Version July 2025
INTRODUCTION —
Autism spectrum disorder (ASD) is a biologically based neurodevelopmental disorder characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests, and activities.
The discussion that follows will focus on pharmacologic interventions for autism. Related topics are presented separately:
●(See "Autism spectrum disorder in children and adolescents: Clinical features".)
●(See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis".)
●(See "Autism spectrum disorder in children and adolescents: Overview of management and prognosis".)
●(See "Autism spectrum disorder in children and adolescents: Behavioral and educational interventions".)
GENERAL PRINCIPLES
Optimize nonpharmacologic services — The primary focus of interventions for individuals with ASD includes educational, behavioral, and other targeted therapies, typically provided as part of Early Intervention, school-based programming, or private therapies.
When psychopharmacologic agents are considered for the treatment of comorbid disorders, they should be initiated only after educational and behavioral interventions are in place and have been maximized without an adequate response. Therapeutic nonpharmacologic interventions should continue whether a patient is receiving psychopharmacologic therapies or not. (See "Autism spectrum disorder in children and adolescents: Behavioral and educational interventions".)
Role of pharmacotherapy — Some studies have been conducted on agents that target the core symptoms of ASD. However, most of this research is still in its infancy, and many of the agents are not available in clinical practice.
The primary role for pharmacotherapy is the treatment of comorbid psychiatric or neurodevelopmental conditions and the treatment of behavioral symptoms that interfere with learning, socialization, health, safety, quality of life, or overall functioning [1-4]. The potential benefits and risks must be weighed on a case-by-case basis.
When pharmacotherapeutic interventions are considered for the treatment of a comorbid psychiatric or neurodevelopmental condition in a child with ASD, the same principles used for neurotypical children should be employed. If first-line treatment for the comorbid condition in neurotypical children includes nonpharmacologic interventions, then those same interventions should be used in children with ASD [5-8].
Identify target symptoms and behaviors — Medications should be used to target specific symptoms and behaviors that are clearly defined. However, it can sometimes be difficult to determine the most impairing target symptom (eg, anxiety, impulsivity, irritability, attention, mood concerns). A thorough clinical assessment, including information collected from multiple sources (eg, caregivers, therapists), may be necessary.
The preferred method for identifying the most impairing behavioral concern depends upon the availability of referral to a behavioral therapist:
●Behavioral therapist referral available – A Functional Behavioral Assessment (FBA) conducted by a board-certified behavior analyst, the child's behavioral therapist, or as part of a school-based assessment can provide valuable information. FBA is a formal, systematic observation to identify target behaviors, antecedents, and outcomes to better understand the function of the behavior.
Understanding the function of the behavior helps the clinician identify an appropriate target for medication. As an example, aggression may result from impulsivity, irritability, anxiety, or another psychiatric problem (eg, mood or psychotic disorder), which are treated with different psychopharmacologic agents. Additionally, the FBA might confirm that the function of the behavior has to do with the conditions of the environment (eg, the individual engages in the behavior to escape a demand), reinforcing the recommendation for increasing behavioral interventions and environmental accommodations.
●Behavior therapist referral unavailable – If an FBA is not available, then the clinician should work to identify and characterize each target behavior (with input from parents, other caregivers, and school staff, if possible) in terms of [1,2,4]:
•How long has it been present?
•How severe is it?
•What triggers it or makes it worse (eg, time, setting, demands)?
•Are medical factors contributing (eg, dental or other pain, constipation or gastrointestinal distress, infection, disordered sleep, seizures, menstrual cycle)?
•What makes it better?
•How does it respond to behavioral interventions?
•How has it progressed?
•Is it getting better or worse?
•Does it interfere with function?
•What supports are available (eg, behavioral services, educational program, respite care, family support)?
The various measures for assessing behavior in children (eg, Vanderbilt scales for attention, Behavior Assessment System for Children – Third Edition [BASC-3], Conners Comprehensive Behavior Rating Scales, Child Behavior Checklist [CBCL]), were not specifically developed for children with ASD [9,10]. Consequently, behavior scales must be used in conjunction with appropriate clinical and historical data (eg, clinician's behavioral observations, developmental testing results, caregiver and teacher report of functioning) to understand contributors to the behavior (eg, sensory hypersensitivity, communication difficulties, anxiety during transitions).
