INTRODUCTION — Autism spectrum disorder (ASD) is a biologically based neurodevelopmental disorder characterized by impairments in two major domains: (1) deficits in social communication and social interaction and (2) restricted repetitive patterns of behavior, interests, and activities [1]. ASD encompasses disorders previously known as autistic disorder (classic autism, sometimes called early infantile autism, childhood autism, or Kanner's autism), childhood disintegrative disorder, pervasive developmental disorder not otherwise specified, and Asperger disorder (also known as Asperger syndrome). (See "Autism spectrum disorder: Evaluation and diagnosis", section on 'Diagnostic criteria' and "Asperger syndrome (a specific autism spectrum disorder): Management and prognosis in children and adolescents".)
The discussion that follows will focus on pharmacologic interventions for autism. Related topics are presented separately:
●(See "Autism spectrum disorder: Clinical features".)
●(See "Autism spectrum disorder: Evaluation and diagnosis".)
●(See "Autism spectrum disorder in children and adolescents: Overview of management".)
●(See "Autism spectrum disorder in children and adolescents: Behavioral and educational interventions".)
●(See "Autism spectrum disorder in children and adolescents: Complementary and alternative therapies".)
●(See "Autism spectrum disorder: Terminology, epidemiology, and pathogenesis".)
GENERAL PRINCIPLES
Overview — The clinical manifestations of ASD vary in intensity, and treatment plans must be individualized. The primary treatments are developmental and behavioral therapies, typically as part of Early Intervention or school-based programming. Psychopharmacologic interventions may be a useful adjunct to behavioral/environmental interventions in children with ASD after behavioral and educational supports have been maximized including supports to improve the child's comprehension and ability to communicate. (See "Autism spectrum disorder in children and adolescents: Behavioral and educational interventions".)
Psychopharmacologic agents do not treat autism itself and should be initiated only after educational and behavioral interventions are in place, comorbid psychiatric or medical illnesses ruled out, and psychosocial/environmental stressors considered [2]. In addition to a thorough medical assessment, formal behavioral analysis conducted by a behavior analyst or behavioral psychologist may be warranted to clarify the nature of the symptoms under consideration for treatment. Depending on regional systems and resources, this may be arranged through the child's educational team at school.
The potential benefits and risks of pharmacologic therapy for children with ASD must be weighed on a case-by-case basis. Parents and caregivers should be informed if the medication is being used off-label (only risperidone and aripiprazole are approved by the US Food and Drug Administration [FDA] specifically for irritability in children with ASD).
The principles for the psychopharmacologic management of individuals with ASD are the same as for individuals with other psychiatric conditions. Medications should be used to target specific symptoms that are clearly defined, and the symptoms should be measured over time (preferably using rating scales) to monitor treatment efficacy. It is also important to periodically re-evaluate the need for continued treatment.
Children with ASD are more sensitive to psychopharmacotherapy and more likely to have adverse effects than children without ASD [3,4]. In addition, given their weaknesses communicating and identifying their emotions, it can be difficult to determine the predominant target symptom (eg, anxiety, impulsivity, anger) and, therefore, the best psychopharmacologic agent. For similar reasons, it can be more challenging to monitor certain side effects of medications (eg, dry mouth, dizziness).
Pretreatment evaluation — Medication may be warranted if the child's behavior interferes with his or her ability to access therapy and other contributing factors (eg, comorbid illness, psychosocial/environmental stressors) have been addressed. However, determining which symptoms to target with medication can be challenging. Few of the various measures for assessing behavior in children (eg, Vanderbilt scales for attention) are standardized for children with ASD [5,6]. Behavior scales must be used in conjunction with appropriate clinical and historical data. Thorough clinical assessment, including information collection from multiple sources (eg, parents, therapists), may be necessary to identify the most relevant target behavior.
If available, Functional Behavioral Assessment (FBA) by the child's behavioral therapist can provide valuable information. FBA is a formal, systematic observation that includes identifying target behaviors, antecedents, and outcomes in order to better understand the function of the behavior. Understanding the function of the behavior helps the clinician to identify an appropriate target for medication. As an example, aggression may result from impulsivity, anxiety, irritability, or other psychiatric problem (eg, mood or psychotic disorder), which are treated with different psychopharmacologic agents.
If FBA is not available, 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 [7-9]:
●How long has it been present? How severe is it?
●What brings it on or makes it worse (eg, time, setting, demands, etc)? Is it amenable to behavioral interventions?
●Are medical factors contributing (eg, dental or other pain, constipation or gastrointestinal distress, infection, sleep, seizures, menstrual cycle, etc)?
●What makes it better? How does it respond to behavioral interventions?
●What is the course? Is it getting better or worse?
●Does it interfere with function?
●What supports are available (eg, behavioral services, educational program, respite care, family support)?
If the symptoms meet criteria for a comorbid psychiatric condition (eg, depression, attention deficit hyperactivity disorder [ADHD], anxiety), 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. (See "Overview of prevention and treatment for pediatric depression" and "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis", section on 'Overview of management' and "Pharmacotherapy for anxiety disorders in children and adolescents" and "Psychotherapy for anxiety disorders in children and adolescents".)
Indications — Pharmacologic therapy for children with ASD may be warranted for the treatment of comorbid psychiatric or neurodevelopmental conditions or for behavioral symptoms that interfere with learning, socialization, health, safety, quality of life, or overall functioning [7-10]. When considering the use of medications for target symptoms in children with ASD, the potential benefits and risks must be weighed on a case-by-case basis. Pharmacologic therapy generally is initiated after behavioral and environmental interventions are in place and have been maximized.
