Attention-Deficit/Hyperactivity Disorder (ADHD) (Comprehensive Concise)

Attention-Deficit/Hyperactivity Disorder (ADHD)

Prevalence

  • Most common childhood behavioral disorder.
  • Worldwide prevalence in children/adolescents: 5.29% (2007), 5.9%-7.1% (2012).
  • US school-aged children diagnosed by 2016: 9.4%.

History

  • 1902: Described by George Still.
  • Early 1900s: Post-influenza behavior problems termed "minimal brain damage syndrome".
  • Early 1960s: Renamed "minimal brain dysfunction".
  • ICD-9 & DSM-II: "Hyperkinetic syndrome of childhood".
  • DSM-III (1980): Renamed attention-deficit disorder (ADD).

Diagnosis (DSM-5)

  • Neurodevelopmental disorder: Pattern of inattention and/or hyperactivity-impulsivity.
  • Diagnostic Criteria:
    • Onset before age 12.
    • Duration > 6 months.
    • Children: ≥6 symptoms; Adolescents/Adults: ≥5 symptoms.
    • Symptoms in ≥2 settings.
    • Symptoms not during schizophrenia/psychotic disorder, or better explained by another mental disorder.
  • DSM-5 allows simultaneous diagnosis of ADHD and Autism Spectrum Disorder (ASD).
  • Specifiers: Combined, predominantly inattentive, or predominantly hyperactive/impulsive presentation; Mild, moderate, or severe; Partial remission.

Inattention Symptoms

  • Fails to give close attention to details/careless mistakes.
  • Difficulty sustaining attention.
  • Doesn't seem to listen.
  • Doesn't follow through on instructions.
  • Difficulty organizing tasks.
  • Avoids tasks requiring sustained mental effort.
  • Loses things.
  • Easily distracted.
  • Forgetful.

Hyperactivity/Impulsivity Symptoms

  • Fidgets/squirms.
  • Leaves seat when expected to remain seated.
  • Runs/climbs inappropriately (restlessness in adults).
  • Unable to play quietly.
  • "On the go," "driven by a motor".
  • Talks excessively.
  • Blurts out answers.
  • Difficulty waiting their turn.
  • Interrupts/intrudes on others.

Comparative Nosology

  • ICD-10: "Hyperkinetic disorder" (HD); stricter criteria than DSM-5.
  • ICD-11: Closer to DSM-5; removes exclusion criterion; may increase diagnosis rates.
  • DSM-5: Symptom lists; ICD-11: Generalized symptoms.
  • Both require symptoms across multiple settings.
  • ICD-11: Describes essential characteristics without precise criteria.

Etiology

  • Complex, multifactorial: genetic and environmental factors.
  • Functional/anatomical dysfunction in cortico-basal ganglia-thalamo-cortical circuitry.

Genetics

  • Strong genetic component: heritability index 0.6-0.98.
  • Reported in rare genetic disorders.
  • Twin studies (\approx 76\% variance): monozygotic higher concordance (59-92%) than dizygotic (29-42%).
  • Sibling studies: higher concordance in full siblings vs. half-siblings.
  • Adoption studies: biological relatives more likely to have ADHD.
  • Family studies: first-degree relatives 2-8x more likely to have ADHD (20-25% risk).
  • Mode of inheritance: polygenetic models proposed.

Molecular Genetic Studies

  • Focus on "risk" genes, especially dopamine-related.
  • Candidate genes account for <5% of genetic variation.
Genes of Interest
  • DAT1 (dopamine transporter gene).
  • DRD2 (dopamine type D2 receptor gene).
  • DRD4 (dopamine-4 receptor gene).
  • SNAP25 (synaptosomal-associated protein 25 gene).
  • DBH, COMT, SLC6A2, SLC6A4, ADRA2A, etc.

Genome-Wide Association Studies (GWAS)

  • Identified 12 independent loci related to dopamine regulation.
  • ADHD heredity due to polygenic effects of common variants.

Copy Number Variants (CNV)

  • Overrepresented in ADHD samples; affect glutamate receptor genes.

Neuroanatomical Aspects

  • Anterior attention network: focusing, executing, sustaining, and shifting functions.
  • MRI studies: structural abnormalities in frontostriatal areas, temporoparietal lobes, cerebellum, basal ganglia, corpus callosum, amygdala, hippocampus, thalamus.
  • Reduced gray matter volume, especially in right lentiform/caudate nucleus; larger volume in left posterior cingulate cortex.
  • 3-5 year delay in cortical thickness maturation, particularly in frontal/temporal regions.
  • DTI studies: white matter tract abnormalities.
  • Lower surface area in frontal, cingulate, and temporal regions.
  • Deficits in frontostriatal/frontoparietal circuit activity.
  • fMRI: reduced frontal lobe activity.
  • EEG: elevated theta/beta ratio (TBR).