If the symptoms meet criteria for a comorbid psychiatric condition (eg, depression, attention deficit hyperactivity disorder [ADHD], anxiety), then the disorder should be managed accordingly, with the caveat that the response to medication may differ in children and adolescents for whom this is a secondary rather than a primary diagnosis. Additionally, in a patient who does not meet specific criteria for a psychiatric condition, but whose symptoms are impairing enough and outweigh the risks of intervention, psychopharmacologic management might be considered. (See "Overview of prevention and treatment for pediatric depression" and "Pharmacotherapy for anxiety disorders in children and adolescents" and "Psychotherapy for anxiety disorders in children and adolescents" and "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis".)
Choice of agent — Factors to consider in choosing pharmacologic therapy for children with ASD include [1,4]:
●Likelihood of improvement in the target symptom or behavior
●Potential adverse effects
●Practical considerations (eg, available formulations, dosing schedule, cost, requirement for laboratory monitoring)
The study of psychopharmacologic interventions in children with ASD is ongoing [11-14]. Most of the existing evidence is extrapolated from studies on comorbid conditions (eg, ADHD, obsessive-compulsive disorder, anxiety, etc) in children without ASD. Studies of pharmacotherapy in children with ASD generally are small, retrospective, and nonblinded; they are hampered by a lack of diagnostic tools that are standardized in the population of children with ASD. Risperidone and aripiprazole for the treatment of disruptive behaviors are notable exceptions [15,16]. These are the only psychotropic medications approved by the US Food and Drug Administration specifically for treatment of individuals with ASD. However, many other medications are used off-label. Parents and caregivers should be informed if the medication is being used off-label. They should also be provided with information about the prescribed medication and its potential adverse effects.
The choice of medication is determined by the most impairing behavioral concern. (See 'Identify most impairing behavioral concern' below.)
PRECAUTIONS —
Due to the challenges that children with ASD have with communication, it can be more challenging to monitor certain side effects of medications (eg, dry mouth, dizziness). Autism Speaks provides a toolkit to help families and providers ensure safe and careful use of medications.
Start low and go slow — Children with ASD are more sensitive to medication effects and more likely to have adverse effects than children without ASD [17,18]. Medications should be started at the lowest possible doses, and doses should be increased more slowly than in patients without ASD.
When prescribing more than one medication — Additional precautions are needed when prescribing more than one psychoactive medication for patients with ASD. Many medications used for treating maladaptive behavior or mood symptoms have sedative effects, and taking more than one may result in excessive daytime sedation. Some medications that share a metabolic pathway may either enhance or inhibit the metabolism of each other, requiring dosing adjustments.
Cardiac effects — Several medications can prolong corrected QT interval (QTc) and may have additive adverse effects on heart conduction when used simultaneously (eg, atomoxetine, risperidone, and citalopram).
It is always good practice to complete an analysis for medication interactions when treating patients with more than one medication. Specific medication interactions may be determined using the drug interactions program included with UpToDate.
SPECIALIST REFERRAL AVAILABLE —
When available, we recommend referral to a specialist familiar with ASD in children and adolescents to determine the appropriate agent to prescribe, to monitor response, and to assess for adverse effects. These specialists include developmental-behavioral pediatricians, child psychiatrists, child neurologists, and advanced practice clinicians with specialized training.
SPECIALIST REFERRAL NOT AVAILABLE —
When referral to a specialist familiar with ASD in children and adolescents is not possible, the following approach may be used.
Identify most impairing behavioral concern — Once nonpharmacologic services (ie, developmental and behavioral therapies) have been optimized and behavioral concerns remain, psychopharmacologic agents are considered. (See 'Optimize nonpharmacologic services' above.)
When considering treatment with a psychopharmacologic agent, it is helpful to identify the behavioral concern that is most impairing (see 'Identify target symptoms and behaviors' above). Alternatively, if there are multiple competing behavioral symptoms, target the one that is most accessible to treatment (ie, with a medication that has the fewest potential side effects). If other impairing behavioral symptoms are still present after treating the initial one, other medications can be added.
Inattention and hyperactivity — Children with ASD may present with inattention, hyperactivity, and/or impulsivity above and beyond what would be expected for a diagnosis of ASD alone. Sometimes these behaviors may be related to comorbid attention deficit hyperactivity disorder (ADHD) or other factors that affect function in children with ASD.
