Prevalence and impact of SARS-CoV-2 infection among patients with acute ischaemic stroke: a nationwide register-based cohort study in Denmark.

OBJECTIVES: An increased risk of stroke has been reported among patients with COVID-19 caused by SARS-CoV-2. We aimed to investigate the nationwide prevalence of SARS-CoV-2 among patients with acute ischaemic stroke and to study the impact on stroke severity, quality of care and mortality on an individual patient level. DESIGN: This was a nationwide register-based cohort study. SETTING: We used data from several Danish registers which were linked at an individual patient level using the unique civil registration number assigned to all Danish citizens. Patients were identified from the Danish Stroke Registry and information on SARS-CoV-2 infection status was collected from the Danish National COVID-19 Registry. Concurrent SARS-CoV-2 infection was defined as a positive PCR test within 31 days prior to, and 1 day after, stroke admission. Information on comorbidity was collected from the Danish National Patient Registry and information on vital status was collected from the Danish Civil Registration System. PARTICIPANTS: A total of 11 502 patients admitted with acute ischaemic stroke from 10 March 2020 to 31 May 2021 were included in the study. RESULTS: Among the included patients, the majority (84.6%) were tested for SARS-CoV-2, but only 68 had a positive test. These patients were more prone to have atrial fibrillation and were more often treated with reperfusion therapy. They had a significantly increased risk of severe stroke (adjusted relative risk (aRR) 1.93, 95% CI: 1.22 to 3.04) and a significantly increased 30-day mortality risk (aRR 2.29, 95% CI: 1.19 to 4.39). There was no difference in the proportion of patients fulfilling relevant performance measures on quality of care. CONCLUSION: In this nationwide study, only 0.6% of patients with acute ischaemic stroke were tested positive for a concurrent SARS-CoV-2 infection. The patients with SARS-CoV-2 presented with more severe strokes.

Effect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST Trial.

BACKGROUND: Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that has proved to be safe and feasible in numerous smaller clinical trials. Mixed results have been found in recent large randomized controlled trials. This is a post hoc subgroup analysis of the RESIST trial (Remote Ischemic Conditioning in Patients With Acute Stroke), investigating the effect of RIC in different acute ischemic stroke etiologies, and whether an effect was modified by treatment adherence. METHODS: Eligible patients were adults (aged ≥18 years), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 hours. They were randomized to RIC or sham. The RIC treatment protocol consisted of 5 cycles with 5 minutes of cuff inflation alternating with 5 minutes with a deflated cuff. Acceptable treatment adherence was defined as when at least 80% of planned RIC cycles were received. The analysis was performed using the entire range (shift analysis) of the modified Rankin Scale (ordinal logistic regression). RESULTS: A total of 698 had acute ischemic stroke, 253 (36%) were women, and the median (interquartile range) age was 73 (63-80) years. Median (interquartile range) overall adherence to RIC/sham was 91% (68%-100%). In patients with a stroke due to cerebral small vessel disease, who were adherent to treatment, RIC was associated with improved functional outcome, and the odds ratio for a shift to a lower score on the modified Rankin Scale was 2.54 (1.03-6.25); P=0.042. The association remained significant after adjusting for potential confounders. No significant associations were found with other stroke etiologies, and the overall test for interaction was not statistically significant (χ2, 4.33, P=0.23). CONCLUSIONS: In patients with acute ischemic stroke due to cerebral small vessel disease, who maintained good treatment adherence, RIC was associated with improved functional outcomes at 90 days. These results should only serve as a hypothesis-generating for future trials. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777.

Impact of prestroke physical activity and citalopram treatment on poststroke depressive symptoms: a secondary analysis of data from the TALOS randomised controlled trial in Denmark.