Who should prescribe? — Psychopharmacotherapy for children and adolescents with ASD ideally is prescribed by specialists familiar with ASD (eg, developmental-behavioral pediatricians, child psychiatrists, child neurologists, etc). However, access to such specialists is not always available. If primary care clinicians undertake the prescription of psychotropic agents for children with ASD, consultation with a developmental-behavioral pediatrician, child psychiatrist, child neurologist, or another mental health professional who is familiar with ASD may be warranted to ensure that an appropriate medication is chosen and efficacy and adverse effects are appropriately monitored.
Choice of agent — Factors to consider in choosing pharmacologic therapy for children with ASD include (table 1) [7,9]:
●Likelihood of improvement in the target symptom
●Potential adverse effects
●Practical considerations (available formulations, dosing schedule, cost, requirement for laboratory monitoring)
Risperidone and aripiprazole are the only psychotropic medications approved by the FDA specifically for treatment of individuals with ASD [11]. However, many other medications are used off-label. Parents and caregivers should be informed if the medication is being used off-label.
The study of psychopharmacologic interventions in children with ASD is ongoing [12,13]. 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 the lack of diagnostic tools that have been standardized in the ASD population. Notable exceptions include risperidone and aripiprazole for the treatment of disruptive behaviors and methylphenidate for the treatment of disruptive behaviors and hyperactivity/inattention [14,15]. (See 'Risperidone' below and 'Aripiprazole' below and 'Stimulants' below.)
Monitoring — Children with ASD are more sensitive to medication effects and more likely to have adverse effects than children without ASD [3,4]. Medications should be started at lower doses, and doses should be increased more slowly than in patients without ASD.
The efficacy and adverse effects of pharmacologic agents should be monitored systematically during therapy [7,9]. In addition to clinical history, an appropriate tool should be used to monitor outcome if such a tool is available. Target symptoms of children receiving intensive behavioral interventions can be monitored using standardized instruments for specific symptoms (eg, attention rating scales) although these instruments have not been validated for use in individuals with ASD. In addition, many children with ASD have structured behavioral programming as a component of their educational and therapeutic program. The data collection techniques included in their behavioral programming can also be used for monitoring 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 of system for monitoring target symptoms and providing feedback about response to medications. (See "Autism spectrum disorder in children and adolescents: Behavioral and educational interventions", section on 'Intensive behavioral interventions'.)
Autism Speaks provides a toolkit to help families and providers ensure safe and careful use of medications.
The schedule for follow-up should permit an adequate trial of therapy, as well as a timely modification (different dose, different medication, discontinuation) if the desired effect does not occur. The specific follow-up interval varies with the medication but generally should be no longer than three months. After successful control of the target symptom for 6 to 12 months, withdrawal of the medication for a period of time may be warranted to determine whether it is still necessary.
The parents and caregivers should be provided with information about the prescribed medication and its potential adverse effects.
Polypharmacy — It is important to consider additional precautions 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. In addition, some medications that share a metabolic pathway may either enhance or inhibit the metabolism of other drugs, requiring dosing adjustments. Finally, several medications can prolong QTc and may have additive effects on heart conduction when used simultaneously (eg, atomoxetine, risperidone, and citalopram). It is always good practice to complete a medication interaction analysis when treating patients with more than one medication.
Specific medication interactions may be determined using the Lexicomp drug interactions tool included with UpToDate.
TARGET SYMPTOMS — Pharmacologic therapy may be warranted for symptom control in children with ASD if behavioral/environmental interventions are ineffective or insufficient for target symptoms. (See 'Pretreatment evaluation' above.)
Target symptoms that may respond to psychotropic medications include [16]:
●Hyperactivity, impulsivity, and inattention
●Maladaptive behaviors/problem behaviors/irritability (eg, aggression, explosive outbursts, self-injury)
●Repetitive behaviors and rigidity
●Anxiety
●Mood lability
●Depression
Inattention and hyperactivity — Children with ASD may be inattentive, hyperactive, and disorganized. These behaviors may be related to comorbid attention deficit hyperactivity disorder (ADHD) or to other factors that affect function in children with ASD (eg, overarousal, anxiety). If the behaviors do not improve with environmental or behavioral interventions, they may respond to pharmacotherapy.
Potential therapies — Potential therapies for symptoms of inattention and hyperactivity in children with ASD include stimulant medications (eg, methylphenidate, dextroamphetamine), alpha-2-adrenergic agonists (eg, guanfacine), atomoxetine, atypical antipsychotics (eg, risperidone), and anticonvulsant mood stabilizers (eg, valproic acid). There is strong evidence that stimulants and risperidone are beneficial for hyperactivity and marginal evidence for the benefit of other atypical antipsychotics [17].
Selective serotonin reuptake inhibitors (SSRI) may be helpful if anxiety is contributing to symptoms. SSRI also may be used for repetitive behaviors and depression. They are discussed separately. (See 'Anxiety' below and 'SSRI' below and 'Depression' below.)
Stimulants — Randomized controlled trials and meta-analyses indicate that stimulant medication improves symptoms in approximately 80 percent of children with ADHD without ASD. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Stimulants versus other medications'.)
Methylphenidate also appears to improve symptoms of hyperactivity and inattention in children with ASD, but the response to methylphenidate is lower in children with ASD than it is in children with isolated ADHD. A systematic review of four-crossover trials (113 children) [18-21] found low quality evidence that short-term treatment with methylphenidate may improve hyperactivity and inattention in children with ASD who can tolerate the medication [22]. In the largest crossover trial, approximately 50 percent of children with ASD responded to methylphenidate (as measured on the hyperactivity subscale of the Aberrant Behavior Checklist [ABC]); the effect size ranged from 0.20 to 0.54, depending upon dose and rater [20], with greater improvement at higher doses [23].
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 [24]. However, amphetamines frequently are used in clinical practice.
