Can serotonin syndrome occur in a patient taking only bupropion (Wellbutrin) without any other serotonergic medications?

Serotonin Syndrome and Bupropion (Wellbutrin)

Bupropion monotherapy does not cause serotonin syndrome, as it primarily inhibits norepinephrine and dopamine reuptake with minimal direct serotonergic activity. However, bupropion can contribute to serotonin syndrome when combined with other serotonergic medications through a critical pharmacokinetic mechanism.

Mechanism of Bupropion's Role in Serotonin Syndrome

• Bupropion inhibits the cytochrome P450 2D6 pathway, which increases blood levels of SSRIs and tricyclic antidepressants, thereby indirectly elevating serotonergic activity 1
• This drug-drug interaction mechanism explains why bupropion can precipitate serotonin syndrome when combined with serotonergic agents, despite having minimal direct serotonergic effects 1
• The combination of bupropion with SSRIs (such as sertraline, fluoxetine, or paroxetine) has been documented to cause serotonin syndrome through this metabolic interaction 1, 2

Clinical Evidence of Bupropion-Associated Serotonin Syndrome

• A documented case involved a patient on therapeutic doses of bupropion and sertraline who developed myoclonic jerks, confusion, altered consciousness, and dysautonomia—classic features of serotonin syndrome 1
• Another case demonstrated serotonin syndrome in a patient taking fluoxetine and bupropion who received methylene blue during cardiac surgery, requiring cyproheptadine treatment 2
• These cases confirm that bupropion acts as a contributing factor only when combined with other serotonergic medications, not as a sole agent 1, 2

Diagnostic Considerations

• The earliest manifestations of serotonin syndrome can be misinterpreted as worsening depression or anxiety, leading to inappropriate escalation of serotonergic medications 1
• Key diagnostic features include myoclonus (occurring in 57% of cases), clonus, hyperreflexia, autonomic instability (tachycardia, diaphoresis, fever), and altered mental status 3, 4
• Symptoms typically develop within 24-48 hours after combining medications or dose increases 3, 5
• Use the Hunter Criteria for diagnosis: presence of spontaneous clonus, inducible clonus with agitation or diaphoresis, ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with temperature >38°C and clonus 6

High-Risk Combinations with Bupropion

• SSRIs combined with bupropion pose significant risk due to CYP2D6 inhibition 1, 2
• MAOIs combined with bupropion create extremely high risk and should be avoided 7
• Methylene blue (used for vasoplegia during cardiac surgery) combined with bupropion and SSRIs has caused documented serotonin syndrome 2
• Opioids with serotonergic properties (tramadol, meperidine, methadone, fentanyl) combined with bupropion and SSRIs increase risk 3, 5

Management Algorithm

If serotonin syndrome is suspected in a patient on bupropion plus serotonergic agents:

1. Immediately discontinue all serotonergic medications, including bupropion 3, 4, 6
2. Provide supportive care with benzodiazepines for agitation and muscle rigidity 3, 4, 6
3. Administer IV fluids, external cooling for hyperthermia, and continuous cardiac monitoring 3, 4
4. Consider cyproheptadine (12 mg initially, then 2 mg every 2 hours for continuing symptoms, maintenance 8 mg every 6 hours) for moderate to severe cases 3, 2
5. Approximately 25% of patients require ICU admission with mechanical ventilation; mortality is approximately 11% 3, 4

Critical Clinical Pitfall

• The most dangerous error is misinterpreting early serotonin syndrome symptoms (confusion, agitation, myoclonus) as worsening depression and adding additional serotonergic medications 1
• This escalation can rapidly progress to severe toxicity with hyperthermia, rhabdomyolysis, renal failure, seizures, and death within 24-48 hours 3, 7

Prevention Strategies

• When prescribing bupropion with SSRIs or other serotonergic agents, educate patients about serotonin syndrome symptoms: confusion, agitation, muscle twitching, fever, rapid heart rate, profuse sweating 5
• Monitor closely during the first 24-48 hours after starting combination therapy or dose increases 3, 5
• Consider patient-specific risk factors including higher medication dosages and concomitant use of CYP2D6 inhibitors 3
• Obtain a complete medication history including over-the-counter medications (dextromethorphan, St. John's Wort) and illicit drugs (MDMA, cocaine) that can contribute to serotonergic toxicity 3, 5