OBJECTIVES: To investigate the association between prestroke physical activity and depressive symptoms up to 6 months after stroke and examine if citalopram treatment modified the association. DESIGN: A secondary analysis of data from the multicentre randomised controlled trial The Efficacy of Citalopram Treatment in Acute Ischemic Stroke (TALOS). SETTING AND PARTICIPANTS: TALOS was conducted at multiple stroke centres in Denmark from 2013 to 2016. It enrolled 642 non-depressed patients with first-ever acute ischaemic stroke. Patients were eligible for this study if a prestroke physical activity level was assessed by the Physical Activity Scale for the Elderly (PASE). INTERVENTIONS: All patients were randomised to citalopram or placebo for 6 months. OUTCOMES: Depressive symptoms 1 and 6 months after stroke measured on the Major Depression Inventory (MDI) ranging from 0 to 50. RESULTS: A total of 625 patients were included. Median (IQR) age was 69 (60-77) years, 410 (65.6%) were men, 309 (49.4 %) received citalopram and median (IQR) prestroke PASE score was 132.5 (76-197). Higher prestroke PASE quartile, compared with the lowest PASE quartile, was associated with fewer depressive symptoms both after 1 month (mean difference third quartile -2.3 (-4.2, -0.5), p=0.013, mean difference fourth quartile -2.4 (-4.3, -0.5), p=0.015) and 6 months after stroke (mean difference third quartile -3.3 (-5.5, -1.2), p=0.002, mean difference fourth quartile -2.8 (-5.2, -0.3), p=0.027). There was no interaction between citalopram treatment and prestroke PASE score on poststroke MDI scores (p=0.86). CONCLUSIONS: A higher prestroke physical activity level was associated with fewer depressive symptoms 1 and 6 months after stroke. Citalopram treatment did not seem to modify this association. TRIAL REGISTRATION NUMBERS: NCT01937182 (ClinicalTrials.gov) and 2013-002253-30 (EUDRACT).

Safety considerations for prescribing SSRI antidepressants to patients at increased cardiovascular risk.

INTRODUCTION: With the development of selective serotonin reuptake inhibitors (SSRI), a relatively uncomplicated treatment of depression and a safer alternative to tricyclic antidepressants was introduced. Any medical treatment has potential safety risks, however, and these risks should also be considered when prescribing SSRIs. AREAS COVERED: The present review focuses on safety considerations when prescribing SSRIs to patients with previous stroke and myocardial infarction, as depression, and the need for antidepressant treatment, is common in these patients. At the same time, patients with stroke and myocardial infarction may be at increased risk of developing adverse events due to higher age, comorbidity, and co-medication. Specifically, the evidence of the risk of QT prolongation and bleeding versus thrombotic events will be discussed in the present review. EXPERT OPINION: No medical treatment comes without risk and SSRIs are no exception. Depression, a common complication after vascular events, is a potentially life-threatening condition in itself and relevant and sufficient treatment is imperative. SSRIs are often the first medical treatment choice in the ambulatory setting, also in patients at increased cardiovascular risk. Relevant comorbidity and co-medication, however, should always be taken into account when initiating treatment and when choosing a specific SSRI.

Pharmacological management of post-stroke depression: an update of the evidence and clinical guidance.

Introduction: Post-stroke depression (PSD) is common, serious and of considerable high risk of being chronic. Pharmacological treatment is highly recommended (class I recommendation) based on level B evidence. Still, treatment is often insufficient and the diagnosis can be challenging.Areas covered: The present paper is an update on pharmacological treatment of PSD and a review of recent clinical guidelines. To put this into perspective, the authors highlight the risk factors that might help clinicians identify patients with PSD, and discuss pharmacological prevention, functional outcome, and safety of antidepressant treatment in stroke patients.Expert opinion: Although there are still gaps in our knowledge of PSD, the seriousness should not be neglected, and pharmacological treatment should be recommended when relevant. A selective serotonin reuptake inhibitor (SSRI) is first choice, but is not always tolerated or effective. Close follow-up and dose adjustments as well as add-on possibilities are therefore important aspects of treatment as well. Antidepressant treatment prevents PSD but the effect on enhancement of stroke recovery is less clear.

Prestroke Physical Activity and Poststroke Cognitive Performance.

