Can These Medications Be Taken Together?
Yes, Zoloft (sertraline) 100 mg, Wellbutrin (bupropion) 150 mg, and trazodone 25 mg can be taken together, but this combination requires careful monitoring for serotonin syndrome, particularly during dose adjustments.
Safety Profile of This Combination
General Safety Considerations
The combination of these three medications is commonly used in clinical practice, though it carries specific risks that must be monitored:
- Sertraline (Zoloft) is well-tolerated compared to other SSRIs and has less effect on metabolism of other medications 1
- Bupropion (Wellbutrin) should have its second dose given before 3 PM to minimize insomnia risk 1
- Trazodone at 25 mg is a low dose typically used for sleep, though guidelines suggest clinicians NOT use trazodone as a treatment for insomnia based on 50 mg dose trials 1
Critical Risk: Serotonin Syndrome
The primary concern with this combination is serotonin syndrome, which can be life-threatening:
- All three medications have serotonergic activity, creating additive risk 2, 3, 4
- Bupropion specifically inhibits cytochrome P450 2D6, which can increase blood levels of sertraline, further elevating serotonin syndrome risk 4
- Case reports document serotonin syndrome with sertraline-trazodone combinations, particularly with rapid titration 3
- Bupropion combined with SSRIs has caused serotonin syndrome even at therapeutic doses 4
Monitoring Requirements
Watch for These Warning Signs
Monitor closely for the classic triad of serotonin syndrome:
- Neuromuscular excitation: myoclonus (especially lower extremities), tremor, rigidity, hyperreflexia, clumsiness 2, 3, 4
- Autonomic instability: diaphoresis, fever (temperature >100°F), tachycardia, labile blood pressure, shivering 5, 3
- Altered mental status: confusion, agitation alternating with lethargy, decreased sensorium 5, 2, 4
Common Pitfall to Avoid
Do not misinterpret early serotonin syndrome symptoms as worsening depression or anxiety 4. Symptoms like confusion, forgetfulness, agitation, and myoclonic jerks can be mistaken for psychiatric deterioration, leading to inappropriate dose increases that worsen the syndrome 4.
Practical Management Strategy
Dosing Timing
- Give bupropion doses with the second dose before 3 PM to prevent insomnia 1
- Administer trazodone 25 mg at bedtime for sleep 1
- Sertraline can be given morning or evening 1
When to Use This Combination
Clinical experience suggests this combination is generally safe and effective when 1:
- Medications are introduced gradually, not rapidly titrated
- The patient has comorbid depression requiring antidepressant therapy
- Sleep disturbance accompanies the depression
- Lower doses of sedating antidepressants (like trazodone 25 mg) are used
Alternative Consideration
If insomnia is the primary concern, consider FDA-approved sleep medications instead of trazodone, as the American Academy of Sleep Medicine suggests NOT using trazodone for insomnia treatment 1. Better alternatives include:
- Zolpidem 10 mg for sleep onset 1
- Eszopiclone 2-3 mg for sleep onset and maintenance 1
- Low-dose doxepin 3-6 mg for sleep maintenance 1
Emergency Response
If serotonin syndrome develops 5, 3:
- Discontinue all serotonergic medications immediately
- Administer benzodiazepines (diazepam 10 mg IV or clonazepam orally) for symptom control
- Consider cyproheptadine as a serotonin antagonist
- Provide supportive care including cooling measures if hyperthermic
- Seek emergency medical attention for severe cases
Bottom Line
This combination can be used safely with appropriate monitoring, particularly avoiding rapid dose escalations and watching vigilantly for early signs of serotonin syndrome 1, 3. The wealth of clinical experience supports the general safety of combining antidepressants from different classes at these doses, but the additive serotonergic effects demand clinical vigilance 1.