IMPORTANCE Selective serotonin reuptake inhibitors (SSRIs) may increase the risk for spontaneous intracranial hemorrhage (ICH), an effect that is in theory linked to the strength of inhibition of serotonin reuptake of an antidepressant. However, whether antidepressants that are strong inhibitors of serotonin reuptake actually increase the risk for ICH and the effect of concomitant use of antithrombotics are unknown.OBJECTIVES To assess the risk for ICH associated with the use of SSRIs compared with tricyclic antidepressants (TCAs) among new users of antidepressants and according to the relative affinity of the antidepressant for the serotonin transporter and to assess whether concomitant use of antithrombotics modifies this risk. DESIGN, SETTING, AND PARTICIPANTSThis population-based cohort study included new users of antidepressants 18 years or older from January 1, 1995, to June 30, 2014. More than 650 general practices in the United Kingdom contributing to the Clinical Practice Research Datalink enrolled patients. with use of a nested case-control approach, each case of a first ICH identified during follow-up was matched with as many as 30 control individuals by age, sex, calendar time, and duration of follow-up. Follow-up was completed on October 31, 2014.INTERVENTIONS Current use of SSRIs compared with TCAs and strong compared with weak serotonin reuptake inhibitors. MAIN OUTCOMES AND MEASURES Incidence rate ratios (RRs) of ICH.RESULTS Among a cohort of 1 363 990 incident users of antidepressants (36.8% male; 63.2% female; mean [SD] age, 47.9 [18.5] years), 3036 cases of ICH were identified during follow-up and matched to 89 702 controls. Current SSRI use was associated with an increased risk for ICH (RR, 1.17; 95% CI, 1.02-1.35) relative to TCAs, highest during the first 30 days of use (RR, 1.44; 95% CI, 1.04-1.99), and translating in very few additional events. Similarly, the risk was increased by 25% with strong inhibitors (RR, 1.25; 95% CI, 1.01-1.54) and highest during the first 30 days of use (RR, 1.68; 95% CI, 0.90-3.12). Concomitant use of anticoagulants may increase the risk substantially (RR, 1.73; 95% CI, 0.89-3.39). CONCLUSIONS AND RELEVANCEThe use of SSRIs and more generally of antidepressants with strong inhibition of serotonin reuptake are associated with an increased risk for ICH, particularly in the first 30 days of use and when used concomitantly with oral anticoagulants.

Time-related biases in cohort studies can produce illusory "beneficial" effects of medications due entirely to an artifact of the analytic design. We describe "time-window bias" in the context of a case-control study, reporting that statin use was associated with a 45% reduction in the incidence of lung cancer. This bias results from the use of time-windows of different lengths between cases and controls to define time-dependent exposures. We illustrate the bias using a population of 365,467 patients from the United Kingdom's General Practice Research Database, including 1786 incident cases of lung cancer during 1998-2004. The case-control approach used in the published study yielded a rate ratio of lung cancer incidence of 0.62 with statin use (95% confidence interval = 0.55-0.71). A case-control approach that properly accounts for time produces a rate ratio of 0.99 (0.85-1.16)-suggesting no benefit of statins on lung cancer risk. We show analytically that the magnitude of the bias is proportional to the ratio of the unequal time-window lengths.

Background Indoor residual spraying (IRS) is widely used as a vector control measure, although there are conflicting findings of its effectiveness in reducing malaria incidence. The objective of this study was to estimate the effect of multiple IRS rounds on malaria incidence and hemoglobin levels in a cohort of children in rural southeastern Uganda. Methods The study was based upon a dynamic cohort of children aged 0.5–10 years enrolled from August 2011 to June 2017 in Nagongera Subcounty. Confirmed malaria infections and hemoglobin levels were recorded over time for each participant. After each of 4 rounds of IRS, malaria incidence, hemoglobin levels, and parasite density were evaluated and compared with pre-IRS levels. Analyses were carried out at the participant level while accounting for repeated measures and clustering by household. Results Incidence rate ratios comparing post-IRS to pre-IRS incidence rates for age groups 0–3, 3–5, and 5–11 were 0.108 (95% confidence interval [CI], .078–.149), 0.173 (95% CI, .136–.222), and 0.226 (95% CI, .187–.274), respectively. The mean hemoglobin levels significantly increased from 11.01 (pre-IRS) to 12.18 g/dL (post-IRS). Conclusions Our study supports the policy recommendation of IRS usage in a stable and perennial transmission area to rapidly reduce malaria transmission.