Clinical Practice Pathways for Evaluation and Medication Choice for Attention-Deficit/Hyperactivity Disorder Symptoms in Autism Spectrum Disorders
BACKGROUND AND OBJECTIVE Hyperactivity, impulsivity, and inattention (referred to as “ADHD [attention-deficit/hyperactivity disorder] symptoms”) occur in 41% to 78% of children with autism spectrum disorders (ASDs). These symptoms often affect quality of life, interfering with learning or interventions that target primary ASD symptoms. This practice pathway describes the guidelines for evaluation and treatment of children and adolescents with ASD and comorbid ADHD symptoms.
METHODS Current research in this area is limited, and, therefore, these recommendations are based on a systematic literature review and expert consensus in the Autism Speaks Autism Treatment Network Psychopharmacology Committee.
RESULTS The recommended practice pathway includes the Symptom Evaluation Pathway for systematic assessment of ADHD symptoms across settings; examination for comorbid sleep, medical, or psychiatric comorbidities that may contribute to symptoms; and evaluation of behavioral interventions that may ameliorate these symptoms. For children for whom medication is being considered to target the ADHD symptoms, the medication choice pathway provides guidance on the selection of the appropriate agent based on a review of available research, assessment of specific advantages and disadvantages of each agent, and dosing considerations.
CONCLUSIONS These recommendations provide a framework for primary care providers treating children who have ASD and ADHD symptoms. Our systematic review of the current evidence indicates the need for more randomized controlled trials of the medications for ADHD symptoms in ASD. There will also be a need for studies of the effectiveness of these practice pathways in the future.
- ADHD —
- attention-deficit/hyperactivity disorder
- ASD —
- autism spectrum disorder
- ATN-PC —
- Autism Treatment Network Psychopharmacology Committee
- DSM-IV —
- Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
- RCT —
- randomized controlled trial
Children with autism spectrum disorders (ASDs) frequently experience medical or neurologic comorbidities, including gastrointestinal symptoms, sleep difficulties, and seizures.1–3 Similarly, co-occurring behavioral or mental health symptoms occur in the majority of children who have ASD,4 with individual children often showing symptoms of ≥2 comorbid disorders.5–7 Recent systematic analyses of comorbidity in ASD indicate that behavioral or mental health conditions increase the need for multiple resources, extra assistance in schools, and therapeutic interventions.8–10
Symptoms of hyperactivity and impulsivity, with or without inattention (attention-deficit/hyperactivity disorder [ADHD] symptoms), are common in children who have ASD. Rates vary from 41% to 78% in large samples.11 These symptoms often lead parents and caregivers to seek medical evaluation and treatment.12 Conversely, autistic features have been reported in children who have ADHD, especially in those with the combined type.13,14 Medical providers often prescribe medications targeting ADHD symptoms in ASD, recognizing the significant impairment that results if these symptoms are left untreated.15,16
Children may manifest all ADHD symptoms as outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)17 criteria for ADHD; however, the DSM-IV does not allow the concurrent diagnosis of ADHD and ASD. The fifth edition of the DSM is anticipated to allow a concurrent diagnosis of the 2 conditions.18 In the interim, we refer to hyperactivity, impulsivity, and inattention in ASD as “ADHD symptoms” to reflect the DSM-IV criteria. Although guidelines exist for evaluating and treating ADHD symptoms in typically developing children,19–22 there are no such guidelines for children with ASD who may have these symptoms. In addition, the evaluation and treatment, although based on guidelines and evidence for the typically developing children, are not always successful because of the multidimensional difficulties that children who have ASD experience. Psychotropic medications, although used commonly for these symptoms, may not be as effective for children who have ASD as in typically developing children. Moreover, children who have ASD are more sensitive to the side effects of these medications. With these considerations, clinicians often seek specialist opinion, which may not be readily available, given the variability in such access regionally. The present effort provides an attempt to address the need for a clinical pathway for practitioners, specifically for evaluating and treating symptoms of ADHD in children who have ASD.
Within the behavioral symptom domains, the Autism Speaks Autism Treatment Network Psychopharmacology Committee (ATN-PC) Medication Choice Subcommittee, composed of specialists in the treatment of children with ASD and comorbid conditions, was charged with the task of developing practice pathways for the symptom evaluation and use of psychotropic medications for target symptoms in children who have ASD. The current practice pathways provide clinicians with critical steps in evaluation of ADHD symptoms and with guidance on the choice of appropriate medications.
