Background and aims Observational studies have suggested increased risk of intracranial haemorrhage (ICrH) in patients receiving selective serotonin reuptake inhibitors (SSRI). We sought to clarify the impact of SSRI on ICrH, accounting for study methodology.

Method A comprehensive search of Medline, Embase and Cochrane from 1960 to December 2017 comparing SSRI with control. ICrH was meta-analysed using a random-effects model and the review was prospectively registered (PROSPERO:CRD42017084513).

Results 25 observational studies, but no randomised trials, were available for meta-analysis, with a combined total of 4,843,857 patient-years follow-up. Those treated with SSRI were more likely to have depression (p<0.001) and be female (p=0.04). Compared to control, SSRI were significantly associated with first-ever ICrH (RR: 1.31; 95% CI: 1.15 to 1.49); however, in survivors of ICrH there was no association between SSRI and recurrence (0.95, 0.83–1.09). Sensitivity analyses revealed a greater association between SSRI and ICrH in studies with a high risk of bias (p<0.001) than those with a lower risk of bias (p=0.10).

Conclusion SSRI are associated with increased risk of first-ever ICrH, but not with recurrence. These findings, based solely on observational data, should be taken with caution due to fundamental differences in patients receiving treatment, highlighting the need for randomised trials.