Sertraline Interactions: What You Need to Know

Sertraline Interactions: What You Need to Know

Sertraline is a 30-year-old antidepressant used for treating mood and anxiety disorders. This serotonin reuptake inhibitor (SSRI), has also been effectively used for panic attacks, obsessive-compulsive disorder, or posttraumatic stress disorder. (1)

While sertraline effectively increases the serotonin levels in the body, its safety profile depends if it is concomitantly used with other medications, aside from side effects. If taken with certain medications like blood thinners or phenytoin, monitoring the effects can be sufficient. (1)

However, some interactions, like concomitant use with Monoamine Oxidase Inhibitors (MAOIs) or pimozide, may cause life-threatening symptoms; therefore, these medications are contraindicated with sertraline. (1)

This article covers the most critical sertraline drug interactions. Keep reading to find out when to take precautions or call your doctor.

1. MAOIs and Other Serotonergic Drugs

If sertraline is used together with MAOIs or other serotonergic drugs, there is a risk of a life-threatening condition named serotonin syndrome. (1-2)

Serotonin Syndrome: A Life-threatening Side Effect

Serotonin is a hormone that improves mood, memory, and personality; therefore, it is called a hormone of happiness. Sertraline works in a way that inhibits the reuptake of serotonin. As a result, the level of serotonin in the body increases, and the health condition is improved. (3-4)

Too much serotonin, due to medication treatment, can cause serotonin syndrome with various symptoms. Symptoms may appear within several hours of beginning a new drug or increasing the doses. The severity of this syndrome depends on the severity of the symptoms. They can be mild such as:

  • Headache;
  • Insomnia;
  • Confusion;
  • Diarrhea;
  • Muscle rigidity;
  • Heavy sweating;
  • Agitation or restlessness;
  • Rapid heart rate;
  • High blood pressure;
  • Loss of muscle coordination or twitching muscles, etc.

In some cases, the symptoms can be severe and life-threatening. If any of the following symptoms occur:

  • High fever;
  • Tremor;
  • Seizures;
  • Irregular heartbeat;
  • Unconsciousness;

it will require emergency treatment immediately. (2)

Sertraline and MAOIs or Other Antidepressants: What Do the Recommendations Say?

MAOIs are another group of antidepressants that inhibit the enzyme monoamine oxidase. This enzyme regularly removes certain chemical messengers, including serotonin, from the brain. As a result of MAOIs activity, the level of serotonin will increase. (5)

When SSRI, including sertraline, is used together with MAOI:

  • Isocarboxazid;
  • Phenelzine;
  • Selegiline;
  • Tranylcypromine;
  • Linezolid; or
  • Methylene blue;

the serotonin level may increase too much and cause serotonin syndrome. Therefore, the use of sertraline with MAOIs is contraindicated. (1)

Unlike MAOIs, other drugs can be used with sertraline:

  • Selective serotonin reuptake inhibitors;
  • Serotonin and norepinephrine reuptake inhibitors;
  • Triptans;
  • Tricyclic antidepressants;
  • Fentanyl;
  • Lithium;
  • Tramadol;
  • Tryptophan;
  • Buspirone;
  • St. John’s Wort.

Although concomitant use is allowed, it is recommended patients monitor for signs and symptoms of serotonin syndrome. If you use dual therapy, be cautious when beginning the treatment or increasing the dose. (1)

Call your doctor immediately if you experience any serotonin syndrome symptoms. Your doctor might consider discontinuing sertraline or the other serotonergic drug. (1)

2. Pimozide

Sertraline interaction with pimozide increases pimozide blood levels, so their concomitant use is not recommended. (1)

Pimozide is a medication used in Tourette’s disorder in individuals who repeat specific movements or sounds without control. Pimozide can help in controlling these motor or verbal tics. (6)

The mechanism of the interaction between sertraline and pimozide is not clear. However, there is evidence of an increased pimozide plasma concentration by about 40% due to sertraline concomitant use. These higher levels are dangerous and can be a reason for an irregular heartbeat. Such a heart rhythm may be serious and life-threatening, followed by:

  • Chest pain,
  • Anxiety,
  • Fainting,
  • Shortness of breath,
  • Lightheadedness, or
  • Dizziness. (1, 7)

Due to the severity of this interaction, pimozide use is contraindicated with sertraline. (1)

Other medications that prolong QTc (the time between the heart muscle contraction and recovery) and may cause irregular heartbeat should also be avoided. Some of them are:

  • Antipsychotics: ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol, etc.;
  • Antibiotics: erythromycin, gatifloxacin, moxifloxacin, sparfloxacin, etc.;
  • Class 1A antiarrhythmics: quinidine, procainamide;
  • Class III antiarrhythmics: amiodarone, sotalol; and
  • Others: pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol, or tacrolimus. (1)

