Adrenergic uptake inhibitors for ADHD

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterized by inattention, hyperactivity, and impulsivity. While stimulants (methylphenidate, amphetamines) remain first-line therapy, adrenergic uptake inhibitors provide valuable non-stimulant alternatives. These drugs work primarily by modulating norepinephrine (and to a lesser extent dopamine) signaling through inhibition of presynaptic reuptake.

The key adrenergic uptake inhibitor used in ADHD is atomoxetine, although other agents with mixed reuptake inhibition (such as viloxazine ER, a selective norepinephrine reuptake inhibitor with additional serotonergic activity) are also clinically relevant.

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Mechanism of Action

• Adrenergic uptake inhibitors act by selectively blocking the norepinephrine transporter (NET) in presynaptic neurons.

• This leads to increased norepinephrine concentration in the synaptic cleft, particularly in the prefrontal cortex, an area crucial for attention and executive function.

• Atomoxetine and viloxazine differ from stimulants because they do not directly increase dopamine release in the striatum, and thus carry a lower risk of abuse or dependence.

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Key Agents

1. Atomoxetine

• Mechanism: Selective norepinephrine reuptake inhibitor (NRI).

• Indications: ADHD in children, adolescents, and adults.

• Typical Dose:

  • Children/adolescents ≤70 kg: start at 0.5 mg/kg/day; increase to ~1.2 mg/kg/day (max 1.4 mg/kg/day or 100 mg, whichever lower).

  • 70 kg or adults: start at 40 mg once daily; increase to 80 mg/day; max 100 mg/day.

• Adverse Effects: GI upset, decreased appetite, somnolence or insomnia, increased heart rate and blood pressure, rare hepatotoxicity, suicidal ideation risk in young patients.

• Advantages: Non-stimulant, once/twice daily dosing, helpful in patients with comorbid anxiety or substance use disorders.

2. Viloxazine Extended-Release (ER)

• Mechanism: Primarily a norepinephrine reuptake inhibitor with some serotonin receptor modulation (5-HT2B antagonist, 5-HT2C agonist).

• Indications: ADHD in children (≥6 years) and adolescents; being studied in adults.

• Typical Dose:

  • Start at 100 mg once daily; titrate weekly to 200–400 mg daily (max 400 mg/day).

• Adverse Effects: Somnolence, decreased appetite, fatigue, irritability, increased BP/HR.

• Advantages: Non-stimulant option, rapid onset compared to atomoxetine, lower abuse potential.

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Clinical Considerations

• Onset of action: Slower than stimulants. Atomoxetine often requires 2–4 weeks for benefit; viloxazine may act sooner.

• Efficacy: Both are generally less potent than stimulants but effective for many patients.

• Patient selection:

  • Good choice for patients who cannot tolerate stimulants,

  • Those with comorbid anxiety,

  • Or those with a history of substance abuse.

• Monitoring: Blood pressure, heart rate, growth parameters in children, mood changes (for suicidality risk).