Attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that manifests in childhood and may persist into adulthood. It is characterized by inattention and/or impulsivity and hyperactivity resulting in functional impairment in social, occupational, and/or academic activities. ADHD is a clinical diagnosis made using the DSM-5 diagnostic criteria for ADHD, and evaluation should include an assessment for differential diagnoses of ADHD. Individuals with ADHD frequently have comorbidities such as anxiety disorder, major depressive disorder, and specific learning disorder. Management of ADHD differs based on the individual's age but typically consists of stimulant medications in combination with behavioral interventions. Untreated ADHD is associated with decreased academic and/or occupational success and an increased risk of developing substance use disorders.

• Sex: : ♂ > ♀ ^[1]
• Age of onset: usually before 12 years ^[2]
• Prevalence: ∼ 10% ^[3]

Epidemiological data refers to the US, unless otherwise specified.

ADHD is a multifactorial disorder; pathogenesis is thought to be related to altered catecholamine metabolism.

• Genetic predisposition: family history of ADHD, polymorphisms of the dopamine, serotonin, or glutamate receptor subtypes
• Environmental factors
  • Prematurity, in-utero exposure to alcohol
  • A subset of patients may have symptoms that are susceptible to dietary factors (e.g., food additives, food sensitivities, mineral deficiencies, sugar). ^[4][5]

• Symptoms of inattention and/or symptoms of hyperactivity and impulsivity (see “DSM-5 diagnostic criteria for ADHD”)
• Additional neuropsychiatric symptoms are not features of ADHD but may be part of common comorbidities, e.g., anxiety.

Poor school performance in children with ADHD is usually due to inattention and/or impulsivity and hyperactivity rather than level of intelligence, which is not directly affected by the disorder. ^[6]

ADHD is a clinical diagnosis made using the DSM-5 diagnostic criteria for ADHD.

Approach ^[7][8][9]

• Evaluate patients using the DSM-5 diagnostic criteria for ADHD.
  • Obtain collateral history from caregivers and individuals who interact closely with the patient.
  • Validated scales are available to distribute to collateral historians. ^[10]
• Screen for comorbidities and rule out differential diagnoses of ADHD. ^[11]
  • Consider laboratory studies (e.g., thyroid function tests, lead level) depending on suspected diagnoses. ^[11]
  • Refer to a specialist for additional diagnostic workup if necessary.

Establishing the diagnosis of ADHD involves identifying comorbid disorders (e.g., learning disability, psychiatric disorders) as well as ruling out differential diagnoses of ADHD (e.g., hearing or visual impairment, thyroid disorders, sleep disorders). ^[7]

Diagnostic criteria

Alternative causes of ADHD symptoms and common comorbidities include: ^[7][8][12]

• Seizure disorders (e.g., absence seizures)
• Thyroid disorders
• Sleep disorders (e.g., sleep deprivation, obstructive sleep apnea) ^[15]
• Hearing loss and/or vision impairment
• Genetic disorders (e.g., fragile X syndrome)
• Medication-induced symptoms of inattention or hyperactivity
• Substance use disorder
• Tic disorders
• Developmental delays (e.g., speech and language disorders, not meeting developmental milestones)
• Reactive attachment disorder
• Specific learning disorder
• Intellectual disability
• Autism spectrum disorder
• Oppositional defiant disorder
• Conduct disorder
• Major depressive disorder
• Bipolar disorder
• Anxiety disorders
• Posttraumatic stress disorder ^[16]
• Personality disorders

The differential diagnoses listed here are not exhaustive.

Approach ^[7][8][11]

• Consider specialist referral for individuals with: ^[14][17]
  • Unclear diagnosis
  • Comorbidities that are severe and/or may affect ADHD management (see “Differential diagnosis of ADHD”) ^[7][11]
  • Inadequate response to management ^[14][17]
  • Suspected ADHD if < 4 years of age or symptoms first manifest at > 12 years of age ^[17]
• Initiate first-line management based on the individual's age. ^[7]
  • Children 4–5 years of age: behavioral interventions alone
  • Children ≥ 6 years of age and adults: pharmacotherapy with adjunctive behavioral interventions ^[7][18]
• Educate patients and caregivers on ADHD. ^[8]
  • Children may be eligible for accommodations at school; caregivers should contact their school district. ^[7][19]
  • Ensure patients get regular physical activity and sufficient sleep.
• Manage comorbid mental health conditions, e.g., anxiety, depression, substance use disorder.
• Schedule regular follow-up for patients with ADHD.

Refer individuals with ADHD and a history of substance use disorder to a psychiatrist. Consider treatment with medications that have a low potential for addiction (e.g., nonstimulants). ^[7]

Behavioral interventions ^[7][16]

• Parent training in behavioral management (PTBM) ^[7]
  • Indication: caregivers with children 4–11 years of age with problematic behaviors (e.g., ADHD) ^[7]
  • Goals: reinforce preferred behaviors and reduce problematic behaviors
• Classroom interventions: behavioral intervention plan (organized via the school district) ^[7][19]
• Cognitive behavioral therapy (CBT): may be considered as adjunctive therapy for adults with ADHD ^[11][16][18]

PTBM can also be utilized for children who do not meet the full criteria for ADHD. ^[7]

Pharmacotherapy ^[8][11][20]

