Autism Spectrum Disorder – Types, Causes, Treatment

Autism spectrum disorder (ASD) refers to a complex group of generally lifelong developmental disorders, usually diagnosed in childhood. Characteristics of ASD may include problems communicating; difficulty relating to people, things, and events; repetitive movements or behaviors; and difficulty adjusting to unfamiliar surroundings or routines. ASD is called a “spectrum” disorder because it can cause very different symptoms. Some people have mild symptoms and others have much more severe ones. Estimates of autism vary and prevalence studies in the United States have looked only at children, but the most recent U.S. Government statistics estimate that about 1 in 68 children has ASD. It’s 4.5 times more common among boys than girls.

Causes of Autism Spectrum Disorder

Treatment

Irritability, aggression, and self-injurious behavior

The irritability symptom cluster includes aggression, self-injurious behavior, and severe tantrums, which are common targets for pharmacologic management for children with ASD and are often greater sources of concern than the core features of ASD. Behavioral interventions can help with understanding and modifying environmental triggers for such behavior, but aggressive behavior can also be a major safety concern that impedes participation in needed therapeutic interventions and other meaningful activities. 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. 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, including a pivotal study by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. In this 8-week, multisite, randomized, 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.

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

Aripiprazole

Aripiprazole is FDA-approved for the 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. 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).

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. Aripiprazole was generally well tolerated, although weight gain, dyslipidemia, and extrapyramidal symptoms were significant concerns with long-term use.

In a comparison trial of aripiprazole and risperidone (n=59) in which children aged 4–18 years were randomized 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 the treatment of irritability and aggression in youth with ASD. Similar rates of adverse effects were also seen, including increased appetite, drooling, and drowsiness. Rates of weight gain with aripiprazole and risperidone treatment appear similar in children with ASD.

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. Weight gain and prolactin elevation were substantial but comparable to other atypical antipsychotics. In a case report, a five-year-old with ASD and severe aggression treated with paliperidone palmitate demonstrated significant improvement in aggressive behavior with improvements noted on the ABC irritability, lethargy, stereotype, and hyperactivity subscales. The patient also had substantial weight gain, but no other notable side effects.

Quetiapine

There are no placebo-controlled trials of quetiapine for the 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. In another small (n=11), 8-week open-label trial of quetiapine in children aged 13–17 years with ASD, aggressive behavior significantly decreased in severity, and sleep disturbances significantly improved from baseline to endpoint. Quetiapine was well tolerated in this trial.

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 in the CGI-I. Substantial weight gain was a significant adverse effect? in this study. Increased appetite and sedation were also common. 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, an improvement in 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.

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 in the CGI-I in one 6-week open-label, pilot study. Significant side effects included sedation, QTc elevation, and dystonic reactions. Ziprasidone did not affect weight or prolactin levels, and the total cholesterol? of participants decreased. QTc interval increased by a mean of 14.7ms. 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.

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, evidence for treatment of aggression in ASD, however promising and well-tolerated, is limited to a six-patient chart review and case reports/case series.

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-center, double-blind, placebo-controlled trial to not improve irritability in children and adolescents with ASD, arguing against its use for this indication.

First-generation antipsychotics

Haloperidol

The short-term safety and efficacy of haloperidol in youths with ASD for behavioral symptom reduction and general clinical improvement have been demonstrated in multiple placebo-controlled studies, an open-label study, and a significant comparative effectiveness trial versus olanzapine (described above). 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. Sedation and weight gain 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. Dyskinesias and withdrawal dyskinesias have been reported with longer-term haloperidol use in children with ASD.

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 which is comorbid with autism; however, clonidine may play a role in the treatment of irritability in some individuals with ASD. 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. Clonidine also correlated with small improvements in aggression in an open-label, retrospective review of 19 children with ASD.

Lithium

Lithium is not considered a first-line treatment for ASD-associated irritability 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 before 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?.

