Second-generation antipsychotics and neuroleptic malignant syndrome: systematic review and case report analysis

Drugs R D. 2015 Mar;15(1):45-62. doi: 10.1007/s40268-014-0078-0.


Background: Neuroleptic malignant syndrome (NMS) is a rare, severe, idiosyncratic adverse reaction to antipsychotics. Second-generation antipsychotics (SGAs) were originally assumed to be free from the risk of causing NMS, however several cases of NMS induced by SGAs (SGA-NMS) have been reported.

Objectives: The aim of this study was to systematically review available studies and case reports on SGA-NMS and compare the presentation of NMS induced by different SGAs.

Data sources: Citations were retrieved from PubMed up to November 2013, and from reference lists of relevant citations.

Study eligibility criteria: Eligibility criteria included (a) primary studies reporting data on NMS, with at least 50 % of the sample receiving SGAs; or (b) case reports and case reviews reporting on NMS induced by SGA monotherapy, excluding those due to antipsychotic withdrawal.

Study appraisal and synthesis methods: A standardized method for data extraction and coding was developed for the analysis of eligible case reports.

Results: Six primary studies and 186 individual cases of NMS induced by SGAs were included. Primary studies suggest that SGA-NMS is characterized by lower incidence, lower clinical severity, and less frequent lethal outcome than NMS induced by first-generation antipsychotics. Systematic analysis of case reports suggests that even the most recently marketed antipsychotics are not free from the risk of inducing NMS. Furthermore, clozapine-, aripiprazole- and amisulpride-induced NMS can present with atypical features more frequently than other SGA-NMS, i.e. displaying less intense extrapyramidal symptoms or high fever.

Limitations: Case reports report non-systematic data, therefore analyses may be subject to bias.

Conclusions and implications of key findings: Clinicians should be aware that NMS is virtually associated with all antipsychotics, including those most recently marketed. Although apparently less severe than NMS induced by older antipsychotics, SGA-NMS still represent a relevant clinical issue.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Antipsychotic Agents / adverse effects*
  • Humans
  • Incidence
  • Neuroleptic Malignant Syndrome / epidemiology
  • Neuroleptic Malignant Syndrome / etiology*
  • Severity of Illness Index


  • Antipsychotic Agents