Mirtazapine and Amitriptyline: 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
Mirtazapine
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.
Both amitriptyline (Elavil) and mirtazapine (Remeron) can raise serotonin levels in your body, and both can affect your heart's electrical rhythm. When taken together, these effects can add up. That means a slightly higher chance of a rare but serious problem called serotonin syndrome (which can cause shakiness, muscle twitching, fast heartbeat, sweating, fever, and confusion), and a higher chance of an irregular heartbeat.
Please know this is a theoretical concern, and many people take these two safely under supervision. The good news is your care team can manage this by watching you closely, especially when you first start or change doses. Don't stop either medicine on your own, just check in with your pharmacist or doctor.
Additive pharmacodynamic interaction. Both agents are serotonergic and both can prolong the QTc interval; neither is a prodrug, so the effects are simply additive.
- Direction: increased risk of serotonin syndrome and increased risk of QT prolongation / torsades de pointes.
- Evidence: theoretical, supported by postmarketing reports (mostly with overdose, known CV disease/QT history, or concomitant QT-prolonging agents).
- Onset: unspecified; serotonin syndrome risk is highest at initiation and dose escalation.
- Management: monitor for neuromuscular abnormalities, autonomic hyperactivity, and mental status changes; consider ECG and electrolyte monitoring in at-risk patients. If serotonin syndrome develops, discontinue offending agents and provide supportive care.
What happens
Increased risk of serotonin syndrome, an increased risk of QT interval prolongation and an increased risk of torsades de pointes
Interaction Deep Dive
Exercise caution when mirtazapine is given alongside other agents that lengthen the QTc interval, because doing so raises the likelihood of QT prolongation and/or ventricular arrhythmias. Postmarketing experience has documented QT prolongation, torsades de pointes, ventricular tachycardia, and sudden death associated with mirtazapine, with most of these events arising in the setting of overdose, existing cardiovascular disease or a family history of QT prolongation, or the simultaneous use of a QTc-prolonging agent. Because of additive serotonergic effects, combining mirtazapine with other serotonergic drugs can heighten the risk of serotonin syndrome. Watch for signs of serotonin syndrome, particularly when starting therapy and when doses are raised, and if a patient develops such signs, treatment with mirtazapine and discontinue any concurrent serotonergic agent23. The manifestations of serotonin syndrome encompass neuromuscular abnormalities, autonomic hyperactivity, and mental status changes. This condition may be life-threatening. Should serotonin syndrome emerge after the responsible agents have been stopped, deliver supportive care along with any other therapy that may be required 1.
Why it happens (mechanism)
Additive serotonin effects; additive QT interval prolongation
How to manage this interaction
If your prescriber has you on both, they have likely weighed the benefits and will keep an eye on things. Here is what typically happens and what you can do:
- Keep taking both as prescribed unless your care team tells you otherwise.
- Your team may monitor you more closely, especially when starting or increasing a dose, and doses may be adjusted and individualized for you.
- They may check your heart rhythm (ECG) if you have heart concerns or a family history of rhythm problems.
- Get urgent help for agitation, confusion, muscle twitching or stiffness, tremor, shivering, sweating, fever, fast or irregular heartbeat, or fainting.
- Raise any new symptoms with your pharmacist or prescriber.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
3 reports — tap to read
a) A 75-year-old woman developed symptoms consistent with serotonin syndrome within a few hours of beginning mirtazapine and shortly after FLUoxetine was stopped. Her ongoing depression treatment included FLUoxetine, chlorproMAZINE, and LORazepam. Because she was not responding, FLUoxetine was stopped and mirtazapine 30 mg/day was begun soon after. Within a few hours of initiating mirtazapine, she developed dizziness, headache, nausea, dry mouth, and severe anxiety and agitation accompanied by suicidal thoughts. Additional symptoms included difficulty walking, pronounced resting tremor of the hands, and insomnia. She grew progressively worse over the following 3 days. Mirtazapine was stopped on day 5. Her symptoms got better the next day. FLUoxetine 20 mg/day was reintroduced on day 7, after which dizziness, nausea, headache, and agitation resolved over the following days. During the next 10 days, tremor, anxiety, difficulty walking, dry mouth, and insomnia improved 4.
b) A 26-year-old woman with anorexia nervosa who had been taking fluvoxaMINE for 4 months developed symptoms of serotonin syndrome after mirtazapine was started. The symptoms of twitching, tremors, agitation, restlessness, and "feeling like she could crawl out of her skin" arose over a 4 day period after mirtazapine 30 mg/day was begun. Symptoms rapidly advanced to twitching, tremors, and restlessness. She was hospitalized with further symptoms of diaphoresis, flushing, fasciculations, and nausea and was treated with cyproheptadine, acetaminophen, and IV fluids. She stayed afebrile throughout the event. Her symptoms completely resolved within 24 hours 5.
c) Postmarketing reports have described mirtazapine associated with QT prolongation, torsades de pointes, ventricular tachycardia, and sudden death, with most cases occurring in connection with overdose, existing cardiovascular disease or a family history of QT prolongation, or the concurrent use of mirtazapine with QTc-prolonging agents 23.
Common questions
Can I take Mirtazapine and Amitriptyline together?
Taking amitriptyline and mirtazapine together adds up their serotonin and heart-rhythm effects, so watch for serotonin syndrome symptoms and heartbeat changes, and let your care team monitor you closely. Do not stop either drug on your own; call your pharmacist or doctor with any new symptoms. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Mirtazapine and Amitriptyline 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 Mirtazapine and Amitriptyline interaction managed?
If your prescriber has you on both, they have likely weighed the benefits and will keep an eye on things. Here is what typically happens and what you can do: Keep taking both as prescribed unless your care team tells you otherwise. Your team may monitor you more closely, especially when starting or increasing a dose, and doses may be adjusted and individualized for you. They may check your heart r… 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Mirtazapine or Amitriptyline 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 (5)
- Boyer EW & Shannon M: The serotonin syndrome. N Eng J Med 2005; 352(11):1112-1120. PubMed
- Product Information: REMERON(R) oral tablets, mirtazapine oral tablets. Merck Sharp & Dohme Corp (per FDA), Whitehouse Station, NJ, 2020. DailyMed
- Product Information: Mirtazapine oral film coated tablets, mirtazapine oral film coated tablets. Apotex Corp (per DailyMed), Weston, FL, 2024. DailyMed
- Benazzi F: Serotonin syndrome with mirtazapine-fluoxetine combination. Int J Geriatr Psychiatry 1998; 13(7):495-496. DOI
- Demers JC & Malone M: Serotonin syndrome induced by fluvoxamine and mirtazapine. Ann Pharmacother 2001; 35:1217-1220. PubMed
Keep reading about Amitriptyline
Keep reading about Mirtazapine
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