INTRODUCTION: Physical activity (PA) is associated with a lower risk of stroke and stroke mortality as well as a favorable stroke outcome. PA may also prevent general cognitive decline. Poststroke cognitive impairment is both common and disabling, and focusing on all possible preventive measures is important. Studies on the effect of PA on poststroke cognitive performance are sparse, however. We therefore aimed to examine the association between prestroke PA and poststroke cognitive performance. METHODS: We studied the correlation between prestroke PA and poststroke cognitive performance in a prespecified analysis in The Efficacy of Citalopram Treatment in Acute Ischemic Stroke (TALOS) trial. We used the Physical Activity Scale for the Elderly (PASE) to collect information on PA during the 7-day period before stroke. PA was quantified, and patients were stratified into quartiles based on their PASE score. Cognitive performance was measured using the Symbol Digit Modalities Test (SDMT) at 1 and 6 months and the Mini-Mental State Examination (MMSE) at 6 months. The functional outcome was assessed using the modified Rankin Scale (mRS). RESULTS: In total, 625 of 642 patients (97%) completed the PASE questionnaire. The median age was 69 (interquartile range [IQR]: 60-77), and the median PASE score was 137 (82-205). Higher prestroke PASE quartiles (2nd, 3rd, and 4th, each compared to the 1st) were independently associated with a higher SDMT score at 1 month in the both the univariable and multivariable analyses (2nd: 3.99 points, 95% confidence interval [CI]: 1.01-6.97; 3rd: 3.6, CI: 0.6-6.61; 4th: 4.1, CI: 0.95-7.24). This association remained at 6 months. PA was not statistically associated with the MMSE score or mRS. CONCLUSION: Higher prestroke PA was associated with a better cognitive performance as measured by the SDMT at 1 and 6 months poststroke. We found no significant association between prestroke PA and functional outcome. Our results are encouraging and support further investigations of PA as a protective measure against poststroke cognitive impairment.

Predictors for wellbeing and characteristics of mental health after stroke.

BACKGROUND: Poor mental health after stroke is common and complex. We aimed to identify predictors of poor wellbeing and to examine the overlap of poor wellbeing, fatigue, and depression. METHOD: Consecutive first-ever ischemic stroke-patients filled in questionnaires on wellbeing, fatigue, and depression at baseline and at one and six months. The World Health Organization 5-Item Wellbeing-Index (WHO-5), the Major Depression Inventory, and the Multidimensional Fatigue Inventory were used. Patients were genotyped according to serotonin-transporter gene polymorphisms. Multivariable logistic regression was used to identify potential predictors of poor wellbeing (WHO-5 score <50). Overlap between wellbeing, fatigue, and depression was examined using an Euler diagram. RESULTS: We included 919 patients. The prevalence of poor wellbeing was 279 (30.4%) six months after stroke. Living alone at stroke onset was the strongest predictor of poor wellbeing with a mutually adjusted odds ratio of 1.53 (95% confidence interval (CI): 1.03 to 2.28) at one month and 1.77 (CI: 1.13 to 2.76) at six months. Severe stroke at admission also predicted poor wellbeing at six months. Abnormal fatigue occurred in half and incorporated almost all patients with poor wellbeing. Less than 5% fulfilled the criteria for depression at any point and almost all of these patients had poor wellbeing and abnormal fatigue. Antidepressants were used by 292 (31.8%) during follow-up. LIMITATIONS: Cognitive impairment was not measured and could interact with wellbeing post-stroke. CONCLUSION: Living alone strongly predicted poor wellbeing after stroke. Satisfactory mental health-recovery seems to require psychosocial interventions when indicated in combination with antidepressant treatment.

Antiplatelet effects of citalopram in patients with ischaemic stroke: A randomized, placebo-controlled, double-blind study.

We evaluated the effect of SSRI treatment on platelet aggregation in patients with ischaemic stroke and included patients from the randomized double-blind controlled study of citalopram in acute ischaemic stroke (TALOS). Patients on clopidogrel were included 6 months after acute ischaemic stroke. Platelet parameters, including P2Y12 platelet reactivity using the VerifyNow System, were measured at the last day of study treatment and repeated after a 14-day wash-out period. A total of 60 patients were included (n = 32 randomized to citalopram). Platelet aggregation levels did not differ between the citalopram group (mean 116, 95% CI 89 to 143) and the placebo group (mean 136, 95% CI 109 to 163) (On-treatment, p = 0.14). Similarly, there was no significant change in platelet aggregation in the citalopram group from on-treatment to post-treatment (mean difference 2.0; 95% CI -18 to 14). Platelet count, size and turnover were not affected by SSRI treatment. In conclusion, SSRI therapy did not lead to statistically significant inhibition of platelet aggregation in ischaemic stroke patients treated with clopidogrel.

