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Antipsychotics and Risk of Neuroleptic Malignant Syndrome: A Population-Based Cohort and Case-Crossover Study

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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.


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.


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.


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).


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.

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We thank Dr Angel Y.S. Wong for her input in addressing reviewers’ comments, and Dr In Hye Suh and Ms Lisa Lam for their review of the manuscript. This work was presented as an abstract at the International Conference on Pharmacoepidemiology & Therapeutic Risk Management, 24–28 August 2019, Philadelphia, USA. JEB is supported by the Hong Kong Research Grants Council as a recipient of the Hong Kong PhD Fellowship Scheme.

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Correspondence to Esther W. Chan.

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This study was partially funded by the Early Career Scheme, Research Grants Council, Hong Kong (project reference 789813) received by Esther W. Chan. The funders had no role in the design, analysis, interpretation, or publication of this study.

Conflict of interest

All authors declare that no other support has been received from any organization for the submitted work; no other financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted study. KSJL was formerly employed by the University of Hong Kong where the majority of the work was completed, and is currently employed by Merck Sharp & Dohme China at submission. EWC has received research grants from the Research Grants Council, Hong Kong, Narcotics Division of the Security Bureau of the Government of the Hong Kong SAR, Research Fund Secretariat of the Food and Health Bureau, National Natural Science Fund of China, National Health and Medical Research Council (NHMRC, Australia), Wellcome Trust, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, and Takeda, outside the submitted work. ICKW received grants from the Research Grants Council (RGC, Hong Kong), Innovative Medicines Initiative (IMI), Shire, Janssen-Cilag, Eli-Lily, Pfizer, Bayer, European Union FP7 program. IW is a member of the National Institute for Health and Clinical Excellence (NICE) ADHD Guideline Group, the British Association for Psychopharmacology ADHD guideline group, and advisor to Shire. All other authors report no conflicts of interest.

Ethics approval

Research ethics approval was obtained from the Institutional Review Board of The University of Hong Kong/Hospital Authority HKWC (Reference Number: UW 15-619).

Consent to participate

This is a retrospective observational study based on unidentified data. Waiver of patient consent was approved by the ethics committee.

Consent for publication

Not applicable.

Code availability

Not applicable.

Data sharing

No additional data available.

Author Contributions

KSJL, ICKW, and EWC had the original idea for the study and contributed to the development of the idea and study design. KSJL and LL conducted the literature search. KSJL wrote the first draft of the study protocol. KSJL retrieved data and undertook the analysis. JZ independently cross-checked all the analyses and results. KSJL, JZ, JEB, ICKW, and EWC contributed to interpretation of the analyses. KSJL wrote the first draft of the paper. KSJL, JZ, ICKW, JEB, and EWC critically reviewed the results and the manuscript. FMCB, WCC, and DJC reviewed the data, the presentation of the paper, and provided clinical input. KSJL, ICKW, and EWC provided oversight to all aspects of this project. KSJL and EWC are the guarantors. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of data analysis.

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Lao, K.S.J., Zhao, J., Blais, J.E. et al. Antipsychotics and Risk of Neuroleptic Malignant Syndrome: A Population-Based Cohort and Case-Crossover Study. CNS Drugs 34, 1165–1175 (2020).

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