Objective: To investigate whether depression and/or antidepressants can be a potential risk factor for the development of dementia and mild cognitive impairment (MCI).

Design: Systematic review and meta-analysis of longitudinal studies.

Setting and participants: Community or clinical settings. Participants included patients with depression, antidepressant users, and the general population.

Measures: Longitudinal studies evaluating the risks of dementia or MCI in patients with depression and/or antidepressant users were identified from the OVID database. The outcomes were the number of patients who developed dementia or MCI among the antidepressant users and nonusers. Relative risk (RR) with 95% confidence interval (95% CI) was used to evaluate the association between the use of antidepressants and the risk of dementia and MCI. Meta-analysis was used for combining the effect sizes of individual studies, and the heterogeneity test was performed. Risk of bias and reporting quality of included studies was assessed. Subgroup analyses were conducted for different types of antidepressants.

Results: A total of 18 studies with 2,119,627 participants with mean age ranging from 55 to 81 years were included. Among patients with depression, antidepressant users showed a significantly higher risk of dementia (RR = 1.37, 95% CI = 1.11-1.70) and MCI (RR = 1.20, 95% CI = 1.02-1.42) than the nonusers. Besides, patients with depression who used antidepressants and who did not use antidepressants also showed significantly higher risk of dementia than the general population (RR = 1.50, 95% CI = 1.26-1.78, and RR = 1.31, 95% CI = 1.15-1.51, respectively).

Conclusions/implications: Patients with depression are associated with a higher risk of dementia, and the use of antidepressants is not shown to be a protective factor of dementia. Further large-scale trials are required for investigation of the benefit-risk ratio between depression relapse and dementia when prescribing antidepressants.