3. Phenytoin

Like with pimozide, sertraline increases the plasma concentration of phenytoin when used together. (1)

Phenytoin is an anticonvulsant, a medication that controls seizures. It is used to prevent or treat seizures due to brain abnormalities. The CYP2C subfamily of the P450 enzyme, present in the liver, is responsible for phenytoin metabolism. (8-9)

Sertraline inhibits the CYP2C subfamily, and it is thought that this can be a reason for the phenytoin level increase. Although phenytoin level is increased by sertraline inhibition, some clinical evidence says that no symptoms or toxicity occur. (9)

Yet, concomitant use of sertraline and phenytoin is possible. When sertraline is initiated or the dose increased, the recommendation is for the doctor to monitor phenytoin levels and, if needed, to reduce the phenytoin dose. (1)

4. Drugs Metabolized by CYP2D6

Sertraline inhibits the activity of the CYP2D6 isozyme (debrisoquin hydroxylase), which is active in drug metabolism. As a result, the concentration of the drugs metabolized by CYP2D6 will increase. (1)

Sertraline interacts with many enzymes from the CYP family. Aside from CYP2C9, it also inhibits CYP2D6 and impacts the metabolism of many medications. E.g., due to sertraline inhibition, imipramine and desipramine have reduced elimination and strengthened effects. (10)

Some studies showed that this inhibitor’s effect weakens when sertraline concentration achieves a steady-state level. Therefore, FDA has listed sertraline in the group of weak CYP2D6 inhibitors. (10-11)

Below, in the list, you may find some of those medications that are affected by sertraline’s CYP2D6 inhibition:

  • Propafenone,
  • Flecainide,
  • Atomoxetine,
  • Desipramine,
  • Dextromethorphan,
  • Metoprolol,
  • Nebivolol,
  • Perphenazine,
  • Thioridazine,
  • Tolterodine,
  • Venlafaxine.

Due to this interaction, some patients might need a dosage adjustment. While using sertraline, your doctor might decrease the dose, while when you stop taking sertraline, the dose should be increased again. (1)

5. Drugs Highly Bound to Plasma Protein

Sertraline hydrochloride bounds to plasma protein that affects the concentration of other tightly-bound drug medications. (1)

Drugs bind to proteins available in plasma (albumin) and, through the blood flow, are transported to the target place to show their therapeutic effect or to be eliminated from the body. (12-13)

Sertraline, when available in the blood, is highly protein bound (98%) to human serum albumin. If another drug is present in the body with a high binding affinity to plasma proteins, the concentration of each drug may vary from regular when not taken together. (10)

For this reason, the recommendation is to monitor the patients and reduce the dose in case of side effects due to a higher concentration of sertraline or the concomitant drug. (1)

6. Antiplatelet Agents and Anticoagulants

In patients who use blood thinners, sertraline may potentiate the risk of bleeding. (1)

Blood thinners are medications that protect the body from abnormally formed blood clots and life-threatening conditions such as:

  • stroke,
  • heart attack, or
  • pulmonary embolism.

Anti-clotting medications, as per Harvard Medical School, are divided into two major groups:

Anticoagulant drugs – slow down the process of blood clotting or prevent formed clots from growing bigger. Anticoagulant medications are:

  • Apixaban;
  • Dabigatran;
  • Edoxaban;
  • Rivaroxaban;
  • Warfarin;
  • Enoxaparin;
  • Heparin.

Antiplatelet drugs – don’t allow platelets to stick together and, by that, prevent forming clots. Antiplatelet medications are:

  • Aspirin;
  • Clopidogrel;
  • Prasugrel;
  • Ticagrelor:
  • Dipyridamole;
  • Abciximab;
  • Tirofiban;
  • Cilostazol;
  • Vorapaxar. (14)

The possible mechanisms of sertraline interaction with blood thinners result from sertraline characteristics, as explained above. Therefore, the effects on the blood thinners can be:

  1. Sertraline, a highly protein-bound chemical, can displace other molecules, e.g., warfarin, which is about 99% protein-bound. As a result, there is an increased amount of free warfarin in the circulation that increases the risk of bleeding; (15)
  2. Warfarin is metabolized with the activity of CYP2C9 enzyme; more precisely, the S isomer of warfarin with higher potency. Since sertraline inhibits this enzyme, the level of warfarin will increase and, therefore, the risk of bleeding; (15)
  3. Platelets store serotonin and, during inflammation or thrombus formation, release this serotonin. Platelets also have a serotonin transporter to reuptake serotonin, transport it, and re-release it during activation. Sertraline, like other SSRIs, blocks the reuptake of serotonin in platelets. This results in an impairment of the platelet activity, aggregation, and response to stop bleeding. (16-18)

In case of increased bleeding, specific signs and symptoms may occur, such as:

  • Bruising;
  • Bleeding gums;
  • Nose bleeding;
  • Intensive bleeding from small cuts;
  • Excessive bleeding after surgery;
  • Dizziness. (19)

If you take any antiplatelet or anticoagulant drug and need to treat depression with sertraline, be aware of the increased risk of bleeding. Inform your doctor if you notice any changes. (1)


Sertraline is a well-established and effective antidepressant. However, its therapeutic effect and safety use is influenced when taken with other medications.

