Interictal Psychosis—A New Reason to Conduct Epilepsy Gene Testing?

Psychoses of Epilepsy: Unraveling the Phenotypic and Genotypic Features Rayner G, Honybun E, Bahlo M, Oliver KL, and Scheffer IE. Ann Neurol . 2025 Jul;98(1):35-47. doi: 10.1002/ana.27209. Objectives: 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 epilepsy genes, and polygenic risk score (PRS) calculation for common risk variants associated with schizophrenia. Results: One hundred twenty-two individuals with POE were identified. Eighty-six of 122 of the individuals (70%) had interictal psychosis, with schizophrenia the most common interictal phenotype (36 of 86, 42%). Twenty-eight of 122 individuals (23%) had postictal psychosis (PIP), 2 of 122 individuals (2%) had antiseizure medication-induced psychosis, and 6 of 122 individuals (5%) had substance-induced psychosis. Focal epilepsies were more frequently associated with PIP (24 of 28, 86%) compared to interictal psychosis (39 of 86, 45%; P < .05). Twenty-nine percent of the patients with POE with genetic data had a rare pathogenic variant: 19 in an epilepsy gene (PCDH19, SCN1A, DEPDC5, KCNT1, CHD2, SLC2A1, NPRL3, CLN3, NPRL3, ATP1A3, and CACNA1A) and 4 had a chromosomal anomaly. Fifty-seven percent of the patients with a rare pathogenic variant had interictal schizophrenia/schizophreniform disorder rather than PIP (9%; P < .05). PRSs showed that schizophrenia-related common risk variants were enriched in patients with POE compared to population controls ( P = .0007), however, among the POE phenotypes, a raised PRS was only observed in interictal schizophrenia ( P = .015) and not in those with PIP or other interictal POEs. Interpretation: 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. Distinguishing between different POE phenotypes enhances clinical practice and our understanding of etiology, paving the way for precision medicine. Prevalence, Clinical Characteristics, and Risk Factors for Psychosis in People With Epilepsy: A Multicenter Retrospective Cohort Study Shen S, Sun H, Dong Z, Yi T, Sander JW, Zhou D, and Li J. Epilepsia . 2025 Aug;66(8):2904-2915. doi: 10.1111/epi.18409. Objective: We aimed to assess the prevalence, clinical characteristics, and risk factors for psychosis in a cohort of people with epilepsy in West China. Methods: We used retrospective information from databases of 3 tertiary epilepsy centers, which included follow-up records from 2006 onward. Those with complete baseline data and at least 1 follow-up record were included. A psychiatrist confirmed the diagnosis of psychosis. Psychiatric features were evaluated using the Brief Psychiatric Rating Scale, Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms. Demographic data and clinical characteristics were used to develop risk models for interictal psychosis (IIP), ictal psychosis (IP), and postictal psychosis (PIP). Results: Eight hundred eighty-two people were identified. Of them, 112 (13%) were diagnosed with psychosis of epilepsy (POE), including 62 with IIP (7%), 29 with IP (3%), and 21 with PIP (2%). Twenty-seven of the 882 (3%) were diagnosed with epilepsy following the onset of psychosis. Individuals with pre-epilepsy psychosis, compared to those with POE, exhibited a lower proportion of refractory epilepsy, less frequent seizures, reduced seizure severity, and higher frequency and severity of hallucinations and delusions. In people with POE, bizarre behavior, avolition, and anhedonia were the 3 most common psychotic symptoms. Modeling identified several risk factors; earlier age at seizure onset, family history of schizophrenia, current frequent seizures, temporal lobe epilepsy (TLE), hippocampal sclerosis, perampanel use, and taking at least 2 antiseizure medications were associated with an increased risk of IIP. Severe head trauma, current frequent seizures, and TLE were risk factors for PIP, whereas current frequent seizures alone were a risk factor for IP. Significance: Psychosis is often comorbid with epilepsy. Our study suggests that the prevalence of POE may be 2 times higher than previously reported. Prompt recognition and early management of psychosis are warranted.