Using antidepressants and the risk of stroke recurrence: report from a national representative cohort study

Stroke is one of the leading causes of adult disability and mortality worldwide, resulting in tremendous socioeconomic burden [1, 2]. The recurrence rate of stroke readmission within one year was 13 % in Taiwan [3]. Compared with incident stroke events, recurrent events were likely to have higher mortality rates, greater levels of disability, and increased costs [4].

Use of antidepressants had positive effect on the management of stroke patients due to the reduction in incidence rate of post-stroke depression [5] and improvement in functional recovery [6, 7], but use of antidepressants also increased side effects [8]. In the cochrane review, the authors concluded that SSRIs might improve recovery after stroke, and that there was heterogeneity between published trials and methodological limitations [9]. Recent epidemiological studies had shown antidepressants use was associated with an increased risk of developing stroke [10]; however, data on stroke recurrence were limited [11, 12]. Moreover, some studies have indicated depression was associated with a higher risk of stroke [13], including recurrent events [11]. The association of fatal stroke in patients with depression who receiving antidepressants was even stronger [14]. The role of depression in the association between antidepressants use and stroke recurrence remains unclear. We used the National Health Insurance Research Database in Taiwan to evaluate whether antidepressants use is associated with increased risk of stroke recurrence.

Of the 16770 stroke patients with mean age of 67.3 years, 4695 (28 %) were taking any antidepressant during follow-up (median, 3.04 years; interquartile range, 1.31–5.64). Table 1 showed the baseline characteristics of subjects with use of antidepressants compared with those with non-use of antidepressants. Stroke patients with use of antidepressants were more female and ischemic stroke, as well as had a higher prevalence of diabetes mellitus, hyperlipidemia, chronic obstructive pulmonary disease, cancer, depression, anti-inflammatory, antithrombotic agents, antipsychotics, and antidepressants use before stroke. Among4695stroke patients with antidepressants use, the most commonly type of antidepressants was TCAs use only (n = 1814 [38 %]) and SSRIs use only (n =661 [14 %]), and MAOIs use only (n = 95 [2 %]) were less common. In dose groups, the group of <0.5 DDDs (50 %) was common, and the proportion of the group of 0.5–1 DDDs and •1 DDDs were 21 % and 28 % respectively.

Figure 2 depicted increased risk of recurrent stroke with antidepressants use. In Cox proportional hazards model with time-varying antidepressants use for the univariate analyses, use of antidepressants was found to have a higher risk of stroke recurrence (HR,1.49;95 % confidence interval [C.I.],1.30–1.70) (Table 2). After controlling for potential confounding variables, use of antidepressants also had a significantly increased risk of stroke recurrence (HR, 1.42; 95 % C.I.,1.24–1.62). A significantly increased risk of stroke recurrence was found with TCAs use only (HR, 1.41; 95 % C.I.,1.14–1.74), SSRIs use only (HR, 1.31; 95 % C.I.,1.00–1.73), other antidepressants use only (HR, 1.46; 95 % C.I.,1.15–1.84), and multiple types use (HR, 1.84; 95 % C.I.,1.04–3.25). We had similar results for the increased risk of recurrent stroke with antidepressants use in different dose groups of <0.5 DDDs (HR, 1.40; 95 % C.I.,1.17–1.67), 0.5–1 DDDs (HR, 1.46; 95 % C.I.,1.10–1.94), and 1 DDDs (HR, 1.43; 95 % C.I.,1.11–1.84). Table 3 summarizes the association between subtype of stroke and antidepressants use category. We found a similar pattern in ischemic stroke recurrence and a non-significantly increased risk of hemorrhagic stroke recurrence.

In subgroup analysis (Table 4), recurrent stroke risk estimates were similar among different depression statuses. The increased risk of recurrent stroke with antidepressants use in prevalent users (HR, 1.23; 95 % C.I.,0.99–1.53) was lower than in new users (HR, 1.57; 95 % C.I.,1.32–1.86). The data provided significant differences (p for interaction = 0.01) in risk between diabetes users (HR, 1.70; 95 % C.I.,1.41–2.05) and non-diabetes users (HR, 1.20; 95 % C.I.,0.99–1.45). The data did not show significant evidence of differences in risk related to other drugs use and other disease. In sensitivity analyses, we found that the stroke risk was slightly lower but still significant with antidepressants use in duration plus 7 days (HR, 1.33; 95 % C.I.,1.17–1.52) and adding inpatient records (HR, 1.19; 95 % C.I.,1.05–1.36).

This study showed that stroke patients prescribed for antidepressants had 40 % greater risk of stroke recurrence. The association was stronger for ischemic stroke than for hemorrhagic stroke. The increased risk was observed in association with prescriptions for antidepressants subclass of TCAs, SSRIs, the group of others, and multiple types. In addition, a higher risk of stroke recurrence with antidepressants among diabetic patients was found.

