Key result
In a real-world cohort, long-term citalopram exposure had better acceptability than fluoxetine (aOR 0.78; 99% CI 0.76-0.81) and effectiveness, but worse tolerability and safety.
Why the study?
Antidepressants' effects are established in randomized controlled trials, but their comparative effects have not been established in the real world.
Do various licensed antidepressants improve acceptability, tolerability, safety, and effectiveness compared to fluoxetine in adults with depressive disorder?
Cohort (n=673,177)
Do various licensed antidepressants improve acceptability, tolerability, safety, and effectiveness compared to fluoxetine in adults with depressive disorder?
Odds Ratio: 0.78 (95% CI 0.76–0.81)
In a real-world primary care setting, antidepressants demonstrated low acceptability and small-to-moderate effectiveness, highlighting a potential efficacy-effectiveness gap compared to RCTs.
Real-world antidepressant acceptability remains low; leaves open whether large observational datasets reliably extend RCT findings beyond common agents.
BACKGROUND: Antidepressants' effects are established in randomised controlled trials (RCTs), but not in the real world. AIMS: To investigate real-world comparative effects of antidepressants for depression and compare them with RCTs. METHOD: We performed a cohort study based on the QResearch database. We included people with a newly recorded diagnosis of depression, exposed to licensed antidepressants in the UK. We assessed all-cause dropouts (acceptability), dropouts for adverse events (tolerability), occurrence of at least one adverse event (safety), and response and remission on the Patient Health Questionnaire (PHQ)-9 (effectiveness) at 2 and 12 months. Logistic regressions were used to compute adjusted-odds ratio (aOR) with 99% CIs, assessing the associations between exposure to each antidepressant against fluoxetine (comparator) and outcomes of interest. We compared estimates from the real world with RCTs using ratio-of-odds ratio (ROR) with 95% CI. RESULTS: A total of 673 177 depressed people were studied: females 57.1%, mean age 42.8 (s.d. 17.7) years, mean baseline PHQ-9 17.1 (s.d. 5.0) (moderately severe depression). At 2 months, antidepressant acceptability was 61.4%, tolerability 94.4%, safety 54.5%, PHQ-9 decreased to 12.3 (s.d. 6.5). At 12 months, acceptability was 12.3%, tolerability 87.5%, safety 28.8%, PHQ-9 12.9 (s.d. 6.8). In the short and long term, tricyclics, mirtazapine and trazodone were worse than fluoxetine for most outcomes; citalopram had better acceptability than fluoxetine (aOR 0.95; 99% CI 0.92, 0.97), sertraline had lower tolerability (aOR 1.12; 99% CI 1.06, 1.18), and both citalopram and sertraline had lower safety (aOR 1.17 and 1.25, respectively). In the long term, citalopram had better acceptability (aOR 0.78; 99% CI 0.76, 0.81) and effectiveness (aOR 1.12 for both response and remission), but worse tolerability (aOR 1.09; 99% CI 1.06, 1.13) and safety (aOR 1.12; 99% CI 1.08, 1.16). Observational and randomised data were similar for citalopram and sertraline, while there was some difference for drugs less prescribed in the real world. CONCLUSIONS: Antidepressants showed low acceptability, moderate-to-high tolerability and safety, and small-to-moderate effectiveness in the real world. Real-world and RCT estimates showed similar findings only when the analyses were carried out using large datasets; otherwise, the results diverged.
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Crescenzo et al. (2024) conducted a cohort in depressive disorder (n=673,177). Antidepressants (e.g., citalopram, sertraline, tricyclics, mirtazapine, trazodone) vs. fluoxetine was evaluated on acceptability (all-cause dropouts) at 12 months (aOR 0.78, 95% CI 0.76-0.81). In a real-world cohort, long-term citalopram exposure had better acceptability than fluoxetine (aOR 0.78; 99% CI 0.76-0.81) and effectiveness, but worse tolerability and safety.
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