The approach to treatment of ADHD symptoms in children with ASD is consistent with the Autism Speaks and the Society for Developmental Pediatrics clinical practice guidelines [19,20].
●First-line agents – The approach to treatment of ADHD is the same for children with and without ASD. In school-aged children, we typically start with a stimulant trial if there are no contraindications. If the initial stimulant is not tolerated, a trial of another stimulant is warranted. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Introduction' and "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis", section on 'Pharmacotherapy'.)
•Methylphenidate – Methylphenidate is often the first choice and appears to improve symptoms of hyperactivity and inattention in children with ASD [21-25]. Although amphetamine-based stimulants might be more effective, methylphenidates are better tolerated [26]. If a methylphenidate trial is unsuccessful secondary to side effects, a trial of dexmethylphenidate can be tried next.
In a meta-analysis of four crossover trials (113 children), short-term treatment with high-dose methylphenidate had a moderate effect on reduction of hyperactivity and inattention scale scores rated by teachers [24]. Limitations of these results include a small sample size, use of a variety of assessment tools, and lack of measurement of long-term treatment effect.
Start with the lowest dose available to minimize adverse effects, which include, but are not limited to, sleep disturbance, decreased appetite, irritability, tics, sadness, dullness, and social withdrawal. Children with ASD have similar adverse effects to those of neurotypical children. However, they occur with greater frequency in children with ASD [17,18]. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulant adverse effects' and "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications".)
In a crossover trial of methylphenidate that included 72 children with ASD and hyperactivity, 18 percent of participants withdrew because of adverse effects [21]. For comparison, in a large, randomized trial of stimulants for attention deficit disorder in children without ASD, the discontinuation rate was only 3.5 percent [27].
•Amphetamines – Studies of amphetamines (dextroamphetamine, dextroamphetamine-amphetamine) in the treatment of attentional symptoms in children with ASD are lacking. It is not clear that the results from trials of methylphenidate can be generalized to amphetamines [28]. However, if methylphenidate and dexmethylphenidate are not effective, amphetamines are a reasonable choice.
Availability of medication (ie, intermittent medication shortages) and method of administration also contribute to first-line medication choice. For example, many patients cannot swallow pills or have sensory issues related to taste or texture that need to be taken into consideration.
●Second-line agents – For those who cannot tolerate a stimulant or in whom stimulant therapy is not effective, we use an alpha-agonist or atomoxetine as second-line treatment [2,19].
•Alpha-2-adrenergic agonists – Limited evidence supports the use of alpha-2-adrenergic agonists (eg, guanfacine, clonidine) to manage symptoms of inattention, hyperactivity, and impulsivity in children with ASD [11,18,28,29]. Although clinicians commonly use these agents as second line in clinical practice for younger patients or those with contraindications to stimulants, these agents may be used as first line.
In small randomized and observational studies in children with ASD, guanfacine was associated with improvement in symptoms of hyperactivity and inattention [29-31]. Similarly, in small observational studies, clonidine was associated with decreased hyperactivity, although the sedative effect may have contributed to the improvement [32,33].
Alpha-2-adrenergic agonists come in both immediate- and extended-release forms. Immediate-release forms often require multiple doses (two to three times daily), while extended-release forms can be dosed once a day but need to be swallowed whole. In children with sleep concerns, it may be beneficial to administer long-acting forms of these medications at bedtime due to their sedative side effects. As with other medications, we recommend starting with the lowest dose and titrating to effect.
Common side effects include sedation, constipation, and low blood pressure. Patients frequently experience sedation in the first two weeks after initiating an alpha agonist; however, this should subside. If sedation continues or is not tolerated, medication will need to be adjusted or discontinued. Additional side effects and adverse effects of alpha-2-adrenergic agonists are listed in the table (table 1).
Children who are treated with alpha-2-adrenergic agonists should have their blood pressure and heart rate monitored at each visit.
•Atomoxetine – Evidence supporting the use of atomoxetine in children with ASD and symptoms of hyperactivity and inattention is limited [34].
In a randomized trial of 97 children (6 to 17 years) with ASD and symptoms of ADHD, atomoxetine moderately improved ADHD rating scale scores compared with baseline (8.2 point reduction versus 1.2 point reduction in the placebo group); among the atomoxetine-treated patients, improvement was greater on the hyperactivity-impulsivity than on the inattention subscore [35]. Similar proportions of patients in the atomoxetine and placebo groups were "improved" or "much improved" on the Clinical Global Impression of ADHD Improvement Scale.
