An Approach to Diagnosing and Managing Neuroleptic Malignant Syndrome, Atypical Neuroleptic Malignant Syndrome and Serotonin Syndrome using a Flowchart Algorithm

Review Article

Austin J Pharmacol Ther. 2015; 3(2).1072.

An Approach to Diagnosing and Managing Neuroleptic Malignant Syndrome, Atypical Neuroleptic Malignant Syndrome and Serotonin Syndrome using a Flowchart Algorithm

PK Chandrasekaran¹* and GS Grewal²

¹Neurobehavioural Medicine, Penang Adventist Hospital, Malaysia

²Department of Psychiatry, Perdana Graduate School of Medicine, Malaysia

*Corresponding author: : Prem Kumar Chandrasekaran, 465 Burmah Road, Georgetown, Penang 10350, Malaysia

Received: July 16, 2015; Accepted: August 18, 2015; Published: August 27, 2015


Background: Increasing co-administration of neuroleptic and antidepressant medications used to treat a variety of psychiatric and medical illnesses can put patients at increased risk of developing iatrogenic adverse drug reactions, including potentially fatal ones such as Neuroleptic Malignant Syndrome (NMS). The reporting of atypical forms of adverse events that do not fulfill the criteria for the diagnosis of NMS have been on the rise, as are varied presentations of Serotonin Toxicity; these have been attributed to drug combinations that may pharmacologically block dopamine and stimulate serotonin receptors, with the typical picture of NMS and frank Serotonin Syndrome (SS) existing on the ends of their respective pathophysiological processes. And the less clinically severe Atypical NMS (aNMS) aligning itself in closer proximity to the NMS portion of the spectrum.

Objective: To propose a simple diagnostic and management flowchart to determine to what extent each process contributes to a given presentation, to detect the likely type of receptor involvement and to suggest paths in the approach to treatment in as flexible a form and most advantageous in outcome. The said algorithm should aid clinicians faced with diagnostic and therapeutic difficulties to critically appraise their patients with these conditions.

Method and Result: A MEDLINE search was performed for case reports, review articles and clinical studies pertaining to NMS, SS and aNMS over a 35- year period from 1980 to 2015. A total of 25 articles were found relevant to this particular manuscript.

Conclusion: Prompt detection and treatment of adverse drug reactions to neuroleptic and antidepressant therapies could halt the progression of NMS, aNMS and SS and reduce their morbidity. An algorithmic management approach should be considered, more especially in the case of NMS, wherein missing such a diagnosis may likely translate to an increased mortality rate.

Keywords: Neuroleptic; Serotonin; Syndrome; Atypical; Algorithm; Abortive; Rechallenge; Mortality


NMS: Neuroleptic Malignant Syndrome; SS: Serotonin Syndrome; aNMS: Atypical Neuroleptic Malignant Syndrome; EPS: Extrapyramidal Symptoms; CPK: Creatinine Phosphokinase; MAOI: Monoamine Oxidase Inhibitor; SSRI: Selective Serotonin Reuptake Inhibitor; LDH: Lactate Dehydrogenase; ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; ECT: Electroconvulsive therapy


Neuroleptic malignant syndrome (NMS) is an idiosyncratic drug reaction that is not dose-related [1] and arises from the excessive blockade of dopamine receptors, namely D2, in the basal ganglia and hypothalamus [2]. The clinical features consist of hyperthermia, rigidity or extrapyramidal symptoms (EPS), autonomic disturbances and confusion with stupor or mutism. The onset is sub-acute [3], ranging from days to weeks, but it can progress within 24-72 hours. It consists of 5 stages [4] (Figure 1) and is a diagnosis of exclusion. A neuroleptic should have been started or increased in dosage prior to the onset of signs and symptoms but this phenomenon has also been known to occur after withdrawal of a dopaminergic agonist [5]. The incidence rate of NMS in psychiatric in-patients range from 0.2% to 3.2% [6]. While the severe and fulminant type of NMS is easily recognizable, there is increasing evidence in favor of the existence of a more easily overlooked milder and atypical form of NMS.