Antidepressants and the Risk of Hemorrhagic Stroke in the Elderly: a Nested Case-Control Study

Drug Saf. 2019 Sep;42(9):1081-1089. doi: 10.1007/s40264-019-00837-y.


Background and purpose: Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed in the elderly due to a more favorable risk profile than other antidepressants (ADs). However, SSRIs are associated with an increased risk of gastrointestinal bleeding, while evidence on the risk of hemorrhagic stroke (HS) is limited. Therefore, we compared the risk of HS associated with the use of ADs in the elderly.

Methods: Based on data from the German Pharmacoepidemiological Research Database (GePaRD), a case-control study matched on age, sex, and health insurance provider, nested in a cohort of incident users of ADs ≥ 65 years of age was performed. Cases were identified from hospital discharge diagnoses, and exposure was identified from outpatient prescriptions. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs).

Results: Based on 4059 cases and 40,590 controls, an increased risk of HS was found in current use of SSRIs (OR 1.39, 95% CI 1.22-1.58), selective serotonin and noradrenaline reuptake inhibitors (1.69, 1.35-2.11), noradrenergic and specific serotonergic ADs (1.44, 1.22-1.69), and noradrenaline reuptake inhibitors (3.81, 1.54-9.43) compared with tri- and tetracyclic antidepressants. An increased risk of HS was seen in patients with a high baseline risk of bleeding and in patients with depression. The risk of HS varied between individual ADs.

Conclusion: Our study shows that the use of medications inhibiting serotonin and/or noradrenaline reuptake increases the risk of HS in patients aged 65 years and older and that the risk varies across individual ADs.

MeSH terms

  • Adrenergic Uptake Inhibitors / administration & dosage
  • Adrenergic Uptake Inhibitors / adverse effects
  • Aged
  • Aged, 80 and over
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / adverse effects*
  • Case-Control Studies
  • Databases, Factual
  • Depression / epidemiology
  • Female
  • Humans
  • Intracranial Hemorrhages / chemically induced*
  • Intracranial Hemorrhages / epidemiology
  • Male
  • Risk Factors
  • Selective Serotonin Reuptake Inhibitors / administration & dosage
  • Selective Serotonin Reuptake Inhibitors / adverse effects*
  • Stroke / chemically induced*
  • Stroke / epidemiology


  • Adrenergic Uptake Inhibitors
  • Antidepressive Agents
  • Serotonin Uptake Inhibitors