Attention-Deficit/Hyperactivity Disorder: Comorbidities and Mimics in Children

Educational Objectives

The goal of this program is to improve the management of attention-deficit/hyperactivity disorder (ADHD) in the pediatric population. After hearing and assimilating this program, the clinicians will be able to:

1. Diagnose ADHD in the pediatric population.
2. Manage adverse effects of medications used to treat ADHD in pediatric population.
3. Prescribe appropriate treatment for cases of ADHD associated with different comorbidities.

Summary

Diagnosing attention-deficit/hyperactivity disorder (ADHD): the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) divides ADHD symptoms into inattentive and hyperactive-impulsive types; diagnosis requires persistence of ≥6 symptoms for ≥6 mo, onset at <12 yr of age, occurrence in multiple settings, and functional impairment; symptoms must not be better explained by another condition; ADHD rating scales, eg, the Vanderbilt Assessment Scale, facilitate rapid feedback from parents and teachers; other scales, such as the Swanson, Nolan and Pelham (SNAP) Parent and Teaching Rating Scale and ADHD Self-Report Scale, are geared toward older children and teens; in addition to aiding diagnosis, these tools assess response to medications; after establishing a treatment regimen, repeat the rating scale every 6 mo; the Vanderbilt Scale is free, easily scored, and specifies cutoffs for an ADHD diagnosis; questions 48 to 55 assess impact on function

Comorbidities and mimics: new guidelines emphasize screening for comorbidities and identifying conditions that may mimic ADHD, such as learning disabilities, autism spectrum disorder (ASD), and anxiety; common comorbidities include disruptive behaviors, anxiety, and depression, especially in older school-age and early teen years; learning disabilities are more prevalent in children with ADHD; the coexistence of ADHD with ASD is now recognized; trauma, posttraumatic stress disorder (PTSD), and substance use can also mimic ADHD; additionally, medical conditions (eg, absence seizures, vision or hearing problems, sleep disorders, hyperthyroidism, Tourette syndrome, tics) can contribute to ADHD-like behaviors

Treatment of ADHD: requires addressing sleep, routines, nutrition, and exercise; for younger children, initial focuses include psychosocial treatment and behavioral therapy; interventions for school-aged children include school accommodations and medications; stimulants are first-line medical therapy, typically starting with the methylphenidate class; if ineffective at an optimized dose or adverse effects (AEs) are not tolerated, switch to a stimulant from the dextroamphetamine class; if stimulants fail, nonstimulant options (α-agonists or norepinephrine reuptake inhibitors) are the next step; if ineffective, reconsider the diagnosis; off-label use of bupropion can be considered; managing sleep problems includes attention to sleep hygiene and use of melatonin and α-agonists, if necessary; behavioral therapy focuses on teaching parents to manage ADHD symptoms; many print and online resources (eg, ADDitude magazine) are available; clinicians may recommend the antecedent-behavior-consequences model; structure, routines, strategic use of rewards, and simple instructions are key principles

School accommodations: options include an individualized education program (IEP) or a Section 504 plan; while an IEP provides more comprehensive services, both plans can specify accommodations, including preferential seating and adjusted conditions for testing (eg, quiet spaces, extended time), facilitate communication between school and home, and establish a behavioral plan; the IEP assessment process allows testing for learning disorders, if suspected (especially when learning gaps persist despite ADHD treatment)

Stimulant medications: short-acting amphetamines (eg, mixed amphetamine salts [Adderall IR]) and long-acting options (eg, Adderall XR, Mydayis) are often the first line of treatment for ADHD; methylphenidate is also available in short-acting (eg, Focalin IR, Methylin, Ritalin) and long-acting (eg, Concerta, Daytrana) formulations, the latter being convenient for older teenagers; short-acting medications require twice-daily administration; lisdexamfetamine dimesylate (Vyvanse) is one of the longest-lasting medications (12-14 hr); stimulants increase dopamine and norepinephrine levels in the synaptic cleft through reuptake inhibition; amphetamines directly induce dopamine release and are more strongly associated with AEs of restlessness or anxiety