Few epidemiological studies have reported the association between antidepressants use and risk of stroke recurrence. A study in China found an elevated risk of recurrent stroke after 1-year follow-up in antidepressants users, but the association was statistically non-significant, partly because of small sample size (RR, 1.96; 95 % C.I.,0.95–4.04) [11]. Another study in Denmark using propensity score–matching analysis focused on SSRI use [12]. SSRI exposure was associated with statistically non-significant lower risk of recurrence of ischemic stroke (RR, 0.67; 95 % C.I.,0.44–1.02), and non-significantly higher risk of intracranial bleedings (RR, 1.14; 95 % CI, 0.62–2.12) [12]. The discrepancy in findings among these studies and ours may reflect different methodology among studies, including differences in patient populations, reported type of stroke, and methods of data analysis. We used Cox models with antidepressant exposure as time-dependent covariates to take into account for switch between classes of antidepressants and use to non-use. The actual number of days prescribed was the days of exposure in our analysis. However, all drugs in the Denmark study were included as time-dependent variables with an assumed average prescription length of 90 days. The extent of drug exposure in their study might be different from that in ours. A cochrane review [9] has concluded that SSRIs might improve recovery after stroke. However, different from our study, the outcomes assessed in the review were neurological impairment or depression after stroke, but not stroke recurrence. Furthermore, the authors of the review found high heterogeneity between trials and methodology limitations in these trials. Well-designed trials are needed before a firm conclusion can be made.

The biological mechanisms have been proposed for the association between antidepressants and stroke. Antidepressant drugs inhibit the re-uptake receptors or the activity of metabolic enzymes, thereby increasing the concentration of serotonin, which induces local vasoconstriction and increases risk of ischemic stroke [18, 19]. In contrast, evidence also revealed that antidepressants may inhibit platelet activity and aggregation, thereby preventing ischemic events [20‐22]. This mechanism also could explain the underlying association between antidepressants and the increased risk of bleeding. However, epidemiological studies showed inconclusive results in the association between antidepressants and risk of hemorrphagic stroke [23‐26]. A study of meta-analysis reported increased risk of brain hemorrhage associated with SSRIs [23], whereas other studies, in line with our analysis, suggested no increased risk [24‐26]. Of note, different from previous studies, our analysis focused on risk of recurrent stroke. More investigations with stroke recurrence as the primary end point are required to confirm our findings.

Our study showed that the greater risk of stroke recurrence with antidepressants in patients with diabetes. Diabetes patients with antidepressants had poor adherence with medication [27], which was associated with adverse outcomes such as higher glycosylated hemoglobin, systolic and diastolic blood pressure, and low-density lipoprotein cholesterol levels [28]. The risk of stroke recurrence associated with antidepressants use did not change materially in the analysis stratified by depression statuses. The indication for antidepressants was not only for the treatment of mood disorders but also for patients with various anxiety disorders and off-label use such as sleep disorder, chronic pain [29]. Although the increased risk of recurrent stroke with antidepressants use in prevalent users was lower but non-significant than in new users, the reduction in the risk with long-term drug users might happened [30] with the attrition for susceptible people [31]. We did not observe dose–response relationship between antidepressants use and stroke recurrence.

The strengths of our study included a large population-based follow-up study and the integrated details of prescription records such as the drug used, dosages, days of supply dispensed from database. However, our study had several potential limitations. First, the history of stroke prior to 1996 was unknown, but patients with any record of stroke before 1999 were excluded to reducing misclassified as an incident case. Second, the validity of diagnosis of stroke and the recording of prescription in database may influence our results, even the accuracy of recording stroke diagnoses and prescriptions in NHIRD was high [32]. Third, the data of antidepressants use in admission were excluded due to no information of the duration of use for each prescription from inpatient records. We used the length of stay for each admission as an estimate for duration of antidepressants exposure, and we found the association weakened but remained statistically significant. Fourth, we not only lacked for lifestyle information such as weight, drinking, or smoking status, but also for any data on stroke location or severity. Fifth, we were unable to assess the adherence of the antidepressants because the information is not available in the claims database. Poor adherence to antidepressant treatment may lead to misclassification of exposures resulting in under-estimation of the drug effect. Sixth, misclassification of depression might occur if a patient did not seek medical care for his or her depressive disorders or if diagnostic codes were accurate. In our analysis, depression was treated as a confounder in multivariable analysis. Misclassification of depression may result in residual confounding. Finally, we cannot draw conclusions on causal association from our analysis, as this is an observational study. This study was national representative and population-based. The results can be generalizable to populations in Chinese ethnicity.

We found that use of antidepressants was associated with an increased risk of stroke recurrence, especially for ischemic stroke. TCAs, SSRIs, the group of others, or multiple types users had increased risk of stoke recurrence. In addition, a higher risk associated with antidepressants was observed in patients with diabetes. Although those patients had low dosage of antidepressants, the closely monitoring the side effects was necessary, particularly for diabetes patients.