Supplementary Material for: Use of Antidepressants and Risk of Incident Stroke: A Systematic Review and Meta-Analysis

Background: Both depression and use of antidepressants have been reported to be risk factors for stroke, but results from the literature are still not conclusive regarding the risk attributable to antidepressants rather than to the underlying disease. Objective: To estimate the risk of incident stroke associated with use of antidepressants, a meta-analysis was performed. Methods: PubMed, Medline, Cochrane, ProQuest, Scopus, and bibliographies of articles were searched up to September 2018. The final meta-analysis included 31 observational studies. STROBE statement-checklist and GRADE guidelines were used for quality assessment. Results: The random-effects meta-analysis on the association between use of any antidepressant and risk of any stroke resulted in meta-risk ratio (RR) of 1.41 (95% CI 1.13–1.69, I² = 93, 7%). The pooled estimate for selective serotonin reuptake inhibitors (SSRIs) resulted in a meta-RR of 1.41 (95% CI 1.13–1.69, I² = 94, 5%) and for tricyclic antidepressants (TCAs) of 1.08 (95% CI 0.93–1.22, I² = 0%). SSRI users displayed a higher risk of ischemic (1.57, 95% CI 1.06–2.09, I² = 96.4%) than hemorrhagic stroke (1.34, 95% CI 1.15–1.53, I² = 72.9%). Meta-RRs were lower for TCA, although with smaller heterogeneity (ischemic 1.22, 95% CI 0.97–1.46; I² = 0%; hemorrhagic: 1.00, 95% CI 0.83–1.18, I² = 0%). Restricting to studies on depressed individuals, both SSRI and TCA remained associated with an increased risk of any stroke type (meta-RR for SSRI: 1.27, 95% CI 1.11–1.43, I² = 76.6%; meta-RR for TCA: 1.21 (95% CI 1.02–1.40, I² = 47, 3%). Conclusions: Despite the high heterogeneity, these results demonstrate that even after adjusting for depression, use of antidepressants retains an independent increased risk of stroke.