Neuroleptic Malignant Syndrome (NMS)

Epidemiology

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

Genetics

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

Etiology

Antipsychotics

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
- Chlorpromazine (Largactil, Thorazine) (see Chlorpromazine)
- Thioridazine (Mellaril, Novoridazine, Thioril) (see Thioridazine)
High-Potency Agents: lower anticholinergic side effects, higher extrapyramidal side effects
- Fluphenazine (Prolixin) (see Fluphenazine)
- Haloperidol (Haldol) (see Haloperidol)
- Loxapine (Loxitane, Adasuve) (see Loxapine)
- Perphenazine (Trilafon) (see Perphenazine)
- Pimozide (Orap) (see Pimozide)
- Thiothixene (Navane) (see Thiothixene)
- Trifluoperazine (Stelazine) (see Trifluoperazine)

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

Aripiprazole (Abilify) (see Aripiprazole)
Asenapine (see Asenapine)
Brexpiprazole (Rexulti) (see Brexpiprazole)
Cariprazine (see Cariprazine)
Clozapine (Clozaril) (see Clozapine)
Iloperidone (Fanapt, Zomaril) (see Iloperidone)
Lurasidone (Latuda) (see Lurasidone)
Olanzapine (Zyprexa) (see Olanzapine)
- Epidemiology
  - Case Series Have Been Reported (Hum Psychopharmacol, 2003) [MEDLINE]
Paliperidone (Invega) (see Paliperidone)
Pimavanserin (Nuplazid) (see Pimavanserin)
Quetiapine (Seroquel) (see Quetiapine)
Risperidone (Risperdal) (see Risperidone)
Ziprasidone (Geodon) (see Ziprasidone)

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]

Physiology

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

Clinical
- Arrhythmias
- Irregular Blood Pressure
  - Hypertension (see Hypertension)
  - Hypotension (see Hypotension)
- Irregular Heart Rate
  - Sinus Bradycardia (see Sinus Bradycardia)
  - Tachycardia (see Sinus Tachycardia)

Hypovolemia (see Hypovolemic Shock)

Epidemiology
- XXXX

Dermatologic Manifestations

Diaphoresis (see Diaphoresis): due to autonomic instability

Epidemiology
- XXXX

Neurologic Manifestations

Altered Mental Status

Epidemiology
- XXXX
Clinical
- Delirium (see Delirium)
- Obtundation-Coma (see Obtundation-Coma)

Rheumatologic/Orthopedic Manifestations

Muscle Rigidity

Epidemiology
- XXXX

Rhabdomyolysis (see Rhabdomyolysis)

Epidemiology
- XXXX

Other Manifestations

Fever/Hyperpyrexia (see Fever)

Epidemiology
- XXXX

Treatment

Dantrolene (see Dantrolene)

xxx

References

Epidemiology

Neuroleptic malignant syndrome. Am J Psychiatry. 1985;142(10):1137 [MEDLINE]
A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry. 1989;146(6):71 [MEDLINE]
Mortality from neuroleptic malignant syndrome. J Clin Psychiatry. 1989;50(1):18 [MEDLINE]
Risk factors for neuroleptic malignant syndrome. A case-control study. Arch Gen Psychiatry. 1989;46(10):914 [MEDLINE]
Neuroleptic malignant syndrome: long-term follow-up of 20 cases. J Clin Psychiatry. 1991;52(5):208 [MEDLINE]
Risk for definite neuroleptic malignant syndrome. A prospective study in 223 consecutive in-patients. Br J Psychiatry. 1992;161:254 [MEDLINE]
Clinical and pharmacologic risk factors for neuroleptic malignant syndrome: a case-control study. Biol Psychiatry. 1998;44(8):748 [MEDLINE]
Neuroleptic malignant syndrome. Recognition, prevention and management. Drug Saf. 1998;19(1):73 [MEDLINE]
Neuroleptic malignant syndrome. Br J Anaesth. 2000;85(1):129 [MEDLINE]
Neuroleptic malignant syndrome after venlafaxine. Lancet. 2000;355(9200):289 [MEDLINE]
A collaborative study on the malignant syndrome in Parkinson’s disease and related disorders. Parkinsonism Relat Disord. 2003;9 Suppl 1:S31 [MEDLINE]
Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome. Am J Med Genet B Neuropsychiatr Genet. 2003;117B(1):57 [MEDLINE]
Clomipramine induced neuroleptic malignant syndrome and pyrexia of unknown origin. BMJ. 2004;329(7478):1333 [MEDLINE]
Neuroleptic malignant syndrome associated with bromocriptine withdrawal in Parkinson’s disease–a case report. Gen Hosp Psychiatry. 2011 May;33(3):301.e7-8 [MEDLINE]
Lamotrigine, quetiapine and aripiprazole-induced neuroleptic malignant syndrome in a patient with renal failure caused by lithium: a case report. BMC Psychiatry. 2020;20(1):179 [MEDLINE]

Etiology

Neuroleptic malignant syndrome. Med Clin North Am. 1993;77(1):185 [MEDLINE]
Olanzapine induced neuroleptic malignant syndrome–a case review. Hum Psychopharmacol. 2003;18(4):301 [MEDLINE]
Neuroleptic malignant syndrome: case report and discussion. CMAJ. 2003;169(5):439 [MEDLINE]
Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870 [MEDLINE]
Neuroleptic malignant syndrome complicating antipsychotic treatment of delirium or agitation in medical and surgical patients: case reports and a review of the literature. Psychosomatics. 2009;50(1):8 [MEDLINE]
Levosulpiride-induced neuroleptic malignant syndrome in rheumatoid arthritis. BMJ Case Rep. 2018;2018 [MEDLINE]