The side effects of stimulant medications in children with ASD are similar to those in other patients. However, they occur with greater frequency [3,4]. In a crossover trial of methylphenidate that included 72 children with ASD and hyperactivity, 18 percent of subjects withdrew because of adverse effects [20]. In comparison, in a large, randomized trial of stimulants for attention deficit disorder in children without ASD, the dropout rate was only 3.5 percent [25]. Adverse effects of stimulant medications include, but are not limited to, sleep disturbance, decreased appetite, irritability, tics, sadness, dullness, and social withdrawal. A systematic review of four cross-over trials of methylphenidate in children with ASD could not adequately assess adverse effects because children intolerant to methylphenidate were excluded [22]. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulant adverse effects'.)
Alpha agonists — Alpha-2-adrenergic agonists (eg, guanfacine, clonidine) also are used to manage symptoms of inattention, hyperactivity, and impulsivity in children with ASD [4,12,24,26].
Studies of alpha-2-adrenergic agonists are limited, and sample sizes are small. In a multicenter randomized trial comparing extended-release guanfacine with placebo in 62 children with ASD, hyperactivity, impulsiveness, and distractibility, guanfacine was effective in reducing behavioral symptoms [27]. Children receiving guanfacine had greater declines in scores on the ABC-hyperactivity subscale (43.6 versus 13.2 percent) and higher rates of "much improved" or "very much improved" on the Clinical Global Impression-Improvement scale (50 versus 9.4 percent). In an open-label prospective trial of guanfacine in 25 children whose hyperactive symptoms did not respond to methylphenidate, 47 percent responded to guanfacine (decrease in the mean parent- and teacher-rated hyperactivity subscale of the ABC from 31.3 to 19.9 and 29.2 to 22.3, respectively) [28]. Retrospective analysis of guanfacine therapy in 80 children with ASD found guanfacine to be well tolerated with response rates of 27 and 21 percent for symptoms of hyperactivity and inattention, respectively [26]. Adverse effects of guanfacine include sedation, constipation, irritability, and aggression [26,28].
Two small crossover trials using clonidine suggest decreased irritability, stereotypy, hyperactivity, inappropriate speech, and oppositional behavior [29,30]. However, side effects included hypotension and sedation. It is uncertain whether some of the reduction in symptoms could be attributed to the sedative effect.
Children who are treated with alpha-2-adrenergic agonists should have their blood pressure and heart rate monitored at each visit. Adverse effects of alpha-2-adrenergic agonists include:
●Sedation
●Hypotension
●Rebound hypertension if discontinued abruptly
●Dry mouth
●Dizziness
●Irritability
●Increased aggression and self-injury
●Decreased appetite
●Sleep disturbance
●Headache
●Nocturnal enuresis
Alpha-2-adrenergic agonists can pose significant harm if provided in excess. It is important to counsel parents about the narrow window of therapeutic safety with these medications and to keep all medications secured from children in the home. (See "Clonidine and related imidazoline poisoning".)
Atomoxetine — Studies of atomoxetine for symptoms of hyperactivity and inattention in children with ASD are limited [31]. In a randomized trial in 97 children (6 to 17 years) with ASD and ADHD, atomoxetine resulted in moderate improvement in ADHD symptoms (eg, reduction in ADHD Rating Scale [ADHD-RS] scores compared with baseline of 8.2 points 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 [32]. However, the difference in the proportion of patients "improved" or "much improved" on the Clinical Global Impression of ADHD Improvement Scale was not statistically significant [32]. Another small randomized crossover trial suggested some improvement in hyperactivity symptoms compared with placebo [33]. 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 [12,34,35].
Side effects of atomoxetine include, but are not limited to, gastrointestinal symptoms, fatigue, sleep problems, mood swings, dizziness, and change in appetite. 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'.)
Other drugs — Other drugs that may be beneficial for symptoms of hyperactivity and inattention in children with ASD include risperidone and antiseizure medications [24].
The use of risperidone for symptoms of hyperactivity in children with ASD is supported by open-label and randomized controlled trials [24,36,37]. In a multicenter, placebo-controlled trial of 101 children with autism, treatment with risperidone (1.8 mg/day) for eight weeks was associated with decreased mean scores on the hyperactivity subscale of the ABC compared with baseline (32 to 17 versus 32 to 28 in the placebo group) [36].
Risperidone also may be used for a range of maladaptive behaviors including irritability, stereotypy, aggression, explosive outbursts, and self-injury and is discussed separately. (See 'Risperidone' below.)
The evidence for antiseizure agents (valproate, topiramate, lamotrigine) is limited to small, open-label, or observational studies [38-40].
Approach — When, after a discussion of the potential risks and benefits, the clinician and parents agree that pharmacotherapy is indicated for symptoms of inattention, hyperactivity, and impulsivity that continue to impair function despite behavioral and environmental interventions and are not thought to be related to other symptoms (eg, anxiety), a trial of a stimulant (usually methylphenidate) may be beneficial. An alternative agent may be chosen if stimulant therapy is not effective or there are other target symptoms that require pharmacologic intervention (eg, risperidone if disruptive behaviors secondary to irritability also require treatment). This approach is consistent with that in the Autism Speaks Autism Treatment Network Psychopharmacology Committee clinical practice pathway for evaluation and medication choice for ADHD symptoms in children with ASD [41].
If methylphenidate is not tolerated, a trial of another stimulant, atomoxetine, or alpha-agonist may be warranted [8,41]. (See "Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications", section on 'Choice of agent' and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Introduction'.)
Maladaptive/problem behaviors — Maladaptive behaviors in children with ASD include irritability, aggression, explosive outbursts (tantrums), and self-injury. These behaviors may occur in response to anxiety or frustration, which should be the first targets of management [3]. Maladaptive behaviors also can be due to anxiety, mood disorders, or impulse control problems; if one of these conditions is identified as a cause for the behavior, medications that target that symptom should be used. (See 'Anxiety' below and 'Mood lability' below and 'Depression' below and 'Inattention and hyperactivity' above.)