Serotonergic Regulation and Cognition after Stroke: The Role of Antidepressant Treatment and Genetic Variation.

INTRODUCTION: Serotonin affects several brain functions including cognition. The serotonin transporter (SERT) regulates brain serotonin levels through reuptake into neurons. The gene encoding this transporter, the SERT gene, has several functional polymorphisms affecting the number of transporters and thereby the serotonin levels. SERT gene expression may be important for cognition and selective serotonin reuptake inhibitors (SSRI) may improve cognition post stroke. We therefore examined the association between SERT genotypes, cognitive function and early treatment with the SSRI citalopram among non-depressed Caucasian stroke patients. PATIENTS AND METHODS: SERT gene polymorphisms in 270 non-depressed first-ever acute ischemic stroke patients randomized to citalopram, n = 130, or placebo, n = 140, were investigated. Patients were genotyped for a length polymorphism (L = long and S = short allele) and a single nucleotide polymorphism (A/G substitution) dividing the L-allele into LA and LG. According to these genotypes, patients were further grouped according to low (S/S, LG/S and LG/LG), medium (S/LA and LG/LA), or high functional gene expression (LALA). Cognition was measured by the Symbol Digit Modalities Test (SDMT) at 1 and 6 months. Mean SDMT scores according to genotype and randomization groups were compared using multiple logistic regression adjusting for age, stroke severity, premorbid functional status, and vascular risk factors including smoking, hypertension, and diabetes. RESULTS: Stratified by genotype groups, there were no statistically significant differences in SDMT scores between randomization groups. Placebo-treated patients with low SERT expression genotypes, however, tended to have lower mean SDMT scores (at 1 month: 30.2, SD 10.8) compared to citalopram-treated patients (33.6, SD 13.7). Within the placebo group, the low genotype expression patients had significantly lower adjusted mean SDMT scores at 1 month compared to the high genotype expression patients (adjusted mean difference of -6 points, CI -12.0 to -0.05). We found similar results at 6 months, although not statistically significant. The genotype expression was not associated with SDMT scores among citalopram-treated patients. CONCLUSION: There was no difference in cognition between citalopram and placebo-treated patients according to the genotype group. Our results indicate, however, that low expression SERT genotype may contribute to reduced cognitive function post stroke as placebo-treated patients with low SERT expression tended to score lower on the SDMT. The significant difference in SDMT scores between low and high expression patients was present only in the placebo-treated group, thereby warranting further exploration of the potential effect of early citalopram treatment on cognitive functioning. Our results are preliminary and need replication in larger-scale studies.

Neuroregeneration and Vascular Protection by Citalopram in Acute Ischemic Stroke (TALOS).

Background and Purpose- Recent studies indicate a possible beneficial effect on neuroregeneration and vascular protection of selective serotonin reuptake inhibitors after stroke. We conducted a national multicentre study to explore these effects. Methods- The TALOS study (The Efficacy of Citalopram Treatment in Acute Stroke) is a Danish placebo-controlled, randomized, double-blind study of citalopram started within 7 days after symptom onset to detect improvement in functional outcomes and cardiovascular protection in nondepressed, first-ever ischemic stroke. Study medication was given as add-on to standard medical care and treatment duration and follow-up was 6 months. There were 2 coprimary outcomes: changes in functional disability from 1 to 6 months on the modified Rankin Scale, and a composite vascular end point of transient ischemic attack/stroke, myocardial infarction, or vascular mortality during the first 6 months. Results- We enrolled 642 patients randomized to either citalopram (n=319) or placebo (n=323). Median National Institutes of Health Stroke Scale was 5.3 (range, 0-27) versus 4.8 (range, 0-28) at admission. Improvement in functional recovery from 1 to 6 months occurred in 160 (50%) patients on citalopram and 136 (42%) on placebo (odds ratio, 1.27; 95% CI, 0.92-1.74; P=0.057). When dropouts before 31 days were excluded (n=90), the analysis population showed an odds ratio of 1.37 (95% CI, 0.97-1.91; P=0.07). During a median follow-up of 150 days, 23 (7%) patients in the citalopram group and 26 (8%) patients in the placebo group had a primary, vascular end point (hazard ratio, 0.89; 95% CI, 0.50-1.60; P=0.24). A total of 28 patients (4%) died (16 versus 12; P=0.42) during the study. Conclusions- Early citalopram treatment did not improve functional recovery in nondepressed ischemic stroke patients within the first 6 months, although a borderline statistical significant effect was observed in the analysis population. The risk of cardiovascular events was similar between treatment groups, and citalopram treatment was well tolerated. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01937182. URL: https://www.clinicaltrialsregister.eu/ . EudraCT number: 2013-002253-30.