There are additionally two case reports of dramatic response to lithium in adolescents with ASD and 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. 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, thyroid? gland makes too little hormone. সহজ বাংলা: থাইরয়েড হরমোন কম।" data-rx-term="hypothyroidism" data-rx-definition="Hypothyroidism means the thyroid gland makes too little hormone. সহজ বাংলা: থাইরয়েড হরমোন কম।">hypothyroidism?, hyperparathyroidism, and weight gain, particularly with longer-term treatment.

Antiepileptics

Epilepsy is commonly comorbid in ASD and the question often arises as to whether antiepileptics may have a role in the treatment of behavioral symptoms associated with the condition. A meta-analysis of seven double-blind, randomized, placebo-controlled studies of antiepileptic medications in ASD (four valproates, 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. 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.

Within the individual studies used in the meta-analysis, lamotrigine and levetiracetam did not separate from the 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 behavior 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 to minimize the risk of cognitive side effects.

Valproic acid

As noted above, studies of valproate targeting irritability in ASD have produced mixed results. Valproate did not separated from a large placebo response in a randomized, double-blind, placebo-controlled trial in 30 youths (aged 6–20 years) with ASD. In another randomized, 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. 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 the mounting evidence of a possible role of glutathione deficiency and oxidative stress in ASD, there has been an investigation into whether NAC may be helpful for the treatment of irritability in youths with ASD. A pilot placebo-controlled trial of NAC in 29 autistic children, aged 3–10 years, showed improvement in the ABC-I. In this study, NAC was well tolerated, with only minor gastrointestinal adverse effects.

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. A recent randomized, 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 behavior, and also no difference between NAC and placebo in adverse effects. NAC has some promising evidence for improving irritability and likely does not improve social responsiveness or repetitive behavior. 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 have 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. Generally, naltrexone is of limited potential use in targeting interfering behavior associated with ASD.

Attention-deficit hyperactivity disorder (ADHD)

ADHD is commonly comorbid with ASD and can contribute to functional impairment. The two disorders have both distinct and overlapping clinical criteria and neurobiological features. 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 the treatment of ADHD symptoms in youths with ASD. A review of the placebo-controlled trials, as well as a meta-analysis, suggests that methylphenidate may be effective for the treatment of ADHD symptoms in youths with comorbid ASD in nearly 50% of cases. Adverse effects in the studies included insomnia, appetite loss, irritability, and social withdrawal.

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 a low dose, 8/66 with a medium dose, and 5/50 with a high dose, versus 2/66 with a placebo. Of those who completed the trial, parent-rated irritability scores did not differ between MPH and placebo. 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.

Additional evidence suggests that preschoolers with ASD or intellectual disabilities appear to have more difficulty tolerating methylphenidate, with adverse effect? rates of about 50%. In children with both ASD and hyperactivity, there is some evidence for methylphenidate improves social functioning, including joint attention. 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. Results of stimulant trials in ASD warrant additionastudiesdy to define who with ASD may best respond to this drug class, given the 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 the treatment of this target symptoms cluster.

Guanfacine

In a 62-patient, double-blind, multi-site, 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. 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?. 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. Hypotension? was the most significant reported adverse effect?. A retrospective review of clonidine use for the treatment of sleep or behavioral problems in ASD indicated small behavioral improvement, decreased sleep initiation time, and decreased frequency of nighttime awakening, according to parental report.

Atomoxetine

Atomoxetine has been studied for the treatment of co-morbid ADHD in individuals with ASD and appears to potentially be an effective treatment option for some individuals. Three RCTs of atomoxetine in children with ASD and comorbid ADHD showed significant improvement in hyperactive symptoms, although not inattentive symptoms 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%). 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. Significant side effects in these studies included nausea? and fatigue? and decreased appetite and delayed sleep onset. In a 28-week, open-label, a follow-up study (n=88, aged 6–17 years), ADHD symptoms continued to improve and adverse effects abated.

