Amitriptyline and Fluoxetine: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Fluoxetine
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.
Taking these two together needs some care. Amitriptyline (Elavil) is a tricyclic antidepressant, and fluoxetine (a Prozac-type medicine) slows down the liver enzyme that clears amitriptyline out of your body. That means amitriptyline can build up to higher levels, which can bring more side effects like drowsiness, dry mouth, constipation, a racing heart, or dizziness.
Both medicines can also affect your heart rhythm and both raise serotonin, so together there's a higher chance of an effect called serotonin syndrome (things like agitation, sweating, shaking, or a fast heartbeat). The good news: your care team can manage this by adjusting your amitriptyline dose and keeping a closer eye on you. Don't stop either medicine on your own, just talk with your doctor or pharmacist.
Mechanism: Fluoxetine is a potent CYP2D6 inhibitor and reduces the metabolism of amitriptyline (a CYP2D6 substrate), raising TCA plasma concentrations. Neither drug is a prodrug here, so this increases amitriptyline exposure and toxicity risk. Added concerns are additive QT prolongation and additive serotonergic effects (serotonin syndrome).
- Direction: increased amitriptyline effect/toxicity
- Evidence: theoretical; documented TCA level increases with related TCAs (desipramine, nortriptyline, imipramine)
- Onset: unspecified; note fluoxetine's long half-life prolongs the effect after discontinuation
Management: Use caution; consider TCA dose reduction if adding fluoxetine, obtain plasma TCA levels, and monitor ECG. Discontinue both if serotonin syndrome occurs; evaluate cardiac status for ventricular arrhythmias.
What happens
Increased risk of tricyclic antidepressant toxicity, QT interval prolongation and serotonin syndrome
Interaction Deep Dive
As a strong inhibitor of CYP2D6, FLUoxetine carries a heightened likelihood of serotonin syndrome, QT prolongation, and ventricular arrhythmias, torsade de pointes among them. When given alongside tricyclic antidepressants (TCAs) that are metabolized by CYP2D6, these hazards may be amplified and TCA toxicity may result1; combining FLUoxetine with desipramine, nortriptyline, and imipramine has produced marked elevations in TCA levels 224567. Exercise caution when FLUoxetine and TCAs are given together. Should FLUoxetine be introduced to a patient already receiving a TCA, a reduction in the TCA dose should be considered. Plasma TCA monitoring should be considered when FLUoxetine and a TCA are administered concurrently or when FLUoxetine has recently been stopped. Discontinue both FLUoxetine and the TCA at once if serotonin syndrome develops. Should ventricular arrhythmias arise, consider stopping FLUoxetine and performing a cardiac evaluation 1.
Why it happens (mechanism)
Reduced CYP2D6-mediated metabolism by FLUoxetine; additive QT interval prolongation; additive serotonergic effects
How to manage this interaction
Keep taking both exactly as prescribed unless your prescriber tells you otherwise. This combination is used, but it needs monitoring.
- Your team may lower your amitriptyline dose, especially if fluoxetine is being added to an existing amitriptyline regimen. The dose may need to be individualized to you.
- They may check your amitriptyline blood levels and monitor your heart rhythm (ECG). Because fluoxetine stays in the body a long time, this care continues even after it is stopped.
- Get urgent help for agitation, confusion, sweating, shaking, fever, or a fast/irregular heartbeat, which can signal serotonin syndrome or a heart rhythm problem.
Bring up any new or worsening side effects with your pharmacist or doctor.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) In two clinical studies, plasma concentrations of imipramine and desipramine that had previously been stable increased by more than 2- to 10-fold when FLUoxetine was given concurrently. This effect can continue for 3 weeks or longer after FLUoxetine is stopped. Reducing the dose and temporarily monitoring tricyclic antidepressant plasma levels may be warranted during concurrent FLUoxetine therapy or following recent FLUoxetine discontinuation 1.
b) In 18 healthy subjects, FLUoxetine produced a statistically and clinically significant rise in desipramine concentrations. When FLUoxetine (20 mg daily) was combined with desipramine (50 mg daily), the mean peak concentration of desipramine rose by 278% and the AUC rose by 342%. Desipramine trough levels remained 198% above baseline for 3 weeks after FLUoxetine was withdrawn. The same investigation examined desipramine pharmacokinetics when given together with sertraline. Sertraline had a modest effect, producing small and brief increases in desipramine plasma concentrations 2.
c) Concurrent use of FLUoxetine and desipramine was reported to cause a rise in the desipramine level and new onset delirium in a 69-year-old man within 10 days after FLUoxetine was added to his regimen 3.
