Abstracts

Rationale: Due to the high comorbidity of epilepsy and depression, antidepressant treatment is commonly indicated for patients with epilepsy. Studies in humans and animal models suggest that selective serotonin reuptake inhibitors (SSRIs) may reduce seizure frequency and severity, but how SSRIs impact epileptogenesis, the neurobiological process underlying the development of the epileptic state, has not been extensively studied. We previously reported that SSRIs accelerate kindling epileptogenesis. Here we expanded this using the post-Status Epilepticus model, and investigated biological mechanisms.Methods: Wistar rats (n=46 in total) underwent Kainic Acid-induced Status Epilepticus (SE). At the conclusion, rats were treated with the SSRI Fluoxetine (10mg/kg/day sc) or vehicle via infusion pump for 10 weeks. Animals were continuously monitored via video-EEG for 10 weeks, when they were transcardially perfused and brains processed for mossy fibre sprouting (ZnT3 immunocytochemistry). The onset of epilepsy and total number of seizures were compared between treatments, as was the extent of mossy fibre sprouting. A second cohort underwent the same procedures, but was treated with a 5-HT2 agonist DOI (1mg/kg/day/sc) or control, and the same outcomes assessed.Results: Fluoxetine significantly accelerated epileptogenesis, leading to a faster onset of epilepsy after SE, compared to control treatment (P<0.0001 Logrank survival curve). Fluoxetine treatment also resulted in greater disease severity, as evidenced by significantly more seizures that control treatment (p<0.0001). Mossy fibre sprouting was evident in all epileptic animals, but the immunoreactivity in the dentate gyrus was significantly more pronounced in fluoxetine-treated rats (P<0.01). In the second experiment, treatment with DOI significantly enhanced epileptogenesis in a similar fashion to that of fluoxetine, accelerating the onset of epilepsy (p<0.0001) and increasing the number of seizures experienced (p=0.001).Conclusions: Following SE, chronic treatment with fluoxetine accelerates epileptogenesis and magnifies disease severity. Pathological reorganisation of hippocampal circuitry was also observed following fluoxetine treatment. The same effects were noted with an agonist at 5-HT2 receptors, suggesting that this receptor may be responsible for the observed effects of the SSRI antidepressant. These findings may have relevance for people taking SSRI antidepressants who are at high risk of developing epilepsy, such as following a traumatic brain injury.