Chronic antidepressant treatment accelerates kindling epileptogenesis in rats☆
Introduction
Mood and anxiety disorders are common co-morbidities in patients with epilepsy, in particular those with drug-resistant epilepsy (Gaitatzis et al., 2004). Mesial temporal lobe epilepsy (MTLE), the most common form of drug-resistant epilepsy in adults, has a particularly strong association with depression (Kanner, 2006a). These mood disorders have a major adverse impact on the quality of life of patients, and are associated with poorer seizure control, increased drug resistance, and a higher likelihood of suicide (Hesdorffer et al., 2006). The presence of psychopathology in patients with epilepsy has been consistently found to be one of the most important determinants of quality of life (Boylan et al., 2004). Active management of depression and anxiety is therefore an essential part of comprehensive treatment of people with epilepsy.
The mainstay of the pharmacological treatment of mood disorders is antidepressant medication. There has been a commonly held concern amongst clinicians about the safety of the use of these medications in people with epilepsy, stemming from the propensity of ‘first generation’ antidepressants, particularly tricyclic antidepressants (TCAs), to induce seizures in a few patients (Salzberg and Vajda, 2001). However, a growing body of evidence suggests that this should be less of a concern for the newer, or ‘second generation’, antidepressants. These newer classes, notably the selective serotonin reuptake inhibitors (SSRIs), may even decrease seizure frequency (Alper et al., 2007, Bagdy et al., 2007, Kanner, 2009). These clinical reports largely agree with animal literature on the influence of SSRIs on experimentally-induced seizures (reviewed in Cardamone et al., 2013).
While previous clinical and experimental studies have examined effects of antidepressants on seizure frequency, to our knowledge, none have investigated the effects of these drugs on epileptogenesis, despite strong reasons to suspect such effects (Cardamone et al., 2013). Epileptogenesis refers to the neurobiological processes which transform normal brain networks into an epileptic state, with an increased propensity to generate seizures (Goldberg and Coulter, 2013). These processes continue even after the epileptic state is reached, and are likely compounded by the effects of the spontaneous recurrent seizures themselves.
There are several good reasons for considering effects of SSRIs on epileptogenesis, especially in MTLE. First, the brain structures where most epileptogenic changes occur in MTLE show considerable overlap with those involved with the neurobiology of mood disorders, notably the hippocampus and amygdala (Nestler et al., 2002). Secondly, serotonergic neurotransmission is a key aspect of the function of both these structures (Bagdy et al., 2007). Thirdly, there is increasing epidemiological evidence that depression and other psychopathologies pre-date, and are a risk factor for the emergence of epilepsy (Hesdorffer et al., 2012), and so the possibility should be considered that treatment with antidepressants of some depressed patients may influence the onset of epilepsy (Hesdorffer et al., 2000). Based on these and other considerations, an emerging theory proposes that the pathogenesis of depression and epilepsy share common mechanisms (Kanner, 2006b, Kanner, 2012), leading to the proposal that antidepressants may have antiepileptic efficacy (Kanner, 2012). The influence of antidepressants on epileptogenesis is thus a question of clear clinical importance: depression in epilepsy is often under-recognised and undertreated; authoritative bodies advocate screening and treatment to address this; however, a serious gap exists regarding knowledge of potential effects of antidepressants on epileptogenesis and disease progression.
With these issues in mind, this study was designed to investigate the effect of chronic SSRI treatment on the progression of epileptogenesis using the amygdala kindling rat model of temporal lobe epilepsy (Morimoto et al., 2004). We also investigated potential molecular mediators underlying any effects by studying key players in the mechanism of action of the antidepressants: the serotonin transporter (SERT) as the primary target of SSRIs, and 5-HT1A receptors which may be relevant to depression in epilepsy (Hasler et al., 2007, Theodore et al., 2007). We tested the effect of two commonly prescribed SSRI antidepressants, fluoxetine and then citalopram, first-line medications for the treatment of depression in epilepsy.
Section snippets
Surgical implantation of osmotic pumps and stimulating/recording electrodes
Male Wistar rats aged 9–11 weeks underwent electrode implantation as previously described (Jones et al., 2009). Briefly, rats were anaesthetised with isofluorane (5% induction, 1.5–2.5% maintenance) and placed into a stereotactic frame. Holes were drilled into the skull to allow implantation of extradural recording electrodes, and a bipolar stimulating electrode (Plastics One, USA) into the left basolateral amygdala complex (AP: − 3.0; ML: − 5.25 relative to bregma; DV: − 6.5 relative to the dura (
Fluoxetine serum drug and metabolite levels
Serum was taken from animals at the completion of the fluoxetine study, and analysed for drug levels. All drug-treated animals had detectable levels of fluoxetine (mean: 0.38 ± 0.03 μmol/l) and norfluoxetine (3.02 ± 0.16 μmol/l), confirming effectiveness of the pumps to deliver drug over the treatment period (Fig. 1). There were no detectable drug levels in vehicle-treated rats. In addition, despite using a very high concentration of DMSO in the pumps, albeit at a very low release rate (60 μl/day), we
Discussion
The key finding of this study was that chronic SSRI antidepressant treatment in rats, using both citalopram and fluoxetine, increases susceptibility to limbic epileptogenesis. This did not appear to be due to effects on the innate excitability of the brain, since neither drug influenced seizure threshold. This finding suggests that the use of antidepressants may adversely impact the onset and progression of limbic epilepsy in patients.
The majority of studies that have examined antidepressant
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