Potential Role of Selective Serotonin Reuptake Inhibitors in Improving Functional Outcome after Stroke.

The great advances in acute stroke treatment during the last decades have changed life after stroke considerably. However, the use of intravenous thrombolysis and endovascular thrombectomy is limited by a relatively narrow time window or contraindications for treatment. Further, patients receiving acute reperfusion therapies may still have cognitive and emotional complications due to underlying brain infarcts even though physical problems may almost disappear. Consequently, stroke is still a frequent cause of adult disability and death worldwide, and an effort to identify additional treatments to enhance recovery, preferably also feasible in the time after the acute phase, is warranted. Albeit several drugs and treatment modalities have been studied for their potential to enhance recovery after stroke, no treatment has unambiguously proven to potentiate the rehabilitation process. A promising candidate for pharmacological treatment is selective serotonin reuptake inhibitors (SSRIs), a group of commonly used antidepressants that may also possess neuro-regenerative properties. The current paper reviews the evidence for SSRIs as potential enhancers of stroke recovery and discusses the potential mechanisms behind the effects reported and the implications for the management of patients post-stoke, including potential adverse events and drug-drug interactions.

The Serotonin Transporter Gene Polymorphisms and Risk of Ischemic Stroke.

INTRODUCTION: Serotonin is known as a neurotransmitter; however, it also plays an important role in platelet aggregation as it is released upon platelet activation. The serotonin transporter (SERT) is responsible for the uptake of serotonin into platelets. Functional polymorphisms in the SERT gene may influence platelet activity, as they result in different levels of transporters and thereby different levels of serotonin in platelets. SERT gene polymorphisms have thus been associated with the risk of myocardial infarction. A similar association may exist between SERT gene polymorphisms and stroke. However, to our knowledge, this potential association has not previously been studied. We therefore aimed to investigate the association between polymorphisms in the SERT gene and the risk of ischemic stroke/transitory ischemic attack (TIA). MATERIALS AND METHODS: We conducted a case-control study including 834 consecutively admitted first-ever Caucasian ischemic stroke patients/TIA from Aarhus University Hospital, Denmark and 571 healthy controls. The control group comprised a sample from the Danish working population, who were all employees in the public sector in the Central Denmark Region. Two polymorphisms, the length variation (short = S/long = L) in the serotonin-transporter-linked polymorphic region and a single-nucleotide (A/G) polymorphism (rs25531) were studied. The genotypes were grouped according to the functional activity: SS, SLG and LGLG (low expression), SLA, LGLA (medium expression), and LALA (high expression). Data were analyzed using logistic regression and results presented as OR with 95% CI. RESULTS: The high-expression genotype was associated with a lower risk of ischemic stroke/TIA when compared to both the medium expression genotype (OR 0.72, 95% CI 0.56-0.93) and the low-expression genotype (OR 0.75, 95% CI 0.55-1.01) as well as the combination of the low and medium expression genotypes (OR 0.73, 95% CI 0.58-0.93). The lower OR estimates associated with the high-expression genotype were consistent across all stroke subtypes, although not statistically significant. The results remained virtually unchanged, although not reaching statistical significance, when adjusting for age and gender. CONCLUSION: The presence of the high expression SERT genotype (LALA) may be associated with a lower risk of ischemic stroke/TIA. This is, to our knowledge, the first study examining the SERT gene polymorphisms and the risk of stroke. The present results raise interesting considerations for future personalized medicine potential, and we argue that further larger-scale studies with sufficient power to study subgroups according to stroke etiology and stroke-onset age are needed.

