Abstracts

Rationale: We analyzed the genotypic and phenotypic features of patients with psychosis of epilepsy (POE).

Methods: Patients with POE recruited to an epilepsy genetics research program underwent phenotyping and genetic analysis. The latter included screening for rare pathogenic variants in established epilepsy genes, and polygenic risk score (PRS) calculation for common risk variants associated with schizophrenia.


Results: 122 individuals with POE were identified: 86/122 (70%) had interictal psychosis, with schizophrenia the most common interictal phenotype (36/86, 42%). 28/122 (23%) had postictal psychosis (PIP), 2/122 (2%) antiseizure medication-induced psychosis, and 6/122 (5%) substance-induced psychosis. Focal epilepsies were more frequently associated with PIP (24/28, 86%) compared to interictal psychosis (39/86, 45%; p< 0.05; see Figure 1).

29% of POE patients with genetic data had a rare pathogenic variant: 19 in an epilepsy gene (PCDH19, SCN1A, DEPDC5, KCNT1, CHD2, SLC2A1, NPRL3, CLN3, NPRL3, ATP1A3, CACNA1A) and 4 had a chromosomal anomaly. 57% of patients with a rare pathogenic variant had interictal schizophrenia or schizophreniform disorder rather than PIP (9%; p< 0.05). PRSs showed that schizophrenia-related common risk variants were enriched in patients with POE compared to population controls (p=0.0007, linear regression), however, amongst the phenotypes a raised schizophrenia PRS was only observed in interictal schizophrenia (p=0.015) and not in those with PIP or other interictal POEs.


Conclusions: Of the POE phenotypes, interictal POE is threefold more common than PIP, and more likely to be associated with both rare pathogenic variants for epilepsy and common risk variants for schizophrenia. Interictal POE is not a single disorder, but a complex entity with diverse phenotypes based on symptom presentation, duration, chronicity and outcomes. Distinction between postictal and interictal psychoses is underscored by distinct neurobiological mechanisms that are both epilepsy- and etiologically-related (see Figure 2). Recognising the heterogeneity of POE informs understanding of the genetic basis and, in the future, will guide diagnosis and the development of targeted therapies for individuals with epilepsy who present with psychosis.


Funding: G.R. is in receipt of a Medical Research Future Fund Australian Epilepsy Research Fund grant as well as a National Health & Medical Research Council (NHMRC) Investigator Grant [APP2008737] that funded the current study, including research assistance from E.H. The authors acknowledge support by the NHMRC Centre for Research Excellence Grant [GNT2006841] and NHMRC Synergy Grant [GNT2010562]. I.E.S. is also supported by a NHMRC Senior Investigator Grant (GNT1172897), M.B. by a NHMRC Investigator Grant [APP1195236] and K.L.O. was supported by the Australian Commonwealth Government and the University of Melbourne Australian Government Research Training Program Scholarship [APP533086]. This work was also supported by the Victorian Government’s Operational Infrastructure Support Program, the NHMRC Independent Research Institute Infrastructure Support Scheme. The QSKIN Study is supported by NHMRC Grants [APP1185416, APP1073898, APP1063061].