Is the recent increase in Wellbutrin (bupropion) dosage from 150mg to 300mg contributing to the patient's new onset of afternoon irritability, anger, and increased anxiety and smoking frequency?

Bupropion Dose Increase is Causing the Patient's Symptoms

The recent increase in Wellbutrin from 150mg to 300mg is directly responsible for this patient's new-onset afternoon irritability, anger, increased anxiety, and paradoxically worsened smoking behavior, and the dose should be immediately reduced back to 150mg or the medication discontinued entirely. 1

Evidence Linking Dose Increase to Symptoms

The FDA drug label explicitly warns that patients and caregivers must be alert to the emergence of anxiety, agitation, irritability, hostility, and aggressiveness, especially when the dose is adjusted up or down, as these symptoms may be severe and abrupt in onset. 1 The patient's description of feeling "hopped up," experiencing new-onset anger ("I get so fucking angry"), and increased morning anxiety with smoking "like crazy" precisely matches this FDA warning profile.

Population pharmacokinetic analyses demonstrate that anxiety incidence is inversely proportional to bupropion plasma concentrations at higher doses, meaning that as the dose increases, anxiety paradoxically worsens in some patients. 2 Additionally, the incidence of insomnia is directly related to bupropion plasma concentrations, which may contribute to afternoon irritability through sleep disruption. 2

The Smoking Cessation Paradox

The patient's increased smoking frequency after dose escalation represents a well-documented phenomenon. For highly nicotine-dependent smokers, bupropion can cause a rebound in symptoms when therapeutic effects are inadequate or when the medication causes intolerable activation. 3 The patient's shift from smoking half a cigarette at a time to smoking much more frequently suggests the medication is causing agitation rather than reducing cravings, leading to compensatory smoking behavior.

Research demonstrates that bupropion's interaction with nicotine dependence is complex, and highly dependent smokers may experience paradoxical worsening of symptoms during active treatment. 3 The patient's report of feeling "hopped up" and anxious in the mornings, leading to increased smoking, indicates the dopaminergic activation from bupropion is creating a hyperaroused state rather than therapeutic benefit.

Neuropsychiatric Toxicity Risk

The FDA specifically warns about neuropsychiatric adverse events including aggression, hostility, agitation, and anxiety when bupropion is used for smoking cessation, instructing patients to discontinue the medication if such symptoms occur. 1 The American Academy of Neurology acknowledges that bupropion carries dose-dependent neuropsychiatric risks beyond seizures. 4

Bupropion-induced aggression and irritability can occur even in patients without psychiatric history, as documented in case reports where the combination of bupropion with other factors (including stress) precipitated aggressive outbursts in previously non-violent individuals. 5 The patient's statement that "I never was like that" regarding his anger is particularly concerning and consistent with drug-induced behavioral changes.

Immediate Management Recommendations

Reduce the bupropion dose back to 150mg immediately or discontinue entirely if symptoms are severe. 6, 1 The standard dosing for smoking cessation is 150mg twice daily (300mg total), but this assumes tolerability. 6 When patients experience significant neuropsychiatric symptoms at 300mg, the dose must be reduced regardless of the indication.

The FDA recommends that families and caregivers observe for the emergence of these symptoms on a day-to-day basis since changes may be abrupt, and such symptoms should be reported to the prescriber immediately, especially if they are severe or abrupt in onset. 1

Alternative Smoking Cessation Strategy

If smoking cessation remains a goal after stabilization, consider:

• Returning to 150mg daily (not twice daily) with close monitoring for symptom resolution 6
• Adding nicotine replacement therapy (NRT) to lower-dose bupropion rather than increasing bupropion dose, as combination therapy shows 35.5% abstinence rates versus 30.3% with bupropion alone 6
• Reassessing in 1-2 weeks after dose reduction to determine if the patient can tolerate any bupropion at all 6

Critical Safety Monitoring

Monitor for:

• Resolution of irritability and anger within 3-7 days of dose reduction 4
• Continued or worsening agitation, which would necessitate complete discontinuation 4, 1
• Emergence of depressive symptoms if bupropion is discontinued, as highly dependent smokers may experience mood rebound 3

The patient's temporal correlation between dose increase and symptom onset, combined with the specific symptom profile matching FDA warnings and pharmacokinetic data, makes this a clear case of dose-related adverse effects requiring immediate intervention.