Neurotransmitters

  • Catecholamine hypothesis: imbalance in norepinephrine, epinephrine, dopamine.
  • Dysfunction in brain norepinephrine systems.
  • Molecular genetic studies: target dopamine receptor genes.
  • PET scans: correlate stimulant-driven dopamine increases.
  • Serotonin: secondary role.
  • Glutamate: CNV in glutamatergic genes associated with impairments.

Environmental Factors

  • In utero: alcohol, nicotine, drugs, glucocorticoids, poor diet, maternal stress.
  • Perinatal: prematurity, low birth weight, obstetric complications.
  • Childhood illnesses: meningitis, encephalitis, cardiac/thyroid disease, epilepsy, head trauma, etc.
  • Psychosocial adversity: poverty, maltreatment, negative parenting, family discord, bullying.

Dietary Influences

  • Controversial; potential link to nutritional deficiencies (omega-3/6, minerals).
  • Sensitivity to food additives, excess sugar, or nutritional deficiencies hypothesized.
  • Elimination diets (Feingold, oligoantigenic, ketogenic) have been tried.
  • FDA (2011): no causal link between additives and behavioral disturbance.

Diagnosis and Clinical Features

  • Integration of clinical interview, observation, rating scales, and reports from parents/teachers.
  • Impairment in academic, family, and/or peer relationships.

Clinical Features

Hyperactivity
  • Excessive motor activity; restlessness, fidgeting, "driven by a motor".
  • Decreases with age, but inner restlessness may persist.
  • High activity levels across settings.
Impulsivity
  • Actions without forethought; desire for immediate rewards.
  • Dangerous activities, yelling out, interrupting.
  • Error-prone performance on tasks.
  • Can persist into adulthood.
Attentional Difficulties
  • Difficulty sustaining focus, organization, easily distracted.
  • Most prominent in elementary school; can be lifelong.
  • Sluggish cognitive tempo (SCT): daydreaming, confusion, mental fogginess, apathy.
Associated Factors
  • Difficulty with time management.
  • Lack persistence; difficulty delaying gratification.
  • Impaired executive functioning.
  • Problems in emotion regulation.
  • Social skills impairment.

Medical and Laboratory Examination

  • Medical evaluation to rule out physical disorders that mimic ADHD.
  • Thorough history: prenatal, perinatal, toddler, preschool phases.
  • Detailed family, medical, and psychiatric history.
  • Screen for cardiovascular history.
  • Document premedication baseline for side effects.
  • Medical examination for tachycardia, arrhythmia, blood pressure abnormalities.
  • No blood, genetic, or neuroimaging tests diagnose ADHD.

Rating Scales

  • Standardized behavioral rating scales (not used independently).
  • Establish presence of core ADHD symptoms in multiple settings.
  • ADHD-specific scales have >90% sensitivity/specificity.
  • Examples: NICHQ Vanderbilt Assessment scales, SNAP scale, SWAN scale, Conners scales, Weiss Functional Impairment Rating Scale.

Differential Diagnosis

  • Distinguish from conditions that mimic ADHD.
  • Medical conditions: hypoglycemia, epilepsy, substance abuse, sleep apnea, thyroid issues.
  • Psychiatric illnesses: anxiety, depression, ODD, early psychosis.
  • Intellectual disability: ADHD only if excessive for mental age.
  • Trauma can mimic symptoms.
  • Medications (akathisia) can mimic symptoms.

Course and Prognosis

  • Often diagnosed in primary school.
  • Comorbidities common: ODD, CD, anxiety/mood disorders, tics, learning/autism spectrum disorders.
  • Adolescents: less external overactivity, but internal restlessness; academic/social problems.
  • Adults: 60% continue to be impaired.
  • Adult symptoms: restlessness, talkativeness, impulsivity, inattention, disorganization, labile moods.
  • Consequences: job/relationship losses, lower income, accidents, unhealthy lifestyle.
  • Comorbidity: anxiety, depression, substance use, personality disorders often found.
  • Male/female ratio in children: 3-4:1; in adulthood: 1:1.

Treatment of ADHD

  • Medication and psychosocial interventions.
  • Preferences and service availability guide treatment choice.

