What are the current pharmacological interventions for Attention Deficit Hyperactivity Disorder (ADHD)?

Current Pharmacological Interventions for ADHD

Stimulant medications (methylphenidate and amphetamines) are the first-line pharmacological treatment for ADHD due to their large effect sizes and rapid onset of action, with non-stimulants recommended as second-line options. 1

First-Line Treatment: Stimulants

Methylphenidate

• Methylphenidate is typically the initial stimulant of choice for ADHD treatment, available in multiple formulations 2, 1
• Short-acting formulations provide 3-5 hours of symptom control, while long-acting/extended-release formulations provide day-long coverage 1
• Mechanism of action: Blocks reuptake of norepinephrine and dopamine, increasing these neurotransmitters in the synaptic space 3
• Common side effects include decreased appetite, insomnia, headache, and potential cardiovascular effects (increased heart rate and blood pressure) 2
• Growth effects (height and weight) should be monitored, particularly in children 1

Amphetamines

• Lisdexamfetamine and other amphetamine formulations are recommended when methylphenidate is ineffective at adequate dosage and duration 1
• Available in short-acting and long-acting formulations 2
• Mechanism of action: Inhibits dopamine and norepinephrine transporters, vesicular monoamine transporter 2, and monoamine oxidase activity 2
• Side effect profile similar to methylphenidate but may be more pronounced 2

Second-Line Treatment: Non-Stimulants

Atomoxetine

• Norepinephrine reuptake inhibitor that increases both noradrenaline and dopamine in the prefrontal cortex 2
• Requires 6-12 weeks for full therapeutic effect 1
• Dosing: Initial dose of 0.5 mg/kg/day in children up to 70 kg, increased to target dose of 1.2 mg/kg/day; 40 mg/day initially in adults and children over 70 kg, increased to 80 mg/day 4
• FDA black box warning for increased suicidality risk; requires monitoring 1
• Advantages include "around-the-clock" effects and not being a controlled substance 2
• May be preferred in patients with comorbid substance use disorders, tic disorders, or anxiety 2

Alpha-2 Adrenergic Agonists

• Extended-release guanfacine and clonidine act through agonism at alpha-2 adrenergic receptors 2
• Take 2-4 weeks for full effect 1
• Common side effects include somnolence/sedation, fatigue, hypotension, and irritability 2
• Require monitoring of blood pressure and pulse 1
• May be particularly beneficial in patients with comorbid sleep disorders, tic disorders, or disruptive behavior disorders 2

Treatment Algorithm

1. Initial Assessment

   • Confirm ADHD diagnosis using DSM criteria 1
   • Screen for bipolar disorder before starting stimulants 4
   • Assess for comorbidities that may influence treatment choice 1

2. First-Line Treatment

   • Start with methylphenidate, preferably extended-release formulation 1
   • Titrate gradually based on response and tolerability 1
   • Monitor height, weight, blood pressure, and pulse 1

3. If Inadequate Response or Intolerance to Methylphenidate

   • Switch to lisdexamfetamine or another amphetamine formulation 1

4. If Inadequate Response or Intolerance to Stimulants

   • Consider atomoxetine (especially with comorbid anxiety, tics, or substance use) 2, 5
   • Consider extended-release guanfacine or clonidine (especially with comorbid sleep issues or tics) 2, 5

5. Ongoing Monitoring

   • Periodically reassess need for continued medication, potentially including medication-free intervals 2
   • Monitor for adverse effects, particularly growth in children and cardiovascular parameters 1

Special Considerations

• Hepatic Impairment: For patients with hepatic insufficiency using atomoxetine, reduce dose to 50% (moderate impairment) or 25% (severe impairment) of normal dose 4
• CYP2D6 Poor Metabolizers: Reduce atomoxetine dosing in patients who are CYP2D6 poor metabolizers or taking strong CYP2D6 inhibitors 4
• Regional Differences: Western guidelines typically recommend stimulants as first-line treatment, while some Asian guidelines (e.g., Japanese 2022 guidelines) recommend psychosocial interventions as first-line with pharmacotherapy as second-line 2

Emerging Treatments

• Several new non-stimulant medications are in late-stage development, including centanafadine, solriamfetol, and L-threonic acid magnesium salt 6
• These may offer alternatives for the significant portion of patients (>33% of children and >50% of adults) who discontinue treatment during the first year 6