Pharmacotherapy may be indicated if nonpharmacologic therapies are unsuccessful. Combined pharmacologic and nonpharmacologic interventions may be more beneficial than medication alone [42,43]. The pharmacologic agent of choice to treat the behavior depends upon the postulated cause of the disruptive behavior.
Potential agents — The atypical antipsychotic agents, risperidone and aripiprazole [11], are the only medications approved by the US Food and Drug Administration (FDA) to treat irritability and self-injurious and aggressive behaviors in children with ASD. Agents that are used off-label include other atypical antipsychotics (olanzapine, clozapine, quetiapine, ziprasidone), haloperidol (a typical antipsychotic), antiseizure medications, alpha-2 agonists, mood stabilizers, SSRI, and beta-blockers. There is strong evidence that risperidone and aripiprazole are beneficial for disruptive behaviors and marginal evidence for benefit with other atypical antipsychotics, antiseizure medications, psychostimulants, and naltrexone [17,44].
Risperidone — Risperidone is the most commonly used antipsychotic for the treatment of maladaptive behaviors in children with ASD [45]. It is approved by the FDA for the treatment of irritability presenting with aggression, tantrums, and/or deliberate self-injury in children (≥5 years) with ASD.
Randomized controlled trials and systematic reviews indicate a positive response to risperidone in individuals with autism and disruptive behaviors [36,37,44,46-51]. In a multicenter, placebo-controlled trial of 101 children with autism and maladaptive behaviors, treatment with risperidone (1.8 mg/day) for eight weeks was associated with [36,52,53]:
●Higher treatment response; treatment response was defined as 25 percent or greater decrease in the irritability score and rating of "much improved" or "very much improved" on the Clinical Global Impression-Improvement (CGI-I) scale (69 versus 12 percent)
●Greater proportion "much improved" or "very much improved" on the CGI-I scale compared with baseline (75 versus 11 percent)
●Greater decrease in mean irritability score compared with baseline (57 versus 14 percent)
●Improvements in repetitive behaviors and restricted interests, but no effects on social function or communication (in secondary analysis) [52] (see 'Repetitive behaviors and rigidity' below)
Dosing of risperidone is discussed separately. See Risperidone drug information.
Adverse effects of risperidone included weight gain, increased appetite, fatigue, drowsiness, dizziness, drooling, tremor, and constipation. However, they were mild and resolved over a few weeks [36]. There was no increase in tardive dyskinesia or other extrapyramidal symptoms compared with the placebo group. No additional adverse effects were noted during the four-month open-label continuation phase [54]. In postmarketing surveillance, there have been reports of cases of extrapyramidal symptoms with concomitant use of risperidone and methylphenidate or dexmethylphenidate with changes to the regimen of one or both medications (eg, initiation, discontinuation, increased dose, decreased dose) [55,56]. Close surveillance is warranted with any of these changes. This drug interaction is discussed in the Lexicomp drug interactions program included with UpToDate.
Adverse effects of atypical antipsychotics and monitoring for adverse effects are discussed in greater detail below. (See 'Side effects of antipsychotics' below.)
Aripiprazole — Aripiprazole is approved by the FDA for the treatment of irritability in children (aged 6 to 17 years) with ASD [11].
In multicenter randomized trials, flexible and fixed dosing regimens of aripiprazole for eight weeks were beneficial in reducing irritability, stereotypy, and hyperactivity in children (aged 6 to 17 years) with autism and irritability (as measured by the ABC and Clinical Global Impressions-Severity scale) [57-59]. In another multicenter randomized trial, among 85 patients who had a stable response to 12 weeks of aripiprazole and were randomly assigned to continuation of aripiprazole or to placebo, the time to relapse did not differ between groups [60]. Given that the efficacy of aripiprazole for the maintenance treatment of irritability in children with autism has not been established, it is important to periodically re-evaluate the need for continued treatment [11].
Adverse effects of aripiprazole included fatigue, vomiting, somnolence, weight gain, tremor, and extrapyramidal symptoms [15,57,58]. With the fixed-dose regimen, approximately 10 percent of subjects withdrew because of adverse events; serious adverse events occurred in two subjects (presyncope and aggression) [58].
Development of new impulse-control problems or uncontrollable urges (eg, gambling, binge eating) also have been reported rarely in adults and children [61]. Indications for aripiprazole in the reported cases included, but were not limited to, schizophrenia, schizoaffective disorder, bipolar mood disorder, major depressive disorder, and anxiety disorder; ASD was not specifically mentioned. Children receiving aripiprazole should be monitored for impulse-control problems; this may be challenging in those with lower cognitive and language function.
Adverse effects of atypical antipsychotics and monitoring for adverse effects are discussed in greater detail below. (See 'Side effects of antipsychotics' below.)
Olanzapine — Several small prospective studies (only one of which was blinded) demonstrated clinical improvement in disruptive behaviors in children with ASD who were treated with olanzapine (an atypical antipsychotic) [62-65]. However, weight gain and other side effects, such as sedation, often prohibit continued use of olanzapine. The risk of extrapyramidal side effects with olanzapine appears to be low.
Other atypical antipsychotics — Other atypical antipsychotics (eg, clozapine, quetiapine, ziprasidone) are used in clinical practice to treat disruptive behaviors in children with ASD. The evidence to support the use of these agents consists primarily of open-label studies or case series [66-69]. Additional research is needed before they can be recommended as the initial medical therapy for disruptive behavior in children with ASD.
