NMS — Maudsley Notes

Neuroleptic malignant syndrome (NMS)

Pages 150–151 · Table 1.33

Definition and presentation

A rare but potentially serious or even fatal adverse effect of antipsychotics and other dopamine antagonists.
An acute disorder of thermoregulation and neuromotor control, characterised by:
- muscular rigidity
- hyperthermia
- altered consciousness
- autonomic dysfunction
There is considerable heterogeneity in the clinical presentation. In many cases the presentation is atypical, lacking key signs and symptoms such as hyperthermia and muscle rigidity.

CK is not diagnostic. Asymptomatic rises in plasma creatine kinase (CK) seem to be fairly common, so CK cannot be used as a diagnostic marker of NMS.

Table 1.33 — Neuroleptic malignant syndrome
Signs and symptoms (presentation varies considerably)	Fever, diaphoresis, muscle rigidity, confusion, fluctuating level of consciousness, labile or high BP, tachycardia Elevated CK, often >1000 units/L; leukocytosis; altered LFTs
Risk factors	Drug-related: high-potency FGAs, recent or rapid dose increase, rapid dose reduction, abrupt withdrawal of anticholinergic agents, antipsychotic polypharmacy Illness-related: psychosis, organic brain disease, alcoholism, Parkinson's disease, hyperthyroidism, psychomotor agitation, cognitive impairment Demographic: male gender, younger age State: agitation, dehydration
Treatments (guideline recommendations vary widely and are based on limited evidence)	In the psychiatric unit: withdraw antipsychotic medication; monitor temperature, pulse, BP. Consider benzodiazepines if not already prescribed — IM lorazepam has been used. In the medical/emergency unit: rehydration, bromocriptine + dantrolene, sedation with benzodiazepines, artificial ventilation if required. L-dopa, apomorphine and carbamazepine have also been used, among many other drugs. ECT may be effective for NMS, even after pharmacotherapy has failed.
Restarting antipsychotics	Antipsychotic treatment will be required in most instances, and rechallenge is associated with acceptable risk. Stop antipsychotic medication for at least 5 days, preferably longer. Allow time for symptoms and signs of NMS to resolve completely. Begin with a very small dose and increase very slowly, with close monitoring of temperature, pulse and blood pressure. CK monitoring may be used but is controversial. Close monitoring of physical and biochemical parameters is effective in reducing progression to "full-blown" NMS. Consider an antipsychotic structurally unrelated to the one previously associated with NMS, or a drug with low dopamine affinity (quetiapine or clozapine). Aripiprazole may also be considered, but it has a long plasma half-life and has been linked to an increased risk of NMS. Avoid depot/LAI antipsychotic preparations (of any kind) and high-potency FGAs.

CK, creatine kinase; FGA, first-generation antipsychotic.

Risk factors and mortality

Risk factors for developing NMS include being male, dehydration, exhaustion and confusion/agitation.
NMS has commonly been reported at standard doses, but there is some evidence that higher dosage or combined antipsychotic medications may also be risk factors.
Young adult males seem to be particularly at risk, while the condition is more likely to be lethal in older people.
Other predictors of mortality: respiratory difficulties, severity of hyperthermia, and failing to stop antipsychotic medication.

Incidence

Incidence and mortality are difficult to establish and probably vary as medication regimens change and recognition of NMS waxes and wanes.

Estimated incidence	0.02–0.03%, with a mortality rate of 5.6%
Drug safety programme 1993–2015	Overall incidence 0.16%
Similar study 2004–2017	Incidence 0.11%

High-potency FGAs seem to be associated with the greatest incidence, while SGAs and low-potency FGAs seem to have a lower incidence.

Which drugs?

Most available antipsychotics have been associated with NMS, including more recently introduced SGAs:

lurasidoneziprasidoneiloperidonearipiprazolepaliperidone (incl. paliperidone palmitate)asenapinerisperidone injection

Mortality is probably lower with SGAs than with FGAs, although the clinical picture is essentially similar, except that rigidity and fever may be less common.
In 2020, NMS had yet to be associated with pimavanserin, cariprazine, brexpiprazole or lumateperone, and no reports of NMS linked to these drugs were found in mid-2024.

Non-antipsychotic causes

NMS is also sometimes seen with antidepressants, valproate, phenytoin and lithium.
Co-prescription of SSRIs or cholinesterase inhibitors with antipsychotics may increase the risk of NMS.
NMS-type syndromes induced by SGA + SSRI combinations may share symptoms and pathogenesis with serotonin syndrome.
Benzodiazepines are a recommended treatment for NMS, but an association between their use and NMS has been reported — possibly confounded by diagnosis, or explained by NMS-like symptoms during benzodiazepine withdrawal.
NMS is occasionally seen with non-psychotropic dopamine antagonists such as metoclopramide and prochlorperazine.