MTA study: ≈70% of children with ADHD responded positively to methylphenidate; ≈10% of nonresponders subsequently responded to a different medication, such as an amphetamine; AEs — ≤30% of participants in the MTA study experienced appetite suppression and insomnia (the 2 most reported AEs); the third most common AE is headache (reported by ≈10% of patients)

Management of stimulant AEs: collaborate with patients and their families to manage AEs rather than immediately discontinuing the medication or switching to a different category; effects on weight and height — primarily stem from appetite decrease; recommendations may include drug holidays or calorie supplementation, if necessary, but the emphasis is on encouraging regular snacking and 3 meals a day; insomnia — advise dosing just after awakening; short-acting medications may be considered to avoid impacting bedtime routines; medications to aid sleep (eg, melatonin, α 2-agonists) may be considered; as the latter are second-line ADHD treatments, they may also augment the beneficial effects of stimulant medications; other AEs — for stomachache or headache, hydration and eating before or while taking the medications are encouraged; rebound symptoms can be managed by switching to a long-acting medication or adding a booster dose

Safety monitoring: screen for personal and family history, with a focus on cardiovascular history; patients with a history of syncope or arrhythmia require electrocardiography and cardiovascular clearance; relative contraindications include substance use disorder, eating disorders (which may cause electrolyte imbalances), and bipolar disorder or schizophrenia, as stimulants may exacerbate psychotic symptoms; baseline medical monitoring includes blood pressure, heart rate, weight, and height; repeat ADHD symptom rating scales every 3 to 6 mo and after each dose change to assess medication effectiveness; the MTA study found greater effectiveness of ADHD medications when visits were more frequent during the initiation and titration phase; follow-up every 1 to 2 wk during this period and then monthly for the first few months to ensure patients are on the correct dose; underdosing of stimulants is common (per the MTA study conclusions, increase to the maximum recommended dose unless AEs are not tolerated)

Atomoxetine (Strattera): a second-line medication; studies show a median effect size of 0.64 and an average number needed to treat of 4; may reduce overall symptoms of ADHD but is more effective for hyperactivity than inattention; stimulants are preferred for patients in whom inattention symptoms predominate; has benefits for oppositional symptoms and quality of life; although more effective than placebo for anxiety, such symptoms are better treated with a selective serotonin reuptake inhibitor (SSRI) or behavioral therapy; approved by the US Food and Drug Administration (FDA) for ages 6 to 18 yr; common AEs are similar to those of SSRIs, including gastrointestinal (GI) upset, headache, and sleep disturbances; the recommended starting dose is 0.5 mg/kg for first week, with gradual weekly increases; GI issues often subside after the first 2 wk

α 2-agonists: eg, clonidine, guanfacine; the other second-line treatment for ADHD; long-acting preparations (Kapvay; Intuniv) are approved by the FDA, but immediate-release preparations (Catapres; Tenex) are used off label; more effective for hyperactivity and impulsivity than for inattention; often used to augment stimulants because associated AEs are mild; may allow stimulants to be given at lower doses, potentially reducing the severity of AEs; common AEs of α 2-agonists include sedation, constipation, hypotension, dizziness, and lightheadedness; parents are advised to give the first dose at night, then ensure good hydration and observe for AEs the following day; doses are uptitrated weekly

Comorbidities with ADHD: anxiety may give the appearance of inattentiveness or “jumpiness"; history (eg, timing of symptom onset) is important for determining which condition is the primary problem; ADHD and anxiety can manifest at the same time and affect the patient equally; to identify comorbidities, determine onset, triggers, environmental factors, and characteristics; oppositional defiant disorder is often comorbid with ADHD, but actions typically have a more deliberate nature (vs the impulsive traits associated with ADHD); inattentive symptoms during academic work but not in other domains of life may indicate a learning disability; consider trauma in cases of significant inattention or behavioral dysregulation; if the child has multiple issues, treat the primary concern first; 66% of patients with ADHD have a comorbid psychiatric condition; multiple rating scales that screen for comorbidities are available

ADHD and anxiety: if ADHD drives anxiety, stimulants may be the initial choice; if anxiety is the primary concern, treat with SSRIs and/or behavioral therapy; clinically, methylphenidate is often preferred as the first stimulant because of its relatively mild AEs; the addition of an α 2-agonist is recommended when sleep problems, hyperactivity, or impulsivity persist or response to stimulants is incomplete; for patients who do not tolerate high doses of stimulant, the synergistic effects of α 2-agonists may be beneficial; atomoxetine is considered when stimulants fail or if the patient has contraindications to stimulants; consider adding SSRIs to stimulants when anxiety is the primary concern or if ADHD improves but anxiety does not

