Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery

Background
Stroke is a major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage
depression and other mood disorders aJer stroke. The 2012 Cochrane Review of SSRIs for stroke recovery demonstrated positive eFects on
recovery, even in people who were not depressed at randomisation. A large trial of fluoxetine for stroke recovery (fluoxetine versus placebo
under supervision) has recently been published, and it is now appropriate to update the evidence.
Objectives
To determine if SSRIs are more eFective than placebo or usual care at improving outcomes in people less than 12 months post-stroke, and
to determine whether treatment with SSRIs is associated with adverse eFects.
Search methods
For this update, we searched the Cochrane Stroke Group Trials Register (last searched 16 July 2018), the Cochrane Controlled Trials Register
(CENTRAL, Issue 7 of 12, July 2018), MEDLINE (1946 to July 2018), Embase (1974 to July 2018), CINAHL (1982 July 2018), PsycINFO (1985 to
July 2018), AMED (1985 to July 2018), and PsycBITE March 2012 to July 2018). We also searched grey literature and clinical trials registers.
Selection criteria
We included randomised controlled trials (RCTs) that recruited ischaemic or haemorrhagic stroke survivors at any time within the first year.
The intervention was any SSRI, given at any dose, for any period, and for any indication. We excluded drugs with mixed pharmacological
eFects. The comparator was usual care or placebo. To be included, trials had to collect data on at least one of our primary (disability score
or independence) or secondaryData collection and analysis
We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. Two
review authors independently extracted data from each trial. We used standardised mean diFerences (SMDs) to estimate treatment eFects
for continuous variables, and risk ratios (RRs) for dichotomous eFects, with their 95% confidence intervals (CIs). We assessed risks of bias
and applied GRADE criteria.
Main results
We identified a total of 63 eligible trials recruiting 9168 participants, most of which provided data only at end of treatment and not at followup.
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 eFect 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; moderatequality
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 eFects 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 diFerence. 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.
Authors' conclusions
We found no reliable evidence that SSRIs should be used routinely to promote recovery aJer 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.