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Purpose: Depression is most commonly associated with epilepsy. Recent reports have suggested a putative relationship between seizure development and onset of depressive behavior, whereas others proposed that two clinical entities might represent different neuropathologic aspects of the same neurologic disorder. The WAG/Rij rat absence epilepsy model has also been proposed as a suitable model to test antidepressant drugs. We previously reported on a long-term study of two antiepileptic drugs (AEDs) to assess their protective role in absence epileptogenesis. Here, we examined the effects of long-term treatment with several AEDs on absence seizure development and onset of depressive-like behavior in WAG/Rij rats at different ages, using a forced swimming test (FST).
Methods: Animals were divided into one untreated control group and four test groups, given ethosuximide, levetiracetam, zonisamide, or carbamazepine. Electroencephalography (EEG) readings were recorded at 6.5 months of age.
Key Findings: Ethosuximide-treated animals showed significant reductions in recorded spike-wave discharges (SWDs), and FST immobility time (IT) compared with untreated same age controls. However, zonisamide- and carbamazepine-treated animals had IT values similar to those of controls, but only zonisamide significantly decreased absence seizure development. Carbamazepine increased SWD incidence. Levetiracetam also protected against seizure development, while augmenting IT, suggesting a prodepressive effect.
Significance: Although treatment with ethosuximide, levetiracetam, or zonisamide reduced appearance of SWDs in WAG/Rij rats, this was not generally linked to a reduced onset of depressive characteristics, as assessed by FST. Therefore, expression of depressive-like behavior seems unrelated to seizure control in this model. Some possible alternative explanations for the observed data are discussed.
Depression is the most common comorbid psychiatric condition associated with epileptic syndromes, with a severe impact on quality of life (Edeh & Toone, 1987; Jacoby et al., 1996); there is also a significantly increased risk of suicide compared with healthy controls (Caplan et al., 2005; Verrotti et al., 2008; Bell & Sander, 2009). The prevalence of clinical depression in epilepsy is also higher than that for other chronic disorders such as asthma or diabetes (Ettinger et al., 2004). Between 20% and 55% of epilepsy patients are estimated to be affected, and the condition often remains underdiagnosed and undertreated (Kanner & Palac, 2000), mainly due to the misconception that antidepressant drugs are generally proconvulsant (see Jobe & Browning, 2005). Interestingly, longitudinal studies in epilepsy and depression have reported a bidirectional temporal association. Therefore, epilepsy is frequently followed by depression, whereas preexisting depression is approximately seven times more common among patients with new-onset epilepsy (usually preceding the seizure disorder), compared with age- and sex-matched controls. In addition, when analyses were restricted to cases with an unprovoked “localized onset” seizure, depression was 17 times more common among affected cases than among nonseizure controls (Forsgren & Nyström, 1990; Hesdorffer et al., 2000); the strong links between temporal or frontal lobe epilepsy and depression are particularly well recognized (Grabowska-Grzyb et al., 2006; García-Morales et al., 2008). Perhaps the more acute neurochemical/structural changes in the brain associated with a partial epileptic focus contribute to depression onset by disrupting neural circuits involved in emotional processing (Giovacchini et al., 2005; Chayasirisobhon, 2009).
Epilepsy is treated with a number of antiepileptic drugs (AEDs) according to etiology, age, and pattern of onset, some of which may themselves alter psychobiologic processes (Andersohn et al., 2010; Arana et al., 2010). Although effective seizure control improves the life quality of patients with epilepsy, the coexistence of depression seems a more important determinant of psychological well-being than seizure frequency/severity or AED-related side effects (Boylan et al., 2004); less is known about the role of AED treatments in comorbid depression onset and maintenance. In 2008, the U.S. Food and Drug Administration (FDA) conducted a study of patients taking AEDs and their increased risk of suicidal ideation and behavior, concluding that AED use was associated with a 1.8-fold higher likelihood of depression, compared to patients taking a placebo. However, this point has remained controversial and many neurologists have raised concerns over methodologic issues in the FDA’s evaluation (Bell et al., 2009; Hesdorffer & Kanner, 2009). Although AEDs might increase the risk of or induce depression, it remains difficult to distinguish between disease-induced depression and AED-induced depression in clinical practice, as also recently supported by other studies (Wen et al., 2010; Bagary, 2011). This confounding difficulty, however, has to be taken into account when studying epilepsy and depression in comorbidity, both in patients and animal models.
