ADHD

General information

Stigma:

• Related to overdiagnosis and potentially inappropriate treatment 

• Related to disability status (“invisible disability”

Who should be evaluated 

• In pediatrics (per AAP)

  • 4-18 yrs

  • Symptoms: inattention, hyperactivity, and/or impulsivity

  • Interference with QOL: academic and/or behavioral problems

• In adults: typically done by self referral due to interference with QOL

Diagnosis (DSM-V)

1st line stimulant

Lisdexamfetamine (Vyvanse): prodrug conjugated to an amino acid that requires cleavage during metabolism to the active dextroamphetamine

• Typically first line, but not according to insurance …

• Longer time to onset of effect (~2 hours)

• Provides 10 to 12 hours of symptom control

• Lower risk for abuse○ NICE guidelines recommend it as a preferred long-actingamphetamine formulation

  • Increased safety

  • Established efficacy

Atomoxetine (Strattera)

• Time to effect: Lower onset to effect (2-4weeks), full benefit in 6-12 weeks

• Place in therapy: monotherapy 

• Common ADRs:

  • BP/HR elevations, dry mouth, insomnia, nausea (can try divided doses), fatigue, sedation, and dizziness

  • In adults: urinary hesitation/retention, sexual adverse effects (decreased libido and ED)

• Warning/precautions: Suicidal ideation in children and adolescents (boxed warning), hepatotoxicity, and psychiatric effects (aggression, psychosis, mania)

  • Discontinue immediately

Viloxazine (Qelbree)

• MOA: SNRI, also increases 5-HT levels in prefrontal cortex

• Place in therapy: monotherapy 

• Time to effect: improvement in symptoms within 1 week 

• Common ADRs: somnolence, decreased appetite, nausea/vomiting, insomnia, BP/HR elevations, and irritability

• Warning/precautions: Suicidal thoughts and behaviors (boxed warning) and psychiatric effects (mania)

• Drug Interactions: strong CYP1A2 inhibitor 

A2-adrenergic agonist: guanfacine and clonidine 

• MOA: acts presynaptically to inhibit norepinephrine release and postsynaptically to increase blood flow in the prefrontal cortex 

  • Enhances working memory and executive functioning 

• Place in therapy: monotherapy (nonstimulant option) or adjunct 

  • Role as adjunct: to reduce disruptive behavior, control aggression, or improve sleep in youth 

• Common ADR (dose dependent): Sedation (subsides in 2-3 weeks), dizziness, hypotension, and constipation. May cause weight gain.

  • For dizziness: check BP and maintain hydration 

• Time to effect: 1-2 weeks 

• Warning/precautions: 

  • Risk for severe ADRs: peripheral vasculopathies, rebound hypertension, rebound/behavioral dyscontrol, heart block, sudden death

    • Prescreen for cardiac abnormalities

    • Make sure to withdraw slowly to prevent rebound effects

• Other: Guanfacine may be preferred due to

  • Longer half life

  • Greater α2a selectivity, so less sedation and dizziness

Bupropion

• MOA: A weak DNRI (dopamine and norepinephrine reuptake inhibitor)

• Place in therapy: Monotherapy

  • Helpful in concomitant depression or for patients experiencing ADRs with stimulants (less appetite suppression and weight loss)

• Time to effect:1-2 weeks, full effects in 6 weeks or more 

• Common ADRs: nausea, rash, insomnia

• Warning/precautions: Suicidal thoughts and behaviors(boxed warning). Avoid in history of eating disorder, seizure, or tics.

Cardiac Effects for All agents

• Screen for

  • Exercise intolerance

  • History of syncope/fainting

  • Arrythmia

  • Structural heart defects

  • Congenital cardiac disease

  • Family history of arrhythmia, early sudden death (<40 years), premature cardiovascular disease or myocardial infarction

• If risk factors are identified, get a baseline ECG and cardiology consult.

• Monitor HR and BP prior to initiation, at dose increases, regularly throughout treatment

Alternative Therapies

• impramine/desipramine (and other TCAs)

• Modafinil

Nonpharmacologic Therapy 

Nutritional and Dietary Interventions

• Eating a balanced diet with lean protein, fiber, and complex carbs to minimise risk of nutritional deficiencies

• Limiting sugar consumption in children

• Avoiding food dyes:

  • Deficiencies in vitamin A, D, iron, magnesium, zinc, and copper may contribute to symptoms

  • Supplement vitamin D and iron in the presence of deficiencies

• Other helpful supplements:

  • omega-3 fatty acids

  • Multivitamin

  • N-acetylcysteine (impulsivity and irritability only)

Other Interventions

• Yoga

• Meditation 

• Regular exercise

• External trigeminal nerve stimulation (eTNS)

• Future therapies: pro/prebiotics 

Common ADRs and Treatment (Stimulants)

• Reduced appetite, weight loss: Eat nutrient dense, high-calorie meals. Administer the medication at or after a meal. Consider appetite stimulant (cyproheptadine) at bedtime

• Stomach ache: admin on full stomach; lower dose if possible 

• Insomnia: Give dose earlier in the day; lower or omit the last dose; switch to a shorter acting agent, consider a sedating medication at bedtime (guanfacine, clonidine, melatonin, or cyproheptadine)

• Headache: divide dose, give with food, or give an analgesic (NSAID or APAP)

• Dry mouth: Nonpharm/OTC recommendation. 

