Psychiatric Annals

CME Article 

Psychopharmacology of Autism Spectrum Disorder

Joseph L. Calles Jr., MD

Abstract

People with autism spectrum disorder (ASD) are at high risk for co-occurring psychiatric and behavioral disorders. Risperidone and aripiprazole are approved by the US Food and Drug Administration for the treatment of irritable mood-associated problems (eg, aggression, self-injury, tantrums, and mood lability) in youth with ASD. Several other medications have been used as adjuncts to risperidone, with some evidence for reduction in irritability and hyperactivity. To date, there are no medications that have been consistently effective in treating the core social and communication deficits seen in people with ASD. There are, however, two investigational drugs that have shown promise in that regard, and they are, or will soon be, in phase III trials. This article presents a brief overview of current and potential psychopharmacologic agents used in the treatment of psychiatric comorbidities in people with ASD. [Psychiatr Ann. 2019;49(3):120–124.]

Abstract

People with autism spectrum disorder (ASD) are at high risk for co-occurring psychiatric and behavioral disorders. Risperidone and aripiprazole are approved by the US Food and Drug Administration for the treatment of irritable mood-associated problems (eg, aggression, self-injury, tantrums, and mood lability) in youth with ASD. Several other medications have been used as adjuncts to risperidone, with some evidence for reduction in irritability and hyperactivity. To date, there are no medications that have been consistently effective in treating the core social and communication deficits seen in people with ASD. There are, however, two investigational drugs that have shown promise in that regard, and they are, or will soon be, in phase III trials. This article presents a brief overview of current and potential psychopharmacologic agents used in the treatment of psychiatric comorbidities in people with ASD. [Psychiatr Ann. 2019;49(3):120–124.]

There is, perhaps, no other neurodevelopmental condition that is as perplexing as autism spectrum disorder (ASD). Much of this perplexity is related to the limited number of psychopharmacological options available for the treatment of the core and comorbid symptoms of ASD. The primary interventions are social and behavioral in nature and are generally provided by nonphysician therapists. Formal psychiatric evaluation and treatment, often involving psychopharmacologic agents, is generally instituted when comorbid behavioral and/or psychiatric disorders are identified, or when affected people are not responding to psychosocial treatments.1,2 To date, there are no medications that have been shown to be consistently effective in treating the core symptoms of ASD—persistent deficits in social communication and social interaction, and restricted, repetitive patterns of behavior, interests, or activities.3 This article presents an overview of the psychiatric comorbidity seen in people with ASD, psychotropic medications that may be used to treat those comorbid conditions, and investigational agents that may hold some promise for the treatment of the core features of ASD.

Co-Occurring Psychiatric Conditions in Autism Spectrum Disorder

It has been known for some time that people with ASD are at risk for developing symptoms of other psychiatric disorders, often at rates greater than the general population.4,5Table 1 lists the most common co-occurring psychiatric diagnoses identified in this population.

Prevalence Rates of Co-Occurring Psychiatric Disorders in Children and Adolescents with Autism Spectrum Disorder

Table 1.

Prevalence Rates of Co-Occurring Psychiatric Disorders in Children and Adolescents with Autism Spectrum Disorder

In addition to psychiatric disorders, people with ASD also routinely present to clinical settings with problematic behaviors. One of the more serious behavioral issues seen in people with ASD is aggression, which frequently leads to emergency department visits, psychiatric hospitalizations, and/or out-of-home placements. Because aggressive behavior is a symptom of an underlying disorder, it is incumbent on clinicians to fully assess patients for co-occurring and potentially treatable medical and/or psychiatric disorders.6 Self-injurious behaviors (ie, aggression towards the self) are also common in people with ASD and may also be external manifestations of undetected physical or emotional disorders.7 Finally, sleep problems are common in children and adolescents with ASD and can contribute to behavioral problems, attentional difficulties, and impairments in social interactions.8

Psychopharmacologic Agents in Autism Spectrum Disorder

Antipsychotics

The atypical or second-generation antipsychotics (SGAs) are the most common psychotropic medications prescribed to young people with ASD and, to date, are the most effective in treating the irritability associated with ASD,9 even in people who are on the higher end of the ASD spectrum.10 Two SGAs, risperidone and aripiprazole, are approved by the US Food and Drug Administration (FDA) for the treatment of irritability (which includes aggression towards others, deliberate self-injury, temper tantrums, and rapid changes in moods) associated with ASD.2

Risperidone. A systematic review of risperidone in children and adolescents with ASD found it to be efficacious in the treatment of “behavioral problems” during short-term, long-term, and withdrawal phases.11 Although acceptability of risperidone was comparable to that of placebo, tolerability was also not significantly different from that of placebo. Some potential adverse effects from risperidone are listed in Table 2. Recommended dosing for risperidone in ASD is shown in Table 3.