Haloperidol — Randomized controlled trials suggest that haloperidol, a typical antipsychotic, is effective in the treatment of behavioral symptoms (tantrums, aggression, hyperactivity, social withdrawal, and stereotypies) in children with ASD [70,71]. However, it is less effective than risperidone [71]. In addition, the risk of dyskinesia and other extrapyramidal symptoms (in approximately one-third of patients) limits its use [72].
Children who are treated with haloperidol should be monitored closely. A drug holiday may be warranted to avoid dyskinesia. Haloperidol should be slowly weaned to prevent withdrawal dyskinesia. The optimal duration of drug holiday is unclear.
Other agents — Alpha-2 agonists (specifically clonidine) and N-acetylcysteine have demonstrated some improvement in symptoms with fewer side effects than atypical anti-psychotics in small, individual studies; however, additional research is needed [44]. Antiseizure medications, mood stabilizers (eg, lithium), SSRI, stimulants, and beta blockers have been used to treat disruptive behaviors in children and adolescents with ASD [12,44,73].
Side effects of antipsychotics — The use of antipsychotic agents often is limited by their side effect profile. Side effects of atypical antipsychotics may include, but are not limited to [8,74-77]:
●Increased appetite
●Weight gain
●Elevated blood sugar secondary to insulin resistance
●Dyslipidemia
●Blood pressure changes
●Electrocardiogram (EKG) changes, such as prolongation of QTc (more common with ziprasidone [78])
●Fatigue and drowsiness
●Dizziness
●Drooling
●Liver function abnormalities
●Increase in prolactin (of unknown clinical significance)
●Gynecomastia
●Cardiac conduction effects (prolonged QTc)
Less common, but serious, side effects include dystonic reactions, tardive dyskinesia, akathisia (subjective sense of restlessness, often accompanied by voluntary movements of the limbs or trunk), neuroleptic malignant syndrome, and agranulocytosis (with clozapine) [36,46,69,79].
Children who are treated with atypical antipsychotic agents should be monitored regularly. At baseline, the child's weight and height should be measured and body mass index calculated ((calculator 1) [for boys] and (calculator 2) [for girls]) [80]. Given the cardiometabolic side effects, it is important to take a thorough patient and family history, asking specifically about obesity, diabetes, dyslipidemia, hypertension, and cardiovascular disease. A baseline EKG should be obtained; the EKG should be repeated when the patient has reached the steady state (particularly in patients treated with ziprasidone).
Follow-up visits should include measurement of weight and blood pressure and evaluation for extrapyramidal findings (the use of a scale, such as the Abnormal Involuntary Movement Scale [available online from various websites], is helpful). Baseline and follow-up laboratory studies may include fasting plasma glucose, fasting lipids, complete blood count, liver function tests, thyroid stimulating hormone (TSH), prolactin, and electrolytes.
The optimal frequency of laboratory monitoring is not clear. We suggest follow-up at three months after starting medication and every six months thereafter for most of the studies listed above and when doses are increased. Prolactin and TSH may be monitored less frequently unless symptoms of abnormalities arise. More frequent testing may be necessary if metabolic abnormalities are identified.
Treatment approach — As with most psychopharmacologic agents used in children with ASD, there are few published clinical guidelines regarding medication use for disruptive or maladaptive behavior such as irritability, aggression, impulsivity, tantrums, and/or deliberate self-injury in children with ASD [51]. The treatment of disruptive behaviors in children with ASD involves a tradeoff between benefits and risks [81]. Risperidone and aripiprazole may be beneficial for aggression and self-injury that are not thought to be related to other symptoms (eg, anxiety) [37,48]. Other medications (eg, stimulants, SSRI, alpha-adrenergic agonists) may be more appropriate, depending upon the underlying cause of aggression and self-injury (eg, hyperactivity, anxiety, impulsivity).
Other atypical antipsychotic agents (eg, clozapine, olanzapine, quetiapine, ziprasidone) and different classes of drugs (eg, alpha-2 agonists, antiseizure medications, mood stabilizers, SSRI, and beta blockers) have been used to treat disruptive behaviors in children and adolescents with ASD [12]. However, there is less evidence to support the use of these agents for this indication.
Switching to another antipsychotic agent is commonly recommended if there is excessive weight gain or other adverse effects. However, discontinuation of medication may be warranted depending upon symptom severity. This is especially true if the individual has been treated for a long interval (ie, a year or more) and would benefit from a trial off medications to reassess efficacy and need for treatment. Withdrawal of risperidone and other antipsychotics is often accompanied by a period of greater behavioral dysregulation. Successful discontinuation of risperidone and other antipsychotic agents requires a gradual taper over several weeks to months. (See 'General principles' above.)
Repetitive behaviors and rigidity — Repetitive behaviors, stereotypies, and rigidity in children with ASD often interfere with function.
Approach — Repetitive behaviors and rigidity are core symptoms of ASD. They also can be exacerbated by anxiety or other conditions. Medication may be warranted if the behaviors interfere with function and have not responded adequately to nonpharmacologic interventions (eg, behavior therapy). Pharmacologic treatment involves a tradeoff between benefits and risks [81]. 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 ASD and repetitive behaviors and rigidity that are thought to be related to anxiety, clinical practice suggests the use of fluoxetine, sertraline, or another SSRI 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 [82], 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. (See 'SSRI' below and 'Anxiety' below.)
Potential treatments — Potential treatments for repetitive behaviors in children with ASD include SSRI, clomipramine, atypical antipsychotics, valproate, and buspirone, although high-quality evidence to support these therapies is lacking [17]. Naltrexone, secretin, and stimulants have been shown to be ineffective [17].
SSRI — The use of selective serotonin reuptake inhibitors (SSRI) for repetitive behaviors in children with ASD is based upon the effectiveness of SSRI in individuals with obsessive-compulsive disorder (OCD), demonstrated in meta-analysis of randomized controlled trials [83].