ADHD and depression: children with ADHD are at high risk for depression; early untreated symptoms of ADHD can affect interpersonal relationships and academic performance; for equally severe, comorbid ADHD and depression, treat the ADHD first because response is more rapid; if depression persists, consider therapy and an SSRI; other options include serotonin-norepinephrine reuptake inhibitors or norepinephrine reuptake inhibitors

ADHD and autism: guanfacine and clonidine are the most popular choices, followed by methylphenidate; methylphenidate is favored over amphetamines for its milder AEs in sensitive autism patients; risperidone and aripiprazole are approved for autism-related irritability

ADHD and trauma: children with ADHD are at risk for developing PTSD; symptoms of ADHD and PTSD overlap; the clinical interview is important for identifying distinguishing symptoms (eg, nightmares in trauma); if equally severe and comorbid, start with behavioral therapy; consider medication for ADHD after reassessment at 1 to 2 mo; clonidine and guanfacine may be started early because they are effective for both conditions

Indications for referral: referral is recommended for failure of therapy, safety concerns, substance abuse, poor family functioning, comorbid psychosis, mood disorders, or age <5 yr

Readings

Epstein JN, Loren RE. Changes in the definition of ADHD in DSM-5: subtle but important. Neuropsychiatry. 2013;3:455-458; Hennissen L, Bakker MJ, Banaschewski T, et al. Cardiovascular effects of stimulant and non-stimulant medication for children and adolescents with ADHD: a systematic review and meta-analysis of trials of methylphenidate, amphetamines and atomoxetine. CNS drugs. 2017;31:199-215; Hirota T, Schwartz S, Correll CU. Alpha-2 agonists for attention-deficit/hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy. J Am Acad Child Adolesc Psych. 2014;53:153-173; Jensen PS, Hinshaw SP, Swanson JM, et al. Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications and applications for primary care providers. J Dev Behav Pediatr. 2001;22(1):60-73. doi:10.1097/00004703-200102000-00008; Mechler K, Banaschewski T, Hohmann S, Häge A. Evidence-based pharmacological treatment options for ADHD in children and adolescents. Pharmacol Ther. 2022;230:107940. doi:10.1016/j.pharmthera.2021.107940; Nichols JQ, Shoulberg EK, Garner AA, et al. Exploration of the factor structure of ADHD in adolescence through self, parent, and teacher reports of symptomatology. J Abnorm Child Psychol. 2017;45(3):625-641. doi:10.1007/s10802-016-0183-3; Paris J, Bhat V, Thombs B. Is adult attention-deficit hyperactivity disorder being overdiagnosed?. Can J Psychiatry. 2015;60(7):324-328. doi:10.1177/070674371506000705; Pearl PL, Weiss RE, Stein MA. Medical mimics: Medical and neurological conditions simulating ADHD. Ann N Y Acad Sci. 2001 Jun;931(1):97-112; Schwartz S, Correll CU. Efficacy and safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression. J Am Acad Child Adolesc Psych. 2014;53(2):174-187; Stevens JR, Wilens TE, Stern TA. Using stimulants for attention-deficit/hyperactivity disorder: clinical approaches and challenges. Prim Care Companion CNS Disord. 2013;15(2):PCC.12f01472. doi:10.4088/PCC.12f01472; Van Steensel FJ, Bögels SM, de Bruin EI. Psychiatric comorbidity in children with autism spectrum disorders: A comparison with children with ADHD. J Child Fam Stud. 2013;22:368-376.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr Jeung's and Dr. Wang's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Jeung and Dr. Wang were recorded at the 55th Annual Advances and Controversies in Clinical Pediatrics, held virtually May 31 to June 3, 2023, and presented by the University of California, San Francisco (UCSF), School of Medicine, and UCSF Benioff Children’s Hospital. For information about upcoming CME events from these presenters, please visit https://meded.ucsf.edu/cme. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

PD700501

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.