Potential Adverse Effects from Selected Antipsychotics

Table 2.

Potential Adverse Effects from Selected Antipsychotics

Dosing of Antipsychotics for the Treatment of Irritability Associated with Autism Spectrum Disorder

Table 3.

Dosing of Antipsychotics for the Treatment of Irritability Associated with Autism Spectrum Disorder

Aripiprazole. In a head-to-head comparison with risperidone, there were no statistical differences in aripiprazole's reduction of irritability and agitation, lethargy and social withdrawal, stereotypic behavior, hyperactivity and noncompliance, and inappropriate speech scores.12 There was also no significant difference between the two groups regarding the rate of adverse effects or discontinuation. Table 2 lists some potential adverse effects from aripiprazole, and Table 3 lists recommended dosing for patients with ASD.

Other antipsychotics. There have been trials of other antipsychotics to treat the symptoms of ASD, but most have been conducted with small numbers of patients or the use of nonrandomized procedures.9 In a retrospective follow-up study of patients with ASD, the use of clozapine led to reductions in disruptive behaviors acutely and in long-term follow-up.13 This medication may be considered for use in patients with ASD who demonstrate severe, potentially dangerous behavioral disturbances and who have not responded to other antipsychotics. Given the risk of developing severe neutropenia or agranulocytosis while taking clozapine, initiation of the medication must be preceded by a blood count that demonstrates an absolute neutrophil count (ANC) that is ≥1500/mcL. Further ANC monitoring proceeds on a weekly basis from initiation to 6 months, every 2 weeks from 6 to 12 months, and then monthly after 12 months of use as long as the ANC is maintained at an acceptable level.

Medications for ADHD

Attention-deficit/hyperactivity disorder (ADHD) commonly co-occurs with ASD, and the two disorders have overlapping symptoms that can complicate assessment. Current diagnostic criteria allow for the diagnosis of both disorders if present in the same individual. If ADHD is identified, methylphenidate (MPH) has the best evidence for efficacy and safety in the treatment of ADHD in people with ASD, although it may be less effective and cause more side effects than in people with ADHD alone.14 In the author's clinical experience, mixed amphetamine salts are usually not as effective as MPH. An alternative to MPH is the nonstimulant atomoxetine, which seems to be more effective in reducing hyperactivity than inattention in youth with both ADHD and ASD.15 Similarly, the alpha2-agonists clonidine and guanfacine have been shown to decrease ADHD symptoms (especially hyperactivity) in children with co-occurring ASD and ADHD.16 MPH, atomoxetine, and the long-acting forms of clonidine and guanfacine are approved by the FDA for the treatment of ADHD in children and adolescents.

Antidepressants

The selective serotonin reuptake inhibitor (SSRI) antidepressants are routinely prescribed to treat depressive and anxiety disorders, as well as obsessive-compulsive disorder (OCD), in young people without ASD. Given the high rates of these disorders in people with ASD, it seems reasonable to assume that they would be effective in this population. Trials of SSRIs to treat OCD in those with ASD have been, unfortunately, inconsistent in their results, and to date there have been no randomized, double-blind, placebo-controlled trials of SSRIs for anxiety and depression in people with ASD.17

Mood Stabilizers

Similar to the SSRIs, the traditional mood stabilizers (anticonvulsants and lithium) have shown inconsistent beneficial effects when used to treat mood symptoms in people with ASD.2 One possible explanation for why the anticonvulsants effectively treat mood and behavioral problems in some patients with ASD may be the bi-directional relationship between ASD and epilepsy (ie, the anticonvulsants are reducing underlying seizure activity that is manifesting as emotional and behavioral symptoms).18

Medications for Sleep Problems

Although sleep disorders are seen in at least one-half of people with ASD, to date there are no FDA-approved medications for that indication. That has not, however, discouraged trials with many classes of psychotropic and some nonprescription medications.19 The drug with the best evidence for efficacy and short-term safety in the treatment of sleep disturbances in people with ASD is melatonin.20 This hormone is involved in the regulation of circadian rhythms. Typical dosing is in the range of 1 to 3 mg nightly, although in one open-label trial doses of 9 mg were used.20 Synthetic versions are available as over-the counter supplements, but their long-term safety has not been established; therefore, long-term use is not recommended.