However, as with methylphenidate, the overall effect size for atomoxetine in children with ASD and symptoms of ADHD is smaller than for children with ADHD without ASD [11,36,37].
Side effects of atomoxetine are listed in the table (table 1). Rare but potentially serious adverse effects include suicidal ideation and hepatotoxicity. These adverse effects are discussed separately. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Atomoxetine adverse effects'.)
●Agents for refractory attention and hyperactivity/impulsivity concerns – For children with ASD who are unresponsive to first- and second-line treatment for ADHD and have severe behavioral symptoms despite behavioral interventions, data from open-label and randomized trials support the use of risperidone [28,38-40].
In a multicenter trial of 101 children with ASD, treatment with risperidone (1.8 mg/day) for eight weeks was associated with decreased mean scores on the hyperactivity subscale of the Aberrant Behavior Checklist compared with baseline (32 to 17 versus 32 to 28 in the placebo group) [39].
There is little evidence for the benefit of other atypical antipsychotics.
As with other medications, we recommend starting with the lowest dose and titrating to effect.
Anxiety — Anxiety in individuals with ASD may present in a classic manner such as with fear, feeling overwhelmed, or avoidance of specific circumstances. It may also present as externalizing behaviors such as aggression, explosive behavior, or self-injurious behaviors. Anxiety in children with ASD is treated with the same pharmacotherapies that are used to treat anxiety in neurotypical children. Selective serotonin reuptake inhibitors (SSRIs) are usually first-line therapy in such patients. (See "Psychotherapy for anxiety disorders in children and adolescents" and "Pharmacotherapy for anxiety disorders in children and adolescents".)
There are few randomized trials that specifically assess the efficacy of SSRIs in individuals with ASD [41,42]. However, in a meta-analysis of trials in children without ASD, SSRIs were more effective than placebo in reducing core symptoms of anxiety in children and adolescents (58 versus 31 percent, relative risk of response 1.9, 95% CI 1.6-2.3) [43].
Common first-line SSRIs include fluoxetine or sertraline in light of evidence of effectiveness for anxiety in children without ASD [44,45]. It is important to "start low and go slow." Individuals with ASD may respond to very low doses of SSRIs and should be started with the lowest dose available. However, typical pediatric doses may be necessary, and the dose should be slowly increased as tolerated. (See 'Precautions' above.)
When using SSRIs to treat anxiety in children and adolescents with ASD, the clinician must be mindful of the increased incidence of behavioral activation (impulsivity, silliness, agitation, and disinhibition) and other side effects, including a potentially increased risk of suicidal ideation. (See "Effect of antidepressants on suicide risk in children and adolescents".)
Buspirone (an anxiolytic) is another agent that may be used to treat anxiety in children with ASD if SSRIs are not effective [46-50].
Mood symptoms
●Depression – Antidepressant therapy may be indicated if depressive symptoms persist despite counseling and psychosocial interventions. The same medications that are used for depression in neurotypical children (typically SSRIs) can be used to treat symptoms of depression in children with ASD. (See "Pediatric unipolar depression and pharmacotherapy: Choosing a medication".)
Few trials have evaluated the efficacy of SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) in the treatment of children with ASD and depression [51]. Nonetheless, SSRIs/SNRIs may be warranted for patients who demonstrate clear symptoms of depression (eg, social withdrawal, sudden change in behavior from baseline). Clinicians often start with fluoxetine or sertraline. Fluoxetine is approved by the US Food and Drug Administration (FDA) for the treatment of adolescent depression but is used off-label in younger children. Use of sertraline in children of any age is also an off-label use. (See "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis".)
It is important to "start low and go slow." Individuals with ASD may respond to very low doses of SSRIs/SNRIs, and they should be started with the lowest dose available. However, typical pediatric doses may be necessary, and the dose should be increased slowly as tolerated.
When using SSRIs to treat depressive symptoms in children and adolescents with ASD, the clinician must be mindful of the increased incidence of behavioral activation (impulsivity, silliness, agitation, and disinhibition) and other side effects, including a potentially increased risk of suicidal ideation. (See "Effect of antidepressants on suicide risk in children and adolescents".)
