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

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: 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 to 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.

Evaluating the use of methods to mitigate bias from non‐transient medications in the case‐crossover design: A systematic review

“…Of the 114 included articles, the case‐crossover design was the most common (100, 88%), 18–117 followed by the case‐time‐control (19, 17%), 38,63,67,71,86,118–131 and case‐case‐time‐control (4, 3%) 33,47,48,86 . (Table 1) The most common outcomes measured in these studies were hospitalization (43, 38%), cardiovascular events (22, 19%) and fall‐related injury/fracture (15, 13%).…”

Serious adverse drug events associated with psychotropic treatment of bipolar or schizoaffective disorder: a 17-year follow-up on the LiSIE retrospective cohort study

“…However, data remain heterogenous; studies are difficult to compare ( 27 , 28 ). The relevant literature often takes substances, substance classes, or adverse effects itself as a starting point rather than diagnoses ( 3 , 29 , 30 ).…”

“…NMS is a rare event, but current incidence estimates continue to vary widely, between 0.016 and 0.1% exposed persons ( 30 , 39 ). One recent study in individuals with schizophrenia or schizoaffective disorder reported incidence rates according to PY exposure.…”

“…Acute respiratory failure, acute kidney injury (AKI), sepsis, and comorbid congestive heart failure were independent predictors of mortality. A recent study has reported an NMS-associated mortality within 30 days of the index event of 6.0% ( 30 ). A systematic review of six primary studies and 186 individual cases of NMS suggested that NMS associated with SGA was less common, less severe, and less lethal than NMS associated with FGA ( 43 ).…”

Antipsychotic-induced catatonia and neuroleptic malignant syndrome: the dark side of the moon

“…The scientific evidence is controversial, as information on symptoms, prevalence, course of disease and prognosis of NMS is mainly based on individual case reports and only a few reviews. In antipsychotic users, the incidence of NMS is ~0.06–1.4% [ 15 ]. Recent studies have shown that NMS is less pronounced among SGA compared to FGA (lethality is higher: 3% for FGA vs. 16.3% for SGA) [ 16 , 17 ].…”