Neuroleptic Malignant Syndrome

Practice Essentials
Neuroleptic malignant syndrome (NMS) is a rare, but life-threatening, idiosyncratic reaction to
neuroleptic medications that is characterized by fever, muscular rigidity, altered mental status,
and autonomic dysfunction. NMS often occurs shortly after the initiation of neuroleptic
treatment, or after dose increases.
Signs and symptoms

The key to diagnosis is that NMS occurs only after exposure to an neuroleptic drug. On average,
onset is 4-14 days after the start of therapy; 90% of cases occur within 10 days. However, NMS
can occur years into therapy. Once the syndrome starts, it usually evolves over 24-72 hours.
Cardinal features are as follows:

Severe muscular rigidity

Hyperthermia (temperature >38C)

Autonomic instability

Changes in the level of consciousness

A summary of the clinical features of neuroleptic malignant syndrome includes the following:

Muscular rigidity (typically, lead pipe rigidity)

Hyperthermia (temperature >38C)

Diaphoresis

Pallor

Dysphagia

Dyspnea

Tremor

Incontinence

Shuffling gait

Psychomotor agitation

Delirium progressing to lethargy, stupor, coma

Other general examination findings indicative of autonomic dysregulation include the following:

Diaphoresis

Sialorrhea

Tachycardia

Tachypnea, respiratory distress (31% of cases)

Increased or labile blood pressure

Hypoxemia (low pulse oximeter reading)

See Clinical Presentation for more detail.

Diagnosis

No laboratory test result is diagnostic for NMS. Laboratory studies are used to assess severity
and complications or rule out other diagnostic possibilities. A summary of the laboratory
abnormalities that may be found in neuroleptic malignant syndrome includes the following:

Increased LDH

Increased creatine kinase (50-100% of cases)

Increased AST and ALT

Increased alkaline phosphatase

Hyperuricemia

Hyperphosphatemia

Hyperkalemia

Myoglobinemia

Leukocytosis (70-98% of cases)

Thrombocytosis

Proteinuria

Decreased serum iron

Increased CSF protein

Hypocalcemia

Myoglobinuria

Metabolic acidosis

[1]

See Workup for more detail.

Management

Treatment of NMS is mainly supportive; it is directed toward controlling the rigidity and
hyperthermia and preventing complications (eg, respiratory failure, rhabdomyolysis, renal
failure). Limited evidence supports the use of dantrolene and bromocriptine to hasten clinical
response; other interventions that have been used include amantadine, lorazepam, and
electroconvulsive therapy.[2, 3] Monitoring and management in an ICU is recommended.
The most important intervention is to discontinue all neuroleptic agents. In most cases,
symptoms will resolve in 1-2 weeks. Episodes precipitated by long-acting depot injections of
neuroleptics can last as long as a month.
See Treatment and Medication for more detail.

Background
Neuroleptic malignant syndrome (NMS) is a rare, but life-threatening, idiosyncratic reaction to
neuroleptic medications that is characterized by fever, muscular rigidity, altered mental status,
and autonomic dysfunction. The syndrome was first described by Delay and colleagues in 1960,
in patients treated with high-potency antipsychotics.[4]
Neuroleptic drugs are primarily used to treat schizophrenia and other psychotic states.
Traditional agents (eg, chlorpromazine, haloperidol) act through inhibition of dopaminergic
receptors, whereas the second-generation (atypical) agents work by causing blockade of
serotonin receptors. These agents also have dopamine-blocking properties, though not as potent
as those of the traditional agents, and while they are not classified accurately as neuroleptics they
can cause NMS. Atypical antipsychotic drugs that may cause NMS include the following:

Olanzapine

Risperidone

Paliperidone

Aripiprazole

Ziprasidone

Amisulpride

Quetiapine

The second-generation antipsychotic agent clozapine may also be associated with the
development of NMS. However, it appears to be less likely to produce extrapyramidal features,
including rigidity and tremor.[5]
In general, over the past 30 years, NMS has been associated with a variety of drugs that lead to
decreased dopamine receptor activation.[6] A drug's potential for inducing NMS seems to parallel
its antidopaminergic activity.
NMS frequently occurs shortly after the initiation of neuroleptic treatment. The mean onset is 10
days after starting the new medication. Onset of NMS may also follow dose increases of an
established medication. No clear relationship has been established between neuroleptic dosage
and risk of developing neuroleptic malignant syndrome, however. Of note, NMS has also been
precipitated by the abrupt withdrawal of anti-Parkinson medication, which effectively decreases
the domaminergic activity of the brain.
While some clear risk factors for NMS have been identified, the low incidence of this syndrome
and the consequent difficulty in studying it in a controlled, prospective manner make clinical
features, predisposing conditions, treatment, and prognosis difficult to define. Successful
treatment requires prompt recognition, withdrawal of neuroleptic agent, exclusion of other
medical conditions, aggressive supportive care, and administration of certain pharmacotherapies
(see Treatment and Medication).
See Neuroleptic Agent Toxicity for discussion of the range of adverse effects seen with
therapeutic doses and overdoses of these drugs.

