Prediction Tools for Psychiatric Adverse Effects after Levetiracetam Prescription

Colin B. Josephson, Jordan D.T. Engbers, Nathalie Jette, Scott B. Patten, Shaily Singh, Tolulope T. Sajobi, Deborah Marshall, Yahya Agha-Khani, Paolo Federico, Aaron MacKie, Sophie MacRodimitris, Brienne McLane, Neelan Pillay, Ruby Sharma, Samuel Wiebe

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48 Scopus citations


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 11194182 patients registered in THIN, this study identified 7400 presumed incident cases (66.1 cases per 100000 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.

Original languageEnglish
Pages (from-to)440-446
Number of pages7
JournalJAMA Neurology
Issue number4
StatePublished - Apr 2019


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