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Pharmacology & Therapeutics

Neuroleptic Malignant Syndrome

Central dopamine blockade, or abrupt loss of dopaminergic therapy, disables thermoregulation and motor control together, so rigid muscle generates heat faster than the body can shed it.

In a nutshell

NMS is a life-threatening reaction to dopamine blockade, or to abruptly stopped dopaminergic therapy, with fever above 38.5°C, lead-pipe rigidity, altered mental state and autonomic instability. Stop the drug, transfer to acute medical care, then cool, fill and treat the hyperkalaemia before anyone reaches for a specialist drug.

Classic presentation

A man started on haloperidol nine days ago is confused and sweating at 39.5°C, with lead-pipe rigidity and a creatine kinase (CK) of 12,000 units/L.

Key points

  • There is no NICE guideline for NMS. The standing UK sources are an NHS Greater Glasgow and Clyde policy, an MHRA learning module and a 2014 Royal College statement.
  • Incidence has fallen from about 3% when NMS was first described in 1960 to roughly 0.01 to 0.02% of people treated with antipsychotics.
  • Mortality possibly exceeds 10%, so severe features are a medical emergency rather than a reason to observe and wait.
  • All antipsychotics cause it at any dose, though risk is higher with first-generation drugs, rapid escalation, polypharmacy and intramuscular administration.
  • Metoclopramide, domperidone, lithium and some antidepressants raise the risk, as do catatonia, dehydration, older age and structural brain disease.
  • CK of at least four times the upper limit of normal supports the diagnosis, over a quoted range of 200 to 100,000 units/L.
  • Rhabdomyolysis is defined differently: an acute rise above five times normal, so above 950 units/L on a 30 to 190 units/L reference range.
  • Potassium release is steepest in the first 12 to 36 hours after muscle injury, so an acceptable result on arrival settles nothing.
  • The joint Royal College statement, now over a decade old, says any debate about transfer must be about the diagnosis alone.

First-line investigation

Core temperature, creatine kinase and potassium with an immediate 12-lead ECG, alongside a full drug history covering the past two weeks.

Management

Stop and transfer

  • Stop the antipsychotic now. The Medicines and Healthcare products Regulatory Agency (MHRA) advises stopping other psychotropics too: antidepressants, lithium and antimuscarinics.2,1
  • Refer as an emergency to A&E stating NMS is suspected. Acute teams accept a diagnosed case whatever the current clinical state.8,3
  • If a Parkinson's dose was missed or failed to absorb, involve neurology and restore dopaminergic therapy: NICE NG71 recommendation 1.3.2.4,5
  • Temperature above 38.5°C is the criterion. Above 40°C, or renal failure from rhabdomyolysis, marks severe NMS and a worse prognosis.1

Cool, fill, and chase the potassium

  • Cool actively and correct dehydration. Monitor temperature, pulse and blood pressure, and send white cell count, U&E, liver function tests and creatine kinase.1,2,3
  • Give isotonic crystalloid containing sodium 130 to 154 mmol/L; sodium chloride 0.9% contains 150 mmol/L. Titrate to reassessment and hourly urine output.9,10
  • No fluid algorithm exists for this. Significant rhabdomyolysis can need up to 10 litres, so fluid balance is charted, not guessed.6,2
  • Potassium is mild at 5.5 to 5.9 mmol/L, moderate at 6.0 to 6.4, severe at 6.5 or more. Any ECG change is an emergency at any level.7
  • Any hyperkalaemic ECG change: calcium gluconate 10% 30 mL IV over 10 minutes. Cardiac arrest or peri-arrest: calcium chloride 10% 10 mL over 5 minutes.7
  • Potassium 6.0 mmol/L or more: 10 units soluble insulin in 25 g glucose, which is 50 mL of glucose 50%, by intravenous infusion.7
  • If pre-treatment glucose is under 7.0 mmol/L, follow with glucose 10% at 50 mL/hour for 5 hours. Nebulised salbutamol 10 to 20 mg is an adjunct only.7

Sedation, and the drugs with no UK dose

  • Sedate with a benzodiazepine as needed, using local rapid-tranquillisation policy. Never use its antipsychotic arm: haloperidol is the trigger class.1,11
  • No UK source gives a dantrolene or bromocriptine dose for NMS, and the BNF dantrolene monograph does not mention NMS at all.12,1
  • Its only numeric regimen is for malignant hyperthermia, a different indication. Do not transfer it. The bromocriptine monograph lists NMS only as a rare adverse effect.12,5
  • Escalate to critical care for severe hyperthermia, airway or respiratory compromise, shock, refractory hyperkalaemia, a rapidly rising creatine kinase or organ failure.1,2