Repetitive behaviors

Restrictive and repetitive behaviors, interests, and activities are a core symptom cluster of ASD and can contribute to behavior problems, difficulty with transitions, and impairment of overall functioning. Few medications have shown a significant impact on this behavioral 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 behavior, such as improvement in a modified Ritvo-Freeman Real Life Rating Scale subscale that focused on sensory-motor behaviors (effect size 0.45), and improvement in the maladaptive behavior domain of the Vineland Adaptive Behavior Scales (effect size 1.03).

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). A placebo-controlled trial of atomoxetine for children with comorbid ASD and ADHD demonstrated improvement in the ABC stereotypic behavior subscale. A small (n=13), 8-week, double-blind, placebo-controlled trial of divalproex sodium targeting repetitive behaviors in children and one adult with autism spectrum disorders (aged 5–17 and one 40-year-old participants) demonstrated significant improvement on the CY-BOCS with a large effect size (d=1.616).

SSRIs and tricyclic antidepressants appear to not have a role in addressing this symptoms cluster in youth. Cochrane reviews of randomized, placebo-controlled trials of these medication classes in ASD demonstrate that these medication classes do not improve the core features including repetitive behaviors. 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 the use of SSRIs in children with ASD for these indications, as adverse effects were commonly greater than placebo despite no evidence of benefit. 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 the 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 randomized to valproic acid or placebo. The mean trough at the endpoint was 58.23–21.63mg/ml. The study demonstrated a significant improvement in the CY-BOCS at the endpoint, with a large effect size of 1.616. 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 the endpoint was observed between valproic acid and placebo.

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, and amantadine as well as GABA modulators such as baclofen and bumetanide 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. 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). 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). Acamprosate was well tolerated in both studies.

Memantine

Memantine may be an emerging treatment targeting social withdrawal, inattention, and anxiety in ASD, although results have been mixed overall. 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 significantly inferior to placebo in a secondary communication measure. In a randomized, 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 behavior, and hyperactivity in the risperidone plus memantine group. Memantine was generally well-tolerated in both studies.

Oxytocin

The oxytocin system plays a role in human social cognition and attachment, making it a substance of great interest as a potential treatment of ASD-associated core social impairment. 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, randomized, clinical crossover trial. Oxytocin-influenced activity in brain regions implicated in social-emotional processing on neuroimaging of 16 children with ASD (mean age 13 years). Oxytocin improved performance on the Reading-the-mind-in-the-eyes test and quality of life in adults with ASD, although a significant improvement was not found in primary measures of social impairment. Oxytocin was well tolerated in the treatment studies.

D-cycloserine

D-cycloserine is a partial NMDA agonist hypothesized as a potential autism treatment through the 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. A subsequent 20-patient randomized, 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. However, two larger randomized, 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.

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. 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 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).

Verbal communication

Verbal communication impairment in ASD is primarily addressed through speech therapy, alternative communication modalities, and other therapeutic interventions; 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. In a recent randomized, 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. This work is preliminary, but the 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 the quality of life and overall functioning. A recent review of the treatment of anxiety in youths with ASD notes that, to date, there are very few studies specific to the 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 the strength of evidence was low. Fluvoxamine targeting various anxiety diagnoses in children with ASD did not correlate with improvement in 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. Behavioral activation was common and resulted in discontinuation for three participants.

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 the benefit was unclear — 41% had a marked response and 32% had a moderate response in the CGI, with no control. 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. There remains no rigorous evidence base supporting buspirone use in ASD. In contrast to pharmacologic management, psychotherapy for anxiety appears to be equally effective in individuals with higher-functioning ASD as those without ASD.

Sleep disorders

Sleep complaints are commonplace in children with ASD and appear to persist through adolescence. Children with ASD also demonstrate notable differences in sleep architecture. Parent training and behavioral approaches to promoting quality sleep are essential and considered the first line in the treatment of sleep disorders in children with ASD. In conjunction with behavioral approaches, melatonin may be particularly helpful as a pharmacologic approach for insomnia in ASD. Benzodiazepines and diphenhydramine can have a paradoxical effect on children with autism and worsen sleep problems. 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.

