Risk of neuroleptic malignant syndrome among patients exposed to antipsychotics

Abstract

Background: Antipsychotics are associated with neuroleptic malignant syndrome (NMS), a rare but serious adverse reaction. However, the epidemiology and risk estimation of NMS among antipsychotic users is unknown. Objectives: 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: This study was a population‐based cohort and case‐crossover study analyzing health records from the Hong Kong Hospital Authority. Among 297,647 antipsychotic users identified from January 1st, 2004 to December 31st, 2016, 328 patients had their incident diagnosis of NMS during the same period. We further extended the NMS identification period to November 30th, 2017 and analyzed data for a total of 336 eligible patients. In the primary analysis, the use of antipsychotics was compared during day 1 to 30 (case period) and day 91 to 120 (reference period) preceding the diagnosis of NMS to estimate the risk of NMS associated with any antipsychotic, haloperidol, olanzapine, quetiapine, and risperidone (case‐crossover study). We also calculated the incidence and case fatality risk of NMS (cohort study). Results: 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. Conclusions: 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.