Early Antidepressant Treatment and All-Cause 30-Day Mortality in Patients with Ischemic Stroke.

BACKGROUND: Antidepressants, in particular selective serotonin reuptake inhibitors, have been associated with antithrombotic and neuroprotective properties and their more widespread use has been suggested in stroke recovery. However, data are sparse on their effects on the clinical outcome, including mortality, associated with early antidepressant treatment after stroke. We aimed to study all-cause 30-day mortality related to early antidepressant treatment in patients with ischemic stroke. METHODS: We did a population-based follow-up study identifying patients from the Danish Stroke Registry admitted in the former Aarhus County from 2003 to 2010. During this time, initiation of antidepressant treatment during admission was registered in the Danish Stoke Registry. The registry also holds clinical information including stroke type, stroke severity and quality of in-hospital stroke care. Information on vital status and covariates including comorbidities and co-medication was obtained from the following population-based medical registries: the Danish Civil Registration System, Danish Medicines Agency's Medical Register and The Danish National Patients Registry. Information was linked using the unique civil registration number assigned to all Danish residents. Multivariable logistic regression was used to compute the adjusted odds ratio (OR) of 30-day mortality in patients treated with antidepressants during admission as compared to patients not treated. In addition, we did stratified analyses on sex, age, stroke severity and propensity score-matched analyses as well as multiple imputation. RESULTS: Among 5,070 consecutive first-ever stroke patients without prior antidepressant treatment, 955 (18.8%) started antidepressant treatment during admission with a median time from admission until treatment of 5 days (interquartile range 2-11). The proportion of patients with severe stroke was higher among treated patients as compared to that among non-treated patients. The adjusted OR of 30-day mortality was 0.28 (95% confidence interval (CI) 0.18-0.43) for patients treated during admission as compared to patients not treated during admission. Stratification by stroke severity showed signs of effect modification, stratification by sex and age did not. Included in the propensity score-matched analyses were 1,908 patients matched 1:1. The propensity score-matched adjusted OR of death within 30 days was 0.31 (95% CI 0.19-0.49). CONCLUSION: Although early antidepressant treatment was more often started in patients with severe stroke, treatment was associated with significantly lower mortality. This result requires replication in randomized trials; however, it indicates that early start of antidepressant treatment after stroke may be safe and a more routine use may be feasible.

TALOS: a multicenter, randomized, double-blind, placebo-controlled trial to test the effects of citalopram in patients with acute stroke.

RATIONALE: Selective Serotonin Reuptake Inhibitors (SSRI) are effective in the treatment of post-stroke depression and may have potential neuroprotective and vascular effects. Data from registry studies have further indicated a protective effect against recurrent ischemic events, but also an increased risk of bleeding in patients with ischemic stroke. Therefore, prospective studies are needed to determine the effects of SSRI treatment after acute ischemic stroke. AIMS AND DESIGN: TALOS is an investigator-initiated, national multicenter randomized- and placebo-controlled, double-blind trial testing citalopram in acute ischemic stroke. We hypothesize that citalopram treatment initiated in the acute phase after ischemic stroke will improve outcome assessed by the modified Rankin Score (mRS) and reduce the risk of death from vascular causes, transient ischemic attack (TIA)/stroke and myocardial infarction. STUDY OUTCOMES: There are two co-primary effect variables: (i) Functional status at six-months, measured by the modified Rankin Scale, and (ii) Vascular death, TIA/stroke and myocardial infarction. Secondary effect variables include: (i) Single primary outcomes; (ii) The Barthel Index; (iii) Mini Mental State Examination at six-months; (iv) Final infarct size (Magnetic Resonance Imaging). DISCUSSION: SSRI treatment is well tolerated and overall beneficial in the wake of stroke; it may also be neuroprotective and prevent new vascular events.

Safety of selective serotonin reuptake inhibitor treatment in recovering stroke patients.

