Antipsychotics and Risk of Neuroleptic Malignant Syndrome: A Population-Based Cohort and Case-Crossover Study
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ORIGINAL RESEARCH ARTICLE
Antipsychotics and Risk of Neuroleptic Malignant Syndrome: A Population‑Based Cohort and Case‑Crossover Study Kim S. J. Lao1,2 · Jiaxi Zhao1 · Joseph Edgar Blais1 · Lam Lam1 · Ian C. K. Wong1,3 · Frank M. C. Besag3,4,5 · Wing Chung Chang6,7 · David J. Castle8,9 · Esther W. Chan1,6 Accepted: 15 September 2020 © Springer Nature Switzerland AG 2020
Abstract Background Neuroleptic malignant syndrome (NMS) is a rare and acute adverse drug reaction associated with antipsychotic therapy. However, few data on the risk and epidemiology of NMS are available. Objectives The aim of this study was to ascertain the incidence risk and all-cause mortality of NMS associated with antipsychotic use, and to assess the association of recent antipsychotic exposure and NMS. Methods We did a population-based study using data from the Hong Kong Hospital Authority’s Clinical Data Analysis and Reporting System database. Cases had a first diagnosis of NMS between 1 January 2004 and 30 November 2017. A case-crossover analysis was used to compare antipsychotic exposure 30 days before the diagnosis of NMS (index date) and a reference period 91–120 days before the index date. To adjust for potential time trends in antipsychotic exposure, we sampled from cases to match current cases and future cases, and further adjusted for select medications and acute medical conditions. Results 297,647 patients were prescribed antipsychotics, and the incidence risk of NMS was 0.11%. Of the 336 cases included in the case-crossover analysis, 20 (6%) died within 30 days after the index date; only one case had NMS recorded as the primary cause of death. When compared with the reference period, cases were more frequently prescribed multiple antipsychotics (15.8% vs 26.8%; standardized mean difference [SMD] 0.27) and short-acting injectable antipsychotics (3.6% vs 13.7%; SMD 0.37) during the 30 days prior to the diagnosis of NMS. Odds ratios for antipsychotic exposure in the case-crossover, case-crossover adjusted for time trend, and case-crossover adjusted for time trend and potential confounders analysis were 8.00 (95% confidence interval 3.42–18.69), 5.88 (2.46–14.04), and 4.77 (1.95–11.66). Conclusions Our results suggest that recent use of antipsychotics is associated with NMS. Although a case-only design inherently controls for confounding by time-invariant factors, residual confounding by acute medical conditions with similar presentations to NMS cannot be fully excluded.
1 Introduction Neuroleptic malignant syndrome (NMS) is a rare and potentially life-threatening adverse drug reaction. Since it was first reported in 1956, most cases have been linked to antipsychotics, although it can occur in patients receiving drugs that inhibit or deplete dopamine such as antiemetics (metoclopramide), benzodiazepines, antiepileptics, and lithium, or due to the withdrawal of dopaminergic therapy Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40263-020-00767-9) contains supplementary mater
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