Risk of Neuroleptic Malignant Syndrome Among Patients Exposed to Antipsychotics

Abstract

Background: Neuroleptic malignant syndrome (NMS), a rare but serious adverse reaction of antipsychotics, however, the little evidence risk and epidemiology of NMS is available. We aimed to determine the risk of NMS associated with exposure to any antipsychotic, and four antipsychotics commonly implicated in cases of NMS: haloperidol, olanzapine, quetiapine, and risperidone. To characterize the incidence and case fatality risk of NMS in patients taking antipsychotics. Methods: We conducted a population-based cohort analyzing health records of 297 647 antipsychotic users identified from January 1st, 2004 to December 31st, 2016 and 328 in patients with incident diagnosis of NMS during the same period, to measure the incidence and case fatality risk of NMS. We further extended the NMS identification period to November 30th, 2017 and conducted a case-crossover study analyzing data for a total of 336 eligible patients to estimate the risk of NMS associated with any antipsychotic, haloperidol, olanzapine, quetiapine, and risperidone, by comparing the use of antipsychotics during day 1 to 30 (case period) and day 91 to 120 (reference period) preceding the diagnosis of NMS. Findings: In the case-crossover study, 336 patients were diagnosed with NMS (210 males [62.5%]; mean age, 49.7 years; case fatality risk 6.0%). After adjustment for time trends in exposure, concurrent medications, and medical conditions, diagnosis of NMS was associated with exposure to any antipsychotic (OR, 4.77; 95% CI, 1.95-11.66), haloperidol (OR, 4.40; 95% CI 1.97-9.81), and quetiapine (OR, 4.32; 95% CI, 1.70-10.97), while there was no observed association for risperidone (OR, 2.00; 95% CI, 0.93-4.32) or olanzapine (OR, 1.23; 95% CI, 0.47-3.18). In the cohort of patients exposed to antipsychotics, NMS occurred with an incidence of 1.10 per 1000 persons. Interpretation: Antipsychotics are associated with an acutely increased risk of NMS. Patients had statistically significant increased odds of exposure to, haloperidol and quetiapine but not risperidone or olanzapine, during the 30 days prior to the diagnosis of NMS, as compared with the earlier reference period. Clinicians who prescribe antipsychotics should weigh the acutely increased risk of NMS with the potential benefits of antipsychotic therapy, especially for haloperidol and quetiapine. Funding: Early Career Scheme, Research Grants Council, Hong Kong. Declaration of Interest: This study was partially funded by Early Career Scheme, Research Grants Council, Hong Kong (project reference 789813) received by Esther W Chan. 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 three years; no other relationships or activities that could appear to have influenced the submitted study. Ethical 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).