Because of the limited evidence base for evaluation and treatment of ADHD symptoms in children who have ASD, we were forced to rely primarily on collective clinical experience, complemented, where possible, with such evidence as does exist, as well as previously available guidelines in ADHD and ASD. Based primarily on group consensus, the ATN-PC Medication Choice Subcommittee developed 2 practice pathways related to ADHD: 1 for the evaluation of ADHD symptoms and 1 for the choice of medication for individuals whose symptoms merit a medication trial. After refinement of the practice pathways, accompanying narratives were composed for each step in the pathway. Individual members drafted narrative subsections corresponding to single steps in the pathway. These drafts underwent further review by 1 or 2 other members of the subcommittee. The entire ATN-PC Medication Choice Subcommittee then discussed and revised each step in detail before the integration for final review by members of the larger ATN-PC.
Systematic Literature Review
To ensure there were no omissions of relevant evidence from the pathway, we conducted a systematic literature review to identify evidence for the benefits and adverse effects of stimulants, atomoxetine, α-agonists, antipsychotic agents, and other medications on ADHD symptoms in ASD. The searches were conducted in Ovid, CINAHL, Embase, Database of Abstracts and Review, and the Cochrane Database of Systematic reviews (Tables 1 and 2) and were limited to research conducted with humans, published in the English language, involving children aged 0 to 18 years, and published between January 2000 and July 2010. The year 2000 was used as a cutoff because the standard diagnostic instruments for ASD (Autism Diagnostic Interview-R23 and Autism Diagnostic Observation Schedule24) were rarely applied before this time. Four primary reviewers graded the research by using a system adapted from GRADE.25 The system systematically assigned numerical values (26 points possible across 16 questions) based on the quality, consistency, directness, and effect size demonstrated (Table 3). Those scoring <40% were removed from the evidence base.23
Results of the Literature Review
The search identified 1255 articles. After removing review articles, commentaries, studies including <10 subjects, nonintervention trials, and articles that did not measure ADHD symptoms, 31 articles remained. These were organized into 2 tables (Tables 4 and 5), 1 for the randomized controlled trials (RCTs) and another for the non-RCT studies (non-RCTs). Based on the review, atypical antipsychotic agents (primarily risperidone) had the most RCTs, although ADHD symptoms were not the primary end points in these studies. These medications were being studied for irritability and behavioral symptoms; the benefit for ADHD was a secondary outcome, with improvement reported primarily in hyperactivity. Surprisingly, there were fewer RCTs for the ADHD-focused studies, with medications commonly used in clinical practice to target these symptoms (eg, stimulant medications, atomoxetine, α2-agonists). Among these medications, most evidence was available for stimulant medications (only methylphenidate), with 3 RCTs, including 1 study of preschool-aged children.24 Non-RCTs included studies of stimulant medications (only methylphenidate), atomoxetine, α2-agonists (primarily guanfacine), atypical antipsychotic agents (risperidone, aripiprazole, ziprasidone, and olanzapine), and others (memantine and levetiracetam).
Results of Guideline Development
Figures 1 and 2 present the recommended ADHD symptom evaluation and medication choice practice pathways for children with ASD. An overview of the accompanying narrative and the systematic review describes the function and flow of evaluation through each step of the 2 practice pathways.*
Pathway 1: Symptom Evaluation
Routine screening for ADHD symptoms by primary care clinicians should follow the American Academy of Pediatrics’ 2011 guideline.25 When a child presents to a clinician with significant ADHD symptoms, along with a suspicion of ASD by the caregivers, an accurate diagnosis of ASD should be made using existing ASD diagnostic guidelines.20,26,27 Language and cognitive testing should be conducted as part of the evaluation for ASD. Educational, speech and language, and behavioral supports should be optimized to target the core ASD symptoms, as well as language or cognitive impairment.
If the child continues to display ADHD symptoms despite these initial steps, a clinical interview focused on ADHD should be conducted, supplemented by commonly used ADHD-focused questionnaires such as the Conners Scale28 and the Vanderbilt ADHD Diagnostic Scales.29,30 (Figure 1, Boxes 1 and 2) Often, children may not exhibit ADHD symptoms on 1 or more clinical visits. Therefore, information about these symptoms in school, home, and community may serve to establish that ADHD symptoms are pervasive and not triggered by a specific environmental context.
Children should also undergo a systemic medical evaluation to rule out any undiagnosed medical problem† that may contribute to the ADHD symptoms, especially if the child has limited ability to communicate (Figure 1, Box 3). For some medical problems, corresponding ATN practice pathways may provide guidance (eg, sleep, constipation). Other comorbid conditions, such as mood or anxiety symptoms, may contribute to the ADHD symptoms (Figure 1, Box 4) and merit assessment and treatment by a mental health provider.
For children who have ASD and symptoms of ADHD who show a discrepancy in symptoms across settings, educational or behavioral interventions may be beneficial (Figure 1, Box 5). Some children may have a decrease in their overall ADHD symptoms with a more structured environment and schedule in school, whereas others may have more difficulty due to excessively demanding school routines. ADHD symptoms occurring only at home might respond to behavioral or family-oriented interventions.
