Dataset Information

HLAs associated with perampanel-induced psychiatric adverse effects in a Korean population.

ABSTRACT: Perampanel (PER) is a new-generation antiepileptic drug that has an occasional but significant shortcoming, psychiatric adverse effects (PAEs). Recently, antiepileptic drug-related adverse reactions, such as skin rash and even PAEs, have been discovered to be correlated with certain human leukocyte antigen (HLA) types. Thus, we aimed to analyze specific HLA alleles as risk factors for PER-PAEs. We prospectively enrolled 17 patients with epilepsy who were prescribed PER between May 2016 and Jul 2018 at Seoul National University Hospital and developed PAEs while taking PER. Their HLA types were analyzed compared to those of 19 patients in the PAE-tolerant group and the general Korean population. In silico docking was performed with two different computational programs, AutoDock Vina and SwissDock, to theoretically evaluate the binding affinity of PER in the grooves of the specific HLA alleles. The HLA-DQB1*06:01, DRB1*08:03, and B*54:01 alleles were significantly associated with the patients who developed PER-PAEs compared with the general Korean population (odds ratio [OR] 3.94, p?=?0.008, OR 9.24, p?=?0.037, and OR 3.25, p?=?0.041, respectively). As a haplotype, the combination of the three alleles was significantly more frequent in the PER-PAE group than in both the PER-tolerant group and the general Korean population. DQB1*06:01 and B*54:01 also demonstrated higher docking scores with PER than other alleles. This is the first study to analyze the association of PER-PAEs with specific HLA genotypes. Our results suggest that an HLA-associated genetic predisposition and a possible immunological mechanism are involved in the occurrence of PER-PAEs.

SUBMITTER: Jang Y

PROVIDER: S-EPMC7423598 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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HLAs associated with perampanel-induced psychiatric adverse effects in a Korean population.

Jang Yoonhyuk Y Kim Tae-Joon TJ Moon Jangsup J Yang Tae-Won TW Kim Keun Tae KT Park Byeong-Su BS Lim Jung-Ah JA Jun Jin-Sun JS Lee Soon-Tae ST Jung Keun-Hwa KH Park Kyung-Il KI Jung Ki-Young KY Chu Kon K Lee Sang Kun SK

Scientific reports 20200812 1

Perampanel (PER) is a new-generation antiepileptic drug that has an occasional but significant shortcoming, psychiatric adverse effects (PAEs). Recently, antiepileptic drug-related adverse reactions, such as skin rash and even PAEs, have been discovered to be correlated with certain human leukocyte antigen (HLA) types. Thus, we aimed to analyze specific HLA alleles as risk factors for PER-PAEs. We prospectively enrolled 17 patients with epilepsy who were prescribed PER between May 2016 and Jul 2 ...[more]

PMID: 32788606

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Project description:Perampanel, a selective, noncompetitive ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is indicated for adjunctive treatment of partial seizures in patients ?12 years based on three phase III clinical studies. The perampanel U.S. Prescribing Information includes a boxed warning for serious psychiatric and behavioral adverse reactions. To provide context for this warning, detail on psychiatric and behavioral safety data from perampanel clinical studies is presented.An analysis of pooled safety data from three phase III studies in patients with partial seizures is presented. Data from phase I and phase II studies in patients with and without epilepsy were also analyzed. Psychiatric and behavioral treatment-emergent adverse events (TEAEs) were evaluated according to Medical Dictionary for Regulatory Activities (MedDRA) terms, using "narrow" and "narrow-and-broad" standardized MedDRA queries (SMQs) for TEAEs suggestive of hostility/aggression.From the three phase III partial-seizure studies, the overall rate of psychiatric TEAEs was higher in the 8 mg (17.2%) and 12 mg (22.4%) perampanel groups versus placebo (12.4%). In the "narrow" SMQ, hostility/aggression TEAEs were observed in 2.8% for 8 mg and 6.3% for 12 mg perampanel groups, versus 0.7% of placebo patients. "Narrow-and-broad" SMQs for hostility/aggression TEAE rates were 12.3% for 8 mg and 20.4% for 12 mg perampanel groups, versus 5.7% for placebo; rates for events resulting in discontinuation were perampanel = 1.6% versus placebo = 0.7%. For events reported as serious AEs (SAEs), rates were perampanel = 0.7% versus placebo = 0.2%. In nonepilepsy patients, psychiatric TEAEs were similar between patients receiving perampanel and placebo. In phase I subjects/volunteers, all psychiatric TEAEs were mild or moderate. These analyses suggest that psychiatric adverse effects are associated with use of perampanel.Patients and caregivers should be counseled regarding the potential risk of psychiatric and behavioral events with perampanel in patients with partial seizures; patients should be monitored for these events during treatment, especially during titration and at higher doses.

