drug safety

Management of neuroleptic
malignant syndrome
Neuroleptic malignant syndrome is a rare but serious adverse reaction resulting from antipsychotic
drug therapy. This article describes the signs and symptoms that pharmacists should look out for and
how this poorly understood syndrome should be managed. By Ewan Maule.

euroleptic malignant syndrome

(NMS) is a rare but potentially
fatal neurological complication
of treatment with antipsychotic drugs
(historically called neuroleptics). It can
also develop upon withdrawal of some
anti-parkinsonian medications, although
this is rare.1 NMS is an idiopathic
condition that occurs in therapeutic doses
in some patients, although its mechanism
is still not fully understood.
About 80% of cases of NMS develop
within the first two weeks of antipsychotic
use but can occur at any point during
therapy.
Drugs associated with NMS are listed in
Figure 1 (p204).2

At a glance...
What is NMS?
A rare but serious adverse event related
to antipsychotic drugs.
What are the main symptoms?
Altered mental status, pyrexia, muscle
rigidity and autonomic dysfunction.
How common is it?
NMS occurs in 0.022.4% of patients
treated with antipsychotic drugs.
How is it managed?
Cessation of causative drug and
provision of supportive care.
Pharmacological interventions (such
as dantrolene and bromocriptine)
are commonly used, despite limited
evidence.
Can the causative drug be restarted?
Yes, but guidelines should be followed
to minimise the risk of relapse.

Supportive care is important in patients with neuroleptic malignant syndrome

Diagnosis

There is no specific test for NMS and

diagnosis is primarily symptom-based.
NMS is associated with four classic
symptoms: altered mental status, pyrexia,
muscle rigidity and autonomic dysfunction.
The clinical and biochemical symptoms
associated with NMS are shown in Figure
2 (p204). Symptoms of NMS progress
rapidly and reach peak intensity about 72
hours after onset.
NMS is a diagnosis of exclusion so
it is important to consider differential
diagnoses when assessing a patient with
suspected NMS (see Figure 3, p205).

Epidemiology

NMS is estimated to effect between

0.02% and 2.4% of patients treated with
antipsychotic drugs.4,5 The incidence of
NMS is thought to be lower in patients
treated with atypical antipsychotic drugs
than in patients treated with conventional
antipsychotic drugs.5 Furthermore, the risk
of developing NMS appears to increase
when antipsychotic drugs are used in high
doses (i.e. above the limits recommended
by the British National Formulary) or
administered as a depot injection.

July/August 2009 Vol. 1 The British Journal of Clinical Pharmacy

Several factors may increase the

risk of developing NMS. For instance,
approximately 50% of patients who
develop NMS have schizophrenia and
about 25% have bipolar disorder. Age
alone does not appear to be a predisposing
factor for NMS, however several studies
have shown that young men are more
likely to be affected than women, usually
at a ratio of 2:1.6 This may be explained by
an increased use of antipsychotic drugs in
this group of individuals.

Pathogenesis

The pathogenesis of NMS is not fully

understood. Reduced dopamine activity
is implicated, either as a result of a
reduction in usable dopamine or as a result
of blockade of dopamine D2 receptors;
a mechanism of action of antipsychotic
drugs. Blockade of dopamine D2 receptors
in the hypothalamus may explain the
hyperthermia associated with NMS, and
blockade of dopamine D2 receptors in the
nigrostriatal pathway may explain the
parkinsonian-like symptoms.
Many other hypotheses have been
proposed involving neurotransmitters
such as gamma-aminobutyric acid,
203

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drug safety
Antipsychotic drugs

Antiemetic drugs

Other causes

Haloperidol (responsible
for 5060% cases)

Domperidone

Lithium

Thioridazine

Droperidol

CNS stimulants

Risperidone

Metoclopramide

Amphetamines

Quetiapine

Prochlorperazine

Cocaine

Perphenazine

Promethazine

Overdose of tricyclic
antidepressants

Paliperidone

Withdrawal of amantadine

Clozapine
Chlorpromazine

Withdrawal of
bromocriptine

Aripiprazole

Withdrawal of levodopa

Figure 1. Drugs associated with the development of neuroleptic malignant syndrome2

acetylcholine and serotonin. In addition,
antipsychotic drugs may be directly toxic
to muscle tissue, perhaps through changes
in mitochondrial function in muscle cells.7

Prognosis and complications

Disease severity and the development of

complications are the most reliable predictors
of outcome in patients with NMS.
Complications of NMS include
rhabdomyolysis, renal failure, seizures,
respiratory failure, aspiration pneumonia,
deterioration of psychiatric disease and
disseminated intravascular coagulation. In
cases reported before 1980, the estimated
rate of mortality was about 22%. This has
since decreased to about 4%, probably
as a result of earlier diagnosis and better
supportive care.4,8,9
The rate of mortality in patients with
NMS is increased by certain conditions.
For example, patients with NMS and renal
disease have a mortality rate of up to 50%.8
However, in the absence of complications
and with good supportive care, the
prognosis for patients with NMS is good.

