Combining Antidepressants with β‐Blockers: Evidence of a Clinically Significant CYP2D6 Drug Interaction

Abstract

BACKGROUND The b-blockers and antidepressants are two of the most commonly prescribed drug classes in the United States. Several antidepressants are potent inhibitors of cytochrome P450 2D6 liver enzymes (CYP2D6) and can increase the plasma concentrations of certain b-blockers when administered concomitantly, potentially leading to serious medical consequences such as hypotension, bradycardia, and falls. OBJECTIVE The primary objective of this investigation was to determine whether initiating an antidepressant in patients receiving b-blockers increased the risk of hemodynamic adverse events. Our primary outcome was time to hospital admissions or emergency department (ED) visits for an International Classification of Diseases-9 diagnosis suggestive of excessive b-blockade. METHODS We conducted a survival analysis for adults continuously enrolled in the California Medicaid system (Medi-Cal) between 2004 and 2012. Eligible patients were required to be receiving b-blocker medications that are primarily CYP2D6 substrates (e.g., metoprolol, propranolol, or carvedilol). Univariate and multivariable analyses were performed for patients who concurrently received antidepressants with b-blockers. An additional multivariable analysis analyzed the association of this combination upon hospitalizations or ED visits for all causes. RESULTS A total of 21,292 beneficiaries met the inclusion criteria, and 4.3% of patients required hospitalization or ED visits within 30 days of co-medication. In multivariable analysis, patients receiving antidepressants with moderate to strong CYP2D6 inhibitory potential (fluoxetine, paroxetine, duloxetine, or bupropion) had a greater risk for hospitalization or ED visits for hemodynamic events than those initiated on antidepressants with weak CYP2D6 inhibition for 30 days or less when each was compared with patients receiving no antidepressants (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.03-2.81; p=0.04 vs HR 1.24; 95% CI 0.82-1.88; p=0.30). Other demographic variables associated with increased morbidity included advanced age, male sex, higher b-blocker doses, and African American race or Hispanic ethnicity. CONCLUSIONS Results of this analysis suggest that initiation of certain antidepressants was associated with an increased risk for serious medical sequelae among patients concurrently receiving b-blockers. Greater risk was observed with antidepressants that potently inhibit the CYP2D6 enzyme, implying that increased morbidity may be mediated by a metabolic drug interaction. KEY WORDS b-blockers, antidepressants, drug interactions, cytochrome P450 2D6, pharmacoepidemiology.

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“…Thus, of the serotonergic agents that inhibit CYP2D6 function, duloxetine has a statistically larger impact. In addition, patients receiving both β-blockers and fluoxetine, paroxetine, duloxetine, or bupropion are at significantly higher risk for emergency department visits and hospitalizations due to hemodynamic instability 7 …”

“…In addition, patients receiving both β-blockers and fluoxetine, paroxetine, duloxetine, or bupropion are at significantly higher risk for emergency department visits and hospitalizations due to hemodynamic instability. 7 Genetic polymorphisms in CYP2D6 can cause changes in pharmacokinetics and metabolism of CYP2D6 substrates, such as metabolism. Some patients are found to be "poor metabolizers," which is associated with greater reduction in heart rate as compared with individuals with active CYP2D6 phenotypes given similar doses of metoprolol.…”

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“…Fluoxetine, its active metabolite (norfluoxetine) and paroxetine are potent inhibitors of CYP2D6 isoenzyme and therefore can significantly increase the plasma concentrations and adverse effects of drugs that are predominantly metabolized by this isozyme [55,115]. For example, co-administration of fluoxetine/paroxetine and b-blockers (e.g., carvedilol, metoprolol, propranolol and timolol) that are metabolized by 2D6 isoenzyme can result in increased b-blocker exposure, which can lead to drug toxicity and events such as decreased heart rate (bradycardia), hypotension and falls, especially in older persons [116,117]. Moreover, there is evidence that fluoxetine can increase the plasma levels of the tricyclic antidepressants several fold even at the usual dosage of 20 mg/day [118].…”