• Options include stimulant and nonstimulant therapy.
• Stimulant therapy is usually first-line treatment for children ≥ 6 years of age and adults. ^[7][8][21]
• Nonstimulants are preferred for individuals with: ^[7][21]
  • Contraindications to or potential for serious adverse effects with stimulants ^[11]
  • A preference for nonstimulants
  • Certain comorbidities ^[22]

Stimulant therapy ^[20]

• Options: methylphenidate; or amphetamine analogues (e.g., lisdexamfetamine, dextroamphetamine)
• Mechanism of action: indirect and central sympathomimetic activity → increased release and blocked reuptake of norepinephrine and dopamine (minor effect on serotonin) → increased concentration of norepinephrine and dopamine in the synaptic cleft → increased mental performance (e.g., improved concentration, cognition; , short-term memory) and fine motor skills ^[20][23]
• Adverse effects ^[8][20]
  • Sympathomimetic effects
    • Anxiety, agitation, restlessness, bruxism, tics ^[8][24][25]
    • Difficulty falling asleep (insomnia)
    • Reduced appetite,; nausea, vomiting, weight loss
    • Increased arterial blood pressure, tachycardia
  • Increased risk of seizure: reduces the seizure threshold ^[26]
  • Decreased growth rate (may be reversible if medication is stopped) ^[8]
  • Psychosis (e.g., hallucinations) ^[8]
  • Priapism ^[27]
• Other indications: : also used in patients with narcolepsy or binge eating disorder ^[28][29]

Methamphetamine has FDA approval for the treatment of ADHD but is rarely prescribed because of its high potential for misuse. ^[30]

Initiation of stimulant therapy

• Review state and federal laws relevant to prescribing controlled substances (stimulants are Schedule II drugs). ^[7]
• Consider implementing a controlled substance agreement. ^[7][11][16]
• Obtain an ECG if either of the following are present: ^[7][31]
  • Symptoms of a cardiac disorder (e.g., syncope, palpitations)
  • A personal or family history of cardiac conduction disorders
• Inform individuals that effects may be noticed within 2–3 days of initiation. ^[21]
• Start on a low dose and slowly titrate medication as necessary, e.g.:
  • Children: every 1–4 weeks ^[8]
  • Adults: every 4–6 weeks ^[11]
• Arrange regular follow-up for patients with ADHD to monitor the effects of pharmacotherapy. ^[11][22]

Stimulants are Schedule II controlled drugs because of their high risk of misuse; consider implementing a controlled substance agreement before prescribing. ^[7][11][33]

Long-acting stimulants are preferred because of increased adherence and reduced risk of misuse compared to short-acting stimulants. ^[8][34]

Nonstimulant therapy

Patients and caregivers should be informed that it may take 4–6 weeks for nonstimulants to reach maximum efficacy. ^[22]

Selective norepinephrine reuptake inhibitors ^[7][8][11]

• Indication: alternative to stimulant medications for ADHD in adults and children ≥ 6 years of age ^[7][11]
• Mechanism of action: block norepinephrine reuptake, which increases synaptic cleft levels of norepinephrine and dopamine in the prefrontal cortex ^[20]
• Options: : atomoxetine or viloxazine ^[8][11]
• Adverse effects ^[8][26]
  • GI symptoms (e.g., appetite suppression, nausea, discomfort)
  • Sedation
  • Rare: liver failure, prolonged QT interval, suicidal ideation

SNRIs are not addictive or Schedule II drugs and therefore may be preferred for individuals with a history of substance use disorder. ^[35]

Atomoxetine has a black box warning for increased suicidal ideation in children and adolescents. Monitor individuals closely, especially during the first few weeks of treatment. ^[7]

Alpha-2 adrenergic agonists ^[26]

• Indications: children 6–17 years of age with either of the following. ^[11]
  • Contraindications to stimulants ^[7]
  • Preference for nonstimulants
  • Inadequate response to stimulants alone (i.e., adjunctive therapy) ^[7]
• Options: guanfacine ; extended-release or clonidine extended-release ^[7][8]

To avoid rebound hypertension, do not abruptly stop alpha-2 adrenergic agonists; taper gradually. ^[7]

Antidepressants ^[11]

• Indication: adults in whom stimulants and nonstimulants are not effective or contraindicated (i.e., an off-label alternative to stimulants) ^[36]
• Options: bupropion (off-label) or tricyclic antidepressants, e.g., desipramine (off-label)

Follow-up for patients with ADHD

• Educate patients and caregivers on how to manage ADHD; see also “Chronic disease management.”
• For patients on pharmacotherapy:
  • Advise patients and/or caregivers that several different medications and dosages may need to be trialed. ^[20]
  • Arrange regular scheduled follow-up appointments. ^[26]
    • Monthly until treatment is optimized
    • Every 3 months for at least the first year
    • Once stable, every 6 months
  • At every visit, assess vital signs and inquire about adverse effects. ^[26]
  • Laboratory studies are not routinely required. ^[26]
  • If the response is insufficient or significant adverse effects occur, consider medication adjustments.
  • Periodically reassess if medication is still required. ^[37]
• For patients not on pharmacotherapy, arrange follow-up to: ^[7]
  • Reassess symptoms
  • Determine if medication is now indicated

In children, routine laboratory studies to monitor for medication adverse effects are generally not recommended. ^[26]

• The persistence of symptoms after treatment predicts prognosis into adulthood.
• In 35–65% of patients, symptoms of ADHD and their associated functional impairment will persist into adulthood. ^[38]
• Patients with untreated ADHD are at higher risk of injury , substance use disorder, and antisocial personality disorder. ^[8][12]

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