●Mood lability – A number of agents have been used to treat dysregulated mood in children and adolescents with ASD, including atypical antipsychotics, SSRIs, and mood-stabilizing agents (eg, lamotrigine). However, none have been studied specifically for mood regulation in children with ASD. These are more commonly prescribed by specialists such as psychiatrists and neurologists with more experience with their use.
Repetitive behaviors and rigidity — Repetitive behaviors and rigidity are core symptoms of ASD; however, they may also be exacerbated by anxiety or other conditions. Specific repetitive behaviors are referred to as stereotypies (eg, hand flapping, finger tapping). Medication may be warranted if the behaviors interfere with function and have not responded adequately to nonpharmacologic interventions. (See 'Optimize nonpharmacologic services' above.)
Pharmacologic treatment involves a tradeoff between benefits and risks [52]. The literature is limited by the lack of tools that specifically measure stereotypies and rigidity. Many studies measure obsessive-compulsive behaviors, which may not be the best proxy for stereotypies and rigidity in children with ASD.
When medication is necessary for children with repetitive behaviors and rigidity that are thought to be related to anxiety or obsessive-compulsive disorder (OCD), beyond what would be expected with ASD alone, we suggest an SSRI (eg, fluoxetine, sertraline) as the initial medication.
Despite the lack of high-quality evidence that SSRIs are directly beneficial for repetitive behaviors and rigidity in children with ASD [53], they may be indirectly helpful by reducing anxiety. In addition, SSRIs have fewer serious adverse effects than other potential treatments. It is unclear whether SSRIs are helpful for stereotypies and rigidity without comorbid anxiety.
For each of the treatments below, start with the lowest doses available for these medications and increase slowly. (See 'Start low and go slow' above.)
●SSRIs – The rationale for using SSRIs for repetitive behaviors in children with ASD is based upon the effectiveness of SSRIs in neurotypical individuals with OCD. This evidence is discussed separately. (See "Obsessive-compulsive disorder in children and adolescents: Treatment overview", section on 'Initial treatment'.)
In patients with ASD, a reduction in repetitive behaviors was found in some, but not all, trials evaluating SSRIs; however, the magnitude was small [54-58].
When used in neurotypical children and adolescents with depression, SSRIs have been associated with increased suicidal ideation (see "Effect of antidepressants on suicide risk in children and adolescents"). Increased suicidal ideation has not been demonstrated in studies of SSRIs used in individuals with ASD. However, most studies did not assess suicidal ideation and included too few participants to detect rare adverse effects, such as suicidal ideation.
Children taking SSRIs should be monitored for additional adverse effects, which are listed in the table (table 1).
●Buspirone – Buspirone, an anxiolytic, is a serotonin partial agonist. In a 24-week trial comparing 2.5 mg twice per day of buspirone, 5 mg twice per day, and placebo in 166 children (2 to 5 years of age) with ASD, the 2.5 mg dose of buspirone had no effect on the core symptoms of ASD (as assessed with the Autism Diagnostic Observation Schedule [ADOS] Composite Total Score) but did slightly improve restricted and repetitive behaviors (as assessed with the ADOS Restricted and Repetitive Behavior score) [46]. The 5 mg dose had no effect on either score. In clinical practice, buspirone is more often used as an adjunct rather than a primary therapy.
●Atypical antipsychotics – In a meta-analysis of seven trials (651 participants), atypical antipsychotics were more effective than placebo for the treatment of repetitive behaviors and rigidity (standard mean difference 0.28, 95% CI 0.8-0.48), although the difference may not be clinically significant [59]. Risperidone or aripiprazole were the antipsychotics evaluated in six of the seven trials included in the analysis.
Disruptive/maladaptive behaviors — Disruptive/maladaptive behaviors in children with ASD include irritability, aggression [60], explosive outbursts (tantrums), and self-injury. Pharmacotherapy may be indicated if nonpharmacologic therapies are unsuccessful or behaviors are severe enough to threaten harm to self or others. (See 'Optimize nonpharmacologic services' above.)
Combined pharmacologic and nonpharmacologic interventions may be more beneficial than medication alone [61,62]. The pharmacologic agent chosen to treat the behavior depends upon the postulated cause of the disruptive behavior.