Pathophysiology
The most widely accepted mechanism by which antipsychotics cause neuroleptic malignant
syndrome is that of dopamine D2 receptor antagonism. In this model, central D2 receptor
blockade in the hypothalamus, nigrostriatal pathways, and spinal cord leads to increased muscle
rigidity and tremor via extrapyramidal pathways.
Hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment
of heat-dissipating mechanisms (eg, cutaneous vasodilation, sweating), while nigrostriatal
blockade results in muscular rigidity. Peripherally, antipsychotics lead to increased calcium

release from the sarcoplasmic reticulum, resulting in increased contractility, which can contribute
to hyperthermia, rigidity, and muscle cell breakdown.
Beyond these direct effects, D2 receptor blockade might cause neuroleptic malignant syndrome
by removing tonic inhibition from the sympathetic nervous system.[7, 8] The resulting
sympathoadrenal hyperactivity and dysregulation leads to autonomic dysfunction. This model
suggests that patients with baseline high levels of sympathoadrenal activity might be at increased
risk. While that has not been proven in controlled studies, several such states have been proposed
as risk factors for neuroleptic malignant syndrome.[9]
Direct muscle toxicity also has been proposed as a mechanism of neuroleptic malignant
syndrome.

Etiology
All classes of antipsychotics have been associated with neuroleptic malignant syndrome,
including low-potency neuroleptics, high-potency neuroleptics, and the newer (or atypical)
antipsychotics. Neuroleptic malignant syndrome has been reported most frequently in patients
taking haloperidol and chlorpromazine. Lithium at toxic levels may also reportedly cause
neuroleptic malignant syndrome.[10]
The clearest risk factors for neuroleptic malignant syndrome relate to the time course of therapy.
Strongly associated factors are as follows[11] :

High-potency neuroleptic use

High-dose neuroleptic use

Rapid increase in neuroleptic dose

Depot injectable (long-acting) neuroleptic use (ie, fluphenazine decanoate,

fluphenazine enanthate, haloperidol decanoate, risperdal consta)

Prior episodes of neuroleptic malignant syndrome

Recent episode of catatonia

[12]

A number of demographic features have been implicated, including male sex (2:1 ratio) and age
younger than 40 years. However, those features may simply indicate the higher usage of potent
neuroleptics in this population.
Other potential risk factors include the following:

Dehydration

[13]

[13]

Agitation

Exhaustion

Malnutrition

Organic brain syndromes

Nonschizophrenic mental illness

Lithium use

Past history of electroconvulsive therapy

Warm and humid environments

Inconsistent use of neuroleptics

Postpartum period

[14]

Genetic factors also might play a role. Case reports have been published on neuroleptic
malignant syndrome occurring in identical twins as well as in a mother and two of her daughters.
[15]

In patients who have experienced an episode of neuroleptic malignant syndrome, the risk of
recurrence is strongly related to the elapsed time between the episode and restarting
antipsychotics.[16] Delaying reintroduction of antipsychotic medication until at least 2 weeks after
the resolution of symptoms is typically recommended for patients who had been taking an oral
antipsychotic and at least 6 weeks for those on a depot form.[17]
The majority of patients who develop neuroleptic malignant syndrome will be able to tolerate an
antipsychotic at some point in the future.[16, 18] Given the potentially life-threatening nature of
neuroleptic malignant syndrome, reintroduction of antipsychotic treatment must be approached
cautiously. The risk of recurrence may be reduced by switching to a different antipsychotic class
and, if possible, using an atypical antipsychotic rather than a traditional agent.

