A systematic review and pooled, patient-level analysis of predictors of mortality in neuroleptic malignant syndrome

Objective: Neuroleptic Malignant Syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited. Methods: Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author-defined NMS published in English until 05/30/2020. Demographic, clinical, treatment and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis-Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs not resulting in death. Results: 683 cases with NMS were analyzed (median age=36 years, males=62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR)=4.39 95% confidence interval(CI)=2.14-8.99; p<0.0001), respiratory problems (OR=3.54 95%CI=1.71-7.32; p=0.0004), severity of hyperthermia (Unit-OR=1.30, 95%CI=1.16-1.46; p<0.0001), and older age (Unit-OR=1.05, 95%CI=1.02-1.07; p=0.0014). Even in univariate, patient level analyses antipsychotic formulation was not related to death (oral antipsychotic (OAP): n=39/554 (7.0%) vs long-acting injectable (LAI): n=13/129 (10.1%); p=0.2413). Similarly, death with NMS was not related to antipsychotic class (first-generation antipsychotic: n=38/433 (8.8%) vs second-generation antipsychotic: n=8/180 (4.4%); p=0.0638). Non-antipsychotic co-treatments were not associated with NMS mortality. Conclusion: Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs OAPs.