Atypical NMS and Third Generation Antipsychotic Medications: A Systematic Literature Review and Comparison with International Expert Consensus NMS Diagnostic Criteria

BACKGROUND/SIGNIFICANCE:
Neuroleptic malignant syndrome (NMS) is a rare and potentially fatal condition caused by antipsychotic medications (APs). Generally, NMS criteria include recent exposure to an antipsychotic, rigidity, and high fever. Atypical case presentations without fever and/or without rigidity occur as well. Diagnostic criteria for atypical NMS vary but Levenson et al.2 report NMS can be diagnosed in absence of fever, rigidity, or elevated creatine phosphokinase (CPK). Reviews of atypical NMS are limited, and case reports/systematic reviews often have not utilized the International Expert Consensus NMS Diagnostic Criteria. Additionally, the cutoff score1 of 74 for the consensus criteria may not adequately capture atypical NMS cases.

Methods:
A literature search of PUBMED, OVID, PSYCHINFO, and EMBASE was conducted in March 2023 with keywords of “neuroleptic malignant syndrome” and one of the following “aripiprazole, brexpiprazole, cariprazine, or lumateperone”. Article requirements were: available online, case reports involving NMS of AP etiology, and data regarding temperature and rigidity to determine if atypical. The search followed the 2020 PRISMA guidelines 3. Data from cases were analyzed with respect to the threshold cutoff score from the consensus criteria.

Results:
After duplicate articles were removed and required search criteria were applied to all third-generation antipsychotics, only aripiprazole with 28 case reports remained. 32% (n=9) of aripiprazole cases had atypical features. 89% (n=8) of atypical cases had no fever. 11% (n=1) had no rigidity. No atypical cases had both fever and rigidity absent. 63% (n=8) of atypical cases were below the threshold of 74. 4 atypical cases and 5 typical cases had adequate data to complete all consensus criterion factors, with respective score means for the two groups, 72 ± 5.8, 95% CI 61 - 84, and 89 ± 3.7, 95% CI 82 – 97. Atypical and typical NMS means had a t-test significance difference (p = 0.002). Levene's test was rejected with samples having equal variance.

Discussion:
Most atypical NMS cases had no fever while most cases had rigidity. We hypothesize that the lack of fever is related to the differences in the mechanism of action of novel APs, mainly the partial agonism of dopamine receptors. Furthermore, over half of the atypical NMS cases were below the cutoff threshold score. Limitations include limited case reports with adequate data, a definition of atypical cases based on temperature and rigidity only, and a lack of case reports meeting criteria for other 3rd generation APs.

CONCLUSION/IMPLICATIONS:
The International Expert Consensus NMS Diagnostic Criteria did not identify a third of atypical NMS cases with novel APs. A lower cutoff threshold will better capture atypical NMS cases. It is unclear if this is a class effect for 3rd generation APs. We are currently expanding our analysis to include other atypical APs.

References:
1.Gurrera RJ et al. A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome. J Clin Psychopharmacol. 2017;37(1):67-71. doi:10.1097/JCP.0000000000000640
2. Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry. 1985;142(10):1137-1145. doi:10.1176/ajp.142.10.1137
3.Page MJ et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71