In a patient on atomoxetine who presents with acute euphoria, vomiting, and mydriasis, could concurrent use of bupropion (Wellbutrin), testosterone, DHEA, B‑complex vitamins, or anastrozole be responsible for these symptoms?

Bupropion and Concurrent Medications as Contributors to Acute Symptoms in an Atomoxetine-Treated Patient

Bupropion is the most likely culprit among the listed medications to contribute to or precipitate acute euphoria, vomiting, and mydriasis in a patient on atomoxetine, primarily through a clinically significant pharmacokinetic drug interaction that increases atomoxetine exposure by approximately 5-fold. 1

Mechanism of the Bupropion-Atomoxetine Interaction

Bupropion and its metabolites are potent CYP2D6 inhibitors, which directly impairs the metabolism of atomoxetine—a drug that is primarily metabolized by CYP2D6. 2 When bupropion is co-administered with atomoxetine:

• Atomoxetine plasma concentrations increase dramatically: AUC rises from approximately 1,580 ng·h/mL to 8,060 ng·h/mL (a 5.1-fold increase), and Cmax increases from 226 ng/mL to 386 ng/mL. 1
• The half-life of atomoxetine is prolonged, leading to sustained elevated drug levels. 1
• The formation of atomoxetine's main active metabolite (4-hydroxyatomoxetine-O-glucuronide) is reduced by 1.5-fold, shifting the pharmacologic burden to the parent compound. 1

This interaction effectively converts an extensive metabolizer (EM) into a phenotypic poor metabolizer (PM), with atomoxetine exposure levels comparable to those seen in genetic PMs. 1

Clinical Manifestations of Elevated Atomoxetine Levels

The triad of euphoria, vomiting, and mydriasis is consistent with excessive noradrenergic and dopaminergic stimulation from elevated atomoxetine concentrations:

• Vomiting is a common adverse effect of atomoxetine, reported in 11% of pediatric patients in controlled trials (vs. 6% with placebo), and is dose-related. 3
• Mydriasis (pupil dilation) is a recognized sympathomimetic effect of atomoxetine, though reported in <2% of patients at standard doses. 3
• Euphoria or mood elevation may reflect excessive dopaminergic activity, as atomoxetine inhibits presynaptic dopamine reuptake, and bupropion further amplifies this effect through its own dopaminergic mechanism. 4

Poor metabolizers of CYP2D6 (who have intrinsically elevated atomoxetine levels) experience higher rates of adverse effects, including vomiting, constipation, and mood changes, compared to extensive metabolizers. 3 The bupropion-atomoxetine interaction pharmacologically mimics this PM phenotype. 1

Bupropion's Independent Contribution

Bupropion itself can cause:

• Nausea and vomiting (2–4% incidence in depression trials). 5
• Mydriasis (reported in <2% of patients). 5
• Agitation, restlessness, or mood elevation, particularly during dose initiation or escalation. 5, 6

However, bupropion monotherapy does not typically produce acute euphoria unless doses exceed therapeutic ranges or in the context of drug interactions. 4

Other Medications: Unlikely Contributors

Testosterone and DHEA

• No evidence links testosterone or DHEA to acute vomiting, mydriasis, or euphoria in the context of atomoxetine use.
• These agents are not known to interact with CYP2D6 or alter atomoxetine metabolism.
• Testosterone can cause mood changes (irritability, aggression) but not the acute sympathomimetic syndrome described.

B-Complex Vitamins

• B vitamins have no pharmacokinetic or pharmacodynamic interactions with atomoxetine or bupropion.
• They do not cause mydriasis, euphoria, or vomiting.

Anastrozole

• Anastrozole (an aromatase inhibitor) does not interact with CYP2D6 and has no known effect on atomoxetine metabolism. 2
• It does not produce sympathomimetic effects or the symptoms described.

Critical Safety Considerations

The combination of atomoxetine and bupropion is not contraindicated but requires extreme caution due to the magnitude of the pharmacokinetic interaction. 1 Key monitoring parameters include:

• Cardiovascular effects: Both drugs can elevate blood pressure and heart rate; combined use may produce additive effects. 5, 3
• Seizure risk: Bupropion lowers the seizure threshold (risk ~0.1% at 300 mg/day), and elevated atomoxetine levels may further increase this risk. 5, 3
• Neuropsychiatric symptoms: Agitation, irritability, mood swings, and behavioral changes should be monitored closely, particularly in patients <24 years old. 5, 3

If this combination is necessary, atomoxetine doses should be reduced to account for the 5-fold increase in exposure, and patients should be monitored for signs of toxicity (tachycardia, hypertension, tremor, agitation, gastrointestinal distress). 1

Recommended Management

Discontinue or taper bupropion immediately if the interaction is suspected, as it is the most modifiable contributor to the acute presentation. 1 Atomoxetine levels will normalize over 10–14 days after bupropion cessation, depending on the patient's intrinsic CYP2D6 activity. 1

Avoid reintroducing bupropion unless atomoxetine is discontinued or the dose is reduced by at least 50% to compensate for the interaction. 1

Testosterone, DHEA, B-complex vitamins, and anastrozole can be continued without concern for contributing to the acute symptoms, as they lack plausible mechanisms for the observed effects.