Can re‑initiating bupropion and atomoxetine (along with testosterone, DHEA, B‑complex vitamins, and anastrozole) after a month off still cause acute euphoria, vomiting, and mydriasis despite prior tolerance?

Can Restarting Bupropion and Atomoxetine After a Month Off Cause Acute Symptoms?

Yes, restarting bupropion and atomoxetine after a month-long gap can absolutely cause acute symptoms—including euphoria, vomiting, and mydriasis—even in a patient who previously tolerated these medications without problems. Loss of tolerance, drug–drug interactions, and the pharmacokinetic effects of concurrent medications all contribute to this risk.

Loss of Tolerance After Discontinuation

• A one-month washout period is sufficient to reset drug tolerance. When bupropion and atomoxetine are stopped for 4 weeks, hepatic enzyme activity returns to baseline, plasma protein binding normalizes, and receptor sensitivity is restored. 1
• Restarting at the previous maintenance dose bypasses the gradual titration that originally allowed tolerance to develop. Bupropion should be initiated at 37.5–150 mg once daily and increased by 37.5 mg every 3 days; atomoxetine requires similar slow escalation. 1, 2
• Abrupt reinitiation at full therapeutic doses (e.g., bupropion 300 mg/day, atomoxetine standard dosing) exposes the patient to peak plasma concentrations without the protective adaptation that occurs during titration. 1, 3, 2

Critical Drug–Drug Interaction: Bupropion Inhibits Atomoxetine Metabolism

• Bupropion is a potent inhibitor of CYP2D6, the enzyme responsible for metabolizing atomoxetine. When both drugs are restarted simultaneously, bupropion blocks atomoxetine clearance, causing a 5.1-fold increase in atomoxetine plasma exposure (AUC₀₋∞ rising from 1,580 to 8,060 ng·h/mL) and a 1.7-fold increase in peak concentration (Cmax rising from 226 to 386 ng/mL). 4
• This interaction converts even extensive metabolizers into functional poor metabolizers. Poor metabolizers of atomoxetine experience significantly higher rates of adverse effects, including nausea (10% vs. 5%), vomiting (11% vs. 6%), somnolence (11% vs. 4%), and mydriasis (2% vs. 1%). 2, 4
• The half-life of atomoxetine is prolonged when bupropion is present, extending the duration of adverse effects and increasing the risk of toxicity. 4

Symptom Profile Consistent With Atomoxetine Toxicity

• Vomiting is the most common gastrointestinal adverse effect of atomoxetine, occurring in 11% of pediatric patients and 6% of placebo recipients in controlled trials. When atomoxetine levels are elevated by CYP2D6 inhibition, vomiting rates increase further. 2
• Mydriasis (pupil dilation) is a recognized adverse effect of atomoxetine, occurring in 2% of poor metabolizers versus 1% of extensive metabolizers. Elevated atomoxetine concentrations from bupropion co-administration would amplify this effect. 2
• Euphoria or mood elevation can occur with noradrenergic agents like atomoxetine, particularly when plasma levels exceed the therapeutic range. The 5-fold increase in atomoxetine exposure caused by bupropion creates conditions for this reaction. 4

Bupropion's Direct Contribution to the Clinical Picture

• Bupropion itself causes nausea in 10% of patients at 300 mg/day and vomiting in 4%. When restarted without titration, these rates are higher. 3
• Bupropion can cause agitation, anxiety, and CNS stimulation, which may be perceived as euphoria, especially in the first days of treatment. These effects occur in 3–9% of patients at therapeutic doses. 3
• Bupropion elevates blood pressure and heart rate, which can contribute to autonomic symptoms. 3

Why Prior Tolerance Does Not Protect Against Reinitiation Reactions

• Tolerance to adverse effects develops over weeks through receptor downregulation, enzyme induction, and neuroadaptation. A 4-week washout reverses these changes. 1, 5
• The patient's previous stable regimen likely involved gradual dose escalation, allowing time for metabolic adaptation. Restarting at full doses bypasses this protective mechanism. 1
• Concurrent medications (testosterone, DHEA, anastrozole) may alter hepatic enzyme activity or protein binding, further modifying drug clearance and increasing the risk of adverse effects. 1

Critical Safety Pitfall: Misinterpreting Symptoms as Serotonin Syndrome

• The triad of euphoria, vomiting, and mydriasis can mimic serotonin syndrome, but bupropion has minimal serotonergic activity and atomoxetine is purely noradrenergic. 6, 7
• True serotonin syndrome requires a serotonergic agent (e.g., SSRI, SNRI, tramadol, MAOI). This patient's regimen does not include such agents. 6, 7
• However, if bupropion were combined with an SSRI (e.g., sertraline, escitalopram), serotonin syndrome becomes a real risk. One case report documented serotonin syndrome from bupropion plus sertraline, attributed to bupropion's CYP2D6 inhibition raising SSRI levels. 7

Recommended Management Strategy

• Immediately discontinue both bupropion and atomoxetine until symptoms resolve (typically 24–48 hours for atomoxetine, given its prolonged half-life in the presence of CYP2D6 inhibition). 2, 4
• Restart bupropion alone first, using the proper titration schedule: 37.5–150 mg once daily for 3 days, then increase by 37.5 mg every 3 days as tolerated, with a target of 150 mg twice daily (maximum 300 mg/day). 1
• Wait 7–10 days after reaching stable bupropion dosing before reintroducing atomoxetine, to allow steady-state CYP2D6 inhibition to establish. 4
• Initiate atomoxetine at 25–40 mg once daily (lower than standard starting doses) and increase slowly over 2–3 weeks, monitoring closely for nausea, vomiting, and mydriasis. 2, 4
• Consider checking blood pressure and heart rate at each visit, as both drugs can cause cardiovascular effects. 3, 2

Alternative Explanation: Testosterone and DHEA Effects

• Testosterone and DHEA can increase dopaminergic and noradrenergic tone, potentially synergizing with bupropion and atomoxetine to produce euphoria and agitation. 8
• Anastrozole (an aromatase inhibitor) prevents testosterone conversion to estrogen, which may amplify androgenic effects and contribute to mood changes. 8
• However, these hormonal agents do not typically cause vomiting or mydriasis, making the bupropion–atomoxetine interaction the more likely culprit. 8

Key Takeaway

The combination of abrupt reinitiation at full doses plus the profound CYP2D6 inhibition by bupropion creates a high-risk scenario for atomoxetine toxicity. Prior tolerance is irrelevant after a 4-week washout. The correct approach is sequential reintroduction with proper titration, starting with bupropion alone and adding atomoxetine only after steady-state enzyme inhibition is established. 1, 4