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Selective serotonin reuptake inhibitors and risk of epilepsy after traumatic brain injury - A population based cohort study.

ABSTRACT: OBJECTIVE:Traumatic brain injury (TBI) is common and associated with a marked increased risk of developing epilepsy. Animal studies indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) may increase the risk of epilepsy after TBI. The aim of this study was to investigate whether use of SSRIs modifies the risk of epilepsy after TBI. METHODS:This was a cohort study of 205,715 persons, who suffered a TBI in Denmark from 1996 to 2013. For each person with TBI, we matched 10 reference persons (N = 2,057,150) who were alive on the day of TBI and who had the same age and gender but had no history of TBI. We used a stratified Cox regression to calculate the relative risk of epilepsy after TBI for persons exposed to TBI, SSRI or both after adjustment for income, civil status, medical and neurological comorbidities, severe mental disease, and substance abuse. RESULTS:The risk of epilepsy was 5.61 times higher for persons who used SSRI at time of TBI (adjusted Hazard Ratio (aHR): 5.61 (95% CI: 4.88; 6.45)), 3.23 times higher for persons who had a TBI but did not use SSRI at time of TBI (aHR: 3.23 (95% CI: 3.12;3.35)), and 1.31 times higher for persons who used SSRI but had no TBI (aHR: 1.31 (95% CI: 1.18; 1.45)) compared to persons unexposed to both TBI and SSRI. CONCLUSIONS:This large population based cohort study showed that people using SSRI at the time of a TBI had higher risk of developing epilepsy compared to people not using SSRI at the time of TBI. The results are in line with those of animal studies and calls for further studies to evaluate whether the association is due to SSRIs or to the underlying disease (e.g. depression or anxiety).

SUBMITTER: Christensen J

PROVIDER: S-EPMC6641473 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Selective serotonin reuptake inhibitors and risk of epilepsy after traumatic brain injury - A population based cohort study.

Christensen Jakob J Pedersen Henrik Schou HS Fenger-Grøn Morten M Fann Jesse R JR Jones Nigel C NC Vestergaard Mogens M

PloS one 20190719 7

<h4>Objective</h4>Traumatic brain injury (TBI) is common and associated with a marked increased risk of developing epilepsy. Animal studies indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) may increase the risk of epilepsy after TBI. The aim of this study was to investigate whether use of SSRIs modifies the risk of epilepsy after TBI.<h4>Methods</h4>This was a cohort study of 205,715 persons, who suffered a TBI in Denmark from 1996 to 2013. For each person with TBI, w ...[more]

PMID: 31323024

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Project description:BackgroundAlthough selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, associations with violence are uncertain.Methods and findingsFrom Swedish national registers we extracted information on 856,493 individuals who were prescribed SSRIs, and subsequent violent crimes during 2006 through 2009. We used stratified Cox regression analyses to compare the rate of violent crime while individuals were prescribed these medications with the rate in the same individuals while not receiving medication. Adjustments were made for other psychotropic medications. Information on all medications was extracted from the Swedish Prescribed Drug Register, with complete national data on all dispensed medications. Information on violent crime convictions was extracted from the Swedish national crime register. Using within-individual models, there was an overall association between SSRIs and violent crime convictions (hazard ratio [HR] = 1.19, 95% CI 1.08-1.32, p < 0.001, absolute risk = 1.0%). With age stratification, there was a significant association between SSRIs and violent crime convictions for individuals aged 15 to 24 y (HR = 1.43, 95% CI 1.19-1.73, p < 0.001, absolute risk = 3.0%). However, there were no significant associations in those aged 25-34 y (HR = 1.20, 95% CI 0.95-1.52, p = 0.125, absolute risk = 1.6%), in those aged 35-44 y (HR = 1.06, 95% CI 0.83-1.35, p = 0.666, absolute risk = 1.2%), or in those aged 45 y or older (HR = 1.07, 95% CI 0.84-1.35, p = 0.594, absolute risk = 0.3%). Associations in those aged 15 to 24 y were also found for violent crime arrests with preliminary investigations (HR = 1.28, 95% CI 1.16-1.41, p < 0.001), non-violent crime convictions (HR = 1.22, 95% CI 1.10-1.34, p < 0.001), non-violent crime arrests (HR = 1.13, 95% CI 1.07-1.20, p < 0.001), non-fatal injuries from accidents (HR = 1.29, 95% CI 1.22-1.36, p < 0.001), and emergency inpatient or outpatient treatment for alcohol intoxication or misuse (HR = 1.98, 95% CI 1.76-2.21, p < 0.001). With age and sex stratification, there was a significant association between SSRIs and violent crime convictions for males aged 15 to 24 y (HR = 1.40, 95% CI 1.13-1.73, p = 0.002) and females aged 15 to 24 y (HR = 1.75, 95% CI 1.08-2.84, p = 0.023). However, there were no significant associations in those aged 25 y or older. One important limitation is that we were unable to fully account for time-varying factors.ConclusionsThe association between SSRIs and violent crime convictions and violent crime arrests varied by age group. The increased risk we found in young people needs validation in other studies.

Project description:The vagus nerve can transmit signals to the brain resulting in a reduction in depressive behavior as evidenced by the long-term beneficial effects of electrical stimulation of the vagus in patients with intractable depression. The vagus is the major neural connection between gut and brain, and we have previously shown that ingestion of beneficial bacteria modulates behaviour and brain neurochemistry via this pathway. Given the high levels of serotonin in the gut, we considered if gut-brain signaling, and specifically the vagal pathway, might contribute to the therapeutic effect of oral selective serotonin reuptake inhibitors (SSRI). Mesenteric nerve recordings were conducted in mice after treatment with SSRI to ascertain if this class of drugs resulted in increased vagal excitability. Patch clamp recordings of enteric neurons were carried out to measure activity of primary afferent neurons in the gut in response to SSRI and to assess the importance of gut epithelium in transducing signal. The tail suspension test (TST) was used following 14d feeding of SSRI in vagotomised and surgical sham mice to measure depressive-like behaviour. Brain mRNA expression was examined via PCR and the intestinal microbiome was assessed. Mesenteric nerve recordings in BALB/c mice demonstrated that oral treatment with SSRI leads to a significant increase in vagal activity. This effect was not observed in mice treated with a representative noradrenaline-dopamine reuptake inhibitor. It is known that signals from the gut can be transmitted to the vagus via the enteric nervous system. Exposure of the gut to SSRI increased the excitability of intrinsic primary afferent neurons in the myenteric plexus, through an intestinal epithelium dependent mechanism, and alpha-diversity of gut microbiota was altered. Critically, blocking vagal signaling from gut to brain, via subdiaphragmatic vagotomy, abolished the antidepressive effects of oral SSRI treatment as determined by the tail suspension test. This work suggests that vagus nerve dependent gut-brain signaling contributes to the effects of oral SSRI and further, highlights the potential for pharmacological approaches to treatment of mood disorders that focus on vagal stimulation and may not even require therapeutic agents to enter the circulation.

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Selective serotonin reuptake inhibitors and risk of epilepsy after traumatic brain injury - A population based cohort study.

Publications

Selective serotonin reuptake inhibitors and risk of epilepsy after traumatic brain injury - A population based cohort study.

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