The influence of selective serotonin reuptake inhibitors on stroke outcome: a systematic review and meta-analysis.

Objective: Selective serotonin reuptake inhibitors (SSRIs) are recognized for their antidepressant effects and their potential role in promoting neuroplasticity. This systematic review and meta-analysis aimed to evaluate whether SSRIs improve prognostic outcomes in patients with stroke compared with placebo or no intervention. Methods: We systematically searched the Cochrane Library, PubMed, and Embase databases to identify randomized controlled trials comparing SSRIs with placebo or no intervention in patients with stroke. Continuous outcomes were pooled using weighted mean differences (WMDs), and dichotomous outcomes were pooled using risk ratios (RRs), both with 95% confidence intervals (CIs). Fixed-effect or random-effects models were selected according to the degree of statistical heterogeneity for each outcome. Results: Eleven reports from nine unique randomized controlled trials, involving 7,604 unique participants, were included. In exploratory analyses stratified by follow-up duration, SSRI use at 3 months was associated with better modified Rankin Scale (mRS) responder status and a greater absolute reduction in National Institutes of Health Stroke Scale score (absNIHSS) (RR 2.46, 95% CI 1.74-3.48; WMD 0.57, 95% CI 0.11-1.03). However, the 3-month mRS finding was derived from a single trial and should therefore be interpreted with particular caution. At 6 months, SSRI use was associated with a smaller absolute reduction in NIHSS score (WMD -0.23, 95% CI-0.45 to -0.02), but this finding should also be interpreted cautiously because the absNIHSS analysis showed substantial heterogeneity. At 12 months, SSRI use was associated with a lower risk of recurrent stroke (RR 0.65, 95% CI 0.47-0.89), particularly recurrent ischemic stroke (RR 0.57, 95% CI 0.40-0.80). These findings suggest that the observed associations between SSRI use and stroke outcomes varied across follow-up-duration subgroups. However, these subgroup patterns should be interpreted cautiously because they may reflect differences in study populations, follow-up designs, attrition, rehabilitation strategies, and trial weighting rather than a confirmed biological time-dependent effect. No statistically significant differences were observed in thrombotic events, bleeding events, mortality, cardiac adverse events, or drug-specific subgroup analyses. Conclusion: SSRI use after stroke may be associated with selected exploratory short-term functional signals and a lower long-term risk of recurrent stroke, particularly recurrent ischemic stroke. However, the apparent short-term mRS benefit was driven by a single trial and should not be interpreted as a robust or generalizable clinical effect. The mid-term absNIHSS findings did not support a sustained functional benefit and were accompanied by substantial heterogeneity. Therefore, the functional outcome findings should be interpreted as exploratory rather than definitive. The observed associations should be interpreted cautiously because they were derived from exploratory follow-up-duration-stratified analyses and represent subgroup-level associations rather than evidence of a causal temporal or biological effect of SSRIs. Further well-designed randomized controlled trials are needed to clarify the optimal timing, duration, and safety of SSRI therapy after stroke.