When ADHD symptoms occur primarily in school, parents should request incorporation of a behavioral intervention plan into a Section 504 plan or Individualized Educational Program. Successful behavioral interventions may include functional behavioral assessment, identification of successful teaching styles, accommodations for learning disorders, tailored curriculum to the developmental and adaptive level of the child, or provision of related services (eg, speech and language therapy, occupational therapy). Comprehensive psychoeducational testing and/or neuropsychological testing help to evaluate the child’s cognitive strengths/weaknesses, which, in turn, will aid in designing an appropriate individualized educational plan.
Once medical, mental health, and educational/behavioral interventions have been optimized, the symptoms of ADHD can be reevaluated to assess the necessity of a medication trial for ADHD as a target symptom domain, depending on the severity of the symptoms and their effect on daily functioning.
Importantly, some children who have ASD and severe ADHD symptoms may require simultaneous evaluation and treatment across multiple steps in the symptom evaluation pathway. The process for implementing the pathway may be sequential or simultaneous across multiple steps for different children, as determined by severity of symptoms and/or availability of resources. Our intention is to provide guidance on the comprehensive medical, psychiatric, and behavioral domains that should be considered when evaluating and treating a child who has ADHD symptoms.
Pathway 2: Medication Choice
As indicated in the systematic review, most of the medications used to treat ADHD symptoms have not been studied in sufficient depth in ASD to allow for accurate assessment of the treatment effects. Therefore, this pathway (Figure 2) represents consensus expert clinician opinion and is based on (1) existing research in ASD; (2) treatment of ADHD in the non-ASD population for which there have been considerably more research studies; and (3) clinical experience. These opinions serve as broad recommendations, and the clinician should continue to use judgment in selecting medications. These are not a substitute for medication handouts or desk references and do not list all the precautions, potential adverse effects, or risks of using a particular medication. For detailed recommendations, including those for initial evaluation and for initiation of individual medications, monitoring for side effects and adverse events, and maintenance on these medications, please see the narrative.† Pathway 2 assumes that the child has been determined to need a medication trial for the ADHD symptoms (Figure 2, Box 1).
Stimulant medications (Figure 2, Box 2) include methylphenidate and amphetamine preparations. They enhance dopaminergic transmission by inhibiting or reversing dopamine reuptake and act, to a lesser degree, on the noradrenergic system.31 Generally, methylphenidate preparations are the first choice for treating ADHD symptoms in ASD because (1) there is extensive clinical experience with them over the past several decades; and (2) they have a relatively well- documented safety record and side effect profile. Compared with typically developing children with ADHD, children who have ASD, as in other developmental disabilities (including intellectual disabilities, Fragile X syndrome, and head trauma), seem to have lower effect sizes with these medications and are more sensitive to side effects, including emotionality and agitation. Although best studied in typically developing children with ADHD,19 there is 1 large RCT of methylphenidate in children with ASD.32,33 Only 49% of children in this study displayed a therapeutic response compared with 69% in the Multimodal Treatment Study of Children with ADHD (MTA) study. In addition, 18% of the children discontinued participation due to adverse events, especially irritability, compared with 1.4% in children with ADHD.
We recommend beginning stimulant treatment with a methylphenidate formulation because of greater evidence in both ASD and ADHD.32 It is often preferable to start with a short-acting formulation to gauge side effects before switching to the corresponding long-acting formulation. Amphetamine salts are an option for children who do not benefit sufficiently from methylphenidate or who experience dose-limiting side effects. We recommend following the American Academy of Pediatrics’ guidelines for screening for cardiac problems before initiating treatment with stimulant medications.21,22
Atomoxetine (Figure 2, Box 3) is a selective norepinephrine reuptake inhibitor. There is limited evidence of its effectiveness in treating ADHD symptoms in ASD, with 1 small, randomized crossover pilot study34; this study produced a 50% response rate with atomoxetine compared with 25% with placebo. One treatment study in typically developing children who have ADHD found that atomoxetine is effective in children with comorbid anxiety symptoms,36 although this agent has not been evaluated in those with ASD.
Guanfacine and clonidine are 2 available α2-agonists (Figure 2, Box 4). Originally developed as antihypertensive agents, they primarily target hyperactivity and impulsivity, and are used as adjuncts to stimulant medications, although they are also prescribed as single medications for these symptoms. They are frequently used in the treatment of ADHD symptoms in ASD.36 Guanfacine has the benefit of being relatively longer-acting and less sedating compared with clonidine. Most studies of these agents have been open-label (Tables 4 and 5).37 RCTs of these medications have included very small sample sizes.38 Although these medications have been studied in typically developing children who have ADHD, leading to the recent approval by the US Food and Drug Administration of their extended-release preparations as adjunct agents in the treatment of ADHD, there is currently limited empirical evidence for their effectiveness for ADHD in ASD.
