Published: December 2012


Neuroleptic Malignant Syndrome or Serotonin Syndrome?

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Prescriber Update 33(4): 31
December 2012

Neuroleptic malignant syndrome (NMS) and serotonin syndrome are rare, life-threatening, medicine-induced disorders1. Both syndromes share clinical features, such as pyrexia, hypertonia and changes in mental state, making differentiation difficult1. Differentiation is important as pharmacologic treatment is dependent on the causative agent.

The presence of neuromuscular excitation such as clonus (involuntary, rhythmic muscular contractions and relaxations) and hyperreflexia are strongly predictive of serotonin syndrome (Table 1). In contrast, NMS is characterised by muscular 'lead-pipe' rigidity, haemodynamic dysregulation and hyporeflexia.

Table 1: Characteristics of NMS and serotonin syndrome2

  Neuroleptic malignant syndrome Serotonin syndrome
Precipitated By Dopamine Antagonists Serotonergic Agents
Onset Variable, 1-3 days Variable, < 12 hours
Identical Features Vital Signs Hypertension
Hyperthermia (> 40°C)
Hyperthermia (> 40°C)
Mucosa Hypersalivation Hypersalivation
Skin Diaphoresis
Mental Status Variable, stupor, coma, alert Variable, agitation, coma
Muscles 'Lead-pipe' rigidity in all muscle groups Increased tone, especially in lower extremities
Distinct Features Reflexes Hyporeflexia Hyperreflexia
Clonus (unless masked by increased muscle tone)
Pupils Normal Dilated
Bowel Sounds Normal or decreased Hyperactive

Knowledge of medication use may also aid diagnosis. Dopamine antagonists including atypical antipsychotics have been implicated in NMS. Serotonergic agents, either alone in high doses or in combination, are associated with serotonin syndrome. However, selective serotonin reuptake inhibitors may contribute to NMS as they are also indirect dopamine antagonists.

Symptoms of NMS and serotonin syndrome have been misinterpreted as symptoms of mental illness. If a patient develops signs and symptoms indicative of NMS or serotonin syndrome, or presents with unexplained high fever without additional clinical manifestations, treatment with dopamine antagonists or serotonergic medicines should be discontinued immediately and supportive therapy administered.

Administration of serotonin antagonists may be considered for serotonin toxicity, whilst dopaminergic agents and dantrolene may be considered for NMS. If treatment for the underlying condition is restarted, knowledge of the causative medicines and resulting syndrome must be considered to prevent recurrence. Specialist advice should be sought and alternative treatments may be required.

Healthcare professionals are encouraged to report these reactions to the Centre for Adverse Reactions Monitoring (CARM) and to include as much information as possible to help identify other risk factors for these syndromes. Reports can be made via the CARM website or by filing in a yellow reporting card found in MIMS.

Key Messages

  • NMS and serotonin syndrome are rare, but potentially life-threatening, medicine-induced disorders.
  • Features of these syndromes may overlap making diagnosis difficult. However, NMS is characterised by 'lead-pipe' rigidity, whilst serotonin syndrome is characterised by hyperreflexia and clonus.
  • Precipitating medicines also allow differentiation. Dopamine antagonists precipitate NMS, whilst serotonergic medicines are indicative of serotonin syndrome.
  • Differentiation is important when considering treatment options and future use of causative medicines.
  1. Sokoro AA, Zivot J, Ariano RE. 2011. Neuroleptic malignant syndrome versus serotonin syndrome: the search for a diagnostic tool. Annals of Pharmacotherapy 45: e50.
  2. Bienvenu OJ, Neufeld KJ, Needham DM. 2012. Treatment of four psychiatric emergencies in the intensive care unit. Critical Care Medicine 40: 2662-70.
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