New paper on serotonin reuptake inhibitors and mortality in epilepsy

26 September 2017

Premature mortality in epilepsy is a major concern facing general practitioners, neurologists, and epileptologists alike. In addition, sudden unexpected death in epilepsy (SUDEP) is a specific cause of death and a major health concern for people with epilepsy. Serotonin reuptake inhibitors (SRIs) may have particular promise as a therapeutic intervention because they increase mental vigilance, promote respiratory activity, and may prevent sudden death.  

There has therefore been interest in exploring the therapeutic role of SRIs as a means of reducing premature mortality, especially for patients at high risk of SUDEP.  However, to date, no large-scale studies in humans have been performed to either confirm or refute this potential indication. We carried out an observational study using large, preexisting linked primary care data in England collected during routine clinical practice to examine the association between SRI use and mortality in patients with epilepsy. We sought to determine whether SRIs are associated with improved all-cause and possible seizure-specific mortality in patients with epilepsy using data from patients with epilepsy and a random 10:1 sample without epilepsy were extracted from The ClinicAl research using LInkedBespoke studies and Electronic health Records (CALIBER) resource. We identified 2,718,952 patients in CALIBER of whom 16,379 (0.60%) met the case definition for epilepsy. Median age was 44 years (interquartile range [IQR] 29–61) and 8,610 (53%) were female. Median follow-up was 6.4 years (IQR 2.4–10.4 years). A total of 2,178 patients (13%) had at least two SRI prescriptions. Hazard of all-cause mortality was significantly elevated following a second prescription for an SRI (HR 1.64 95% confidence interval [95% CI] 1.44-1.86; p < 0.001). The HR was similar in 163,778 age, sex, and general practitioner (GP) practice-matched controls without epilepsy. Exposure to an SRI was not associated with seizure-related death (HR 1.08, 95% CI 0.59-1.97; 0.796).  

This study paradoxically demonstrated that, contrary to evidence yielded from animal models, SRI use in patients with active epilepsy is associated with an elevated, rather than a decreased, risk of mortality. However, the risk appears generalizable to the overall population, as similar results were seen in age, sex, and GP practice-matched patients without epilepsy. There is no evidence in this large population-based cohort that SRIs protect against all-cause mortality or seizure-specific mortality. Rather, SRI use was associated with increased mortality, irrespective of epilepsy, which is probably due to various factors associated with the use of antidepressants. Larger studies with systematically collected clinical data are needed to shed further light on these findings.

Josephson CB, Gonzalez-Izquierdo A, Denaxas S, Fitzpatrick NK, Sajobi TT, Engbers JDT, Patten S, Jette N, Wiebe S. Serotonin reuptake inhibitors and mortality in epilepsy: A linked primary-care cohort study. Epilepsia. 2017 Sep 24. doi: 10.1111/epi.13904. [Epub ahead of print]