Pimazide and MAOIs are contraindicated with sertraline. Other antidepressants, blood thinners, and phenytoin require monitoring when used with sertraline. Inform your doctor in case you experience any adverse events.

You may find all possible interactions in the Medication Guide. For safe sertraline therapy, inform your doctor of the medications you use.

Frequently Asked Questions

How sertraline improves depression?

Sertraline is a serotonin reuptake inhibitor, a medication that increases the level of serotonin in the body, helping relieve depressive symptoms.

Are there medications that are contraindicated with sertraline?

Yes, using Monoamine Oxidase Inhibitors or pimozide with sertraline is contraindicated.

How can high levels of serotonin be dangerous?

When the serotonin level is too high, it may cause side effects. High fever, tremors, seizures, irregular heartbeat, and unconsciousness are severe, life-threatening symptoms requiring immediate emergency treatment.

Why the doctor decreased my dose of nebivolol while taking sertraline? Is it enough to control my high blood pressure?

Sertraline inhibits the enzyme CYP2D6, which impacts the metabolism of some medications. Due to this effect, the level of nebivolol will increase. For this reason, your doctor might decrease the nebivolol dose while using sertraline to avoid the possible side effect of higher exposure to the drug.

See Also

Drug Interaction Checker

Sertraline Side Effects

Amlodipine Interactions

Pantoprazole Interactions

Metronidazol Interactions

Tramadol Contraindications

Meloxicam Interactions

Lisinopril Contraindications

  1. Food and Drug Administration, SERTRALINE HYDROCHLORIDE tablets, for oral use, Oct 2022
  2. Mayo Clinic, Serotonine Syndrome, Jan 2022
  3. Harvard Medical School, Serotonin, Jul 2021
  4. H. K. Singh and A. Saadabadi, Sertraline, National Library of Medicine, Feb 2023
  5. T. S. Laban and A. Saadabadi, Monoamine Oxidase Inhibitors (MAOI), National Library of Medicine, Jul 2022,and%20depression%20with%20atypical%20features.
  6. MedlinePlus, Pimozide, Jul 2017,by%20motor%20or%20verbal%20tics).
  7. Mayo Clinic, Heart arrhythmia, Apr 2023
  8. MedlinePlus, Phenytoin, Dec 2019
  9. M B Haselberger 1, L S Freedman, S Tolbert, Elevated serum phenytoin concentrations associated with co-administration of sertraline, J Clin Psychopharmacol. 1997 Apr;17(2):107-9.
  10. PharmGKB, Sertraline Pathway, Pharmacokinetics, Jan 2020
  11. Food and Drug Administration, Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers, Aug 2022
  12. Keen, P., Effect of Binding to Plasma Proteins on the Distribution, Activity, and Elimination of Drugs. Handbook of Experimental Pharmacology, 1971, vol 28 / 1. Springer, Berlin, Heidelberg.
  13. W. E. Lindup and M. C. L’E Orme, Clinical Pharmacology: Plasma Protein Binding Of Drugs, British Medical Journal, Jan 1981, Vol. 282, No. 6259, pp. 212-214 (3 pages)
  14. Blood Thinners, MedlinePlus, January 31, 2022,
  15. S. N. Allen, S. John, J. Shannon, and J.Ferrara, Treatment of Depression in Patients on Anticoagulation Therapy: Antidepressant-Warfarin Drug Interactions, US Pharm. 2013;38(11):23-26.
  16. M. Mauler, N. Herr, et al., Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation, Circulation, Volume 139, Issue 7, 12 February 2019; Pages 918-931,and%20modulates%20the%20inflammatory%20response.
  17. I.Lopez-Vilchez, M. Diaz-Ricart, J. G. White, G. Escolar, and A. M. Galan, Serotonin enhances platelet procoagulant properties and their activation induced during platelet tissue factor uptake, Cardiovascular Research, Volume 84, Issue 2, 1 November 2009, Pages 309–316,
  18. David N.Juurlink, MD PhD, Antidepressants, antiplatelets and bleeding: One more thing to worry about?, CMAJ. 2011 Nov 8; 183(16): 1819–1820.
  19. American Society of Hematology, Bleeding Disorders,

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