CYP2D6 Drug Interaction Between Aripiprazole and Atomoxetine
Yes, aripiprazole (Abilify) can inhibit CYP2D6 and reduce atomoxetine (Strattera) metabolism, leading to increased atomoxetine levels that may manifest as insomnia and other adverse effects.
Mechanism of Interaction
Aripiprazole requires dose reduction in poor CYP2D6 metabolizers, indicating it is a CYP2D6 substrate and potential inhibitor 1. When aripiprazole competes for CYP2D6 metabolism, it can transform extensive metabolizers of atomoxetine into functional poor metabolizers.
Atomoxetine's CYP2D6 Dependence
- Atomoxetine is primarily metabolized by CYP2D6 through aromatic ring-hydroxylation to form 4-hydroxyatomoxetine 2
- In extensive metabolizers, atomoxetine has a plasma half-life of 5.2 hours, but in poor metabolizers this extends to 21.6 hours 2
- Average steady-state plasma concentrations are approximately 10-fold higher in poor metabolizers compared with extensive metabolizers 2
- Potent CYP2D6 inhibitors reduce atomoxetine clearance in extensive metabolizers, producing pharmacokinetic changes similar to those in poor metabolizers 2
Clinical Manifestation of Elevated Atomoxetine
Insomnia is a documented adverse effect of atomoxetine, occurring more frequently in CYP2D6 poor metabolizers 3. The FDA label specifically notes:
- Insomnia occurred in 11% of CYP2D6 poor metabolizer children/adolescents versus 6% of extensive metabolizers 3
- Middle insomnia occurred in 3% of poor metabolizers versus 1% of extensive metabolizers 3
- Early morning awakening occurred in 2% of poor metabolizers versus 1% of extensive metabolizers 3
Additional Adverse Effects from This Interaction
Beyond insomnia, elevated atomoxetine levels in functional poor metabolizers may cause:
- Weight decrease (7% in poor metabolizers vs 4% in extensive metabolizers) 3
- Constipation (7% in poor metabolizers vs 4% in extensive metabolizers) 3
- Depression (7% in poor metabolizers vs 4% in extensive metabolizers) 3
- Tremor (5% in poor metabolizers vs 1% in extensive metabolizers) 3
- Sedation (4% in poor metabolizers vs 2% in extensive metabolizers) 3
- Syncope (3% in poor metabolizers vs 1% in extensive metabolizers) 3
Management Strategy
When combining aripiprazole with atomoxetine, monitor closely for signs of atomoxetine toxicity and consider empiric dose reduction of atomoxetine by approximately 50% 2. This mimics the dosing adjustment recommended when atomoxetine is combined with known potent CYP2D6 inhibitors like paroxetine.
Monitoring Parameters
- Heart rate and blood pressure changes (≥20 beats/min or ≥15-20 mmHg) 3
- Sleep disturbances, particularly insomnia onset or worsening 3
- Mood changes, including depression or irritability 3
- Gastrointestinal symptoms (nausea, constipation, decreased appetite) 3
- Cardiovascular symptoms (palpitations, syncope) 3
Alternative Considerations
If insomnia becomes problematic, consider low-dose doxepin 3-6 mg for sleep maintenance, which does not interact with CYP2D6 4, 5. Avoid trazodone and atypical antipsychotics like quetiapine for insomnia management due to limited evidence and significant side effects 4.
Critical Caveat
The frequency and severity of adverse events in atomoxetine trials were similar regardless of CYP2D6 phenotype 2, suggesting that while plasma levels differ dramatically, clinical tolerability may be acceptable in many patients. However, this population-level finding does not preclude individual patients from experiencing significant adverse effects when transformed into functional poor metabolizers by aripiprazole co-administration.