Abstract: We identified a total of 63 eligible trials recruiting 9168 participants, most of which provided data only at end of treatment and not at follow-up. There was a wide age range. About half the trials required participants to have depression to enter the trial. The duration, drug, and dose varied between trials. Only three of the included trials were at low risk of bias across the key 'Risk of bias' domains. A meta-analysis of these three trials found little or no effect of SSRI on either disability score: SMD −0.01 (95% CI −0.09 to 0.06; P = 0.75; 2 studies, 2829 participants; moderate-quality evidence) or independence: RR 1.00 (95% CI 0.91 to 1.09; P = 0.99; 3 studies, 3249 participants; moderate-quality evidence). We downgraded both these outcomes for imprecision. SSRIs reduced the average depression score (SMD 0.11 lower, 0.19 lower to 0.04 lower; 2 trials, 2861 participants; moderate-quality evidence), but there was a higher observed number of gastrointestinal side effects among participants treated with SSRIs compared to placebo (RR 2.19, 95% CI 1.00 to 4.76; P = 0.05; 2 studies, 148 participants; moderate-quality evidence), with no evidence of heterogeneity (I2 = 0%). For seizures there was no evidence of a substantial difference. When we included all trials in a sensitivity analysis, irrespective of risk of bias, SSRIs appeared to reduce disability scores but not dependence. One large trial (FOCUS) dominated the results. We identified several ongoing trials, including two large trials that together will recruit more than 3000 participants. We found no reliable evidence that SSRIs should be used routinely to promote recovery after stroke. Meta-analysis of the trials at low risk of bias indicate that SSRIs do not improve recovery from stroke. We identified potential improvements in disability only in the analyses which included trials at high risk of bias. A further meta-analysis of large ongoing trials will be required to determine the generalisability of these findings.

Plain-language summary: In total we found 63 trials recruiting 9168 stroke survivors within one year of their stroke. There was a wide age range. About half the trials required participants to have depression to enter the trial. The duration, drug, and dose varied between trials. However, only three of these trials were at low risk of bias; the participants in these trials did not have to be depressed to enter the trial, and they were all recruited soon after the stroke. When we combined data from these three studies at low risk of bias, which recruited 3249 participants, SSRIs did not affect disability score or dependency. SSRIs reduced the risk of future depression but increased the risk of problems with the digestive system. There was no evidence of a substantial difference in seizures. When we combined data from all the studies, irrespective of risks of bias, there appeared to be a beneficial effect on recovery, but this was almost certainly because the studies at high risk of bias tended to give the positive results. The evidence is current until July 2018. We are confident that the results are reliable when we included just the studies at low risk of bias. When we included all studies regardless of risk of bias we found that SSRIs reduced disability. When they become available, we will include the results from two large ongoing trials in a future update.