Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery

Abstract

BACKGROUND: Stroke is the major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression. Recently, small trials have demonstrated that SSRIs might improve recovery after stroke, even in people who are not depressed. Systematic reviews and meta-analyses are the least biased way to bring together data from several trials. Given the promising effect of SSRIs on stroke recovery seen in small trials, a systematic review and meta-analysis is needed. OBJECTIVE: To determine whether SSRIs improve recovery after stroke, and whether treatment with SSRIs was associated with adverse effects. To identify further published, unpublished and ongoing trials we searched trials registers, pharmaceutical websites, reference lists, contacted experts and performed citation tracking of included studies. Selection criteria: We included randomized controlled trials that recruited stroke survivors (ischaemic or haemorrhagic) at any time within the first year. The intervention was any SSRI, given at any dose, for any period. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. In order to be included, trials had to collect data on at least one of our primary (dependence and disability) or secondary (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early) outcomes. Data collection and analysis: We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. For trials in English, two review authors independently extracted data. For Chinese papers, one review author extracted data. We used standardized mean differences (SMD) to estimate treatment effects for continuous variables, and risk ratios (RR) for dichotomous effects, with their 95% confidence intervals (CIs). MAIN RESULTS: We identified 56 completed trials of SSRI versus control, of which 52 trials (4059 participants) provided data for meta-analysis. There were statistically significant benefits of SSRI on both of the primary outcomes: RR for reducing dependency at the end of treatment was 0.81 (95% CI 0.68 to 0.97) based on one trial, and for disability score, the SMD was 0.91 (95% CI 0.60 to 1.22) (22 trials involving 1343 participants) with high heterogeneity between trials (I2 = 87%; P < 0.0001). For neurological deficit, depression and anxiety, there were statistically significant benefits of SSRIs. For neurological deficit score, the SMD was -1.00 (95% CI -1.26 to -0.75) (29 trials involving 2011 participants) with high heterogeneity between trials (I2 = 86%; P < 0.00001). For dichotomous depression scores, the RR was 0.43 (95% CI 0.24 to 0.77) (eight trials involving 771 participants) with high heterogeneity between trials (I2 = 77%; P < 0.0001). For continuous depression scores, the SMD was -1.91 (95% CI -2.34 to -1.48) (39 trials involving 2728 participants) with high heterogeneity between trials (I2 = 95%; P < 0.00001). ...

Explanatory factors for the increased mortality of stroke patients with depression

“…There are 2 systematic reviews reporting an association between SSRIs and a reduced mortality of patients with acute cardiovascular events, 27 and a limited but significant improvement in dependence, disability, and neurologic impairment in the first few years after stroke. 28 Most studies included in these reviews had short follow-up; therefore, the long-term negative effects of SSRIs may not have been observed. A large cohort study observing more than 60,000 primary care patients in the United Kingdom reported that SSRIs were associated with increased risk of falls, strokes, ischemic heart disease, self-harm, fractures, and all-cause mortality.…”

“…The association between depression and mortality is not explained by other individual medical factors. Neurology ® 2014;83:2007-2012 GLOSSARY CI 5 confidence interval; GCS 5 Glasgow Coma Scale score; HADS 5 Hospital Anxiety and Depression Scale; HR 5 hazard ratio; SLSR 5 South London Stroke Register; SSRI 5 selective serotonin reuptake inhibitor.…”

“…The association between depression and mortality is not explained by other individual medical factors. Neurology ® 2014;83:2007-2012 GLOSSARY CI 5 confidence interval; GCS 5 Glasgow Coma Scale score; HADS 5 Hospital Anxiety and Depression Scale; HR 5 hazard ratio; SLSR 5 South London Stroke Register; SSRI 5 selective serotonin reuptake inhibitor.Depression has a prevalence of around 30% in the long term after stroke, with most patients developing their first symptoms shortly after the acute event.1,2 Depression after stroke is more prevalent among those with severe strokes, disability, and cognitive impairment, and has been found to be independently associated with higher mortality.3,4 A number of medical and social factors have been proposed to underlie the relationship between depression and mortality. They include younger age, lifestyle factors such as smoking and heavy alcohol use, lack of compliance with medication, comorbidities such as diabetes and heart failure, use of antidepressants, and social isolation.…”

Immuno-Thrombotic Effects of Platelet Serotonin

“…SSRI treatment of stroke patients has been described to enhance brain function recovery, indicating a therapeutic benefit of the direct blockade of 5-HTT function. Neuroblast proliferation and cell migration have been shown to be enhanced and associated with increased microvessel density during SSRI treatment, explaining the possible role of 5-HTT in tissue repair after ischemic insults [81][82][83]. 5Htt −/− mice have been studied in the tMCAO (transient intraluminal filament model of middle cerebral artery occlusion) model of ischemic stroke.…”

Effect of Fluoxetine on Motor Recovery after Acute Haemorrhagic Stroke: A Randomized Trial

“…Chollet et al showed that fluoxetine significantly improved motor score in stroke patients at 3 months [13]. A recent Cochrane database review concluded that there were statistically significant benefits of SSRI's in reducing dependency and disability after stroke [14].…”