d) FLUoxetine raised the level of tricyclic antidepressants (nortriptyline, imipramine, desipramine) in 4 patients. Following the addition of FLUoxetine, the ratio of antidepressant level to dose rose by 109% to 486% in these patients. Three patients developed clinical symptoms (anticholinergic effects, constipation, urinary hesitancy, sedation, unstable gait) because of the elevated levels 4.
e) A 39-year-old woman had symptomatic increases in her desipramine levels while taking FLUoxetine concurrently. Before FLUoxetine therapy, the patient's measured desipramine levels had ranged from 148 to 160 nanograms/milliliter (ng/mL; 556 to 601 nanomol/L) on a regimen of 300 mg daily. Five weeks after FLUoxetine 20 mg daily was added, she reported anticholinergic symptoms, sedation, and confusion, with a desipramine level of 527 ng/mL (1978 nanomol/L). The desipramine dose was reduced to 200 mg/day; 11 days later the level was 244 ng/mL (916 nanomol/L); the patient reported decreased energy, impaired short-term memory, and some "garbled" speech, along with an episode of nausea, dizziness, and syncope. The desipramine dose was lowered to 50 mg/day, and the adverse effects resolved within 6 days. Eight days later, the desipramine level was 122 ng/mL (458 nanomol/L) 5.
f) A 33-year-old depressed man developed the adverse effects of dry mouth, tinnitus, and problems with alertness and memory while taking FLUoxetine 40 mg daily and desipramine 150 mg daily for 5 weeks; FLUoxetine was stopped and the desipramine blood levels fell from 938 to 48 nanograms/mL (3521 to 180 nanomol/L) with resolution of the clinical symptoms 6.
g) A 75-year-old woman had symptomatic increases in her desipramine serum concentrations when FLUoxetine was added. Desipramine serum levels ranged from 109 to 150 ng/mL (409 to 563 nanomol/L) with oral doses of 300 mg at bedtime before FLUoxetine therapy. After oral FLUoxetine 20 mg daily was added to the regimen, the desipramine serum level rose to 212 ng/mL (796 nanomol/L) within five days. The FLUoxetine dose was raised to 40 mg/day three days later, and the desipramine serum level was 419 ng/mL (1573 nanomol/L) after four days. A worsening of depression and severe fatigue occurred at the same time as the increases in desipramine serum levels. Discontinuing FLUoxetine and reducing the desipramine dose to 200 mg daily lowered the desipramine serum level to 231 ng/mL (867 nanomol/L) within two weeks 7.
Common questions
Can I take Amitriptyline and Fluoxetine together?
Fluoxetine can raise amitriptyline levels and both drugs add to serotonin and heart-rhythm effects, so your care team may lower your amitriptyline dose and monitor you more closely. Keep taking both as prescribed and report any unusual symptoms. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Fluoxetine 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 is the Amitriptyline and Fluoxetine interaction managed?
Keep taking both exactly as prescribed unless your prescriber tells you otherwise. This combination is used, but it needs monitoring. Your team may lower your amitriptyline dose, especially if fluoxetine is being added to an existing amitriptyline regimen. The dose may need to be individualized to you. They may check your amitriptyline blood levels and monitor your heart rhythm (ECG). Because fluo… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
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Questions for your pharmacist
- Does my dose of Amitriptyline or Fluoxetine 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 (7)
- Product Information: PROZAC(R) oral capsules, fluoxetine oral capsules. Lilly USA LLC (per FDA), Indianapolis, IN, 2023. DailyMed
- Preskorn SH, Alderman J, Chung M, et al: Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 1994; 14:90-98. DOI
- Preskorn SH, Beber JH, Faul JC, et al: Serious adverse effects of combining fluoxetine and tricyclic antidepressants (letter). Am J Psychiatry 1990; 147:532. PubMed
- Aranow AB, Hudson JI, Pope HG Jr, et al: Elevated antidepressant plasma levels after addition of fluoxetine. Am J Psychiatry 1989; 146:911-913. PubMed
- Downs JM, Downs AD, Rosenthal TL, et al: Increased plasma tricyclic antidepressant concentrations in two patients concurrently treated with fluoxetine. J Clin Psychiatry 1989; 50:226-227.
- Goodnick PJ: Influence of fluoxetine on plasma levels of desipramine (letter). Am J Psychiatry 1989; 146:552. PubMed
- Bell IR & Cole JO: Fluoxetine induces elevation of desipramine level and exacerbation of geriatric nonpsychotic depression. J Clin Psychopharmacol 1988; 8:447-448. PubMed
Keep reading about Amitriptyline
Keep reading about Fluoxetine
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