Behavioral Approaches

Behavioral approaches focus on changing behaviors by understanding what happens before and after the behavior. Behavioral approaches have the most evidence for treating symptoms of ASD. They have become widely accepted among educators and healthcare professionals and are used in many schools and treatment clinics. A notable behavioral treatment for people with ASD is called Applied Behavior Analysis (ABA). ABA encourages desired behaviors and discourages undesired behaviors to improve a variety of skills. Progress is tracked and measured.

Two ABA teaching styles are Discrete Trial Training (DTT) and Pivotal Response Training (PRT).

• DTT uses step-by-step instructions to teach a desired behavior or response. Lessons are broken down into their simplest parts and desired answers and behaviors are rewarded. Undesired answers and behaviors are ignored.
• PRT takes place in a natural setting rather than a clinical setting. The goal of PRT is to improve a few “pivotal skills” that will help the person learn many other skills. One example of a pivotal skill is initiating communication with others.

Developmental Approaches

Developmental approaches focus on improving specific developmental skills, such as language skills or physical skills, or a broader range of interconnected developmental abilities. Developmental approaches are often combined with behavioral approaches.

The most common developmental therapy for people with ASD is Speech and Language Therapy. Speech and Language Therapy helps to improve the person’s understanding and use of speech and language. Some people with ASD communicate verbally. Others may communicate through the use of signs, gestures, pictures, or an electronic communication device.

Occupational Therapy teaches skills that help the person live as independently as possible. Skills may include dressing, eating, bathing, and relating to people. Occupational therapy can also include:

• Sensory Integration Therapy to help improve responses to sensory input that may be restrictive or overwhelming.
• Physical Therapy? can help improve physical skills, such as fine movements of the fingers or larger movements of the trunk and body.

The Early Start Denver Model (ESDM) is a broad developmental approach based on the principles of Applied Behavior Analysis. It is used with children 12-48 months of age. Parents and therapists use play, social exchanges and shared attention in natural settings to improve language, social, and learning skills.

Educational Approaches

Educational treatments are given in a classroom setting. One type of educational approach is the Treatment and Education of Autistic and Related Communication-Handicapped Children (TEACCH) approach. TEACCH is based on the idea that people with autism thrive on consistency and visual learning. It provides teachers with ways to adjust the classroom structure and improve academic and other outcomes. For example, daily routines can be written or drawn and placed in clear sight. Boundaries can be set around learning stations. Verbal instructions can be complemented with visual instructions or physical demonstrations.

Social-Relational Approaches

Social-relational treatments focus on improving social skills and building emotional bonds. Some social-relational approaches involve parents or peer mentors.

• The Developmental, Individual Differences, Relationship-Based model (also called “Floor time”) encourages parents and therapists to follow the interests of the individual to expand opportunities for communication.
• The Relationship Development Intervention (RDI) model involves activities that increase motivation, interest, and ability to participate in shared social interactions.
• Social Stories provide simple descriptions of what to expect in a social situation.
• Social Skills Groups provide opportunities for people with ASD to practice social skills in a structured environment.

Psychological Approaches

Psychological approaches can help people with ASD cope with anxiety, depression, and other mental health issues. Cognitive-Behavior Therapy (CBT) is one psychological approach that focuses on learning the connections between thoughts, feelings, and behaviors. During CBT, a therapist and the individual work together to identify goals and then change how the person thinks about a situation to change how they react to the situation.

Complementary and Alternative Treatments

Some individuals and parents use treatments that do not fit into any of the other categories. These treatments are known as Complementary and Alternative treatments. Complementary and alternative treatments are often used to supplement more traditional approaches. They might include special diets, herbal supplements, chiropractic care, animal therapy, art therapy, mindfulness, or relaxation therapies. Individuals and families should always talk to their doctor before starting a complementary and alternative treatment.

References