To study the pathogenic mechanisms of depression in epilepsy and to assist the development of adequate therapies, several animal models have been used. In particular, WAG/Rij rats, genetic absence epileptic rats from Strasbourg (GAERS), and Long-Evans rats with spontaneous spike-wave discharges (SWDs) represent well-validated animal models of absence-type epilepsy (Danober et al., 1998; Coenen & Van Luijtelaar, 2003; Shaw et al., 2009) with depression-like symptoms (Jones et al., 2008; Shaw et al., 2009; Sarkisova & van Luijtelaar, 2011). Other epilepsy/seizure models have been tested for depression-like behavior; however, results have been controversial and inconclusive (Mazarati et al., 2008; Müller et al., 2009). Furthermore, animal studies have never focused on a possible pharmacologic correlation between AED effects and the development of either seizures or depressive-like symptoms.
Absence-type seizures (van Luijtelaar & Sitnikova, 2006) are particularly prevalent in children, have strong genetic links, and are characterized by brief absences, where consciousness is compromised. Electroencephalography (EEG) recording in epileptic patients reveals bilateral, synchronous symmetrical SWDs (3–4 Hz), on a normal background (Commission, 1989). However, the precise origin of these oscillations is still unclear. Studies in WAG/Rij rats have revealed a cortical focus within the SmI (somatosensory cortex) responsible for SWD generation (Meeren et al., 2005). This model is now widely regarded as a valid animal model of human absence epilepsy (for a review see Coenen & Van Luijtelaar, 2003). We previously reported that early long-term treatment (from 1.5 to 5 months) of WAG/Rij rats with the antiabsence drug ethosuximide (ETH) or levetiracetam (LEV) suppressed absence seizure development (Russo et al., 2010). Recently, Sarkisova et al. (2010) reported that similar ETH treatment not only prevented SWDs, but also inhibited depressive-like behavior in these animals, concluding that seizures were responsible for depression onset. It remains unclear, however, whether this applies more generally to AEDs and depression, or merely a particular feature of the action of ETH. Here, we wished to test how some other AEDs [zonisamide (ZNS), carbamazepine (CBZ), and LEV] with proposed mechanisms of action different from those of ETH (Czapiński et al., 2005) would affect development of absence seizures and depression-like symptoms in WAG/Rij rats, with a view to a better understanding of depression management in epilepsy. LEV was chosen because of its proven efficacy in absence epilepsy (for a review see Hughes, 2009) and its known antiepileptogenic effects in this animal model (Russo et al., 2010). ZNS was chosen considering its efficacy in the treatment of absence epilepsy (Hughes, 2009), its neuroprotective/antiepileptogenic properties (Willmore, 2005), and a high associated risk of developing depression in patients (Mula & Sander, 2007). CBZ is known to aggravate absence seizures, both in human patients (Gansaeuer & Alsaadi, 2002) and experimentally (Liu et al., 2006); it was chosen as a negative control for absence epilepsy while having antiepileptogenic properties (Capella & Lemos, 2002), and also since its use has been associated with some beneficial effects in patients with major depressive disorder (Vigo & Baldessarini, 2009; for drug choice rationale see also Discussion).
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Data S1. Preparation of carbamazepine solution for oral administration.
Data S2. Brief description of EEG analysis.
Data S3. Rationale for carbamazepine dose titration, serum drug concentrations, and animal growth.
Figure S1. Schematic representation of control and test animal groups.
Figure S2. Effects of carbamazepine focally administered in the perioral region of the somatosensory cortex (S1po) of WAG/Rij rats.
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