Antidepressant Use Is Associated With an Increased Risk of Developing Microbleeds
Background and Purpose—Serotonin-specific antidepressants may increase the risk of adverse bleeding events. In a previous cross-sectional study, we did not observe an association between antidepressant use and presence of subclinical cerebral bleedings. In this study, we investigated longitudinally whether antidepressant use is associated with an increased risk of new subclinical cerebral microbleeds.
Methods—In total, 2559 participants aged ≥45 years of the population-based Rotterdam Study, all without microbleeds at baseline, underwent baseline and repeat brain magnetic resonance imaging between 2005 and 2013 (mean time interval, 3.9 years; SD, 0.5) to determine the incidence of microbleeds. Antidepressant use (yes versus no) was assessed between baseline and follow-up scan. In additional analyses, antidepressants were classified as low, intermediate, or high affinity for the serotonin transporter, and alternatively as selective serotonin reuptake inhibitors or non-selective serotonin reuptake inhibitors. We used multivariable logistic regression models to investigate the association of antidepressants with incident microbleeds.
Results—Antidepressant use was associated with a higher cerebral microbleed incidence (odds ratio, 2.22; 95% confidence interval, 1.31–3.76) than nonuse. When stratified by affinity for the serotonin transporter, intermediate serotonin affinity antidepressant use was associated with an increased risk of developing microbleeds (odds ratio, 3.07; 95% confidence interval, 1.53–6.17). Finally, selective serotonin reuptake inhibitor and non-selective serotonin reuptake inhibitor use were both associated with increased microbleed incidence.
Conclusions—Antidepressant use was associated with an increased risk of developing microbleeds. Our results may support findings from previous clinical studies about increased intracranial and extracranial bleeding risk in antidepressant users.
- antidepressive agents
- cerebral microbleeds
- cerebral small vessel diseases
- magnetic resonance imaging
Observational studies suggest that the biological effects1 of antidepressants predispose users to symptomatic hemorrhagic adverse events, such as gastrointestinal and intracerebral hemorrhages.2–4 Because even symptomatic hemorrhages are not always acknowledged and reported, it is likely that the number of subclinical and thus nonrecognized hemorrhages is much larger and that symptomatic hemorrhages are just the tip of the iceberg.5 This is in line with the finding that the prevalence of intracranial microbleeds in the Rotterdam Study is much higher than that of stroke.
In the brain, reduced platelet activation because of antiplatelet drug use has been associated with a higher prevalence of subclinical microbleeds.6 The question arises whether antide pressants have comparable effects on platelet function because it was shown that selective serotonin reuptake inhibitors (SSRIs) block the reuptake of serotonin by platelets and decrease serotonin platelet concentration, which may lead to impaired aggregation and prolonged bleeding times.7,8 We previously showed that in the general population, the use of antidepressants, with a high serotonin affinity, did not associate with a higher frequency of subclinical microbleeds on brain magnetic resonance imaging (MRI).9 This study however was limited by its cross-sectional design. Therefore, we now investigated the association between antidepressant use (and their degree of serotonin reuptake inhibition) and incident cerebral microbleeds.
This study was embedded within the Rotterdam Study, a large prospective population-based cohort.10 The study comprises 14 926 participants, and investigates the prevalence, incidence of, and risk factors for diseases in an aging population. The study started in 1990 and after baseline examination, follow-up assessments were conducted every 4 to 5 years, including interviews, an extensive set of examinations, and brain MRI.10,11 The Rotterdam Study has been approved by the Medical Ethics Committee of the Erasmus MC and by the Ministry of Health, Welfare and Sport of the Netherlands, implementing the Wet Bevolkingsonderzoek: ERGO (Population Studies Act: Rotterdam Study).
For this study, we included 3054 participants who were affiliated with one of the pharmacies serving the study area and underwent both baseline and repeat brain MRI between August 2005 and July 2013. Participants with microbleeds on baseline MRI were excluded (N=495), leaving a total of 2559 participants for analyses.