Our approach to managing disruptive/maladaptive behaviors is as follows:
●Address anxiety, mood disorders, or inattention/hyperactivity – Disruptive/maladaptive behaviors may occur in response to frustration, which should be the first target of management [17]. Maladaptive behaviors also can be due to anxiety, mood disorders, or impulse control symptoms; if one of these conditions is identified as a cause for the behavior, medications that target that symptom should be used. (See 'Anxiety' above and 'Mood symptoms' above and 'Inattention and hyperactivity' above.)
●When behavioral symptoms persist despite initial treatments – These patients may benefit from a trial of an atypical antipsychotic [16,39,40,63-83]. Evidence of effectiveness is strongest for risperidone and aripiprazole, which are also the only two agents that are FDA approved for the treatment of disruptive and maladaptive behaviors in children with ASD [60,84,85]. Risperidone is approved for children ≥5 years of age and aripiprazole for children ≥6 years.
In a meta-analysis of 13 trials (1425 participants), antipsychotics were significantly more effective (both clinically and statistically) than placebo for the treatment of irritability and emotional dysregulation in children and adolescents with ASD, as measured by various scales that assess these issues (mean standard difference 1.03, 95% CI 0.82-1.23) [60]. Eleven of the 13 trials included in the analysis evaluated risperidone or aripiprazole.
Despite the known efficacy of risperidone and aripiprazole and their FDA approval, their side effect profiles and need for regular laboratory test and vital sign monitoring limit their use. Children treated with atypical antipsychotics should be monitored regularly for cardiometabolic side effects (table 1) [2,83,86-89]. (See "Second-generation and other antipsychotic medications: Pharmacology, administration, and side effects".)
Other psychiatric conditions — Individuals with ASD may have other coexisting psychiatric conditions that can be challenging to diagnose. Examples include disorders with disorganized thought, delusions, or hallucinations. We suggest referral to a psychiatrist for children and adolescents with ASD who are suspected to have an emerging thought disorder. Treatment of thought disorders in children with ASD is similar to treatment in neurotypical children. (See "Schizophrenia in children and adolescents: Treatment overview" and "Pediatric bipolar disorder: Overview of choosing treatment".)
Response to medication
Assessing response to medication — The efficacy and adverse effects of pharmacologic agents should be monitored systematically during therapy [1,4]. If available, an appropriate tool (eg, Vanderbilt scales for attention, Conners Comprehensive Behavior Rating Scales, Behavior Assessment System for Children [BASC], Child Behavior Checklist [CBCL], Aberrant Behavior Checklist [ABC], etc) should be used in addition to the clinical history.
Many children with ASD have structured behavioral programming as a component of their educational and therapeutic intervention. The data collection techniques included in their behavioral programming can also be used for monitoring their response to medications. For children who do not have this type of programming, the prescribing clinician can work with the child's family and school staff to develop a system for monitoring target symptoms and behaviors and providing feedback about response to medications. (See "Autism spectrum disorder in children and adolescents: Behavioral and educational interventions", section on 'Overview of intervention programs'.)
Allowing enough time for an adequate trial of therapy needs to be balanced with timely modification of dose, change of medication, or discontinuation if the desired effect does not occur. We recommend close follow-up (every four to six weeks) when initiating and titrating medication. We also instruct caregivers to notify their care provider at any time that side effects arise or are suspected.
Follow-up intervals are extended to every three to six months once a patient is stable on their medication. Additionally, patients on an atypical antipsychotic require periodic metabolic screening. Although there is no specific recommendation on timing, we do this every six to nine months if the patient can tolerate having their blood drawn.
Adequate response — The next steps for a patient who is responding well to the prescribed medication depend upon whether additional behavioral concerns are causing impairment.
Additional impairing behavioral concerns — If the patient is responding well to medication but has additional behavioral concerns causing impairment, we recommend identifying the next most impairing behavioral concern and using the same approach to treatment as was used for the most impairing behavior. (See 'Identify most impairing behavioral concern' above.)
No additional impairing behavioral concerns — If the patient is responding well to medication and does not have any other impairing behavioral concerns, we suggest follow-up every 3 to 6 months. After successful control of the target symptom for 6 to 12 months, a trial withdrawal of the medication allows for an assessment of whether the medication is still necessary. The length of time required to determine if the medication is still needed varies by the half-life of the agent. For example, if a stimulant is still needed, target symptoms will return quickly after withdrawal. In contrast, SSRIs have longer half-lives such that the medication will continue to have some effect as it is slowly metabolized.
