The BDNF Val Met polymorphism
The BDNF Val66Met polymorphism is also associated with decreased dendritic arborization and impaired long-term potentiation . This is particularly important for the hippocampus, and healthy individuals with a BDNF Val66Met allele have decreased hippocampal volumes . Hippocampal atrophy is common in epilepsy  and is observed in individuals exposed to significant prolonged stress , 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  and following anterior temporal lobectomy , , , , and are at increased risk for sudden unexplained death in epilepsy (SUDEP) . Our results also suggest a relationship between the COMT rs4680 polymorphism and psychiatric symptomatology in epilepsy. As a group, Val carriers had higher scores on the Schizophrenia, Antisocial Features, and Alcohol Problems scales of the PAI than those without a Val allele. The Val allele has previously been variably associated with schizophrenia , antisocial behavior , and alcoholism . Results of the current study suggest a similar association with psychiatric symptomatology in people with epilepsy. While differences in group mean/median scores were statistically significant, it is important to note that mean/median scores on these measures were within the normal range for both GSK2656157 receptor groups, and there was no difference in the proportion of patients with elevated scores on these measures at the individual patient level. At the individual level, a larger proportion of COMT Val carriers endorsed clinically elevated anxiety symptoms on the PAI scale. Again, the functional role of COMT Val is informative in understanding the potential mechanism underlying the range of psychiatric symptoms associated with its presence. Catechol-O-methyltransferase is an enzyme responsible for dopamine degradation. The Val allele confers higher enzymatic activity resulting in lower synaptic dopamine in the prefrontal cortex . This is consistent with studies reporting that patients with drug-resistant temporal lobe epilepsy and psychiatric comorbidities exhibited a decrease in D2 receptor neurotransmission, compared to those without psychiatric comorbidities , . Notably, administration of D2 agonists reverses depression-like behavior in rats with genetic absence epilepsy . Dysregulation of dopaminergic signaling has been implicated in the development of various psychiatric disorders , . The association of the Val allele with schizophrenia has been hypothesized to be due to the selective decrease of dopamine within the prefrontal cortex . However, dopaminergic signaling in the brain also influences many aspects of cognitive functioning including motivation, emotion, reward, attention, and decision-making. The Val allele has been reliably associated with impaired cognitive functioning , so it is possible that the cognitive symptoms included in the Schizophrenia PAI scale may be driving the observed differences between the genotype groups. Regardless, our results provide further evidence for the role of aberrant dopaminergic signaling in the etiology of psychiatric comorbidities in epilepsy. Studies indicate that COMT Val carriers tend to have a poorer treatment response with antidepressant/anxiolytic therapy , , . In our cohort, Val carriers were taking significantly more psychotropic medications than those without a Val allele. It is possible that the variation in the proportion of patients with clinically elevated scores was due to differences in treatment response, rather than differences in predisposition to anxiety. Further studies will be needed to clarify whether the COMT Val allele influences risk for anxiety, treatment response, or both, in individuals with epilepsy.