Stimulants

  • First-line agents: decrease hyperactivity, impulsivity, inattention.
  • MPH (Methylphenidate) and amphetamines (AMP).
  • Classified as schedule II-controlled substances.
  • Factors to consider: duration, dosing flexibility, time of impairment, pill-swallowing ability, availability, cost.
  • Single-day dosing improves compliance.
Pharmacology and Pharmacokinetics
  • Increase CNS activity, blood pressure, and pulse.
  • Increase dopamine and norepinephrine in the synaptic cleft.
  • MPH: dopamine/norepinephrine reuptake inhibitor.
  • AMPs: block reuptake and facilitate dopamine release.
  • Dextro methylphenidate (d-MPH) is twice as potent as MPH.
Formulations
  • Short-acting (3-6 hours), intermediate-acting (8-10 hours), long-acting (12-16 hours) available.
  • Administered as tablets, capsules, suspensions, chewables, or patches.
  • Choice of formulation depends on the length of time that a child needs medication and what time of day they are most impaired.
Efficacy
  • Meta-analysis shows large effect sizes for AMPs and MPH.
  • The majority (52%) of children being treated are on MPH products, whereas the majority (76%) of adults are on AMP products.
  • Significant reductions in ADHD symptoms compared with placebo.
  • Placebo response rates: 17-40%.
  • Preschoolers: require lower doses, higher adverse event rates, diminished response.
  • Reduce overactivity, increase attention, reduce impulsive responses.
Cognitive and Behavioral Effects
  • Greater effects in behavioral domains than cognitive.
  • Reduce overactivity, improve self-perception/academic productivity/peer interaction.
  • Improve vigilance, reaction time, memory.
Adverse Effects
Short-Term Adverse Effects
  • Decreased appetite, weight loss, delayed sleep onset, headaches, stomach aches, increased blood pressure/pulse.
  • Psychiatric side effects: dysphoria, anxiety, irritability, social withdrawal, emotional dysregulation.
  • Rebound effect when medication wears off.
  • Infrequent: tics, Tourette syndrome.
  • Rare: paranoia, psychotic symptoms, priapism, choreiform movements, self-directed behavior.
  • Not increase risk of severe cardiovascular events.
Long-Term Adverse Events
  • Growth suppression (temporary).
  • No increased risk for later Substance Use disorder (SUD).

Nonstimulant Medication

  • Alternatives for those who don't respond to/tolerate stimulants.
  • Longer duration of action; absence of psychostimulant effects.
  • Moderate effect size.
Atomoxetine (ATX)
  • Norepinephrine reuptake inhibitor (NRI).
  • Used when stimulants fail or are refused.
  • May ameliorate anxiety/tics.
  • 24-hour coverage.
  • Metabolized by CYP 2D6 hepatic enzyme system; requires slow titration.
  • Common adverse events: abdominal discomfort, nausea, decreased appetite, sedation, headache, dizziness, irritability, mood swings.
  • Rare: priapism, sexual dysfunction, increased suicidality, liver toxicity.
  • Black box warning: possible suicidal ideation.
α-Adrenergic Agonists
  • Guanfacine ER and clonidine ER: FDA approved.
  • Improvement of inattention, impulsivity, and hyperactivity.
  • Less efficacious than stimulants; moderate effect size.
  • Common side effects: sedation, fatigue, hypotension, syncope, bradycardia.
  • Must be discontinued slowly to prevent rebound.
Bupropion
  • Antidepressant with dopaminergic/noradrenergic properties.
  • Less effective than stimulants or ATX.
  • May be used for patients presenting with Depression.
  • Side effects include fatigue, dry mouth, insomnia, headaches, nausea, vomiting, constipation, tremor, and skin rash.

Treatment Alternatives and Comorbidities

Treatment of ADHD Comorbidities

Tic Disorder
  • Stimulants, clonidine, guanfacine, ATX may reduce ADHD symptoms in those with tic disorders.
Seizure Disorder
  • Extremely rare to experience a first seizure when starting a psychostimulant.
Aggression, ODD, and Conduct Disorder
  • comprehensive intervention includes pharmacotherapy and psychosocial treatments.
Anxiety Disorder
  • Benefit significantly from psychosocial treatment as well as medication.
Mood Disorder
  • Combination of pharmacotherapy and psychosocial interventions is recommended for patients who have both ADHD and major depression.
Developmental Disorders
  • Seen in children with intellectual and developmental delays, Autistic Spectrum Disorders (ASD) or both.

Psychosocial Treatment of Children with ADHD

  • Nonmedication treatment. Psychoeducation, academic organization skill teaching and remediation, parent training, behavior modification, CBT, social skills training, and individual therapy.

Summary and Conclusions

  • ADHD is a prevalent condition that begins in childhood but often continues into adolescence and adulthood.
  • Pharmacotherapy and psychosocial treatment as well as appropriate academic programs and support are needed for optimal outcome.
  • ADHD is a chronic condition for which ongoing long-term monitoring and treatment is required to optimize functioning.

Specific case of childhood ADHD

  • Ben is an 8.5-year-old adopted boy who lives with his parents and 11-year-old brother. Ben was started on extended-release MPH at 18 mg daily, which was later increased to 27 mg daily.