Atomoxetine is More Likely to Cause Sleepiness and Fatigue Than Bupropion
Atomoxetine causes significantly more sedation and fatigue compared to bupropion, which is actually associated with lower rates of sedating side effects among antidepressants. This difference is clinically meaningful and should guide medication selection when daytime alertness is a priority.
Evidence for Atomoxetine's Sedating Profile
Atomoxetine has well-documented sedating effects:
- Fatigue occurs in 8% of children and adolescents treated with atomoxetine compared to 3% with placebo 1
- Somnolence occurs in 11% of pediatric patients versus 4% with placebo, making these effects significantly more frequent than placebo 1
- Somnolence is listed among the most common adverse effects alongside nausea, vomiting, and decreased appetite 1, 2, 3
- Initial somnolence is particularly common if dosage is increased too rapidly, with sedating effects most prominent early in treatment or with rapid dose escalation 1
Evidence for Bupropion's Non-Sedating Profile
Bupropion stands out among antidepressants for causing less sedation:
- Bupropion is associated with lower rates of somnolence compared to other second-generation antidepressants like fluoxetine and sertraline 4
- Among second-generation antidepressants, bupropion has a favorable side effect profile regarding sedation, with its main distinguishing feature being lower rates of sexual dysfunction rather than sedating effects 4
Clinical Management Considerations
When prescribing atomoxetine, implement these strategies to minimize sedation:
- Split dosing (morning and evening) can reduce the intensity of sedating side effects 1, 5
- Consider evening dosing if daytime sedation is problematic, as sedating effects are typically most prominent during initial treatment phases 1
- Use slow titration with dose increases at 1-2 week intervals to minimize initial somnolence 1, 2
- Increase doses by small increments (typically 10-25 mg) no more frequently than every 1-2 weeks 2
Important Caveats
CYP2D6 poor metabolizers experience significantly higher plasma levels and longer half-lives of atomoxetine, which may lead to increased adverse effects including fatigue and somnolence 1. This genetic variation can substantially worsen sedating effects.
Tolerability may improve over time, as atomoxetine's full therapeutic effects take 6-12 weeks to develop, suggesting that side effect profiles may also evolve during this timeframe 2, 5.