Effects of selective serotonin reuptake inhibitors on the risk of mortality in patients with epilepsy: a CALIBER study using linked data

Date of ISAC Approval: 
Lay Summary: 
Sudden Unexpected Death in EPilepsy (SUDEP) is the most devastating problem facing people with epilepsy. It occurs when someone dies with epilepsy dies without an obvious explanation. SUDEP is estimated to occur in 1 out of every 1000 people with epilepsy. The mechanism of SUDEP has also yet to be understood. It is thought that some combination of sudden changes in the breathing pattern, heart rhythm, and 'shutdown' of normal brain rhythms all contribute to SUDEP. These abnormalities typically occur after a seizure. Serotonin, an important chemical found in the brain, may be able to reverse these processes. It has been shown to increase wakefulness and breathing in animal models. Furthermore, selective serotonin reuptake inhibitors have been shown to reduce abnormal breathing following seizures in animals. Hence, there is a belief that selective serotonin reuptake inhibitors, a type of medication that increases the amount of serotonin available to the brain, may improve mortality in people with epilepsy by improving breathing and vigilance following a seizure. We therefore propose to study this in a large pre-existing dataset to determine if concurrent use of selective serotonin reuptake inhibitors in patients with epilepsy is associated with a lower risk of death.
Technical Summary: 
The objective of this study determine whether selective serotonin reuptake inhibitors (SSRI) use is associated with decreased mortality in patients with epilepsy. Data will be extracted from the CALIBER database that links electronic medical records and administrative data from the Clinical Practice Research Datalink, Hospital Episode Statistics, the Myocardial Ischaemia National Audit Project, and the Office of National Statistics. We will extract an epilepsy cohort using a previously validated case definition. Data will then be provided to the analyst by the CALIBER data manager in a secure network in text files that can be directly uploaded to the statistical packages for further analysis. We will approach the problem using two different analysis plans. First, we will use Cox proportional survival analysis to follow patients forward from the point of SSRI prescription to last follow-up or death. The hazard of death will be compared between those receiving SSRIs to those who are not. Second, we will perform an analysis using by identifying all patients with epilepsy and comparing them to a control group without epilepsy. We will evaluate those who died of sudden death in each group and compare SSRI use in between populations over the final 6 months.
Health Outcomes to be Measured: 
The primary outcome of interest is overall all-cause death. We will restrict the outcome to sudden death in a sensitivity analysis. In the sensitivity analysis, the group will be composed of an amalgam of primary and secondary codes for sudden death and for sudden cardiac death. We will also exclude sudden cardiac death in a subsequent analysis and compare the results to the first two analyses.

Colin Josephson - Chief Investigator - O'Brien Institute for Public Health & Hotchkiss Brain Institute
Dr Alireza Moayyeri - Researcher - UCB Pharma SA - UK
Arturo Gonzalez-Izquierdo - Researcher - University College London (UCL)
Colin Josephson - Corresponding Applicant - O'Brien Institute for Public Health & Hotchkiss Brain Institute
Spiros Denaxas - Researcher - University College London (UCL)

HES Admitted;MINAP;ONS;Patient IMD