Project description:Importance:Levetiracetam is a commonly used antiepileptic drug, yet psychiatric adverse effects are common and may lead to treatment discontinuation. Objective:To derive prediction models to estimate the risk of psychiatric adverse effects from levetiracetam use. Design, Setting, and Participants:Retrospective open cohort study. All patients meeting the case definition for epilepsy after the Acceptable Mortality Reporting date in The Health Improvement Network (THIN) database based in the United Kingdom (inclusive January 1, 2000, to May 31, 2012) who received a first-ever prescription for levetiracetam were included. Of 11 194 182 patients registered in THIN, this study identified 7400 presumed incident cases (66.1 cases per 100 000 persons) over a maximum of 12 years' follow-up. The index date was when patients received their first prescription code for levetiracetam, and follow-up lasted 2 years or until an event, loss to follow-up, or censoring. The analyses were performed on April 22, 2018. Exposure:A presumed first-ever prescription for levetiracetam. Main Outcomes and Measures:The outcome of interest was a Read code for any psychiatric sign, symptom, or disorder as reached through consensus by 2 authors. This study used regression techniques to derive 2 prediction models, one for the overall population and one for those without a history of a psychiatric sign, symptom, or disorder during the study period. Results:Among 1173 patients with epilepsy receiving levetiracetam, the overall median age was 39 (interquartile range, 25-56) years, and 590 (50.3%) were female. A total of 14.1% (165 of 1173) experienced a psychiatric symptom or disorder within 2 years of index prescription. The odds of reporting a psychiatric symptom were significantly elevated for women (odds ratio [OR], 1.41; 95% CI, 0.99-2.01; P = .05) and those with a preexposure history of higher social deprivation (OR, 1.15; 95% CI, 1.01-1.31; P = .03), depression (OR, 2.20; 95% CI, 1.49-3.24; P < .001), anxiety (OR, 1.74; 95% CI, 1.11-2.72; P = .02), or recreational drug use (OR, 2.02; 95% CI, 1.20-3.37; P = .008). The model performed well after stratified k = 5-fold cross-validation (area under the curve [AUC], 0.68; 95% CI, 0.58-0.79). There was a gradient in risk, with probabilities increasing from 8% for 0 risk factors to 11% to 17% for 1, 17% to 31% for 2, 30% to 42% for 3, and 49% when all risk factors were present. For those free of a preexposure psychiatric code, a second model performed comparably well after k = 5-fold cross-validation (AUC, 0.72; 95% CI, 0.54-0.90). Specificity was maximized using threshold cutoffs of 0.10 (full model) and 0.14 (second model); a score below these thresholds indicates safety of prescription. Conclusions and Relevance:This study derived 2 simple models that predict the risk of a psychiatric adverse effect from levetiracetam. These algorithms can be used to guide prescription in clinical practice.

Project description:BackgroundKnowledge of the adverse problems related to SARS-CoV-2 infection in marginalised and deprived groups may help to prioritise more preventive efforts in these groups. We examined adverse outcomes associated with SARS-CoV-2 infection among vulnerable segments of society.MethodsUsing health and administrative registers, a population-based cohort study of 4.4 million Danes aged at least 15 years from 27 February 2020 to 15 October 2021 was performed. People with 1) low educational level, 2) homelessness, 3) imprisonment, 4) substance abuse, 5) supported psychiatric housing, 6) psychiatric admission, and 7) severe mental illness were main exposure groups. Chronic medical conditions were included for comparison. COVID-19-related outcomes were: 1) hospitalisation, 2) intensive care, 3) 60-day mortality, and 4) overall mortality. PCR-confirmed SARS-CoV-2 infection and PCR-testing were also studied. Poisson regression analysis was used to compute adjusted incidence and mortality rate ratios (IRRs, MRRs).FindingsUsing health and administrative registers, we performed a population-based cohort study of 4,412,382 individuals (mean age 48 years; 51% females). In all, 257,450 (5·8%) individuals had a PCR-confirmed SARS-CoV-2 infection. After adjustment for age, calendar time, and sex, we found that especially people experiencing homelessness had high risk of hospitalisation (IRR 4·36, 95% CI, 3·09-6·14), intensive care (IRR 3·12, 95% CI 1·29-7·52), and death (MRR 8·17, 95% CI, 3·66-18·25) compared with people without such experiences, but increased risk was found for all studied groups. Furthermore, after full adjustment, including for status of vaccination against SARS-CoV-2 infection, individuals with experiences of homelessness and a PCR-confirmed SARS-CoV-2 infection had 41-times (95% CI, 24·84-68·44) higher risk of all-cause death during the study period compared with individuals without. Supported psychiatric housing was linked to almost 3-times higher risk of hospitalisation and 60-day mortality following SARS-CoV-2 infection compared with the general population with other living circumstances.InterpretationSocially marginalised and psychiatrically vulnerable individuals had substantially elevated risks of adverse health outcomes following SARS-CoV-2 infection. The results highlight that pandemic preparedness should address inequalities in health, including infection prevention and vaccination of vulnerable groups.FundingNovo Nordisk Foundation.

Dataset Information

HLAs associated with perampanel-induced psychiatric adverse effects in a Korean population.

Publications

HLAs associated with perampanel-induced psychiatric adverse effects in a Korean population.

Similar Datasets

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