Neuroleptic Malignant Syndrome (NMS)


Timing of Onset of Neuroleptic Malignant Syndrome

  • While Neuroleptic Malignant Syndrome Symptoms Usually Develop During the First 2 wks of Antipsychotic Therapy, the Association of the Syndrome with Drug Use is Idiosyncratic (J Clin Psychiatry, 1991) [MEDLINE]
    • Neuroleptic Malignant Syndrome Can Occur After a Single Dose or After Treatment with the Same Agent at the Same Dose for a Period of Many Years (J Clin Psychiatry, 1991) [MEDLINE]

Risk Factors for Neuroleptic Malignant Syndrome (Defined in Case-Control Studies) (J Clin Psychiatry, 1989) [MEDLINE] (Arch Gen Psychiatry, 1989) [MEDLINE] (Br J Psychiatry, 1992) [MEDLINE] (Biol Psychiatry, 1998) [MEDLINE]

  • Parenteral Administration of Antipsychotic Medication
  • Rapid Dose Escalation of Antipsychotic Medication
  • Specific Psychiatric Conditions (Such as Acute Catatonia or Extreme Agitation)
    • These Conditions May Be Associated with Higher Risk of Neuroleptic Malignant Syndrome Simply Because They are Conditions in Which Higher Antipsychotic Medication Doses, More Rapid Escalation of Antipsychotic Medication, or Parenteral Use of Antipsychotic Medication Might Be Employed
  • Switch from One Antipsychotic Medication to Another
  • Withdrawal of Antiparkinson L-Dopa or Dopamine Agonist) Medication (see Parkinson Disease) (J Clin Psychiatry, 1989) [MEDLINE] (Drug Saf, 1998) [MEDLINE] (Parkinsonism Relat Disord, 2003) [MEDLINE] (Gen Hosp Psychiatry, 2011) [MEDLINE]
    • Infection, Dehydration, and Surgery are Possible Precipitants
    • Since This May Be a Distinct Disorder from Neuroleptic Malignant Syndrome, it Has Been Termed “Neuroleptic Malignant-Like Syndrome”, “Parkinsonism Hyperpyrexia Syndrome”, “Acute Akinesia”, and “Malignant Syndrome in Parkinson Disease”
    • Prognosis is Variable (Some Cases are Mild, But More Severe Cases and Fatalities Have Been Reported)

Risk Factors without a Clear Association with Neuroleptic Malignant Syndrome

  • General Comments
    • These Risk Factors Have Not Been Substantiated in Case-Control Studies (Am J Psychiatry, 1985) [MEDLINE] (Med Clin North Am, 1993) [MEDLINE] (Lancet, 2000) [MEDLINE] (Br J Anaesth, 2000) [MEDLINE] (CMAJ, 2003) [MEDLINE] (BMJ, 2004) [MEDLINE] (BMC Psychiatry, 2020) [MEDLINE]
  • Acute Medical Illness (Trauma, Surgery, and Infection)
  • Comorbid Neurologic Disease
  • Comorbid Substance Abuse
  • Concomitant Use of Lithium or Other Psychotropic Medications
  • Dehydration
    • While Dehydration is Present in 92% of Patients (and it May Be an Early Complication of Neuroleptic Malignant Syndrome), it is Not Clear that Dehydration is a Risk Factor for the Development of Neuroleptic Malignant Syndrome (Am J Psychiatry, 1989) [MEDLINE] (Med Clin North Am, 1993) [MEDLINE]
  • Higher-Potency Medications
  • Use of Depot Medication Formulations


  • Familial Clusters of Neuroleptic Malignant Syndrome Suggest a Genetic Predisposition
  • Genetic Studies Have Demonstrated the Presence of a Specific Allele of the Dopamine D2 Receptor Gene Being Over-Represented in Neuroleptic Malignant Syndrome Patients (Am J Med Genet B Neuropsychiatr Genet, 2003) [MEDLINE]
    • This Allele is Associated with the Following
      • Decreased Density and Function of Dopamine Receptors
      • Decreased Dopaminergic Activity and Metabolism



General Comments

  • Neuroleptic Malignant Syndrome is Most Commonly Observed with the Use of High-Potency First-Generation Antipsychotic Agents (Haloperidol, Fluphenazine, etc) (CMAJ, 2003) [MEDLINE] (Am J Psychiatry, 2007) [MEDLINE] (Psychosomatics, 2009) [MEDLINE]
    • However, All Classes of Antipsychotic Agents Have Been Implicated

First-Generation Antipsychotic Agents (see Antipsychotic Agents)

  • Low-Potency Agents: higher anticholinergic side effects, lower extrapyramidal side effects
  • High-Potency Agents: lower anticholinergic side effects, higher extrapyramidal side effects

Second-Generation Antipsychotic Agents (Atypical Antipsychotics) (see Antipsychotic Agents)

Antiemetic Agents

  • Amisulpride (Solian, Barhemsys, Socian, Deniban) (see Amisulpride)
  • Domperidone (Motilium) (see Domperidone)
  • Droperidol (Inapsine) (see Droperidol)
  • Levosulpiride (Neoprad) (see Levosulpiride)
    • Epidemiology
      • Cases Have Been Reported (BMJ Case Rep, 2018) [MEDLINE]
  • Metoclopramide (Reglan) (see Metoclopramide)
    • Epidemiology
      • Well-Documented Etiology of Neuroleptic Malignant Syndrome (Med Clin North Am, 1993) [MEDLINE]
  • Prochlorperazine (Compazine) (see Prochlorperazine)
  • Promethazine (Phenergan) (see Promethazine)
    • Epidemiology
      • Well-Documented Etiology of Neuroleptic Malignant Syndrome (Med Clin North Am, 1993) [MEDLINE]


Dopamine Receptor Blockade is the Most Commonly-Described Mechanism

  • Central (Hypothalamic) Dopamine Receptor Blockade Causes Hyperthermia and Dysautonomia
  • Inhibition of Nigrostriatal Dopamine Pathways Results in Parkinsonian-Type Symptoms (Rigidity, Tremor)

Involvement of Gamma Aminobutyric Acid, Epinephrine, Serotonin, and Acetylcholine Neurotransmitter Symptoms

  • May Be Involved Either Directly or Indirectly

Direct Effects of Medication on Muscle Mitochondrial Function

  • This Alternative Mechanism Has Been Proposed
  • May Result in Rigidity and/or Muscle Damage

Disrupted Modulation of the Sympathetic Nervous System

  • This Alternative Mechanism Has Been Proposed
  • Results in Increased Muscle Tone and Metabolism, Unregulated Sudomotor and Vasomotor Activity
    • Causes Ineffective Heat Dissipation
    • Causes Labile Blood Pressure
    • Causes Labile Heart Rate
  • Dopamine Antagonists Precipitate Clinical Symptoms by Destabilizing Normal Dopamine Regulation of Efferent Sympathetic Activity

Clinical Manifestations

Cardiovascular Manifestations

Autonomic Instability

Hypovolemia (see Hypovolemic Shock)

  • Epidemiology
    • XXXX

Dermatologic Manifestations

Diaphoresis (see Diaphoresis): due to autonomic instability

  • Epidemiology
    • XXXX

Neurologic Manifestations

Altered Mental Status

Rheumatologic/Orthopedic Manifestations

Muscle Rigidity

  • Epidemiology
    • XXXX

Rhabdomyolysis (see Rhabdomyolysis)

  • Epidemiology
    • XXXX

Other Manifestations

Fever/Hyperpyrexia (see Fever)

  • Epidemiology
    • XXXX


Dantrolene (see Dantrolene)

  • xxx