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Medicines Q&As
Q&A 324.3
Which drugs can cause Neuroleptic Malignant Syndrome?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 25th March 2014
Background
Neuroleptic Malignant Syndrome (NMS) is a rare but potentially serious idiosyncratic reaction to drugs
which is characterised by a tetrad of symptoms including altered mental status, fever, extrapyramidal
symptoms, and autonomic instability.(1) For more information on the symptoms and diagnosis of
NMS, please refer to Medicines Q&A number 309 ‘What is Neuroleptic Malignant Syndrome?’
It is most commonly caused by antipsychotics, although it may rarely be linked to the use of other
dopaminergic drugs. The pathogenesis of NMS is not fully understood, but it is thought that it is
caused by reduction in dopamine or dopamine D2 receptor blockade.(2)
Due to the rarity of NMS, most of the published information in the medical literature takes the form of
case reports and series, making reliable estimates of incidence difficult. All cases of NMS should be
reported via the MHRA’s Yellow Card Scheme. For more information on how to report, visit
www.mhra.gov.uk/yellowcard
Answer
Typical Antipsychotics
NMS was first described in the literature in 1960, following the introduction of the first typical
antipsychotic agents, originally known as neuroleptic drugs.(3, 4) Typical antipsychotic agents have
been reported in the literature to cause NMS more frequently than other agents which may reflect
their longer history of use, although it has proven difficult to estimate differences in incidence between
the two groups.(5, 6) Use of high potency agents may be a risk factor for developing NMS.(1)
Estimates of incidence of NMS with typical antipsychotics range from 0.2 to 1% of patients treated.(1,
4)
Haloperidol
Haloperidol is a widely prescribed typical antipsychotic drug, which is recommended as a first line
agent for treatment of delirium, and is often used parenterally at high doses. As parenteral
antipsychotics and agitation are both risk factors for developing NMS,(4, 5) it is particularly important
that healthcare professionals are aware of the propensity for haloperidol to cause NMS. In addition,
diagnosis of NMS may be difficult in delirious patients as delirium may be one of earliest symptoms of
NMS. In a review of NMS occurrence in the treatment of delirium, haloperidol accounted for 22 out of
25 cases. This reflects the increased usage of this agent in delirium.(5)
In an unpublished assessment of calls to the NMS Information Service in the USA, haloperidol
accounted for 44% of all cases reported to the service. One epidemiological report suggested that
haloperidol had a greater risk of NMS associated with it in comparison to atypical antipsychotics(6).
Atypical Antipsychotics
Initially, atypical antipsychotics were thought to have little or no chance of causing NMS than typical
agents, but case reports have since emerged suggesting that all atypical agents have the potential to
induce the syndrome. Assessing the incidence of NMS with these agents is difficult. As the syndrome
is very rare, it is unlikely to be detected during controlled trials, and determining causality on the basis
of case reports is difficult. Confounding factors such as polypharmacy, differences in diagnostic tools
used, and author bias may lead to varying incidence rates being stated. There is some evidence of an
atypical presentation, particularly following the use of clozapine.(4)
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Clozapine
Clozapine adverse reactions include temperature elevations, tachycardia, stiffness, increased CK
levels, and delirium,(7) which have significant overlap with the symptoms of NMS. Some debate has
occurred in the literature regarding whether clozapine induced NMS is an extension of these adverse
effects or a distinct syndrome, which appears to present differently to NMS caused by other drugs.
Clozapine induced NMS seems to have an atypical onset, characterized by less likelihood of tremor
and rigidity. A different time course may occur in NMS produced by clozapine, with delayed onset of
extrapyrimidal effects, which would account for this atypical presentation.(4)
Olanzapine
Olanzapine induced NMS was first reported in 1998 and since then multiple case reports have linked
olanzapine with NMS onset. Only a minority of these cases seem to suggest an atypical onset, with
most cases describing typical NMS features.(4)
Risperidone
The majority of case reports regarding NMS caused by risperidone indicate that its onset is typical,
although one theory suggests that a less severe form, particularly with less severe hyperthermia may
be produced by risperidone, although this has not been investigated.(4) One case report describes a
woman who suffered both an atypical and a typical presentation of NMS on exposure to risperidone.
