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  • br Discussion We examined the relationship between APOE


    Discussion We examined the relationship between APOE, BDNF, and COMT polymorphisms and psychiatric symptomatology in people with pharmacoresistant epilepsy. The strongest relationship was observed between BDNF Altiratinib australia and the PAI Depression scale. The BDNF Met carriers showed greater depressive symptoms on this scale than those without a Met allele. Further, at the individual level, a larger proportion of Met carriers had clinically elevated symptoms of depression on this Altiratinib australia measure (59% of carriers versus 34% of noncarriers). These findings are consistent with existing literature in healthy individuals and other patient populations that have shown BDNF Met carriers have an increased susceptibility to depression [9], [23], [24]. The functional consequences of BDNF polymorphisms inform how this might contribute to the pathogenesis of both depression and epilepsy. The BDNF Val66Met polymorphism results in decreased secretion of the protein, BDNF. This protein is highly expressed in the CNS and is a key modulator of neuronal plasticity and synaptogenesis [25]. Serum BDNF levels are decreased in patients with depression and normalize with antidepressant treatment [26]. Additionally, individuals with epilepsy who have more frequent seizures have lower BDNF levels than those with less frequent seizures, independent of depressive symptoms [27]. This may help to account for the high incidence of depression in patients with epilepsy. This mechanism has treatment ramifications for both seizure control and depression symptoms. First, patients treated with selective serotonin reuptake inhibitors (SSRIs) have increased serum BDNF levels and decreased seizure frequency [28]. Second, animal studies have demonstrated that the development of depression following epilepsy onset can be prevented through treatment with a BDNF analog [29]. The BDNF Val66Met polymorphism is also associated with decreased dendritic arborization and impaired long-term potentiation [25]. This is particularly important for the hippocampus, and healthy individuals with a BDNF Val66Met allele have decreased hippocampal volumes [30]. Hippocampal atrophy is common in epilepsy [31] and is observed in individuals exposed to significant prolonged stress [32], which is a model for depression. Individuals with epilepsy who carry the BDNF Val66Met allele may have an increased vulnerability to depression because of epilepsy and genotype-related reduction in the volume and/or plasticity in these structures. Interestingly, depression symptoms as reported on the BDI-II were not related to BDNF genotype. This may be due to the short time frame referenced on this measure; the BDI-II assesses acute depressive symptoms within the last two weeks, whereas the PAI assesses more stable, longstanding personality traits. The duration of mental health symptoms is relevant to the natural history of seizure disorders. Prior research in epilepsy has demonstrated that individuals with a lifetime history of a psychiatric diagnosis, including depression, are more likely to have poor seizure outcomes with pharmacotherapy [33] and following anterior temporal lobectomy [34], [35], [36], [37], and are at increased risk for sudden unexplained death in epilepsy (SUDEP) [5].