ASSOCIATED CONDITIONS
Seizures — Seizures are more common in children with ASD than in the general population. (See "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis", section on 'Associated conditions and syndromes'.)
Pharmacologic management of seizures in children with ASD is similar to that of seizures in children without ASD. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)
Gastrointestinal problems — Children with ASD have a higher prevalence of gastrointestinal symptoms than the general population of children [90].
Gastrointestinal problems in children with ASD are generally managed in the same way as in children without ASD [2,91]. However, because children with ASD may not tolerate certain aspects of the examination (eg, rectal examination) or diagnostic procedures, trials of pharmacologic therapy for constipation or gastroesophageal reflux may be undertaken based upon symptoms alone [91].
Pharmacologic interventions for specific gastrointestinal problems in children are discussed separately:
●Constipation (see "Chronic functional constipation and fecal incontinence in infants, children, and adolescents: Treatment")
●Gastroesophageal reflux disease (see "Gastroesophageal reflux disease in children and adolescents: Management")
●Chronic abdominal pain (see "Functional abdominal pain in children and adolescents: Management in primary care")
●Chronic diarrhea (see "Approach to chronic diarrhea in children >6 months in resource-abundant settings")
Sleep disturbance — Many children with ASD have associated sleep problems or disorders, including bedtime resistance, sleep anxiety, sleep-onset disturbances, frequent awakening, restlessness, or abnormal sleep architecture [92-95]. Sleep disturbance may be related to abnormalities in melatonin, serotonin, or gamma-aminobutyric acid [96,97].
The evaluation of sleep disturbance in children with ASD should include a thorough sleep history and screening for obstructive sleep apnea and other sleep disorders. Referral to a specialist (eg, sleep specialist, neurologist, otolaryngologist) may be warranted if a specific sleep disorder is identified or suspected. (See "Assessment of sleep disorders in children" and "Behavioral sleep problems in children" and "Evaluation of suspected obstructive sleep apnea in children".)
Before considering pharmacologic interventions, it is important to ensure that the patient has appropriate sleep hygiene [98]. Medications are unlikely to be effective in the absence of an appropriate sleep schedule. It is also important to use behavioral interventions to decrease sleep associations (ie, behaviors associated with disrupted sleep), such as a caregiver lying with the child until they fall asleep, because this makes it harder for the child to fall asleep without the caregiver [98-102].
For children who require antiseizure, antipsychotic, or antidepressant medications, the timing of administration can be manipulated to take advantage of the sedative effects. The sedating medication can be administered at bedtime, or, if more than one dose is recommended, the higher dose can be administered at bedtime, if appropriate.
There is little evidence for pharmacologic management of sleep disturbance in children. No medications are approved by the US Food and Drug Administration (FDA) for use for sleep in ASD. However, several are used in clinical practice.
●Melatonin – Melatonin can be considered for patients with ASD who have difficulty falling asleep despite appropriate sleep hygiene and behavioral and/or environmental interventions. We usually start with a dose of 0.5 to 1 mg, depending upon age, and increase by 1 mg as needed to a maximum of 6 mg (although in clinical practice, others may use a higher dose). We advise providing melatonin 30 to 60 minutes before bedtime. These suggestions are in line with the American Academy of Neurology practice guidelines [98].
Several observational, open-label studies and randomized trials suggest that melatonin is effective for improving sleep onset and maintenance in children with ASD [98,103-114]. In a meta-analysis of four trials that included a pooled sample of 213 patients with ASD, melatonin increased sleep duration by 61 minutes (95% CI 50-72 minutes) and decreased sleep onset latency by 35 minutes (95% CI 25-46 minutes) compared with placebo [115]. Side effects were similar in both groups. In individual studies, the doses ranged from 0.75 to 10 mg/day, and the duration of treatment ranged from 14 days to 6 months [106,107,110-112,114,116].
These results suggest that melatonin may be effective in helping children with ASD to fall asleep and sleep longer. However, there are no dosing guidelines for administration and no information on long-term use or side effects. Side effects of melatonin are listed in the table (table 1).
Melatonin is sold over the counter, is not regulated by the FDA, and does not require a prescription. However, practice guidelines suggest that providers either write a prescription or advise parents/caregivers to purchase a high-purity pharmaceutical grade of melatonin when available [98]. If this is not possible, they should seek a formulation that contains melatonin as the only active ingredient and select a product with the US Pharmacopeia (USP) Verified mark, which is more likely to be of higher quality.
