Inhibition of Serotonin Reuptake

The use of antidepressant medication in the general population has increased considerably in past decades, in particular the use of selective serotonin reuptake inhibitors (SSRIs). This increase in SSRI use may be explained by a broadened indication of SSRI, a different adverse effect profile, and a lower toxicity compared with classic tricyclic antidepressants. Yet, despite a more favorable adverse effect profile, the use of SSRIs is not entirely risk free. SSRIs block the reuptake of serotonin by platelets and decrease serotonin platelet concentration, which may lead to impaired aggregation and prolonged bleeding times. SSRIs have, therefore, extensively been studied in relation to intracerebral hemorrhages, and a recent meta-analysis of controlled observational studies showed an increased risk of intracerebral hemorrhages in SSRI users compared with nonusers. In addition, via the same pathophysiological pathway of reducing platelet aggregation, antidepressants with a high inhibition for serotonin reuptake may also reduce the risk of ischemic stroke, although to date this hypothesis is scarcely supported by literature. Apart from major cerebrovascular events, it has not yet been investigated whether SSRIs or strong inhibitors of serotonin reuptake are associated with subclinical cerebrovascular lesions and more particularly with subclinical bleedings. Cerebral microbleeds have increasingly been recognized on MRI in stroke patients and mostly in association with larger intracerebral hemorrhages. Yet, microbleeds are also highly prevalent in the general population, and microbleeds may Background and Purpose—Serotonin reuptake inhibiting antidepressants decrease platelet aggregation. This may cause an increased risk of intracerebral hemorrhage. However, the risk of subclinical microbleeds, which are highly prevalent in middle-aged and elderly people, is unknown. We studied whether serotonin reuptake inhibiting antidepressants increase the frequency of cerebral microbleeds and secondarily whether they lower the presence of ischemic vascular damage. Methods—Within the population-based Rotterdam Study, information on antidepressant use was obtained from continuously monitored pharmacy records. Brain MRI was available in 4945 participants (55% women, mean age 64 years) between 2005 and 2011. We categorized antidepressants based on affinity for the serotonin transporter: high, intermediate, or low. Microbleeds (presence and location) and ischemic lesions (lacunes, white matter lesions) were rated on MRI. Logistic and linear regression, adjusted for age, sex, depressive symptoms, and cardiovascular risk were used to study the association of antidepressants with microbleeds and ischemic vascular lesions. Results—Antidepressant use with strong serotonin reuptake inhibition was not associated with microbleed presence (odds ratio compared with nonuse, 1.03; confidence interval, 0.75–1.39) irrespective of microbleed location in the brain. Exclusion of antithrombotic users or persons with cortical infarcts did not change our results. Furthermore, serotonin reuptake inhibition was not related to ischemic vascular brain damage. Conclusions—In the general population, use of serotonin reuptake inhibiting antidepressants is not related to presence of cerebral microbleeds. This strengthens the idea that the platelet inhibitor effects of antidepressant drugs with affinity for serotonin are minimal and further supports the safety of selective serotonin reuptake inhibitors for nongastrointestinal bleedings. (Stroke. 2014;45:00-00.)