From the FDA Drug Label
CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) and selective serotonin reuptake inhibitors that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. Modafinil tablets may cause elevation of the levels of the tricyclics in this subset of patients [see Drug Interactions (7)] CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Therefore, exposure to some drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be increased when used concomitantly with modafinil tablets [see Drug Interactions (7)].
The possible interactions between SSRIs and modafinil are related to the CYP2C19 enzyme. Modafinil may cause elevation of the levels of certain tricyclic antidepressants and SSRIs that are metabolized by CYP2C19.
- Key points:
- Modafinil may increase the levels of SSRIs that are metabolized by CYP2C19.
- The interaction is more significant in patients who are poor metabolizers of CYP2D6.
- The combined effect of modafinil and its metabolite, modafinil sulfone, may produce sustained partial inhibition of the CYP2C19 enzyme.
- Concomitant administration of modafinil with SSRIs may increase the exposure to these drugs 1.
From the Research
Concurrent use of SSRIs and modafinil is generally considered safe for most patients, though caution is warranted due to potential interactions, as evidenced by a study published in 2004 2. When combining these medications, patients should be monitored for increased side effects, particularly related to serotonin levels. Some key points to consider when using SSRIs and modafinil together include:
- SSRIs like fluoxetine, sertraline, escitalopram, and paroxetine may experience mild pharmacokinetic interactions with modafinil, as modafinil is a weak inducer of CYP3A4 and inhibitor of CYP2C19 liver enzymes which metabolize certain SSRIs.
- Common side effects to watch for include increased anxiety, insomnia, headaches, or gastrointestinal disturbances.
- While rare, there is a theoretical risk of serotonin syndrome when combining these medications, though documented cases are extremely uncommon, as noted in a study published in 2018 3.
- Patients should start with standard doses of both medications (typically 100-200mg daily for modafinil and standard SSRI dosing) and report any unusual symptoms to their healthcare provider.
- The combination may be particularly beneficial for patients with depression accompanied by fatigue or excessive sleepiness, as modafinil's wakefulness-promoting effects can complement the antidepressant action of SSRIs, as shown in a study published in 2006 4. It's also important to note that the use of modafinil with MAOIs is contraindicated due to the risk of acute hypertensive episodes, as reported in a case study published in 2018 3. However, the interaction between SSRIs and modafinil is not as well-studied, and more research is needed to fully understand the potential risks and benefits of this combination, although a study from 2004 2 provides some insight into the safety and efficacy of this combination.