Pharmacotherapy
Medications cannot resolve core features of ASD.21 However, certain medications may help address associated comorbidities, such as attention-deficit/hyperactivity disorder (ADHD), depression, or others, when these conditions have not responded to nonpharmacologic interventions.7,22 Common symptoms that are often treated with pharmacotherapy include aggression, irritability, hyperactivity, attentional difficulties, tics, self-injurious behavior, obsessive-compulsive symptoms, and mood dysregulation/lability.23 Generally speaking, medications might be considered if symptoms are severe and markedly impair functioning. For mild to moderate conditions, psychotherapy and other nonpharmacologic interventions are generally considered first-line. Since none of the medications described below are specific to ASD and psychiatrists generally receive training in prescribing them for other indications, a comprehensive review of their risks and benefits is beyond the scope of this article. No psychotropic medications are known to have robust evidence for safety in preschool children with ASD, and thus are best avoided.
Antipsychotics. Risperidone (for age 5 and older) and aripiprazole (age 6 to 17) are the only medications FDA-approved for use in children and adolescents with ASD, specifically for irritability associated with ASD.21,24 These 2 second-generation antipsychotics may also assist in lowering aggression in patients with ASD.24 First-generation antipsychotics such as haloperidol have been shown to be effective for irritability and aggression in ASD, but the risk of significant adverse effects such as dyskinesias and extrapyramidal symptoms limit their use.24 Two studies (a double-blind study and an open-label extension of that study) in children and adolescents with ASD found that risperidone was more effective and better tolerated than haloperidol in behavioral measures, impulsivity, and even in the social domain.25,26 In addition to other adverse effects and risks, increased prolactin secondary to risperidone use requires close monitoring and caution.24-26 As is the case with the use of other psychotropic medications in children and adolescents, those with ASD who receive antipsychotics should also be periodically reassessed to determine the need for continued use of these medications.27 A multicenter relapse prevention RCT found no statistically significant difference in the time to relapse between aripiprazole and placebo.27 Metabolic syndrome, cardiac risks, and other risks need to be considered before prescribing an antipsychotic.28 Given their serious adverse effects profile, use should be considered only when there is severe impairment or risk of injury, after carefully weighing risks/benefits.
Medications for attentional difficulties. A multisite, randomized, placebo-controlled trial evaluating the use of extended-release guanfacine in children with ASD (N = 62) found the rate of positive response on the Clinical Global Impressions–Improvement scale was 50% for guanfacine vs 9.4% for placebo.29 Clinicians need to monitor for adverse effects of guanfacine, such as fatigue, drowsiness, lightheadedness, lowering of blood pressure and heart rate, and other effects.29 A randomized, double-blind trial of 97 children and adolescents with ASD and ADHD found that atomoxetine had moderate benefit for ADHD symptoms.30 The study reported no serious adverse effects.30 However, it is especially important to monitor for hepatic and cardiac adverse effects (in addition to monitoring for risk of increase in suicidal thoughts/behavior, as in the case of antidepressants) when using atomoxetine, in addition to other side effects and risks. Some evidence suggests that methylphenidate may be effective for attentional difficulties in children and adolescents with ASD21 but may pose a higher risk of adverse effects in this population compared with neurotypical patients.31
Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are sometimes used to reduce obsessive-compulsive symptoms, repetitive behavior, or depressive symptoms in children with ASD, but are not FDA-approved for children or adolescents with ASD. In general, there is inadequate evidence to support the use of SSRIs for ASD in children.31-34 In addition, children with ASD may be at a greater risk of adverse effects from SSRIs.32,34 Despite this, SSRIs are the most commonly prescribed psychotropic medications in children with ASD.32
An RCT examining the efficacy of fluoxetine in 158 children and adolescents with ASD found no significant difference in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score after 14 weeks of treatment; activation was a common adverse effect.35 A 2005 randomized, double-blind, placebo-controlled trial of 45 children/adolescents with ASD found that low-dose liquid fluoxetine was more effective than placebo for reducing repetitive behaviors in this population.36 Larger studies are warranted to further evaluate the efficacy and safety of fluoxetine (and of SSRIs in general, particularly in the long term) for children and adolescents with ASD.36 A 2009 randomized, placebo-controlled trial of 149 children with ASD revealed no significant difference between citalopram and placebo as measured by Clinical Global Impressions scale or CY-BOCS scores, and noted a significantly elevated likelihood of adverse effects.37
Other antidepressants. There is insufficient evidence to support the use of any other antidepressants in children and adolescents with ASD. A few studies38,39 have examined the use of venlafaxine in children with ASD; however, further research and controlled studies with large sample sizes are required to conclusively establish its benefits. There is a dearth of evidence examining the use of the tetracyclic antidepressant mirtazapine, or other classes of medications such as tricyclic antidepressants or mood stabilizers, in children with ASD; only a few small studies have assessed the efficacy and adverse effects of these medications for such patients.31
Polypharmacy. Although there is no evidence to support polypharmacy in children and adolescents with ASD, the practice appears to be rampant in these patients.28,40 A 2013 retrospective, observational study of psychotropic medication use in children with ASD (N = 33,565) found that 64% were prescribed psychotropic medications, and 35% exhibited evidence of polypharmacy.40 In this study, the total duration of polypharmacy averaged 525 days.40 When addressing polypharmacy, systematic deprescribing or simplification of the psychotropic medication regimen may be needed,28 while taking into account the patient’s complete clinical situation, including (but not limited to) tolerability of the medication regimen, presence or absence of current stressors, presence or absence of adequate supports, use of nonpharmacologic treatments where appropriate, and other factors.
