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Antipsychotic dose escalation as a trigger for Neuroleptic Malignant Syndrome (NMS): literature review and case series report

Julie Langan1, Daniel Martin1, Polash Shajahan2 and Daniel J Smith1*

Author Affiliations

1 Institute of Health an Wellbeing, Mental Health and Wellbeing, Gartnavel Royal Hospital, University of Glasgow, 1055 Great Western Road, Glasgow, G12 0XH, Scotland, UK

2 NHS Lanarkshire, Greenmoss Community Health centre, University of Glasgow, Greenmoss Place, Bellshill, ML4 1PS, Scotland, UK

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BMC Psychiatry 2012, 12:214  doi:10.1186/1471-244X-12-214

Published: 29 November 2012



“Neuroleptic malignant syndrome” (NMS) is a potentially fatal idiosyncratic reaction to any medication which affects the central dopaminergic system. Between 0.5% and 1% of patients exposed to antipsychotics develop the condition. Mortality rates may be as high as 55% and many risk factors have been reported. Although rapid escalation of antipsychotic dose is thought to be an important risk factor, to date it has not been the focus of a published case series or scientifically defined.


We aimed to identify cases of NMS and review risk factors for its development with a particular focus on rapid dose escalation in the 30 days prior to onset. A review of the literature on rapid dose escalation was undertaken and a pragmatic definition of “rapid dose escalation” was made. NMS cases were defined using DSM-IV criteria and systematically identified within a secondary care mental health service. A ratio of titration rate was calculated for each NMS patient and “rapid escalators” and “non rapid escalators” were compared. 13 cases of NMS were identified. A progressive mean dose increase 15 days prior to the confirmed episode of NMS was observed (241.7 mg/day during days 1–15 to 346.9 mg/day during days 16–30) and the mean ratio of dose escalation for NMS patients was 1.4. Rapid dose escalation was seen in 5/13 cases and non rapid escalators had markedly higher daily cumulative antipsychotic dose compared to rapid escalators.


Rapid dose escalation occurred in less than half of this case series (n = 5, 38.5%), although there is currently no consensus on the precise definition of rapid dose escalation. Cumulative antipsychotic dose – alongside other known risk factors - may also be important in the development of NMS.

Neuroleptic malignant syndrome; NMS; Rapid dose escalation; Rapid dose titration; Antipsychotics