• Hypertension/tachycardia: lower dose or consider alternative therapy 

• Rebound symptoms: Use longer-acting (or higher dose of long-acting) stimulant. Add a short acting agent near the end of day/time of rebound. Consider nonstimulant therapy.

• Irritability/jitteriness: Assess for comorbid condition (eg, bipolar disorder); reduce dosage; consider mood stabilizer or second-generation antipsychotic

• Other mood lability: 

  • During peak→  reduce dose or change to long acting formulation

  • During wearing off → add an additional dose or change to long acting formulation

Child’s growth (stimulants)

• Dose dependent height deficits

  • Mainly in the first 2 years

  • 1-1.4 cm/year

• Weight deficits are more prominent

  • Mean of 3 kg (6.6 lbs) in first year

  • Mean of 1.2 kg (2.6 lbs) in second year

• Less deficits with inconsistent use

  • Consider medication free weekends or summers

Less common/Rare ADRs (stimulants)

Stimulant Warnings

Warnings

• Boxed warning: Abuse, dependence, misuse, addiction, and overdose

• Psychosis, severe anxiety, or panic attacks

  • Often in patients with other underlying conditions (such as GAD or bipolar disorder)

  • Risk increased with cannabis/multi-substance use

    • Treat the underlying cause or condition FIRST

• Mood disturbance (ie, irritability, lability, or depression) in pediatrics

  • Often in patients with underlying depression

  • Pre-school aged patients are most susceptible to sadness, irritability, and mood lability with stimulant treatment

    • Focus on non-pharmacologic care in this population

Warning: Stimulant withdrawal 

• Risk with abrupt discontinuation or substantial dose reduction following prolonged use, particularly with high doses

• Initial phase (crash)

  • Lasts 1-2 days

  • Symptoms: prolonged sleep, depressed mood, irritability, overeating, slight cravings

• Dysphoria phase

  • Days to weeks

  • Symptoms: difficulty sleeping (insomnia) or excessive sleeping (hypersomnia), fatigue, unpleasant/vivid dreams, psychomotor agitation or retardation, cravings, lethargy, psychosis

Lines

• LDX/DEX- Lisdexamfetamine/Dextroamphetamine

• AMPH/MXA- Amphetamines/mixed amphetamines

• MPH/DMPH- Methylphenidate/dexmethylphenidate

Methylphenidates vs. amphetamines

• Amphetamines are typically more effective

• Amphetamines cause more adverse effects in children compared tomethylphenidates○

  • Significant increased in systolic blood pressure and weight loss

• Children need to start stimulants at very low doses due to low weight and high risk for ADRs

• Amphetamines are not readily available at low doses

• Conclusion: Methylphenidates are preferred 1st line in children and amphetamines are preferred 1st line in adults

Treatment summary

Monitoring and switching

Monitoring 

• Monthly visits until symptoms are stabilized

• Maintenance: Every 3-6 months

• Safety: HR/BP, height, weight, eating patterns, and sleeping patterns

• Efficacy: Monitor for change in validated scale as well as assessment of:

  • Overall functioning (work/school and relationships)

  • Real-world collateral information (grades, report cards, work evaluation, attendance records)

• Titration typically weekly (3-7 days)

Switching between meds 

• Stimulant to atomoxetine or viloxazine

  • Continue stimulant for the first few weeks to allow atomoxetine or viloxazine to reach full effect

• Atomoxetine or viloxazine to a stimulant

  • Can stop atomoxetine or viloxazine abruptly

• Alpha-2-adrenergic agonists can be used as adjuncts to stimulant medications (so cross over is ok!)

Personalized care and special pops

Personalized Pharmacotherapy 

• Metabolism differences: CYP2D6

  • Amphetamines, atomoxetine, and bupropion are eliminated by CYP2D6

  • Poor metabolizers increased (risk ofADRs)

  • Rapid metabolizers (reduced efficacy)

  • CYP2D6 inhibitors (bupropion, fluoxetine) increase concentrations

• Males have higher bioavailability of methylphenidate than females

Special Populations

• Pregnancy

  • Mild symptoms: Drug holiday for 1st trimester

  • Significant impairment: continuation of treatment after discussion of risks vs. benefits 

• Pediatrics 

  • Neurologic, physiologic, and psychosocial changes throughout development.

  • Age-related pharmacodynamic and pharmacokinetic differences/changes

Patients with Comorbidities 

• Treat underlying conditions first