Novel Agents in Autism Spectrum Disorders

Progress in the psychopharmacology of ASD has been hampered by the lack of clearly identified pathophysiologic factors. There are several hypotheses regarding the etiology of ASD, and pharmacologic studies have been based primarily on presumed neurochemical and neurohormonal abnormalities.19,21 One of the more common experimental treatment strategies is the augmentation of risperidone with other medications to target symptoms such as irritability and hyperactivity. Agents that have been tried in that regard (and that show some efficacy) include the antidiabetic and anti-inflammatory drug pioglitazone,22 the anti-inflammatory endocannabinoid palmitoylethanolamide,23 the cholesterol-lowering drug simvastatin,24 the N-methyl-D-agonist receptor antagonist amantadine,25 and the antiglutamatergic antioxidant N-acetylcysteine.26

As important as the above-noted adjunctive agents may prove to be, they still do not address the core features of ASD. That may change in the near future, however. In January 2018, the FDA granted “breakthrough therapy” designation to the investigational oral medicine balovaptan (previously known as RG7314), a vasopressin 1a receptor antagonist for people with ASD.27 This drug has reportedly shown the potential to improve social interactions and communication in people with ASD. As of this writing, the researchers are recruiting participants for phase III human trials. In May 2018, the FDA granted a “fast track” designation to another investigational drug, L1-79, a tyrosine hydroxylase inhibitor.28 During the phase II safety study, L1-79 reportedly “demonstrated improvement in the core social domains affected by” ASD, although the sample size was small, and the duration of the study was only 28 days. It remains to be seen whether positive effects can be obtained in a larger, phase III study.

Conclusion

People with ASD are at high risk for co-occurring psychiatric and behavioral disorders. The FDA has approved risperidone and aripiprazole for the treatment of irritable mood-associated problems (aggression, self-injury, tantrums, and mood lability) in youth with ASD. Several other medications have been used as adjuncts to risperidone, with some evidence for declines in irritability and hyperactivity. To date, there are no medications that have been consistently effective in treating the core social and communication deficits seen in people with ASD. However, there are two investigational agents that have shown promise in that regard, and they currently are, or soon will be, in phase III trials.

References

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Prevalence Rates of Co-Occurring Psychiatric Disorders in Children and Adolescents with Autism Spectrum Disorder

Disorder Prevalence Rate (%)
Overalla 70–72
Anxiety disorders 39.6
Obsessive-compulsive disorder 17.4
Depressive disorders 0.9–29
Bipolar disorders 0.7–1.9
Attention-deficit/hyperactivity disorder 21–30
Oppositional defiant disorder 25–28.1
Schizophrenia/psychotic disorders 0–0.3
Posttraumatic stress disorder 0–3
Gender variance 5.4–7.2

Potential Adverse Effects from Selected Antipsychotics

Antipsychotic Adverse Effect
Risperidone Neuroleptic malignant syndrome Extrapyramidal syndromes (tardive dyskinesia, parkinsonism/tremors, akathisia, dystonia) Metabolic changes (hyperglycemia, diabetes mellitus, dyslipidemia, weight gain) Hyperprolactinemia Gastrointestinal symptoms Salivary hypersecretion Sedation Anxiety
Aripiprazole Similar to risperidone; in addition, increased risk of suicidal thinking and behavior in children, adolescents, and young adults

Dosing of Antipsychotics for the Treatment of Irritability Associated with Autism Spectrum Disorder

Antipsychotic Dosing Amounts
Initial Dose Recommended Dose Maximum Dose
Risperidone 0.25 mg (weight <20 kg) 0.5 mg (weight ≥20 kg) 0.5 mg (<20 kg) 1 mg (≥20 kg) 0.5–3 mg
Aripiprazole 2 mg 5–10 mg 15 mg
Authors

Joseph L. Calles, Jr., MD, is an Associate Professor of Psychiatry, Western Michigan University, Homer Stryker M.D. School of Medicine.

Address correspondence to Joseph L. Calles, Jr., MD, Department of Psychiatry, Western Michigan University, Homer Stryker M.D. School of Medicine, 1717 Shaffer Road, Suite 010, Kalamazoo, MI 49048; email: joseph.calles@med.wmich.edu.

Disclosure: The author has no relevant financial relationships to disclose.

10.3928/00485713-20190206-01

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