●Fluoxetine – Evidence regarding fluoxetine for repetitive behaviors in children with ASD is mixed. In a multicenter trial in 146 children (age 7.5 to 18 years) with ASD and a score of ≥6 on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), a 20-point scale with a minimal clinically important difference of two points, who were randomly assigned to 16 weeks of fluoxetine or placebo, a clinically important difference was not detected after prespecified adjustment for potential confounding factors (eg, sex, verbal ability) [84]. CY-BOCS scores decreased from baseline in both groups (from 12.8 to 9.02 in the fluoxetine group and from 13.13 to 10.89 in the placebo group; adjusted mean difference between groups -1.17, 95% CI -3.01 to 0.67). Another multicenter randomized trial in 158 children (age 5 to 17 years) with ASD also did not detect a clinically important difference in CY-BOCS scores between very low dose fluoxetine and placebo groups; similar proportions of children achieved >25 percent reduction in CY-BOCS from baseline (36 and 41 percent, respectively) [85]. In an earlier randomized, placebo-controlled crossover study in 44 children with ASD, fluoxetine was beneficial in reducing repetitive behaviors as measured on the CY-BOCS [86].
The frequency and severity of adverse effects was similar with fluoxetine and placebo [84,85].
●Fluvoxamine – In an unpublished randomized trial in children, fluvoxamine had limited efficacy in reducing repetitive behaviors and was poorly tolerated [87]. However, it may be beneficial in adults with ASD [88].
●Sertraline – Open-label trials of sertraline in adults with ASD have noted improvements in repetitive and disruptive behaviors [89,90]. There are no randomized controlled trials in adults or children.
●Paroxetine – Studies of paroxetine in children with ASD are lacking. Small open-label studies in individuals with intellectual disability suggest that it may be beneficial in reducing aggression [91].
●Citalopram – In a multicenter randomized trial in 149 children with ASD, citalopram did not improve repetitive behaviors and was associated with increased risk of adverse events, including increased energy level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, dry skin, and pruritus [92]. Citalopram also may cause cardiac conduction effects (prolonged QTc).
●Escitalopram – An open-label trial of escitalopram demonstrated some improvement in irritability, lethargy, stereotypy, hyperactivity, and inappropriate speech [93]. There was a wide variability in therapeutic dose that was not related to patient weight.
Children taking SSRI should be monitored for adverse effects, including activation, sedation, anorexia, agitation, headaches, aggression, anxiety activation, insomnia, gastrointestinal upset, and drowsiness. Blood pressure and heart rate should be monitored at follow-up visits.
When used in children and adolescents with depression, SSRI 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 SSRI in individuals with ASD. However, most studies did not assess suicidal ideation and included too few subjects to detect rare adverse effects, such as suicidal ideation.
Clomipramine — Clomipramine is a serotonin-selective tricyclic antidepressant. The use of clomipramine for repetitive behaviors in children with ASD is based upon its effectiveness in individuals with OCD, as demonstrated in controlled trials [94].However, studies of clomipramine for repetitive behavior in children with ASD have inconsistent findings [95-97]. The use of clomipramine often is limited by its side effects, which may include lethargy, tremors, tachycardia, insomnia, diaphoresis, nausea, decreased appetite, urinary retention, and severe constipation.
Risperidone — In secondary analysis of a multicenter placebo-controlled trial of 101 children with autism and disruptive behavior, treatment with risperidone (1.8 mg/day) for eight weeks was associated with greater decrease in mean CY-BOCS compulsion scale (15.5 to 11.65 versus 15.2 to 14.2) [52]. Adverse effects of risperidone are discussed above. (See 'Side effects of antipsychotics' above.)
Valproate — Valproate, an antiseizure medication, is also used to treat repetitive behaviors in children with ASD. It use is supported by a small, blinded randomized controlled trial that demonstrated improvement in repetitive behaviors as measured by the CY-BOCS [98].
Side effects of valproic acid may include, but are not limited to, irritability, weight gain, anxiety, and aggression. The pharmacology and use of valproate is discussed separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)
Buspirone — Buspirone, an anxiolytic, is a serotonin partial agonist. In a randomized trial comparing two doses of buspirone with placebo in 166 children with ASD, low-dose buspirone (2.5 mg twice per day) had no effect on core symptoms of ASD (as assessed with the Autism Diagnostic Observation Schedule [ADOS] Composite Total Score), but improved scores on the ADOS Restricted and Repetitive Behavior score (a secondary outcome) [99]. Although these results suggest that buspirone may be a useful adjunct to behavioral interventions for the treatment of repetitive behaviors, additional study is necessary.
Anxiety — Anxiety is common in individuals with ASD and may contribute to aggressive, explosive, or self-injurious behaviors. (See 'Maladaptive/problem behaviors' above.)
Anxiety in children with ASD is treated with the same therapies that are used to treat anxiety in other children. Pharmacotherapy is one arm of a multimodal approach that may include individual therapy, cognitive behavioral therapy, behavioral interventions/incentives; accommodations to address sensory sensitivities; and special education services [100-103]. The components of the multimodal therapy may vary from patient to patient. (See "Psychotherapy for anxiety disorders in children and adolescents" and "Pharmacotherapy for anxiety disorders in children and adolescents".)
Symptoms related to anxiety in children with ASD often are treated with SSRI. There are no randomized trials that specifically assess the efficacy of SSRI in individuals with ASD. However, in a meta-analysis of randomized controlled trials in children without ASD, SSRI 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 1.6-2.26) [104]. (See 'SSRI' above.)
The use of SSRI in children with repetitive behaviors is discussed above. (See 'SSRI' above.)
Buspirone (an anxiolytic), and mirtazapine (an alpha-2 antagonist) are other agents that may be used to treat anxiety in children with ASD [99,105,106].