Risperidone and aripiprazole are 2 atypical antipsychotic medications (Figure 2, Box 5) that have received approval by the US Food and Drug Administration for the treatment of irritability and agitation in children who have ASD. These studies have also demonstrated reduction in ADHD symptoms in children with ASD who have co-occurring irritability and agitation.39,40 Among all the medications used to treat ADHD symptoms, these antipsychotic agents have the most empirical evidence (including most RCTs). However, children who have ASD are more sensitive than typically developing children to the side effects and adverse events of these medications; their use is limited by the risk of weight gain/metabolic syndrome and movement disorders, including tardive dyskinesia. Therefore, these medications should be reserved only for children who have severe impulsivity leading to safety concerns (eg, dangerous and impulsive running or jumping) or those with comorbid irritability,40 agitation, or aggression.
Consultation or referral to an autism or mental health specialist should be considered when risperidone, aripiprazole, or another antipsychotic medication is being considered for a child who has ADHD symptoms in ASD. Choice of these medications depends primarily on the side effect profile, with risperidone more likely to lead to weight gain and aripiprazole more likely to lead to a movement disorder.39,40
Assuming an accurate ASD diagnosis, in most cases, the symptom evaluation pathway (Fig 1) may be completed in 1 or 2 visits that begin with a clinical evaluation, obtaining a description of ADHD symptoms in different settings, extend to identifying possible causes or triggers for the ADHD symptoms, and finish with developing a treatment plan. If medication is part of that treatment plan, the practitioner should follow the medication choice pathway (Fig 2), involving the family in the decision-making process so that they can understand the evidence, the target symptoms that may improve, and the potential side effects or adverse events. Because initiating a medication is a significant choice by the family, >1 visit may be necessary to discuss the pros and cons of a given treatment plan. This action may also allow time for medical, behavioral, or educational interventions to be implemented, providing further evidence for or against the need for a medication trial. As part of the discussion, the clinician should explore the caregivers’ beliefs and values related to using medications for ADHD symptoms and provide an evidence-based, realistic appraisal of the risks and benefits of the use of these medications.
Included in any discussion of medication should also be the definition of target symptoms and the time frame during which they can be expected to improve. To prevent potentially beneficial medications from being stopped prematurely at low doses, or inadequate duration of treatment, clinicians should explain that identification of an effective medication usually takes time and careful evaluation. This will also help prevent disappointment with inadequate or lack of response to the medication. Even more concerning, however, are situations in which side effects and adverse events of medications are not recognized or are allowed to continue too long between clinic visits. Families should be carefully educated about potential side effects and adverse events before they emerge, emphasizing both the ones that are most likely and those that are severe and should prompt a call to the clinician’s office. Monitoring for effectiveness and safety of these medications should be done at each visit to gauge their usefulness.
Children who have ASD and co-occurring ADHD symptoms should undergo careful symptom evaluation and, if indicated, trials of medications, following the recommended practice pathways as outlined in this article. At all steps, clinical judgment should be used in evaluating ADHD symptoms and choosing an appropriate medication. ‡ Stimulant medications are considered first, although they have fewer RCTs and a response rate of ∼50%, with higher rates of side effects. As shown in our systematic review, atypical antipsychotic medications currently have the most evidence for efficacy in the treatment of ADHD symptoms in ASD. These benefits, however, have only been studied in the context of irritability and agitation and are accompanied by significant adverse effects that should limit their use. This review highlights the need for more RCTs to evaluate medications for ADHD symptoms in children who have ASD, especially as new medications and preparations of the existing medications are added to the available formulary. Future research could also focus on the effectiveness of the recommended practice pathway in clinical practice.
The authors gratefully acknowledge the valuable assistance of the members of the ATN, especially the ATN-PC, in reviewing this document.
- Accepted August 8, 2012.
- Address correspondence to Rajneesh Mahajan, MD, Kennedy Krieger Institute, Center for Autism and Related Disorders, 3901 Green Spring Ave, Baltimore, MD 21211. E-mail:
This Manuscript has been read and approved by all authors. This paper is unique and not under consideration by any other publication and has not been published elsewhere.
FINANCIAL DISCLOSURE: Dr Veenstra-VanderWeele has received research funding from Seaside Therapeutics, Roche Pharmaceuticals, Forest Pharmaceuticals and Novartis Pharmaceuticals. Dr Anagnostou has consulted without fees for Neuropharm Group, Proximagen Group, and Novartis Pharmaceuticals; she has received consultation fees from Seaside Therapeutics. Dr Handen has received research support from Bristol-Myers Squibb Company, Curemark, Eli Lilly and Company and Autism Speaks. Dr Hardan has also received research funding from Forest Pharmaceuticals and Bristol-Myers Squibb Company and has consulted for IntegraGen and Forest Pharmaceuticals. The other authors have indicated they have no financial relationships relevant to this article to disclose.
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