Modafinil and Fluoxetine Interaction
Modafinil can be safely combined with fluoxetine without significant pharmacokinetic interactions, and this combination may actually enhance antidepressant efficacy and speed of response in patients with major depression and fatigue. 1, 2
Pharmacokinetic Interaction Profile
No clinically significant pharmacokinetic interaction exists between modafinil and fluoxetine. The two medications can be administered together without dose adjustments based on metabolic considerations. 3, 1
Key Metabolic Considerations
Modafinil metabolism: Primarily eliminated via amide hydrolysis with minor contributions from CYP-mediated pathways (CYP3A4, CYP2C19). 3
Fluoxetine as CYP2D6 inhibitor: While fluoxetine is a potent CYP2D6 inhibitor that can increase plasma concentrations of CYP2D6 substrates by 3.9-fold to 11.5-fold, this does not affect modafinil since modafinil is not primarily metabolized through CYP2D6. 4, 5
Modafinil's enzyme effects: Modafinil causes mild induction of CYP3A4, CYP1A2, and CYP2B6, but these effects do not significantly impact fluoxetine metabolism. 3
Clinical Evidence Supporting Combined Use
The combination of fluoxetine plus modafinil demonstrates superior efficacy compared to fluoxetine alone for treating major depression. 1
Efficacy Data from Controlled Trials
In a 6-week double-blind randomized trial, fluoxetine 40 mg/day plus modafinil 400 mg/day (200 mg twice daily) was significantly superior to fluoxetine plus placebo in reducing Hamilton Depression Rating Scale scores (F = 4.42, P = 0.046). 1
When modafinil is initiated simultaneously with an SSRI (fluoxetine or paroxetine 20 mg/day), patients experience rapid symptom improvement within 1 week (mean SIGH-D score reduction of -9.3, p <.001), with 42% achieving response by week 2 and 79% by week 6. 2
The combination rapidly reduces fatigue (FSS score reduction of 0.7 at week 1, p <.01) and improves wakefulness (ESS score reduction of 3.6 at week 1, p <.01). 2
Dosing Algorithm for Combined Therapy
Start both medications at standard doses without adjustment:
Modafinil: Titrate to 200-400 mg/day (can be given as 200 mg twice daily for higher doses) 1, 2
Timing: Modafinil should be administered in the morning, or split into morning and early afternoon doses if using 400 mg/day to avoid insomnia. 1
Safety and Tolerability Profile
The combination is generally well-tolerated with minimal additional adverse effects beyond those expected from each agent individually. 1, 2
Common Adverse Effects
Most frequent side effects: headache, nausea, nervousness, rhinitis, diarrhea, insomnia, and dizziness (occurring in approximately 35% of patients on modafinil). 6
In combination studies, nausea and headache were the most common adverse events, with most being mild to moderate in severity. 2
No significant differences in side effect profiles were observed between fluoxetine plus modafinil versus fluoxetine plus placebo groups. 1
Important Clinical Caveats
Contraceptive Considerations
- Modafinil induces CYP3A4 and may reduce efficacy of oral contraceptives. Women of childbearing potential should use alternative or additional contraceptive methods during modafinil treatment and for one month after discontinuation. 7
Cardiovascular Monitoring
- Check blood pressure and pulse at baseline and regularly during treatment, as both medications can affect cardiovascular parameters. 7
Avoid Common Pitfalls
Do not assume fluoxetine will interfere with modafinil metabolism simply because fluoxetine is a potent CYP2D6 inhibitor—modafinil does not rely on CYP2D6 for elimination. 4, 3
Do not delay modafinil initiation if starting fluoxetine in patients with depression and significant fatigue—simultaneous initiation enhances both speed and degree of therapeutic response. 2
Do not confuse this interaction profile with other SSRI-stimulant combinations—each pairing has unique metabolic considerations. 4