Mood lability — A number of agents have been used to treat dysregulated mood and symptoms related to dysregulated mood in children and adolescents with ASD. These include atypical antipsychotics, SSRI, and mood-stabilizing agents (eg, lithium). None of these agents has been studied specifically for mood regulation in children with ASD.
Atypical antipsychotics also may be used to treat maladaptive behaviors. Their use is discussed above. (See 'Treatment approach' above and 'Side effects of antipsychotics' above.)
SSRI also may be used to treat repetitive behaviors and anxiety. Their use is discussed above. (See 'SSRI' above.)
Depression — Antidepressant therapy may be indicated if depressive symptoms persist despite counseling and psychosocial interventions. The same medications that are used for depression in typical children can be used to treat symptoms of depression in children with ASD. (See "Pediatric unipolar depression and pharmacotherapy: Choosing a medication".)
The efficacy of SSRI and serotonin norepinephrine reuptake inhibitors (SNRI) in the treatment of children with ASD and depression has not been documented through a sufficient number of randomized controlled trials to draw any firm conclusions [107]. Nonetheless, SSRI/SNRI may be warranted for patients who demonstrate clear symptoms of depression (eg, terminal insomnia, psychomotor disturbance, anorexia, changes in mood from baseline, etc). (See "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis".)
When using antidepressants 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 "Pediatric unipolar depression and pharmacotherapy: Choosing a medication", section on 'Adverse side effects' and "Effect of antidepressants on suicide risk in children and adolescents".)
Individuals with ASD may respond to very low doses of SSRI/SNRI, but typical pediatric doses may be necessary. It is important to "start low and go slow." (See 'Overview' above.)
Other psychiatric conditions — Individuals with ASD may have other coexisting psychiatric conditions that can be challenging to diagnose. As an example, disorders with disorganized thought, delusions, or hallucinations may be difficult to diagnose in children with ASD. Referral to a psychiatrist is suggested for children and adolescents with ASD who are suspected to have an emerging thought disorder. Treatment of psychosis in children with ASD is similar to that in children without ASD.
INVESTIGATIVE THERAPIES FOR SOCIAL DEFICITS
Oxytocin — Although small or open-label studies suggested that oxytocin may improve social interaction or function in children with ASD [108-113], a blinded, randomized trial did not detect a benefit [114]. Among 290 children with ASD (age 3 to 17 years, stratified for age and verbal fluency) randomly assigned to a 24-week course of intranasal oxytocin (target dose of 48 international units daily) or placebo, the least-squares mean change from baseline scores on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW) were similar (-3.7 to -3.5, mean difference -0.2, 95% CI -1.5 to 1.0). The ABC-mSW consists of 13 items, scores range from 0 to 13, and higher scores indicate less social interaction. Secondary measures of social interaction, including the Social Responsiveness Scale-2 Social Motivation subscale, Sociability Factor, and Stanford–Binet Intelligence Scale: Fifth Edition Abbreviated IQ, were also assessed, given the difficulty of capturing changes in social function over time. The least-squares mean change from baseline scores on the secondary measures were also similar between groups. In subgroup analysis, no difference was detected among participants with fluent verbal speech, among participants with minimal verbal fluency, or when analyzed according to baseline oxytocin levels.
Additional randomized trials are necessary before oxytocin can be recommended to improve social interaction in children with ASD.
Other investigative therapies — Other pharmacologic agents that demonstrated potential benefit for social deficits in individuals with ASD in small or open-label studies include D-cycloserine [115], tetrahydrobiopterin [116], and cognition enhancers used in the treatment of Alzheimer disease (eg, galantamine, memantine, and rivastigmine) [17,117-122]. Additional controlled studies are necessary to confirm efficacy and safety before these therapies can be recommended.
Naltrexone has been shown to be ineffective in the treatment of social deficits [17,122].
ASSOCIATED CONDITIONS
Seizures — Seizures are more common in children with ASD than in the general population (see "Autism spectrum disorder: 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 — A 2014 meta-analysis found a higher prevalence of gastrointestinal (GI) symptoms in children with ASD than in the general population [123]. The American Academy of Pediatrics and Scottish Intercollegiate Guidelines Network recommended that GI disorders in children with an ASD generally should be managed in the same way as in children without an ASD [8,124]. However, because children with ASD may not tolerate certain aspects of the examination or types of diagnostic studies (eg, rectal examination), trials of pharmacologic therapy for constipation or gastroesophageal reflux may be undertaken based upon symptoms [124].
Pharmacologic interventions for specific GI problems in children are discussed separately:
●Constipation (see "Chronic functional constipation and fecal incontinence in infants, children, and adolescents: Treatment")
●Gastroesophageal reflux disease (see "Management of gastroesophageal reflux disease in children and adolescents")
●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-rich countries")
Sleep disturbance — Many children with ASD have associated sleep problems or disorders, including bedtime resistance, sleep anxiety, sleep-onset disturbances, frequent waking, restlessness, or abnormal sleep architecture [125-128]. Sleep disturbance may be related to abnormalities in melatonin, serotonin, or gamma-aminobutyric acid [129,130].
The evaluation of sleep disturbance in children with ASD should include a thorough sleep history and screen for obstructive 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".)
It is important to ensure appropriate sleep hygiene and use behavioral interventions to decrease sleep associations before considering pharmacologic interventions [131-135]. Medications are unlikely to be effective in the absence of an appropriate sleep schedule.
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 — The benefits of melatonin for sleep onset and maintenance in children with ASD have been suggested in observational, open-label studies and randomized placebo-controlled trials [135-147]. In a meta-analysis of five randomized crossover trials (including a total of 57 patients) of melatonin in children with ASD, melatonin increased sleep duration by 73 minutes and decreased sleep onset latency by 66 minutes compared with placebo but did not affect nighttime awakenings [142]. Side effects were minimal. 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 [139,140,143-145,147,148].