Epidemiology
In the United States, neuroleptic malignant syndrome has been variably reported as occurring in
0.07-2.2% of patients taking neuroleptics.[19] Data largely come from case control studies rather
than prospective randomized trials. Because of increased awareness of this syndrome and efforts
at prevention, the incidence is probably lower now than in the past.[20]
The frequency of neuroleptic malignant syndrome internationally parallels the use of
antipsychotics, especially neuroleptics, in a given region. No data suggest geographic or racial

variation. The one large randomized trial conducted in China showed an incidence of 0.12% in
patients taking neuroleptics.[21] A retrospective study conducted in India showed an incidence of
0.14%.[22]
Onset of neuroleptic malignant syndrome ranges from 1-44 days after initiation of neuroleptic
drug therapy; mean onset is 10 days. Lazarus et al reported neuroleptic malignant syndrome
occurring in 67% of patients within 1 week and 96% of patients within 30 days following
administration of neuroleptics.[23, 24]
Sex- and age-related variations in incidence

Neuroleptic malignant syndrome has been reported to be more common in males, although that
most likely reflects greater neuroleptic usage rather than greater susceptibility. The male-tofemale ratio is 2:1.
The reported mean age of patients experiencing neuroleptic malignant syndrome is 40 years, but
the syndrome may occur in patients of any age who are receiving neuroleptics or other
precipitating medications.[24] Differential incidence simply might reflect a population that has a
high rate of antipsychotic usage. Some small case series suggest that onset in elderly patients
might occur after a longer duration of antipsychotic use.
Although NMS is rare in children, studies suggest that clinicians should maintain a high level of
suspicion in children. Symptoms of NMS in children are consistent with those described in
adults.[25]

Prognosis
The prognosis in patients with neuroleptic malignant syndrome depends on how promptly
treatment is instituted and on the presence of associated complications. In the absence of
rhabdomyolysis, renal failure, or aspiration pneumonia, and with good supportive care, the
prognosis for recovery is good.
In patients who develop neuroleptic malignant syndrome after taking an oral agent, the syndrome
may last 7-10 days after discontinuation of the drug. In those who have received depot
neuroleptics (eg, fluphenazine), the syndrome may last up to a month.
The mortality rate in patients with neuroleptic malignant syndrome, once reported at 20-30%, is
now estimated at 5-11.6%. The mortality rate rises to about 50% if neuroleptic malignant
syndrome is complicated by renal failure.
Patients who have previously experienced episodes of neuroleptic malignant syndrome are at risk
for recurrences, especially if antipsychotics are restarted shortly afterward. However, the
majority of these patients will be able to tolerate another antipsychotic, which is very important

because most patients taking neuroleptics require them to maintain a reasonable functional
status.
Complications

Complications of neuroleptic malignant syndrome include dehydration from poor oral intake,
acute renal failure from rhabdomyolysis, and deep venous thrombosis and pulmonary embolism
from rigidity and immobilization.
Avoiding antipsychotics can cause complications related to uncontrolled psychosis. Most patients
taking antipsychotic medicines are being treated for a severe and persistent psychiatric disorder;
a high likelihood exists that a patient will relapse while off antipsychotics.
A summary of the potential complications of neuroleptic malignant syndrome includes the
following:

Rhabdomyolysis

Renal failure

Cardiovascular arrhythmias and collapse

Aspiration pneumonia

Respiratory failure

Seizure

Pulmonary embolism and deep venous thrombosis (DVT)

Hepatic failure

Disseminated intravascular coagulation (DIC)

Decompensation of psychiatric disease following the withdrawal of

neuroleptics

Mortality/morbidity

Mortality from neuroleptic malignant syndrome is very difficult to quantify, because the
literature on this subject consists largely of case reports and because the diagnostic parameters
used have been inconsistent. In some series, mortality rates as high as 76% have been reported.
Most series suggest, however, that the mortality rate is 10-20%. When reporting bias is factored
in, the true rate of mortality from neuroleptic malignant syndrome might be much lower.

Studies have also found that the mortality rate has been decreasing over the past 2 decades. In a
US populationbased study of cases from the years 2002-2011, the unadjusted mortality rate was
5.6%.[26]
Mortality is caused by one or more complications (eg, respiratory failure, cardiovascular
collapse, renal failure, arrhythmias, thromboembolism, DIC).[27] Renal failure is associated with a
50% mortality rate.
No consistent long-term physical, neurological, cognitive, or laboratory sequelae have been
attributed to neuroleptic malignant syndrome alone, although sequelae may result from such
secondary complications as prolonged hypoxia or ischemic encephalopathy. Researchers have
noted sporadic cases of prolonged rigidity and long-term neuropsychological deficits.