Treatment and management

The most important and effective

intervention in the treatment of NMS is
cessation of the causative drug and any
other implicated psychotropic medication,
followed by supportive care. The recovery
time after cessation of the causative drug
is usually seven to 10 days.10 However,
this may be longer if the causative drug
was administered by a depot injection; rare
204

cases of residual catatonia and motor signs

have been reported up to six months after
cessation of causative drugs.
If NMS developed following withdrawal
of anti-parkinsonian medication, this
should be restarted.
Supportive care includes:

Maintenance of blood volume

Temperature lowering using cooling
blankets and ice packs (paracetamol
may be useful, however its efficacy
has not been established in this
situation)

Pharmacological management of
hypertension, if applicable
Administration of low molecular
weight heparin to prevent venous
thromboembolism

There is no gold standard treatment for

NMS and drug use is largely unsupported
by evidence. However, pharmacological
interventions are frequently used because
of the relatively high rates of morbidity
and mortality in patients with NMS, the
anecdotal evidence of efficacy and the lack
of established alternative treatments.
Dantrolene The skeletal muscle relaxant,
dantrolene, is suggested to be the most
appropriate pharmacological intervention
for NMS. It acts via the ryanodine receptor
to inhibit muscle contraction and heat
production and is also effective in treating
malignant hyperthermia. It is usually
given at a dose of 0.252mg/kg every
six to 12 hours, with a maximum dose of
10mg/kg/day. Effects can be seen within
minutes of intravenous administration. The
optimal length of dantrolene treatment is
debated. Some recommendations suggest
withdrawing treatment after a few days,
while others suggest decreasing the
dose for 10 days prior to withdrawal to
minimise the risk of relapse. Dantrolene
carries a risk of hepatotoxicity and should
be avoided in patients with abnormal liver
function.

Clinical symptoms
Altered mental status: drowsiness and confusion, progressing to stupor and coma
Pyrexia: temperature typically over 38C
Autonomic dysfunction: usually tachycardia or labile blood pressure
Muscle rigidity: often described as lead pipe rigidity
Tachypnea (rapid breathing)
Diaphoresis (excessive sweating)
Drooling
Incontinence
Biochemical symptoms
Raised creatine kinase: usually in excess of 1,000 IU/L. Levels up to 100,000 IU/L have
been reported3
Leucocytosis: present in up to 75% of cases3
Iron deficiency
Liver function abnormalities
Figure 2. Symptoms associated with neuroleptic malignant syndrome
The British Journal of Clinical Pharmacy Vol.1 July/August 2009

Copyright of the The British Journal of Clinical Pharmacy. No reproduction in any format is allowed unless permission is granted by the publisher

drug safety
Serotonin syndrome

treated patients compared with those

receiving supportive care (10.3% and 21%,
respectively).16

Malignant hyperthermia

Restarting causative drugs

Differential diagnosis

Drug-induced catatonia or parkinsonism

Idiopathic malignant catatonia
Infection (sepsis, meningoencephalitis,
pneumonia)

The risk of a second episode of NMS

is difficult to quantify and estimates of
recurrence vary between 10% and 90%.4,8
There are no definitive rules for restarting
antipsychotic drugs, however the following
guidelines may minimise risk:2,17

Baclofen withdrawal
Environmental heat stroke
Alcohol or sedative withdrawal
Lithium or monoamine oxidase inhibitor
overdose/toxicity

Recreational drug abuse, particularly

cocaine
Figure 3: Differential diagnoses of neuroleptic
malignant syndrome
Bromocriptine The dopamine agonist
bromocriptine is often co-prescribed with
dantrolene and is well tolerated. It is
given at a dose of 2.5mg every six to eight
hours and is continued until 10 days after
NMS becomes well controlled. It is then
decreased gradually.
Dantrolene and bromocriptine have
been shown to reduce recovery times
(from 15 days with supportive treatment
alone to nine days with dantrolene and 10
days with bromocriptine).11 Dantrolene
and bromocriptine have also been shown
to reduce mortality (8.6% and 7.8%,
respectively) in patients with NMS.12
An alternative to bromocriptine is
amantadine, given at a maximum dose of
200mg every 12 hours.
Other pharmacological treatments Other
interventions that may be effective in
the treatment of NMS (mainly based
on individual case reports) include
carbamazepine,13 benzodiazepines,
apomorphine14 and levodopa.15
Electroconvulsive therapy If
pharmacological agents are ineffective
despite adequate dosing, electroconvulsive
therapy (ECT) can be considered. The
evidence supporting ECT is not easily
comparable because of the wide variation
in how and when it is used with respect
to the onset of NMS. However, a study
has shown a lower mortality rate in ECT-

Wait at least two weeks before

restarting drugs (longer if any
residual symptoms are present)
Use the lowest potency drug
possible and avoid depot injections
Use a drug with low dopamine
receptor affinity (e.g. quetiapine
or clozapine), if possible and
appropriate
Start with a low dose and titrate up
cautiously
Avoid concomitant lithium

Conclusions

Pharmacists can play an important role in

the management of NMS by recognising
symptoms, identifying causative
medication, establishing a treatment plan
and reporting the outcomes.
As our understanding of NMS and
its treatment improves, and as newer
antipsychotics are developed, the incidence
of NMS should reduce and survival rates
should improve.
Ewan Maule is a clinical pharmacist
for emergency and critical care
at Northumbria Healthcare NHS
Foundation Trust.
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