These results suggest that in the short-term (ie, up to six months), 1 to 10 mg of melatonin may be effective in helping children with ASD to fall asleep and sleep longer when provided 30 minutes before bedtime. However, there are no dosing guidelines for administration and no information on long-term use or side effects. Side effects of melatonin may include difficulty waking, daytime sleepiness, and enuresis [137,138].
We suggest melatonin for patients with ASD who have difficulty falling asleep and staying asleep despite appropriate sleep hygiene and behavioral or environmental interventions. We usually start with 0.5 to 1 mg, depending upon age, and increase by 1 mg as needed to a maximum of 10 mg (although in clinical practice, others may use a higher dose).
Melatonin is sold over the counter and does not require a prescription. It is not regulated by the FDA. When parents/caregivers purchase melatonin, they should seek a formulation that contains melatonin as the only active ingredient.
Other agents — Some data suggest that low serum ferritin levels in children with ASD may contribute to symptoms of restless sleep (even in children with normal iron levels) [149]. In an observational study, oral iron supplementation was beneficial in improving restless sleep in children with ASD and decreased serum ferritin [149].
Other agents that have been studied in the management of sleep disturbance (increased sleep latency, night wakings, and decreased total sleep) in children with ASD include niaprazine, clonidine, and risperidone [17]. In addition, for children who require antiseizure or antidepressant medications, the timing of administration can be manipulated to take advantage of the sedative effects.
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.
●Niaprazine is a histamine H1-receptor antagonist with sedative properties that is available in Europe [150,151]. In an open study in 25 patients with ASD and sleep disorder, niaprazine (1 mg/kg per day for 60 days) was associated with improvement in behavior and sleep disorders; no side effects were observed [151].
●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 [152]. Side effects of clonidine include hypotension.
●If a patient who presents with sleep difficulties also is prescribed a medication with a sedating effect (eg, risperidone, some antiseizure medications, some antidepressants), the sedating medication could be administered at bedtime; or, if more than one dose is recommended, the higher dose can be administered at bedtime, if appropriate. However, given the potential adverse effects, the use of sedating medications for sleep disturbance alone is not recommended.
Parasomnias — Parasomnias or nonrapid eye movement (NREM) arousal disorders include sleep walking, sleep terrors, and confusional arousals (see "Parasomnias of childhood, including sleepwalking", section on 'Disorders of arousal from non-rapid eye movement sleep'). Clonazepam and tricyclic antidepressants have been used to treat NREM arousal disorders in children with ASD [131]. However, high-quality evidence to support their use is lacking.
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
●The target symptom(s) for pharmacotherapy in children with autism spectrum disorder (ASD) should be clearly defined. Medical causes for the behavior should be excluded, and behavioral interventions should be maximized before pharmacotherapy is initiated. (See 'Pretreatment evaluation' above.)
●When considering the use of medications for target symptoms, the potential benefits and risks must be weighed on a case-by-case basis. (See 'Indications' above.)
●Psychopharmacotherapy for children and adolescents with ASD ideally is prescribed by specialists familiar with ASD (eg, developmental pediatrician, child psychiatrist, child neurologist). Primary care clinicians who undertake the prescription of psychotropic agents for children with ASD should consider consultation with a specialist. (See 'Who should prescribe?' above.)
●Children with ASD who are receiving pharmacologic therapy for target symptoms must be monitored regularly for efficacy and side effects. Additional precautions may be necessary for children receiving more than one psychoactive medication. (See 'Monitoring' above and 'Polypharmacy' above.)
●When, after careful assessment of the patient and a discussion of the potential risks and benefits, the clinician and parents/patient agree that pharmacotherapy is indicated for target symptoms in children with ASD:
•For inattention and hyperactivity that are not thought to be related to other symptoms, such as anxiety, we suggest methylphenidate (Grade 2C). Other stimulants, alpha agonists, and atomoxetine also have been used. (See 'Approach' above.)
•For maladaptive behaviors including aggression and self-injury that are not thought to be related to other symptoms, we suggest risperidone or aripiprazole (Grade 2A). Other medications (eg, stimulants, selective serotonin reuptake inhibitors [SSRI], alpha-adrenergic agonists) may be more appropriate, depending upon the underlying cause of aggression (eg, hyperactivity, anxiety, impulsivity). (See 'Treatment approach' above.)
•For isolated repetitive behaviors, evidence is lacking to recommend a specific SSRI; however, we suggest fluoxetine, sertraline, or another SSRI as the initial medication for interfering repetitive behavior (Grade 2C), especially if the behaviors are exacerbated by anxiety. (See 'Repetitive behaviors and rigidity' above.)
•For anxiety, we suggest an SSRI as the initial medication (Grade 2B). (See 'Anxiety' above.)
•For dysregulated mood, we suggest an atypical antipsychotic or SSRI as the initial medication (Grade 2C). (See 'Mood lability' above.)
•For depressive symptoms, we suggest an SSRI or serotonin norepinephrine reuptake inhibitor as the initial medication (Grade 2B). (See 'Depression' above.)
●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 disorders in children with ASD generally should be managed in the same way as in children without ASD. (See 'Gastrointestinal problems' above.)
●Melatonin may be beneficial for sleep disturbance (late onset, frequent waking, restlessness) that persists despite appropriate sleep hygiene and behavioral interventions. (See 'Melatonin' above.)
ACKNOWLEDGMENT — We are saddened by the death of Carolyn Bridgemohan, MD, who passed away in August 2019. UpToDate wishes to acknowledge Dr. Bridgemohan's many contributions to pediatrics, in particular, her work as our Section Editor for Developmental and Behavioral Pediatrics.
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