Maprotiline and Paroxetine: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Paroxetine
Maprotiline
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased CYP2D6 substrate exposure
Interaction Deep Dive
Exert caution when PARoxetine (a CYP2D6 inhibitor) is coadministered with a CYP2D6 substrate2 as it may increase the exposure of the CYP2D6 substrate. If coadministration is required, decrease the dosage of the CYP2D6 substrate as necessary; conversely, an increase in the dosage of a CYP2D6 substrate may be needed with discontinuation of PARoxetine 213.
Why it happens (mechanism)
Inhibition of CYP2D6 substrate metabolism by PARoxetine
Literature reports
2 reports — tap to read
a) In drug interactions studies, PARoxetine demonstrated the following effects on drugs metabolized by CYP2D6. PARoxetine 20 mg once daily at steady-state increased a single dose of desipramine 100 mg Cmax, AUC, and t(1/2) by approximately 2-, 5-, and 3-fold, respectively. In patients stabilized on risperiDONE 4 to 8 mg/day, daily PARoxetine 20 mg increased mean plasma concentrations of risperiDONE by 4-fold, decreased 9-hydroxyrisperiDONE concentrations by 10%, and increased concentrations of the active moiety by 1.4-fold. In healthy volunteers who were extensive CYP2D6 metabolizes, steady-sate atomoxetine AUC values were 6- to 8-fold higher and Cmax values were 3- to 4-fold higher with concomitant PARoxetine compared with atomoxetine alone. Mean digoxin steady-state AUC decreased by 15% in the presence of PARoxetine. In a study with propranolol 80 mg twice daily for 18 days, the steady-state plasma concentrations of propranolol were unaltered during coadministration with PARoxetine 30 mg once daily for the final 10 days 1.
b) PARoxetine significantly inhibited the metabolism of perphenazine in 8 healthy volunteers, resulting in increased plasma concentrations and side effects of perphenazine. All subjects were extensive metabolizers in CYP2D6 isoenzyme activity as determined by a dextromethorphan metabolism study. Subjects were randomized to receive a single dose of perphenazine 0.11 mg/kg or placebo alone in a crossover design. Then subjects received PARoxetine 20 mg/day for 10 days and then another dose of perphenazine or placebo on the tenth day. The average Cmax of perphenazine was significantly increased from 2.2 nanomol/L when given alone, compared to 13.5 nmol/L when given with PARoxetine. The average AUC (0 to 8 hours) was significantly increased from 9.4 mg x hr/L, with perphenazine alone, to 65.4 mg x hr/L when perphenazine was given with PARoxetine. Side effects of perphenazine were significantly increased as demonstrated by oversedation, extrapyramidal side effects, and impaired performance on psychomotor tests. In patients receiving PARoxetine the dose of perphenazine should be reduced and patients should be monitored for perphenazine side effects 4.
Common questions
Can I take Maprotiline and Paroxetine together?
Increased CYP2D6 substrate exposure Always confirm with your pharmacist or prescriber before making any change.
How serious is the Maprotiline and Paroxetine interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Maprotiline or Paroxetine need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (4)
- Product Information: PEXEVA(R) oral tablets, paroxetine mesylate oral tablets. Sebela Pharmaceuticals Inc (per FDA), Roswell, GA, 2023.
- Product Information: BRISDELLE(R) oral capsules, paroxetine oral capsules. Legacy Pharma Inc (per FDA), Scottsdale, AZ, 2025. DailyMed
- Product Information: PAXIL(R) oral tablets, oral suspension, paroxetine oral tablets, oral suspension. Apotex Corp (per FDA), Weston, FL, 2023. DailyMed
- Ozdemir V, Naranjo CA, Herrman N, et al: Paroxetine potentiates the central nervous system side effects of perphenazine. Contribution of cytochrome P4502D6 inhibition in vivo. Clin Pharmacol Ther 1997; 62:334-347. PubMed
Keep reading about Paroxetine
Keep reading about Maprotiline
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist