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.