Meta-analysis favours citalopram in poststroke recovery

Selective serotonin reuptake inhibitors (SSRIs) can prevent and treat depression following stroke, in addition to improving anxiety, dependence, motor function, and cognitive function—benefits that are only reproducible with citalopram but not fluoxetine, according to a meta-analysis said to be the most up to date.

Pooled data from 44 randomized controlled trials revealed that compared with placebo, SSRIs had a significant effect on the Hamilton Rating Scale for Depression score, both in prevention (weighted mean difference [WMD], −7.05, 95 percent confidence interval [CI], −11.78 to −2.31]) and treatment (WMD, −1.45, 95 percent CI, −2.77 to −0.14). [J Am Heart Assoc 2022;doi:10.1161/JAHA.122.025868]

SSRIs also conferred superior beneficial effects on the Hamilton Anxiety Scale score (relative risk, 0.23, 95 percent CI, 0.09–0.61), the Barthel Index score (WMD, 8.86, 95 percent CI, 1.23–16.48), the National Institutes of Health Stroke Scale score (WMD, −0.79, 95 percent CI, −1.42 to −0.15), and the Montreal Cognitive Assessment and the Mini‐Mental State Examination (WMD, 1.00, 95 percent CI, 0.12–1.89).

Meanwhile, poststroke disability, assessed using modified Rankin Scale scores, did not significantly improve with SSRIs vs placebo.

“We conducted a subanalysis to investigate the effect of different SSRI agents on poststroke recovery. Similar to the primary analysis, the … results showed that citalopram was significantly associated with [improvements in] the poststroke recovery of depression, cognitive function, and motor function. However, fluoxetine was only effective in treating poststroke depression,” the investigators noted.

“This indicates that the beneficial effects of SSRIs on poststroke recovery that we found in the primary analysis were driven by citalopram not fluoxetine… These differences in the efficacy between fluoxetine and citalopram can be explained by the fact that fluoxetine has an extremely long half‐life compared with citalopram; hence, a much longer duration is required with fluoxetine to reach a steady state concentration and exert its action,” they added. [Lancet 2018;391:1357-1366; Handb Exp Pharmacol 2019;250:135-144]

Heightened seizure risk

In terms of safety, treatment with SSRIs increased the risk of seizures (relative risk, 1.44, 95 percent CI, 1.13–1.83), whereas there was no difference in the incidence of gastrointestinal symptoms or bleeding between SSRIs and a placebo.

This heightened seizure risk with SSRIs, according to the investigators, can be confounded by many variables including the low sodium and serotonin levels, which were both described in patients after stroke and can induce seizures. [Clin Invest Med 2008;31:E351-356; Geriatr Psychol Neuropsychiatr Vieil 2019;17:13-19; Cephalalgia 2011;31:1580-1586]

“It is important to mention that none of the included studies accounted for the serotonin or sodium level among their patients before starting the intervention. Furthermore, several observational studies and open‐label trials showed that SSRIs were not associated with seizures, and in contrast, they were associated with reduction in seizure frequency and duration among patients with epilepsy,” they pointed out. [Epilepsy Behav 2017;70:5-9]

The current meta-analysis, the investigators claimed, is the most updated of its kind, having been conducted after the implementation of the international collaboration core guidelines in conducting trials for the effect of SSRIs on poststroke recovery. “In addition, this is the first review to show that citalopram could improve poststroke recovery,” which requires further placebo‐controlled trials.

Nevertheless, the investigators acknowledged the presence of several limitations, such as the inclusion of trials published in the English language only, which might limit generalizability. Also, many of the included studies had low to moderate quality, and they used different scales to measure the same outcome.