Pharmacy records were available from 1991 onwards and provided information on prescription date of antidepressants, number of drug units, prescribed daily number of units, and Anatomic Therapeutic Chemical (ATC) code. Exposure was defined as antidepressants use between baseline and follow-up MRI, irrespective of previous antidepressant use. Nonuse between the MRIs was defined as the reference group. Antidepressants were categorized based on their affinity for the serotonin transporter into low, intermediate, and high degree of serotonin reuptake inhibition, as described previously.9 Furthermore, antidepressants were categorized into SSRIs (ATC code=N06AB) and non-SSRIs (respectively, all other N06A). Also, the duration of treatment and the average number of prescribed defined daily doses were assessed.
Participants were scanned at both time points on the same 1.5-Tesla MRI scanner (GE Healthcare, Milwaukee, WI), as described previously.11 In short, cerebral microbleeds were rated by 5 trained research-physicians with good intraobserver and interobserver agreement (κ=0.87 and κ=0.85). Raters were blinded to clinical data, including antidepressant use. Microbleeds were defined as focal areas of low-signal intensity on an accelerated 3-dimensional T2*-weighted gradient-recalled echo sequence.12 Scans rated positive for microbleeds were included in a side-by-side comparison to determine the incidence of microbleeds.13
We used multivariable logistic regression to investigate if any antidepressant use between baseline and follow-up MRI was associated with an increased risk of incident microbleeds, when compared with nonusers. We repeated the analysis for the degree of serotonin reuptake inhibition (high, intermediate, and low)—based on our a priori hypothesis—9 and for SSRIs and non-SSRIs, after exclusion of participants who used antidepressants from >1 group (for both classifications, n=43, n=39 switchers, respectively). All analyses were adjusted for age, sex, and time (in years) between baseline and repeat MRI scan. We additionally adjusted for potential confounders at baseline, including the presence of depressive symptoms based on the Center for Epidemiological Studies Depression Scale (CES-D), and a propensity score of cardiovascular risk (diabetes mellitus, smoking, total and high-density lipoprotein cholesterol, systolic and diastolic blood pressure, use of lipid-lowering (ATC code C10), blood pressure–lowering (ATC codes C02, C03, and C07–C09), and antithrombotic drugs (ATC codes B01AA, B01AB, B01AC, and B01AX). Post-hoc analyses were done to additionally adjust for all separate cardiovascular risk factors, duration of treatment, and average number of prescribed defined daily doses and to test the interaction of antidepressant with antithrombotic drug use between baseline and follow-up scan. Analyses were performed using IBM SPSS Statistics for Windows, version 21.0, using an α=0.05.
Baseline characteristics of the study population are presented in Table 1. The median age was 58.7 years (IQR 53.2–62.8) and 1403 (54.8) were women. The incidence of microbleeds >3.9 years (SD 0.5) of follow-up was 3.7%.
Antidepressant use was associated with incident cerebral microbleeds (age, sex, and scan interval–adjusted odds ratio, 2.22; 95% confidence interval, 1.31–3.76), compared with nonuse (Table 2). When categorized by affinity for the serotonin transporter, only intermediate serotonin affinity antidepressant use was associated with an increased risk of developing microbleeds (odds ratio, 3.07; 95% confidence interval, 1.53–6.17), also after additional adjustment for depressive symptoms and a propensity score of cardiovascular risk and cardiovascular drugs (odds ratio, 3.29; 95% confidence interval, 1.59–6.79). Antidepressants with a high serotonin affinity were associated with incidence of microbleeds, although results did not reach statistical significance (odds ratio, 2.18; 95% confidence interval, 0.90–5.29; Table 2). Both SSRIs and non-SSRIs were associated with an increased risk of incident cerebral microbleeds, compared with nonuse (Table 2). Additional adjustment for all separate cardiovascular risk factors and drugs did not materially change the results (not shown). Also, additional adjustments for duration and dose of antidepressant treatment only marginally changed effect estimates, although associations were nonsignificant, possibly because of loss of statistical power (results not shown). We found no effect modification by antithrombotic drug use in a post hoc analysis on the association of antidepressant use with incident microbleeds (P=0.772).
