Can a patient taking Zoloft (sertraline) and paroxetine take trazodone?

Concomitant Use of Trazodone with Sertraline and Paroxetine

A patient taking both Zoloft (sertraline) and paroxetine should not take trazodone due to the significantly increased risk of serotonin syndrome from combining multiple serotonergic medications. 1, 2

Risk of Serotonin Syndrome

Combining multiple serotonergic agents creates a dangerous situation:

• Trazodone's FDA label explicitly warns that SSRIs can precipitate serotonin syndrome when used with other serotonergic drugs 1
• The risk is particularly high when combining three serotonergic medications (sertraline, paroxetine, and trazodone) simultaneously
• A recent 2024 case report documents serotonin syndrome occurring with just two of these medications (sertraline and trazodone) even with standard dosing 2

Signs and Symptoms of Serotonin Syndrome

Serotonin syndrome presents with:

• Mental status changes (agitation, hallucinations, delirium, coma)
• Autonomic instability (tachycardia, labile blood pressure, hyperthermia)
• Neuromuscular symptoms (tremor, rigidity, myoclonus, hyperreflexia)
• Gastrointestinal symptoms (nausea, vomiting, diarrhea) 1

Additional Risks with This Combination

Beyond serotonin syndrome, this combination presents other significant risks:

• Cardiac arrhythmias: Trazodone can be arrhythmogenic, particularly in patients with pre-existing cardiac disease 1
• QT prolongation: Trazodone prolongs the QT interval and should be avoided in combination with other drugs that may affect cardiac conduction 1
• Orthostatic hypotension: All three medications can contribute to this effect 1
• Increased bleeding risk: SSRIs like sertraline and paroxetine increase bleeding risk, which trazodone may further compound 1

Alternative Approaches for Insomnia

If the patient needs treatment for insomnia (a common reason trazodone is prescribed), consider:

1. Non-pharmacological approaches first:

   • Sleep hygiene therapy
   • Cognitive behavioral therapy for insomnia (CBT-I)
   • Stimulus control therapy
   • Sleep restriction therapy 3

2. If medication is necessary:

   • Benzodiazepine receptor agonists (eszopiclone, zolpidem, zaleplon) may be safer alternatives 3
   • Consider discontinuing one of the current SSRIs if trazodone is strongly indicated

Important Monitoring if Combination Cannot Be Avoided

If for some reason this combination absolutely cannot be avoided (which is strongly discouraged):

• Monitor closely for signs of serotonin syndrome
• Start with the lowest possible dose of trazodone
• Educate patient and caregivers about warning signs requiring immediate medical attention
• Consider ECG monitoring due to risk of cardiac arrhythmias 1

Conclusion

The combination of sertraline, paroxetine, and trazodone presents an unnecessary and significant risk to the patient. The safest approach is to avoid adding trazodone to this regimen. If sleep is the primary concern, non-pharmacological approaches or alternative hypnotics should be considered first.