●Other agents – Other agents that are sometimes considered in the management of sleep disturbance in children with ASD include clonidine, antihistamines (eg, diphenhydramine, hydroxyzine), and trazodone. However, there are few data to support the use of these medications for sleep in children with ASD. When used, they should be started at the lowest available dose and titrated as necessary.
•Clonidine (an alpha-2-adrenergic receptor agonist) has sedative effects. In an observational study, clonidine was effective in reducing sleep latency and nighttime awakening in children with ASD [117]. Side effects of clonidine include hypotension.
•Diphenhydramine and hydroxyzine are first-generation or "nonselective" H1 receptor antagonists. In one trial, diphenhydramine was more effective than placebo in reducing sleep latency time and the number of overnight awakenings among neurotypical children with a variety of sleep disorders [118]. However, no studies assessing the effectiveness of diphenhydramine or hydroxyzine in children with ASD have been conducted.
•Trazodone antagonizes serotonin 5-HT2A receptors and exerts moderate antihistamine action. While data on the use of trazodone in the pediatric population are limited overall, a national survey suggests it is commonly prescribed in children with ASD [119].
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Autism spectrum disorder".)
SUMMARY AND RECOMMENDATIONS
●Optimize nonpharmacologic services – Medical causes for the behavior should be excluded and behavioral interventions maximized before pharmacotherapy is initiated. (See 'Optimize nonpharmacologic services' above.)
●Identify target symptoms and behaviors – The target symptom(s) and behavior(s) for pharmacotherapy in children with autism spectrum disorder (ASD) should be clearly defined and the potential benefits and risks weighed on a case-by-case basis. (See 'Identify target symptoms and behaviors' above.)
●Precautions – Children with ASD are more sensitive to medication effects and more likely to have adverse effects than children without ASD. Thus, they should be monitored closely. Medications should be started at the lowest possible doses, and doses should be increased more slowly than in patients without ASD. (See 'Start low and go slow' above.)
●Refer to a specialist, if available – Ideally, a specialist familiar with ASD (eg, developmental pediatrician, child psychiatrist, child neurologist) will prescribe pharmacotherapy for children and adolescents.
●If specialist not available, identify most impairing behavioral concern
•Inattention and hyperactivity – For children with inattention and hyperactivity, we suggest methylphenidate as first-line treatment rather than amphetamines (Grade 2C). Dexmethylphenidate is a reasonable alternative (See 'Inattention and hyperactivity' above.)
•Anxiety – For children with anxiety, we suggest a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) rather than other medications as first-line treatment (Grade 2C). (See 'Anxiety' above.)
•Depression/mood symptoms – For children with depressive symptoms, we suggest an SSRI or SNRI rather than other medications as first-line treatment (Grade 2C). (See 'Mood symptoms' above.)
•Repetitive behaviors and rigidity – For children with repetitive behaviors and/or rigidity, we suggest an SSRI rather than other medications as first-line treatment (Grade 2C), especially if the behaviors are exacerbated by anxiety. (See 'Repetitive behaviors and rigidity' above.)
•Disruptive/maladaptive behaviors – For children with disruptive/maladaptive behaviors that are not thought to be related to other symptoms, we suggest risperidone or aripiprazole rather than other atypical antipsychotics or other medications as first-line treatment (Grade 2C). Other medications may be more appropriate if the underlying cause of the behaviors is anxiety, depression, or inattention/hyperactivity. (See 'Disruptive/maladaptive behaviors' above.)
•Mood lability – Although not well studied in children with ASD, some experts use atypical antipsychotics, SSRIs, or mood-stabilizing agents (eg, lamotrigine) to treat dysregulated mood.
●Monitor response to medication – Allowing enough time for an adequate trial of therapy needs to be balanced with timely modification of dose, change of medication, or discontinuation if the desired effect does not occur. We advise follow-up every four to six weeks when initiating and titrating medication and extending to every three to six months once the patient is stable on their medication. (See 'Response to medication' above.)
Additional precautions may be necessary for children receiving more than one psychoactive medication. (See 'Precautions' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Carolyn Bridgemohan, MD, who contributed to earlier versions of this topic review.