In this population-based study, we found that antidepressant use was associated with an increased risk of incident first-ever microbleeds after 4 years of follow-up. Associations were similar for different categories of antidepressants users, and persisted after adjusting for depressive symptoms and cardiovascular risk. These findings are in line with previous cross-sectional results from other studies, although our study is the first to describe a temporal association between antidepressants and subclinical cerebral hemorrhages.4
The increased risk of developing microbleeds in antidepressant users might be a direct consequence of the inhibiting effects on the serotonin transporter by antidepressants. Platelet motility may decrease because of reduced intraplatelet serotonin concentrations.1 In line with this, we expected strongest associations for users in the group with a high affinity for the serotonin transporter and in SSRIs because they selectively block serotonin reuptake and impair platelet aggregation most. Stratification on the degree of serotonin reuptake inhibition, however, yielded small subgroups and hampered our ability to study these trends. Because we found that both SSRIs and non-SSRIs increased the risk of incident microbleeds with similar effect sizes, this suggests that the association may not be because of the affinity for the serotonin transporter. Another yet unidentified mechanism, other than platelet impairment, may cause hemorrhagic tendencies in persons using antidepressants. More likely, the lack of difference in association of high and intermediate affinity SSRIs with incident microbleeds is the result of insufficient statistical power. Also, we have to consider the possibility of reverse causality as incident microbleeds could have occurred at some time before antidepressant use during follow-up, and biologically it has been hypothesized that microbleeds may contribute to the progression of depression.14
In our previous cross-sectional study, we did not find an association between antidepressants and microbleed presence.9 An explanation for this could be that our previous results were underestimated because of nondifferential misclassification of antidepressant drug exposure because microbleeds might have occurred before antidepressant use. Although this issue may also be present in this study, we think that using a narrow antidepressant drug exposure window and identifying first-ever incident microbleeds made our current longitudinal results more robust than the previous cross-sectional results.
The results of our study should be interpreted in light of some limitations. The number of incident microbleed cases during follow-up was small and limited our ability to perform microbleed subgroup analysis, for example about their location in the brain. Also, our results may be confounded by the indication for treatment because depression has a bidirectional association with cardiovascular disease, and cardiovascular diseases are associated with microbleeds. We adjusted for depressive symptoms at baseline, but because we lacked data to control for depressive symptoms during follow-up potential residual confounding by depression may still be present. Also, as we mentioned reverse causality may have been present in our study. We tried to minimize the effects of reverse causality by excluding participants with prevalent microbleeds at baseline and by studying first-ever incident microbleeds.
In conclusion, antidepressant use was associated with an increased risk of developing microbleeds. Our results support findings from previous clinical studies about bleeding risk in antidepressants, and suggest that these risks may also apply to subclinical bleeding manifestations.
Sources of Funding
This study was supported by Erasmus MC, University Medical Center and Erasmus University Rotterdam; the Netherlands Organisation of Scientific Research (NWO); the Netherlands Organisation for Health Research and Development (ZonMW); The Research Institute for Diseases in the Elderly; the Ministry of Education, Culture, and Science; the Ministry of Health, Welfare, and Sports; the European Commission (DG-XII); and the Municipality of Rotterdam. This study was funded by the Netherlands Organization for Health Research and Development (ZonMW) Priority Medicines Elderly program (113101002; noncommercial) and by a ZonMW clinical fellowship (90700435). Dr Tiemeier received a NWO-ZonMW VIDI grant (number: 017.106.370, the Netherlands Organization for Scientific Research—the Netherlands Organization for Health Research and Development).
Dr Vernooij received an Erasmus MC fellowship grant. The other authors report no conflicts.
↵* Dr Akoudad and N. Aarts contributed equally.
- Received September 20, 2015.
- Revision received October 10, 2015.
- Accepted October 14, 2015.
- © 2015 American Heart Association, Inc.
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