Antidepressant pharmacotherapy in epilepsy: the effects of chronic fluoxetine and citalopram treatments in a rat model of epileptogenesis

Introduction: In patients with epilepsy there is a high incidence of comorbid psychiatric illnesses, especially mood and anxiety disorders, which have been associated with lower quality of life, impaired function and an elevated risk of suicide. In fact, the occurrence of these illnesses in patients with epilepsy has been reported to be a stronger predictor of quality of life than epilepsy variables such as illness duration or seizure frequency. In addition, there is evidence that the depressed state itself may predispose to seizures and epilepsy. For these reasons, effective management of depressive and anxiety symptoms and syndromes in epilepsy is essential. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depression in epilepsy, therefore it is important to consider their impact on epilepsy. To date, many studies have suggested that SSRI are safe for use in epilepsy, but the majority of these studies administered SSRIs only acutely or for short periods, and investigated effects only on acute seizure endpoints. There is no indication of the effect that chronic SSRI treatment may have on epileptogenesis and the associated neurobiological changes that continue after seizures emerge. This thesis aimed to investigate the effects of chronic SSRI treatment in a rat model of epileptogenesis, as well as investigating common neurobiological substrates of SSRI treatment and epileptogenesis that may also influence the disorder. It was hypothesised that chronic SSRI treatment would slow the rate of kindling epileptogenesis, as well as mitigate effects on common neurobiological substrates. Methods: The amygdala kindling model was used to assess the effects of chronic SSRI treatment (with fluoxetine or citalopram) on epileptogenesis. 9-11 week old male Wistar rats were surgical implanted with a bipolar electrode into the left amygdala for electrical kindling and a subcutaneously implanted osmotic pump filled with fluoxetine (10mg/kg/day, n=19) or vehicle (50% DMSO, n=22) or citalopram (10mg/kg/day, n=26) or vehicle (50% DMSO, n=22), comprising two separate cohorts. All rats were given 30 stimulations and then kindling rate, seizure duration and seizure threshold before and after kindling were monitored. Effects on anxiety- and depressive-like behaviours were also investigated after kindling using two well-validated tests, the elevated plus maze and forced swim test respectively, as well as assessing the corticosterone response to stress and dentate gyrus neurogenesis. Results: The key finding of this study was that rats chronically treated with SSRIs, either fluoxetine or citalopram, demonstrated accelerated rates of kindling epileptogenesis, showing a more rapid progression through the different stages of kindling compared to vehicle treated rats. The increase in seizure duration was also accelerated in the early stages of kindling in both cohorts of SSRI treated rats, however seizure threshold was not significantly different between vehicle and fluoxetine or vehicle and citalopram treated rats, either before or after kindling. This indicates that while epileptogenesis itself progressed at a faster rate during chronic SSRI treatment, accelerating the increase in seizure severity and duration, the local excitability and the threshold at which a seizure occurred was not affected by SSRI treatment. In order to investigate potential mechanisms underlying this, neurobiological alterations common to epileptogenesis and SSRI treatment were also investigated. Behavioural analyses found that both fluoxetine and citalopram treatments did not affect anxiety- or depressive-like behaviours, while kindling increased anxiety-like behaviour, but only in the fluoxetine treated cohort. Dentate gyrus neurogenesis was not significantly affected by kindling or drug treatment while stress-induced corticosterone levels were significantly reduced only by fluoxetine treatment. These investigations do not suggest that these alterations are associated with accelerating kindling rate during chronic SSRI treatment, however how these are affected during or immediately after kindling was not investigated. Conclusions: Chronic treatment with fluoxetine and citalopram, at clinically relevant doses, accelerated kindling epileptogenesis in rodents. This highlights the need to investigate the effects of SSRI treatment on epileptogenesis over time in both animal models and people with epilepsy, rather than focusing solely on acute seizure time points. While the investigations in this study do not suggest that alterations in behaviour, neurogenesis or neuroendocrine responses are associated with accelerating kindling rate during chronic SSRI treatment, how these are affected during or immediately after kindling was not investigated. Therefore, future studies should further investigate the mechanisms underlying the effects of SSRIs on epileptogenesis at appropriate time points, such as during kindling epileptogenesis and also in complementary animal models of epilepsy, such as post-status epilepticus and post-traumatic models. It is essential to treat the depressive symptoms that manifest in people with epilepsy; however whether these medications affect the course of epilepsy and how they may do so should become priority areas for future research.