In vitro evidence suggests that some serotonin-specific reuptake inhibitors (SSRIs) inhibit P-glycoprotein, a multidrug efflux pump responsible for the elimination of several drugs including digoxin.  This study sought to determine if some SSRIs cause digoxin toxicity in the clinical setting and looked at population-based nested case-control study set in Ontario from 1994 to 2001.  Researchers studied all patients 66 years or older treated with digoxin.  Prescription and hospital admission records were analysed to determine the relationship between the initiation of SSRI therapy and hospital admission for digoxin toxicity in the subsequent 30 days.

Among 245,305 older patients treated with digoxin, the researchers identified 3,144 cases of digoxin toxicity.  After adjusting for potential confounders, an increased risk of digoxin toxicity following initiation of paroxetine [odds ratio (OR) 2.8; 95% confidence interval (CI) 1.6, 4.7], fluoxetine (OR 2.9; 95% CI 1.5, 5.4), sertraline (OR 3.0; 95% CI 1.9, 4.7), and fluvoxamine (OR 3.0; 95% CI 1.5, 5.7) was observed.  However, an elevated risk was also seen with tricyclic antidepressants (OR 1.5; 95% CI 1.0, 2.4) and benzodiazepines (OR 2.1; 95% CI 1.7, 2.5), drug classes having no known pharmacokinetic interaction with digoxin.  There was no statistical difference in the risk of digoxin toxicity among any of the agents tested.