Can serotonin syndrome be caused by Wellbutrin (bupropion)?

Serotonin Syndrome and Bupropion

Bupropion alone is unlikely to cause serotonin syndrome as it does not significantly inhibit serotonin reuptake or have direct serotonergic effects, but rare cases have been reported in overdose situations or when combined with other serotonergic medications. 1, 2

Mechanism of Action and Risk Assessment

Bupropion's primary mechanism of action involves norepinephrine and dopamine reuptake inhibition, with minimal effects on serotonergic activity:

• According to the FDA drug label, bupropion "is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin" 1
• Bupropion is chemically unrelated to SSRIs and other traditional serotonergic antidepressants 1

Evidence for Serotonin Syndrome with Bupropion

While the risk is low with bupropion alone at therapeutic doses, there are several important considerations:

1. Bupropion in combination with serotonergic medications:

   • Case reports exist of serotonin syndrome when bupropion is combined with SSRIs 3
   • The mechanism may involve bupropion's inhibition of cytochrome P450 2D6, which can increase blood levels of SSRIs 3

2. Bupropion overdose:

   • Rare cases of serotonin syndrome have been reported following significant bupropion overdose 4, 5
   • A case report described a 15-year-old with serotonin syndrome after bupropion overdose with serum levels of 280 ng/mL (therapeutic range 50-100 ng/mL) 4

Clinical Presentation and Diagnosis

Serotonin syndrome is diagnosed using the Hunter criteria, which require:

• Recent use of a serotonergic agent (within 5 weeks)
• Presence of one or more of the following: spontaneous clonus, inducible clonus with agitation/diaphoresis, ocular clonus with agitation/diaphoresis, tremor with hyperreflexia, hypertonia with temperature >38°C and ocular/inducible clonus 2

Management Recommendations

If serotonin syndrome is suspected with bupropion:

1. Discontinue bupropion and all other serotonergic medications immediately 2

2. Provide supportive care:

   • IV fluid administration
   • Benzodiazepines for agitation control (first-line) 2
   • Monitor for complications including rhabdomyolysis, metabolic acidosis, and renal failure 2

3. For moderate to severe cases:

   • Consider cyproheptadine (a 5-HT2A antagonist) at an initial dose of 12 mg orally, with a maximum daily dose of 32 mg 2, 5
   • In severe cases with temperatures above 41°C, consider neuromuscular paralysis and mechanical ventilation 2

Important Cautions

• Avoid combining bupropion with MAOIs or multiple serotonergic medications 2
• Physical restraints should be avoided as they may worsen hyperthermia 2
• Be vigilant when prescribing bupropion to patients already on serotonergic medications 3
• Symptoms of early serotonin syndrome (confusion, agitation) may be misinterpreted as worsening of the underlying psychiatric condition 3

Monitoring

Symptoms of serotonin syndrome typically resolve within 1-3 days after removing the offending agent(s), but may take up to 7 days in some cases 2. Without proper treatment, mortality rates can reach approximately 11%, highlighting the importance of prompt recognition and treatment 2.