The patient was found to have a CYP2D6 phenotype associated with reduced metabolism of
risperidone.(8)
Amisulpride
The limited numbers of cases of NMS reported with amisulpride appear to describe a slightly altered
onset, in that more cases are reported in older patients, and cases seemed to appear more rapidly
after initiation of the drug.(4, 9)
Aripiprazole
Given that aripiprazole has partial dopamine agonist action, as opposed to other antipsychotics which
act as dopamine antagonists, an atypical presentation of NMS may have been expected. Case
reports do seem to indicate that there is less likelihood of altered mental status and hyperthermia in
the early stages of aripiprazole-induced NMS compared with typical NMS.(4) Diaphoresis is the main
symptom in 37.5% of cases associated with aripiprazole.(10)
Quetiapine
The case studies reported in the literature suggest that cases of NMS caused by quetiapine are of a
typical nature. However, many of the reports are confounded by other factors such as co-prescription
of another serotonergic drugs or lack of full clinical information.(4) One case report describes the
development of severe confusion, somnolence, elevated creatine kinase, and extreme agitation in a 4
year old child who was taking 400mg quetiapine per day. The authors report that the fact the child had
XYY syndrome may be a contributory factor to the development of NMS, along with the high dose
administered.(11) Indeed, a dose of 400mg in a child would be considered to be a potentially toxic
dose.(12)
Paliperidone
To date, only a few case reports have emerged in which NMS has occurred in response to
paliperidone treatment. An atypical presentation appears to be associated with use of this drug.(13)
Dopamine Agonists
A number of case reports appear in the literature of an NMS-like syndrome (NMLS) following
withdrawal of levodopa preparations. Withdrawal of dopamine agonists mimics the dopamine
antagonist action of antipsychotics and reduces the amount of usable dopamine in the brain, which is
thought to be part of the pathogenesis of NMS.(14)
Three cases following withdrawal of levodopa-carbidopa during a drug holiday period have been
reported. In all three cases, the patients suffered the classic tetrad of symptoms. One of the cases
occurred prior to complete drug withdrawal. The authors suggest that NMLS following drug holiday
may be under-reported due to lack of recognition of the syndrome, and delayed presentation of
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symptoms.(15) Another case study reports an elderly woman who developed NMLS following slow
withdrawal of levodopa.(16) Other, similar cases continue to be reported in the literature.(17, 18)
One case involved an elderly male with Parkinson’s Disease whose levodopa therapy was reduced
gradually following implantation of a Deep Brain Stimulator. Selegiline was also discontinued.(19) An
interaction between levodopa and a high-protein enteral feed led to the development of NMLS in one
case.(20)
Withdrawal of other dopamine agonists including bromocriptine and amantadine can also lead to
NMLS.(2) One case report of NMLS following amantadine withdrawal has established causality. The
patient experienced symptoms of NMS due to a reduced dose of amantadine which resolved on the
dose being increased. The symptoms recurred following re-challenge, then resolved the dose was
increased.(21) Bromocriptine and levodopa have been used successfully as treatments for NMS
caused by dopamine antagonist drugs.(4)
Antidepressants
There have been several reports of NMS occurring following antidepressant administration, but in
many cases they were co-prescribed with antipsychotic drugs, or pre-medication with antipsychotics
had occurred. In cases reported following antidepressants alone, some of the diagnoses have been
dubious. Tricyclic antidepressants (TCAs) appeared to be more likely to cause NMS than selective
serotonin reuptake inhibitors. A review of the case reports concludes that NMS associated with
antidepressants alone is a very rare occurrence, but that antidepressants may increase serum levels
of antipsychotics, leading to an increased risk of NMS due to the antipsychotic itself.(22)
Monoamine Oxidase Inhibitors (MAOIs) produce a similar reaction to NMS when used in combination
with TCAs, which may consist of agitation, delirium, hyperthermia and even death. If patients are
taking a combination of an MAOI and an antipsychotic, MAOI toxicity needs to be ruled out before
NMS is diagnosed.(18)
Other
Other drugs with dopaminergic activity have been reported to cause NMS. Of note are the prokinetic
agents metoclopramide and domperidone, which act by blocking dopamine receptors.(23, 24) It may
be the case that, as patients prescribed these drugs are often not neurology patients, physicians are
less likely to consider NMS as a cause of symptoms, as well as having less experience of diagnosing
and recognizing the syndrome.
Metoclopramide
The anti-emetic metoclopramide was first described as a cause for NMS in 1985.(25) A case report
describes a six month old child with Freeman-Sheldon Syndrome who suffered NMS following
administration of metoclopramide syrup. This is the youngest patient who has been reported to
experience NMS, confirming that children are also at risk of developing the syndrome.(26)
Domperidone
One case report describes NMS following domperidone administration in a 47 year old female with a
family history of malignant hyperthermia.(27)
Substances of Abuse
Cocaine, amphetamines and ecstasy may cause an NMS like presentation. Alcohol and Sedative
withdrawal and hallucinogen intoxication may cause symptoms which are easily confused with
NMS.(2)
Lithium
It is thought that combinations of lithium and antipsychotic drugs may increase the risk of NMS
presentation. In overdose, lithium alone has been reported to cause NMS, and lithium toxicity may
contribute to an increased risk of permanent brain damage following an NMS episode.(28)
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Summary




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NMS is a rare but potentially fatal adverse reaction to drugs.
It is most commonly seen with antipsychotic agents
Atypical agents may have a lower incidence of NMS than typical agents, although this is yet to be
proved and case reports of NMS associated with most antipsychotic agents continue to emerge in
the medical literature.
NMS associated with clozapine may present atypically
It may also rarely be associated with withdrawal or reduction of dose of dopamine agonists such
as levodopa, amantadine and bromocriptine
Metoclopramide and domperidone have reportedly caused NMS in some patients.
Combinations of antipsychotics, or antipsychotics with lithium or antidepressants, may increase
the risk of NMS developing.
Limitations.
Due to the rarity of NMS, published information is mainly in the form of case reports and postmarketing pharmacovigilance data. A detailed review of case reports in the literature is beyond the
scope of this document. All information is correct at the time of writing.
Quality Assurance
Prepared by
Hayley Johnson, Regional Drug & Therapeutics Centre, Newcastle upon Tyne
Date Prepared
25th March 2014
Checked by
Nancy Kane, Regional Drug & Therapeutics Centre, Newcastle upon Tyne
Date of check
25th March 2014
Search strategy
EMBASE (including Medline)
*Neuroleptic malignant
syndrome/
PsychINFO
*Neuroleptic malignant
syndrome
AND
*neuroleptic agent/
*haloperidol
*atypical antipsychotic agent
*clozapine
*olanzapine
*risperidone
*amisulpiride
*aripiprazole
*quetiapine
*paliperidone
*dopamine receptor stimulating agent
*antidepressant agent
*metoclopramide
*domperidone
*lithium
AND
*typical antipsychotic drugs
*haloperidol
*atypical antipsychotic drugs
*clozapine
*olanzapine
*risperidone
Available through NICE Evidence Search at www.evidence.nhs.uk
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*amisulpiride
*aripiprazole
*quetiapine
*paliperidone
*dopamine agonists
*antidepressant drugs
Metoclopramide.af
Domperidone.af
In-house resources
References
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