What medications interact with Zoloft (sertraline) to cause serotonin syndrome?

Medications That Interact with Zoloft (Sertraline) to Cause Serotonin Syndrome

Zoloft (sertraline) can cause potentially life-threatening serotonin syndrome when combined with other serotonergic medications, particularly MAOIs, but also with various other drug classes including triptans, tricyclic antidepressants, opioids, and certain over-the-counter medications. 1

High-Risk Drug Interactions with Sertraline

Absolutely Contraindicated Combinations

• Monoamine Oxidase Inhibitors (MAOIs): Concomitant use of sertraline with MAOIs (psychiatric or others like linezolid and intravenous methylene blue) is contraindicated due to significantly increased risk of severe, potentially fatal serotonin syndrome 1
• Switching between sertraline and MAOIs: Requires a washout period; sertraline should be discontinued before initiating MAOI treatment 1

High-Risk Serotonergic Medications

• Other Antidepressants:

  • SSRIs (fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine) 2, 3
  • SNRIs (venlafaxine, desvenlafaxine, duloxetine) 3, 1
  • Tricyclic antidepressants 1
  • Trazodone 3, 4
  • Atypical antidepressants 2

• Pain Medications:

  • Opioids (particularly tramadol, meperidine, methadone, fentanyl) 2, 1, 5
  • Combination with tramadol requires particular caution but is not absolutely contraindicated 5

• Other Prescription Medications:

  • Triptans (sumatriptan, etc.) 1, 6
  • Lithium 1, 6
  • Buspirone 1
  • Linezolid (antibiotic with MAOI properties) 1
  • Methylene blue (intravenous) 1

• Stimulants:

  • Amphetamine class medications 2
  • Possibly methylphenidate 2

• Over-the-Counter and Supplements:

  • St. John's Wort 2, 1
  • L-tryptophan supplements 2, 1
  • Dextromethorphan (in cough medicines) 2
  • Chlorpheniramine (in allergy medications) 2
  • Diet pills 2

• Illicit Drugs:

  • Ecstasy (MDMA) 2
  • Methamphetamine 2
  • Cocaine 2
  • LSD 2

Mechanisms of Interaction

• Pharmacodynamic interactions: Direct additive serotonergic effects when multiple agents that increase serotonin availability are combined 7, 8
• Pharmacokinetic interactions: Sertraline may interact with drugs metabolized by CYP2D6, potentially increasing blood levels of other medications 2, 3
• Dose-dependent risk: Higher doses of either sertraline or the interacting medication increase serotonin syndrome risk 3, 5

Clinical Presentation of Serotonin Syndrome

Serotonin syndrome typically presents with a triad of symptoms 1, 8:

• Mental status changes: Agitation, confusion, hallucinations, delirium, coma
• Autonomic instability: Tachycardia, labile blood pressure, hyperthermia, diaphoresis, flushing
• Neuromuscular abnormalities: Tremor, rigidity, myoclonus, hyperreflexia, incoordination

Risk Mitigation Strategies

• Start the second serotonergic medication at a low dose when adding to sertraline 2, 3
• Increase doses slowly with careful monitoring, especially in the first 24-48 hours after dosage changes 2, 3
• Use extra caution in elderly patients, those on higher medication doses, or with concomitant CYP2D6 inhibitors 5
• Avoid adding multiple serotonergic agents simultaneously 3, 7
• Educate patients to report symptoms immediately 1

Management of Suspected Serotonin Syndrome

• Immediately discontinue all serotonergic agents 3, 1
• Provide supportive care including IV fluids and cardiac monitoring 3
• Consider serotonin antagonists like cyproheptadine for severe cases 3, 8
• Aggressive external cooling for hyperthermia 8
• Benzodiazepines may help manage agitation 4

Common Pitfalls

• Failure to recognize that even therapeutic doses of combined serotonergic medications can cause serotonin syndrome 5
• Not considering over-the-counter medications and supplements as potential contributors 2, 1
• Assuming that only MAOIs pose a significant risk (though they are the highest risk) 1, 5
• Rapid titration of multiple serotonergic agents significantly increases risk 4