br Funding sources br Introduction Psychiatric comorbidities
Introduction Psychiatric comorbidities affect up to 70% of people with pharmacoresistant epilepsy and significantly impact quality of life . Psychiatric comorbidities in epilepsy have been thought to be due to psychosocial stress. However, recent evidence suggests a more complex pathogenesis. Not only are individuals with epilepsy two times more likely to develop depression, but also individuals with depression are 2.5 times more likely to develop epilepsy . Individuals with psychiatric comorbidities show greater abnormalities on neuroimaging   and have a poorer seizure prognosis  and an increased risk of sudden death . This suggests that there may be genetic differences in patients with epilepsy and psychiatric comorbidities. Genetic factors play a significant role in psychiatric disorders with heritability estimates of up to 75% , . Apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), and catechol-O-methyltransferase (COMT) polymorphisms have been studied as candidate Mifepristone in a number of psychiatric conditions. APOE4 has been variably associated with depression and bipolar disorder , and BDNF Val66Met has been reliably associated with stress-induced depression . The COMT Val158Met has been associated with obsessive compulsive and bipolar disorders, and the COMT Val allele has been associated with schizophrenia and panic disorder , . Despite this knowledge and the high prevalence of psychiatric disorders in individuals with epilepsy , genetic associations with psychiatric comorbidities in patients with epilepsy have remained largely unexplored. The aim of the current study was to determine whether these three common genetic polymorphisms are associated with increased psychiatric symptomatology in people with pharmacoresistant epilepsy.
Results A total of 148 patients met all inclusion criteria. Patients were taking an average of 2.36 (SD = 0.96) antiepileptic drugs (AEDs) at the time of their neuropsychological evaluation. These medications were categorized with respect to potential psychiatric side effects based on the current literature , , . Seventy-four percent of participants were taking at least one AED with favorable psychotropic effects (i.e., carbemazepine, oxycarbazepine, lamotrigine, pregabalin, gabapentin, and valproic acid), and 64% of participants were taking at least one AED with unfavorable psychotropic effects (i.e., phenobarbital, primidone, levetiracetam, zonisamide, and topiramate). Forty-three percent were taking at least one drug from each category. A summary of the sample characteristics is provided in Table 2. There were no significant differences in demographic or disease characteristics between APOE ε4+ and ε4− groups or between BDNF Met+ and Met− groups. The COMT Val+ group had a higher proportion of nonwhite individuals (13.7% vs. 0%) and a lower mean education (13.1 vs. 14.0) than the Val− group. The observed difference in race is consistent with population data showing a higher frequency of the Val allele in the African and Hispanic populations .
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 alleles 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 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 , , . 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 . Serum BDNF levels are decreased in patients with depression and normalize with antidepressant treatment . Additionally, individuals with epilepsy who have more frequent seizures have lower BDNF levels than those with less frequent seizures, independent of depressive symptoms . 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 . Second, animal studies have demonstrated that the development of depression following epilepsy onset can be prevented through treatment with a BDNF analog .