Sertraline and Dothiepin: 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
Sertraline
No brand names on recordDothiepin
No brand names on record
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.
You've been prescribed two antidepressants that work in different ways: sertraline (an SSRI) and dothiepin (an older tricyclic). Sertraline can slow down the liver's breakdown of dothiepin, so a bit more dothiepin may build up in your body. That can lead to stronger side effects like dry mouth, trouble urinating, or feeling extra drowsy.
There's also a small chance of a reaction called serotonin syndrome, which can cause things like a racing heart, high fever, shakiness, or feeling confused. Please don't stop either medicine on your own. This is very manageable, and your care team can adjust your dose and keep an eye on you.
Effect: Sertraline (CYP2D6 inhibitor) may modestly increase dothiepin (dosulepin) serum concentrations via inhibition of TCA metabolism. Additive serotonergic activity also raises a small risk of serotonin syndrome.
- Direction: Increased dothiepin exposure and effect (neither is a prodrug here).
- Magnitude: Modest; often little clinical impact. Smaller than fluoxetine/desipramine.
- Onset: Delayed. Evidence: Probable. Severity: Major.
- Monitor: TCA toxicity (dry mouth, urinary retention, CNS/anticholinergic effects, QT if applicable) and signs of serotonin syndrome (hyperthermia, myoclonus, autonomic instability, mental status change).
Dothiepin dose may need individualized reduction; use caution when combining these classes.
What happens
Modest elevations in dothiepin serum levels or possible serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
Interaction Deep Dive
Some, though not extensive, evidence points to the possibility that sertraline could hinder the metabolism of tricyclic antidepressants (TCAs), leading to elevated TCA serum levels. By suppressing the activity of the cytochrome P450 2D6 enzyme, sertraline can raise plasma levels of drugs that are cleared through this route, tricyclic antidepressants among them213. Nevertheless, this interaction may carry little or no clinical significance. When sertraline was given together with a TCA, the rise in TCA serum concentrations was modest in comparison with the increases seen when another selective serotonin reuptake inhibitor, fluoxetine, was used alongside desipramine4. Patients receiving dothiepin together with sertraline should be watched for indications of TCA toxicity (dry mouth, urinary retention, CNS depression). A reduction in the dothiepin dose may be required.
Why it happens (mechanism)
Inhibition of dothiepin metabolism
How to manage this interaction
Good news: this combination can be managed by your care team.
- Keep taking both exactly as prescribed unless your doctor tells you otherwise.
- Your dothiepin dose may be reduced and individualized by your team, and they may monitor you more closely, especially in the first weeks.
- Watch for signs of too much tricyclic: dry mouth, trouble urinating, constipation, drowsiness or confusion.
- Get urgent help for possible serotonin syndrome: high fever, muscle twitching, racing heart, agitation, or shakiness.
Bring up any of these symptoms with your pharmacist or prescriber promptly.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) The pharmacokinetics of desipramine were evaluated in 18 healthy male volunteers. The participants received desipramine alone (50 mg daily) for 7 days, and then desipramine together with sertraline (50 mg daily) for 21 days. Upon adding sertraline to desipramine therapy, the mean peak concentration of desipramine rose by 34% and the area under the concentration-time curve rose by 26%. One week after sertraline was stopped, desipramine trough concentrations were near baseline. The alterations in desipramine concentrations were modest, and the interaction may not be clinically significant 1.
Common questions
Can I take Sertraline and Dothiepin together?
Sertraline can modestly raise dothiepin levels and slightly add to serotonin effects, so watch for tricyclic side effects and rare serotonin syndrome. Keep taking both as prescribed and let your care team adjust the dose and monitor you. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Sertraline and Dothiepin interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Sertraline and Dothiepin interaction managed?
Good news: this combination can be managed by your care team. Keep taking both exactly as prescribed unless your doctor tells you otherwise. Your dothiepin dose may be reduced and individualized by your team, and they may monitor you more closely, especially in the first weeks. Watch for signs of too much tricyclic: dry mouth, trouble urinating, constipation, drowsiness or confusion. Get urgent he… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Sertraline or Dothiepin 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)
- Preskorn SH, Alderman J, Chung M, et al: Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 1994; 14:90-98. DOI
- Product Information: Zoloft(R), sertraline hydrochloride. Roerig Division of Pfizer Inc, New York, NY, 2002. DailyMed
- Lydiard RB, Anton RF, & Cunningham T: Interactions between sertraline and tricyclic antidepressants. Am J Psychiatry 1993; 150:1125-1126. PubMed
- von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al: Inhibition of desipramine hydroxylation in vitro by serotonin- reuptake-inhibitor antidepressants, and by quinidine and ketoconazole; a model system to predict drug interactions in vivo. J Pharmacol Exp Ther 1994; 268:1278-1283. DOI
Keep reading about Sertraline
Keep reading about Dothiepin
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