigler KA et al. A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacol 2007;191:141–147. doi: 10.1007/s00213-006-0518-9

[90] Rossignol DA & Frye RE. The use of medications approved for Alzheimer’s disease in autism spectrum disorder: a systematic review. Frontier Pediatr 2014;2:87. doi: 10.3389/fped.2014.00087

[91] Aman MG, Findling RL, Hardan AY et al. Safety and efficacy of memantine in children with autism: randomized, placebo-controlled study and open-label extension. J Child Adolesc Psychopharmacol 2016. doi: 10.1089/cap.2015.0146

[92] Ghaleiha A, Asadabadi M, Mohammadi MR et al. Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 2013;16:783–789. doi: 10.1017/s1461145712000880

[93] 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. doi: 10.1016/j.bbr.2012.08.011

[94] Teng BL, Nikolova VD, Riddick NV et al. Reversal of social deficits by subchronic oxytocin in two autism mouse models. Neuropharmacol 2016;105:61–71. doi: 10.1016/j.neuropharm.2015.12.025

[95] Yatawara CJ, Einfeld SL, Hickie IB et al. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry 2016;21:1225–1231. doi: 10.1038/mp.2015.162

[96] Gordon I, Jack A, Pretzsch CM et al. Intranasal oxytocin enhances connectivity in the neural circuitry supporting social motivation and social perception in children with autism. Sci Rep 2016;6:35054. doi: 10.1038/srep35054

[97] 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. doi: 10.1186/2040-2392-3-16

[98] Posey DJ, Kem DL, Swiezy NB et al. A pilot study of D-cycloserine in subjects with autistic disorder. Am J Psychiatry 2004;161:2115–2117. doi: 10.1176/appi.ajp.161.11.2115

[99] Urbano M, Okwara L, Manser P et al. A trial of d-cycloserine to treat the social deficit in older adolescents and young adults with autism spectrum disorders. J Neuropsychiatry Clin Neurosci 2015;27:133–138. doi: 10.1176/appi.neuropsych.13070155

[100] Minshawi NF, Wink LK, Shaffer R et al. A randomized, placebo-controlled trial of D-cycloserine for the enhancement of social skills training in autism spectrum disorders. Mol Autism 2016;7:2. doi: 10.1186/s13229-015-0062-8

[101] Posey D, Stigler KA, Erickson CA et al. A double-blind placebo-controlled study of d-cycloserine in children with autistic disorder. Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Chicago, IL. 2008. 

[102] Wink LK, Minshawi NF, Shaffer RC et al. d-Cycloserine enhances durability of social skills training in autism spectrum disorder. Mol Autism 2017;8:2. doi: 10.1186/s13229-017-0116-1

[103] Frye RE, Slattery J, Delhey L et al. Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry 2016. doi: 10.1038/mp.2016.168

[104] Vasa RA, Carroll LM, Nozzolillo AA et al. A systematic review of treatments for anxiety in youth with autism spectrum disorders. J Autism Dev Disord 2014;44:3215–3229. doi: 10.1007/s10803-014-2184-9

[105] Couturier JL & Nicolson R. A retrospective assessment of citalopram in children and adolescents with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2002;12:243–248. doi: 10.1089/104454602760386932

[106] Namerow L, Thomas P, Bostic JQ et al. Use of citalopram in pervasive developmental disorders. J Dev Behav Pediatr 2003;24:104–108. PMID: 12692455

[107] Martin A, Koenig K, Anderson GM et al. Low-dose fluvoxamine treatment of children and adolescents with pervasive developmental disorders: a prospective, open-label study. J Autism Dev Disord. 2003;33:77–85. PMID: 12708582

[108] 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;59:56–59. PMID: 9501886

[109] Chugani DC, Chugani HT, Wiznitzer M et al. Efficacy of low-dose buspirone for restricted and repetitive behavior in young children with autism spectrum disorder: a randomized trial. J Pediatr 2016;170:45–53.e41-44. doi: 10.1016/j.jpeds.2015.11.033

[110] Goldman SE, Richdale AL, Clemons T et al. Parental sleep concerns in autism spectrum disorders: variations from childhood to adolescence. J Autism Dev Disord 2012;42:531–538. doi: 10.1007/s10803-011-1270-5

[111] Devnani PA & Hegde AU. Autism and sleep disorders. J Pediatr Neurosc 2015;10:304–307. doi: 10.4103/1817-1745.174438

[112] Malow BA, Byars K, Johnson K et al. A practice pathway for the identification, evaluation, and management of insomnia in children and adolescents with autism spectrum disorders. Pediatrics 2012;130 Suppl 2:S106–124. doi: 10.1542/peds.2012-0900I

[113] Tordjman S, Najjar I, Bellissant E et al. Advances in the research of melatonin in autism spectrum disorders: literature review and new perspectives. Int J Mol Sci 2013;14:20508–20542. doi: 10.3390/ijms141020508

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The Pharmaceutical Journal, Pharmacologic treatment options for children and adolescents with autism spectrum disorder;Online:DOI:10.1211/PJ.2017.20203390

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