Rechallenge, and document

  • Let symptoms resolve completely, then leave at least two weeks before restarting an antipsychotic. Recurrence runs as high as 30%.1
  • Avoid the causative agent, high-potency first-generation antipsychotics, and depot or long-acting injectable preparations.1
  • Choose a structurally unrelated drug, or one with low dopamine affinity such as quetiapine or clozapine. Start low and titrate slowly: NICE CG178, 1.3.6.3.1,13
  • Monitor temperature, blood pressure, pulse, muscle tone and creatine kinase during titration, and record NMS as an adverse drug reaction and an allergy.1,13,3

Exam traps

  • Do not wait for the full tetrad or any CK threshold. Second-generation antipsychotics can produce NMS with rigidity or fever delayed, or absent altogether.
  • It is not only a starting-dose problem: NMS also occurs during long-term treatment on a stable dose, and on restarting after a previous episode.
  • Clonus and hyperreflexia point to serotonin syndrome; the MHRA notes rigidity, leucocytosis and raised CK may all be absent there.
  • Dantrolene's BNF dose is for malignant hyperthermia. There is no BNF dose for NMS, and relabelling one for the other invents a UK recommendation.
  • Do not treat the agitation with an antipsychotic. The usual alternative to lorazepam in rapid tranquillisation is haloperidol, the class that caused this.
  • A missed Parkinson's dose, from vomiting, nil-by-mouth status or a slow drug round, is a genuine trigger. NICE forbids abrupt antiparkinsonian withdrawal.
  • Sepsis and CNS infection never leave the list, and can coexist with NMS rather than replace it.

