Why do viloxazine and atomoxetine (Attention Deficit Hyperactivity Disorder (ADHD) medications) cause fatigue and drowsiness in some patients?

Why Viloxazine and Atomoxetine Cause Fatigue and Drowsiness in Some ADHD Patients

The fatigue and drowsiness experienced by some patients taking viloxazine and atomoxetine are primarily due to their serotonergic effects, which distinguish these non-stimulant medications from traditional stimulants used for ADHD treatment. 1, 2

Mechanism of Action and Neurotransmitter Effects

Viloxazine

• Functions as a serotonin norepinephrine modulating agent with:
  • Increases serotonin levels in the prefrontal cortex
  • Moderate inhibitory effects on norepinephrine transporter
  • Moderate activity on noradrenergic and dopaminergic systems 1
• Serotonin modulation is considered "an important (if not the predominant) component of its mechanism of action" 1
• Originally developed as an antidepressant in the 1970s before being repurposed for ADHD 1, 3

Atomoxetine

• Acts primarily as a selective norepinephrine reuptake inhibitor 4
• Has high affinity and selectivity for norepinephrine transporters
• Little or no affinity for various neurotransmitter receptors 4
• Preferentially binds to areas with high distribution of noradrenergic neurons 4

How These Mechanisms Lead to Fatigue/Drowsiness

1. Serotonergic Effects:

   • Increased serotonin levels, particularly with viloxazine, can promote sedation and drowsiness 1, 2
   • This effect is similar to what's seen with some antidepressants that increase serotonin

2. Noradrenergic Modulation:

   • Both medications affect norepinephrine pathways, which regulate arousal and alertness
   • Individual variations in noradrenergic system response can lead to fatigue in some patients 2

3. Lack of Dopaminergic Stimulation:

   • Unlike stimulant ADHD medications, these non-stimulants don't significantly increase dopamine in reward pathways 3
   • This reduced dopaminergic effect may contribute to the fatigue profile compared to stimulants

Clinical Implications and Management

Patient Variability

• Side effect profiles vary significantly between patients
• Common side effects of atomoxetine include somnolence, fatigue, and irritability 5, 4
• Viloxazine may cause fatigue in some patients, though at potentially lower rates than atomoxetine 5

Dosing Considerations

• Starting with lower doses and gradually titrating can minimize fatigue symptoms
• Atomoxetine: Start at 0.5 mg/kg/day and titrate to 1.2 mg/kg/day 2
• Viloxazine: Follow FDA-approved dosing guidelines with careful monitoring for fatigue 5

Timing of Administration

• Taking the medication at bedtime may help mitigate daytime drowsiness
• Morning dosing may be preferred for patients who don't experience significant fatigue 2

Monitoring and Adjustment

• Fatigue symptoms often diminish after the initial adjustment period
• If fatigue persists and significantly impacts quality of life, consider:
  1. Dose adjustment
  2. Timing modification
  3. Switching to an alternative medication

Comparative Considerations

• Atomoxetine appears more likely to cause fatigue than stimulant medications 4
• Some studies suggest viloxazine may have a more favorable side effect profile regarding fatigue compared to atomoxetine 5
• In a comparative study, 36% discontinued atomoxetine due to side effects including fatigue (5 patients), versus only 4% who discontinued viloxazine due to fatigue 5

Conclusion

The fatigue and drowsiness associated with viloxazine and atomoxetine stem primarily from their effects on serotonin and norepinephrine pathways. Viloxazine's pronounced serotonergic activity (originally developed as an antidepressant) particularly contributes to these effects. Understanding these mechanisms can help clinicians anticipate, monitor, and manage these side effects to optimize ADHD treatment outcomes.