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are widely used for psychiatric complications after stroke. Studies have indicated additional effects, and SSRIs could potentially be used as enhancers of stroke recovery. However, beneficial effects should be weighed against potential adverse effects. In particular, the possible association with cerebrovascular events has raised concern. AREAS COVERED: We review the literature on cerebrovascular events associated with SSRI treatment after stroke. The possible beneficial effects of SSRI treatment for stroke recovery and survival, and potential safety concerns, are discussed. EXPERT OPINION: Evidence suggests that SSRIs may enhance stroke recovery. Most studies on cerebrovascular risk are from non-stroke populations and little is known about recurrent events and mortality post-stroke. In non-stroke populations treatment has been associated with increased risk of intracerebral and intracranial hemorrhage; however the absolute risk is low. The association between SSRIs and ischemic stroke is less clear. Randomized stroke trials indicate that treatment is safe and well tolerated, and the most common side effects are often benign and transient. The trials are small however and not powered to detect potential differences in cerebrovascular events. We await several ongoing large randomized trials before SSRIs can be recommended as a routine pharmacotherapy in stroke recovery.

Impact of prestroke selective serotonin reuptake inhibitor treatment on stroke severity and mortality.

BACKGROUND AND PURPOSE: Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of bleeding but also a possible neuroprotective effect in stroke. We aimed to examine the implications of prestroke SSRI use in hemorrhagic and ischemic stroke. METHODS: We conducted a registry-based propensity score-matched follow-up study among first-ever patients with hemorrhage and ischemic stroke in Denmark (2003-2012). Multiple conditional logistic regression was used to compute adjusted odds ratios of severe stroke and death within 30 days. RESULTS: Among 1252 hemorrhagic strokes (626 prestroke SSRI users and 626 propensity score-matched nonusers), prestroke SSRI use was associated with an increased risk of the strokes being severe (adjusted propensity score-matched odds ratios, 1.41; confidence interval, 1.08-1.84) and an increased risk of death within 30 days (adjusted propensity score-matched odds ratios, 1.60; confidence interval, 1.17-2.18). Among 8956 patients with ischemic stroke (4478 prestroke SSRI users and 4478 propensity score-matched nonusers), prestroke SSRI use was not associated with the risk of severe stroke or death within 30 days. CONCLUSIONS: Prestroke SSRI use is associated with increased stroke severity and mortality in patients with hemorrhagic stroke. Although prestroke depression in itself may increase stroke severity and mortality, this was not found in SSRI users with ischemic stroke.

Post stroke use of selective serotonin reuptake inhibitors and clinical outcome among patients with ischemic stroke: a nationwide propensity score-matched follow-up study.

BACKGROUND AND PURPOSE: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed after stroke. We aimed to investigate whether potential antiplatelet or vasospastic effects have important clinical implications. METHODS: Using data from Danish medical registries, we did a nationwide follow-up study among ischemic stroke patients between 2003 and 2009. We identified 5833 SSRI users, and propensity score matched these patients with nonusers in a 1:1 ratio, followed by Cox regression analysis to compute hazard ratios (HRs) of acute myocardial infarction, recurrent stroke, major bleeding, and death. RESULTS: Median follow-up time (from 30 days after discharge to death/end of follow-up) was 1159 days. In total, 2.9% had myocardial infarction, 8.1% recurrent ischemic stroke, 20.2% major bleeding, 1.4% intracranial bleeding, and 34.4% died during follow-up. SSRI users had a lower risk of the combined outcome of myocardial infarction or recurrent ischemic stroke (adjusted HR, 0.77; confidence interval [CI], 0.62-0.96). However, the SSRI users also experienced a higher risk of overall major bleeding (adjusted HR, 1.33; CI, 1.14-1.55) and a nonsignificantly higher risk of intracranial bleedings (adjusted HR, 1.14; CI, 0.62-2.12). Mortality increased in SSRI users (adjusted HR, 1.13; CI, 1.00-1.28) and death caused by bleeding increased (adjusted HR, 1.89; CI, 0.97-3.66) as compared with death by other causes (adjusted HR, 1.11; CI; 0.98-1.26). CONCLUSIONS: SSRI use after ischemic stroke was associated with a lower risk of new cardiovascular events and also with an increased bleeding risk. There was an increased mortality among SSRI users, which may be related to the increased bleeding risk.