Key sources

  1. NHS Greater Glasgow and Clyde, Mental Health Services Prescribing Management Group: Neuroleptic Malignant Syndrome (NMS) (Document MHS-MRG-31, approved March 2025, review March 2028. Source of the two-week onset window, the incidence fall from 3% in 1960 to 0.01 to 0.02%, the risk-factor table, the hyperthermia criterion above 38.5°C, the creatine kinase range of 200 to 100,000 units/L and the at-least-four-times-normal threshold, the severe-NMS markers of temperature above 40°C or renal failure from rhabdomyolysis, the differential table, the treatment list (withdraw causative medicines, correct dehydration and hyperthermia, sedate with benzodiazepines, transfer to acute care, dantrolene and bromocriptine, all without doses), and the rechallenge rules including the 30% recurrence risk and the minimum two-week gap. There is no NICE guideline for neuroleptic malignant syndrome; this is the most complete readable UK document)Published 1 Mar 2025
  2. Medicines and Healthcare products Regulatory Agency (MHRA), Antipsychotics learning module: section 3.2.3, Neuroleptic malignant syndrome (Section 3.2.3. Source of the mortality figure (possibly exceeding 10%), onset within about two weeks of starting an antipsychotic or increasing the dose, the feature list, the instruction to stop other psychotropics including antidepressants, lithium and antimuscarinics, the supportive care of hydration (especially if creatine kinase is highly raised), cooling and correction of metabolic abnormalities, the discriminator that muscle rigidity, leucocytosis and raised creatine kinase may be absent in serotonin syndrome, and the ceiling statement that specialists may use specific medicines for severe cases. The page carries no publication date, so none is asserted here)
  3. Royal College of Psychiatrists, Neuroleptic Malignant Syndrome staff poster (Undated; the document footer carries the version code 0000036/V1.0/0913/MB. Source of the statements that NMS can occur during long-term treatment on a stable dose and on restarting an antipsychotic in someone with a previous episode, of the immediate blood set (creatine kinase, liver function tests, full blood count), and of the instruction to record a confirmed episode as an allergy in the patient record and in the risk assessment. The URL redirects to a longer path carrying an sfvrsn query)
  4. NICE NG71, Parkinson's disease in adults (Recommendation 1.3.2 (antiparkinsonian medicines should not be withdrawn abruptly or allowed to fail suddenly through poor absorption, to avoid acute akinesia or neuroleptic malignant syndrome), 1.3.3 (no drug holidays, for the same reason) and 1.3.4 (inpatient doses given at the appropriate times, which may mean allowing self-medication, and adjusted only after discussion with a Parkinson's specialist). All three numbers were read in the linked PDF; the most recent change listed in the guideline's own update information is May 2022)Published 19 Jul 2017
  5. BNF, Bromocriptine (The monograph gives no dose for treating neuroleptic malignant syndrome. It mentions the syndrome twice: as a rare or very rare side-effect ('neuroleptic malignant-like syndrome'), and under treatment cessation, where it states that antiparkinsonian drug therapy should never be stopped abruptly as this carries a small risk of neuroleptic malignant syndrome)
  6. Royal College of Emergency Medicine, RCEMLearning: Acute Rhabdomyolysis (Source of the rhabdomyolysis definition (an acute rise in creatine kinase to more than five times the upper limit of normal; normal range 30 to 190 units/L, so anything over 950 units/L is diagnostic), the 12 to 36 hour peak of potassium release, the statement that no specific fluid algorithm exists and that up to 10 litres may be needed in significant rhabdomyolysis, and that creatine kinase does not determine prognosis. It lists neuroleptic malignant syndrome among the heat-related causes of rhabdomyolysis. Same document and figures as the rhabdomyolysis chapter)Published 11 Feb 2022 | Updated 16 Mar 2026
  7. UK Kidney Association, Clinical Practice Guideline: Treatment of Acute Hyperkalaemia in Adults (Final version October 2023, published 19 December 2023. Source of the severity bands (mild 5.5 to 5.9, moderate 6.0 to 6.4, severe 6.5 mmol/L or more), guidelines 16.2a and 16.2b for the calcium salts and their rates, guidelines 16.3.1 to 16.3.3 for insulin-glucose and the follow-on 10% glucose infusion, and guidelines 16.4.1 to 16.4.3 for nebulised salbutamol as an adjunct and never as monotherapy. Same document and thresholds as the hyperkalaemia and rhabdomyolysis chapters)Published 19 Dec 2023
  8. Royal College of Psychiatrists and Royal College of Physicians, statement on neuroleptic malignant syndrome (Position Statement PS03/2014, approved November 2014 and published December 2014, and still the standing joint UK statement more than a decade later. It makes two recommendations only: that all psychiatrists practising without immediate on-site supervision should be able to diagnose NMS, and that NMS is best considered a medical emergency properly managed in an acute hospital, where clinicians should be prepared to accept diagnosed cases without reference to the patient's current clinical state. It states nothing about investigations, rhabdomyolysis, differential diagnosis or rechallenge, and is not cited for any of those here)Published 1 Dec 2014
  9. NICE, 2020 exceptional surveillance of intravenous fluid therapy in adults in hospital (NICE guideline CG174) (Reproduces CG174's fluid-resuscitation recommendation together with its number: the resulting recommendation (1.3.1) was to use crystalloids that contain sodium in the range 130 mmol/L to 154 mmol/L for intravenous fluid resuscitation. Cited here rather than CG174 itself because this page carries the locator alongside the text, and because CG174's own renderings returned empty pages during this pass. Same figure as the rhabdomyolysis chapter)
  10. BNF, Sodium chloride (Prescribing and dispensing information: sodium chloride 0.9% intravenous infusion contains sodium and chloride each 150 mmol/litre, which sits inside the 130 to 154 mmol/litre range NICE specifies for intravenous fluid resuscitation)
  11. BNF, Lorazepam (The monograph carries no neuroleptic malignant syndrome indication and no rapid-tranquillisation indication. Its dosed indications are short-term use in anxiety, insomnia associated with anxiety, acute panic attacks, conscious sedation, premedication and status epilepticus. There is therefore no BNF benzodiazepine dose for sedation in neuroleptic malignant syndrome)
  12. BNF, Dantrolene sodium (The monograph does not mention neuroleptic malignant syndrome anywhere. Its indications are malignant hyperthermia, chronic severe spasticity of voluntary muscle and, unlicensed, muscle cramps in motor neurone disease. The only numeric intravenous regimen it carries is for malignant hyperthermia, a different indication with a different evidence base, and it is deliberately not reproduced in this chapter)
  13. NICE CG178, Psychosis and schizophrenia in adults: prevention and management (Recommendation 1.3.6.3, which requires an antipsychotic to be started at a dose at the lower end of the licensed range and titrated slowly upwards within the dose range given in the BNF or summary of product characteristics, and 1.3.6.4, which requires response and side effects to be monitored and recorded regularly and systematically, especially during titration. Both numbers were read in the linked PDF, which declares publication 12 February 2014 and last update 18 March 2014)Published 12 Feb 2014 | Updated 18 Mar 2014

This page is exam revision material, not medical advice, and must not be used for patient care. Always check drug doses against the BNF and current guidance. Full disclaimer.