More studies assessing the efficacy and safety of psychotropic medications for children and adolescents with ASD are needed,32 especially studies that evaluate the effects of long-term use, because evidence for pharmacologic treatments for children with ASD is mixed and insufficient.33 There is also a need for evidence-based standards for prescribing psychotropic medications in children and adolescents with ASD.
Psychotropic medications, if used in ASD, should be used only in conjunction with other evidence-based treatment modalities, and not as monotherapy.21 Children and adolescents with ASD may be particularly susceptible to side effects or adverse effects of certain psychotropic medications.31 When considering medications, carefully weigh the risks and benefits.7,21,24,28 Starting low and going slow is generally the preferred strategy.31,32 As always, when recommending medications, discuss in detail with parents the potential side effects, benefits, risks, interactions, and alternatives.
Other agents. Several double-blind, placebo-controlled trials have evaluated using melatonin for sleep difficulties in children and adolescents with ASD.41 A randomized, placebo-controlled, 12-week trial that assessed 160 children with ASD and insomnia found that melatonin plus cognitive-behavioral therapy (CBT) was superior in efficacy to melatonin alone, CBT alone, or placebo.41
The evidence regarding oxytocin use for children with ASD is mixed.31 Some small studies have associated improvement in the social domain with its use. Guastella et al42 conducted a randomized, double-blind, placebo-controlled trial of oxytocin nasal spray for 16 participants (age 12 to 19) with ASD, and found oxytocin enhanced emotional identification. Gordon et al43 conducted a functional MRI study of brain activity with oxytocin use in children with high-functioning ASD (N = 17). They found that oxytocin may augment “salience and hedonic evaluations of socially meaningful stimuli in children with ASD” and thus help social attunement. Further research is needed to evaluate the impact of oxytocin on social behavior.
Complementary and alternative medicine. Although there is limited and inconclusive evidence about the use of complementary and alternative medicine in children and adolescents with ASD, these therapies continue to be commonly used.44-46 A recent survey of parents (N = 211) of children with ASD from academic ASD outpatient clinics in Germany found that 46% reported their child was using or had used some type of complementary and alternative medicine.44 There is inadequate evidence to support the use of a gluten-free, casein-free diet for children/adolescents with ASD.46 A recent cross-sectional study assessing supplement use in 210 children with ASD in Canada found that 75% used supplements, such as multivitamins (77.8%), vitamin D (44.9%), omega 3 (42.5%), probiotics (36.5%), and magnesium (28.1%), despite insufficient evidence to support their safety or efficacy for children with ASD.47 Importantly, 33.5% of parents in this study reported that they did not inform the physician about all their child’s supplements.47 Some of the reasons the parents in this study provided for not disclosing information about supplements to their physicians were “physician lack of knowledge,” “no benefit,” “too time-consuming,” and “scared of judgment.”47 Semi-structured interviews of parents of 21 children with ASD in Australia revealed that parents found information on complementary and alternative medicine and therapies complex and often conflicting.45 In addition to recommendations from health care professionals, evidence suggests that parents often consider the opinions of media, friends, and family when making a decision on using complementary and alternative medicine modalities for children/adolescents with ASD.46 Such findings can inform physician practices regarding supplement use, and highlight the need to educate parents about the evidence regarding these therapies and potential adverse effects and interactions of such therapies,46 along with the need to develop a centralized, evidence-based resource for parents regarding their use.45
Omega 3 supplementation has in general shown few adverse effects47; still, risks/benefits need to be weighed before use. Some evidence suggests that it may decrease hyperactivity in children with ASD.31,48 However, further research, particularly controlled trials with large sample sizes, are needed for a definitive determination of efficacy.31,48 A meta-analysis that included 27 RCTs assessing the efficacy of dietary interventions for various ASD symptoms found that omega 3 supplementation was more effective than placebo, but compared with placebo, the effect size was small.49 A RCT of 73 children with ASD in New Zealand found that omega 3 long chain polyunsaturated fatty acids may benefit some core symptoms of ASD; the authors suggested that further research is needed to conclusively establish efficacy.50
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