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Prediction Tools for Psychiatric Adverse Effects After Levetiracetam Prescription

Educational Objective
To determine whether routine clinical data can be used to predict which patients with epilepsy will experience a psychiatric adverse effect from levetiracetam.
1 Credit CME
Key Points

Question  Can routine clinical data be used to predict which patients with epilepsy will experience a psychiatric adverse effect from levetiracetam?

Findings  Among 1173 patients with epilepsy receiving levetiracetam in this open cohort study, 2 prediction models were created: one for the overall population and one for those without a history of a psychiatric sign, symptom, or disorder during the study period. The corresponding areas under the curve were 68% and 72%, respectively, and 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.

Meaning  Levetiracetam has rapidly become a drug of first choice, and these models can be used to predict the risk of psychiatric adverse effects.

Abstract

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.

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Article Information

Accepted for Publication: November 8, 2018.

Published Online: January 28, 2019. doi:10.1001/jamaneurol.2018.4561

Correction: This article was corrected on March 18, 2019, to fix a typographical error in the second risk score model in the Prediction Modeling subsection of the Results.

Corresponding Author: Colin B. Josephson, MD, MSc, FRCPC, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Foothills Medical Centre, 1403 29th St NW, Calgary, AB T2N 2T9, Canada (cbjoseph@ucalgary.ca).

Author Contributions: Dr Josephson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Josephson, Engbers, Jette, Macrodimitris, Wiebe.

Acquisition, analysis, or interpretation of data: Josephson, Engbers, Jette, Patten, Singh, Sajobi, Marshall, Agha-Khani, Federico, Mackie, McLane, Pillay, Sharma, Wiebe.

Drafting of the manuscript: Josephson, Engbers, Agha-Khani, Sharma.

Critical revision of the manuscript for important intellectual content: Josephson, Jette, Patten, Singh, Sajobi, Marshall, Federico, Mackie, Macrodimitris, McLane, Pillay, Wiebe.

Statistical analysis: Josephson, Engbers, Sajobi.

Administrative, technical, or material support: Engbers, Pillay.

Supervision: Jette, Marshall, Macrodimitris, Wiebe.

Conflict of Interest Disclosures: Dr Josephson reported being the recipient of the American Brain Foundation/American Epilepsy Society/Epilepsy Foundation/American Academy of Neurology Susan S. Spencer Clinical Research Training Fellowship in Epilepsy and of an Alberta Innovates Health Solutions Clinician Fellowship. Dr Engbers reported being supported by an Alberta Innovates Health Solutions Postdoctoral Fellowship. Dr Jette reported being the holder of a Canada Research Chair Tier 2 in Neurological Health Services Research and reported receiving operating grants (paid to her institution) from the Canadian Institutes of Health Research, National Institute of Neurological Disorders and Stroke of the US National Institutes of Health, Alberta Health, and the University of Calgary Cumming School of Medicine. Dr Sajobi reported being supported by an M.S.I. Foundation New Investigator Grant. Dr Marshall reported being supported by a Canada Research Chair (Health Services and Systems Research) and the Arthur J. E. Child Chair in Rheumatology Outcomes Research and reported receiving operating grants (paid to the University of Calgary) from the Canadian Institutes of Health Research, Alberta Innovates Health Solutions, EuroQoL Research Foundation, Colorectal Cancer Association of Canada, Genome Canada, Canadian Initiative for Outcomes in Rheumatology cAre (CIORA), and the University of Calgary Cumming School of Medicine. Dr Wiebe reported being the holder of the Hopewell Professorship of Clinical Neurosciences Research at the University of Calgary.

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