1. Concomitant antidepressant and benzodiazepine therapy was associated with an increased risk of all-cause mortality over antidepressant monotherapy in patients with depression.
Evidence Rating Level: 2 (Good)
As antidepressants (ADs) may take several weeks to show therapeutic effect, benzodiazepines (BZDs) are often prescribed concomitantly to manage anxiety or insomnia in patients with depression starting on these medications. However, patients often continue taking benzodiazepines beyond this initial period, with one study finding approximately 12% of patients who received AD+BZD concomitantly, continuing BZDs long-term. There is limited real world data on the efficacy and safety outcomes associated with long-term concomitant BZD+AD use. This population-based cohort study classified 612 729 patients with incident depression, who filled prescriptions from 2002 to 2017 within 6 months of diagnosis according to South Korea’s nationwide healthcare database, into two groups: patients who were taking AD+BZD therapy and those on AD monotherapy. These groups were matched in a 1:1 ratio to balance baseline characteristics; however, while subgroup analyses were performed based on age and sex, their model did not include the history of other anxiolytic use as a confounding variable. Compared to AD monotherapy, AD+BZD therapy was associated with an increased risk of all-cause mortality (adjusted HR 1.04, 95% CI 1.02-1.06) and all-cause hospitalization (adjusted HR 1.05, 95% CI 1.04-1.06). This effect was increased among males (adjusted HR 1.11, 95% CI 1.08-1.15) and those younger than 65 years old (adjusted HR 1.33, 95% CI 1.29-1.38), while the opposite effect, a reduction in all-cause mortality, was seen in females and patients over 65 years old. This increased risk of mortality was also similar between patients who discontinued BZDs and those who continued BZDs. Finally, a 74% increased risk of suicide attempts and self-harm were seen in the AD+BZD group. These results suggest that prescribers should weigh the risks against the benefits when prescribing concomitant AD+BZD therapy for depression. Further studies would be needed to fully describe how age, gender, or other underlying factors responsible, may impact this associated risk with all-cause mortality.
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