Patient Education
When prescribing neuroleptic medications, clinicians should explain and educate the patient and
caretakers about possible adverse effects of the medications. After an episode of neuroleptic
malignant syndrome, educational approaches can help patients and their relatives to understand
what has happened to the patient, why the neuroleptic malignant syndrome has developed in the
past, and the possibility of recurrence if antipsychotic therapy is restarted.
This education may help patients and their relatives to decide about giving consent to restart
antipsychotics. If they give consent, they have to be aware of the early signs of neuroleptic
malignant syndrome (eg, rigidity, hyperthermia, and changes of consciousness) and the
importance of immediately seeking medical care if these arise.
For patient education information, see Neuroleptic Malignant Syndrome. Helpful Web sites for
patients include the following:

Neuroleptic Malignant Syndrome Information Service

NINDS Neuroleptic Malignant Syndrome Information Page (National Institute

of Neurological Disorders and Stroke)

History
The diagnosis of neuroleptic malignant syndrome is based on clinical features. Cardinal features
are as follows:

Severe muscular rigidity

Hyperthermia

Autonomic instability

Changes in the level of consciousness

The syndrome occurs only after exposure to a neuroleptic drug. Most cases develop shortly after
initiation of therapy or increasing the dose. The onset can be within hours, but on average is 4-14
days, after the start of therapy; 90% of cases occur within 10 days. However, neuroleptic
malignant syndrome can occur at any time during neuroleptic use, even years into therapy. Once
the syndrome starts, it usually evolves over 24-72 hours.
A summary of the clinical features of neuroleptic malignant syndrome includes the following:

Rigidity

Hyperthermia

Diaphoresis

Pallor

Dysphagia

Dyspnea

Tremor

Incontinence

Tachycardia

Shuffling gait

Psychomotor agitation

Delirium progressing to lethargy, stupor, coma

Patients with atypical presentations of neuroleptic malignant syndrome may not exhibit muscle
rigidity or hyperthermia initially; those features may develop over time or not at all.[28]
Clozapine-induced neuroleptic malignant syndrome may be more likely to manifest without
extrapyramidal features, including rigidity and tremor, but cases involving other atypical
antipsychotic drugs generally present in a typical manner.[2]

Physical Examination
Neuroleptic malignant syndrome tends to start with muscular rigidity and progress to
hyperthermia with autonomic instability and a fluctuating level of consciousness. Compared with

adults, children and adolescents with neuroleptic malignant syndrome tend to present with more
dystonia and less tremor.
General examination findings indicative of autonomic dysregulation include the following:

Hyperthermia (temperature >38C)

Diaphoresis

Sialorrhea

Tachycardia

Tachypnea, respiratory distress (31% of cases)

Increased or labile blood pressure

Hypoxemia (low pulse oximeter reading)

Incontinence

Patients may exhibit signs of dehydration secondary to hyperpyrexia and inadequate oral intake.
Pallor or rash may be present. In rare cases, a reversible cardiomyopathy mimicking cardiac
infarction may develop.[29]
Signs and symptoms of decreased dopaminergic activity include the following:

Muscular rigidity (typically, lead pipe rigidity)

Dysphagia

Short, shuffling gait

Resting tremor

Dystonia

Dyskinesia

Excessive or purposeless motor activity and tremor can reflect psychomotor agitation. Mental
status may be altered, ranging from agitation to drowsiness, confusion, and coma. Delirium is
characterized by the following:

Loss of awareness of both the internal and external worlds

Loss of orientation in time and space

Reduced ability to direct and sustain attention

Speech that is often mumbled and incoherent

Delusions and hallucinations, especially visual

Fluctuating level of consciousness, from lethargy to stupor and coma

WORK UP

Approach Considerations
No laboratory test result is diagnostic for neuroleptic malignant syndrome (NMS). However, the
following laboratory studies may be indicated, to assess severity and complications or rule out
other diagnostic possibilities:

Complete blood count (CBC)

Blood cultures

Liver function tests (LFTs)

Blood urea nitrogen (BUN) and creatinine levels

Calcium and phosphate levels

Creatine kinase (CK) level

Serum iron level

Urine myoglobin level

Arterial blood gas (ABG) levels

Coagulation studies

Serum and urine toxicologic screening (eg, salicylates, cocaine,

amphetamines)

General laboratory features in neuroleptic malignant syndrome include leukocytosis,

thrombocytosis, and evidence of dehydration. The serum iron concentration might be decreased.
The cerebrospinal fluid (CSF) protein concentration might be elevated.[38]
The rigidity and hyperthermia in neuroleptic malignant syndrome contribute to muscle damage
and necrosis, which is reflected in elevated blood levels of the following:

CK

LFTs (aspartate aminotransferase [AST], alanine aminotransferase [ALT])

Lactate dehydrogenase (LDH)

Muscle damage and necrosis can progress quickly to rhabdomyolysis with hyperkalemia,
hyperphosphatemia, hyperuricemia, and hypocalcemia. Elevated levels of myoglobin can be
observed in blood and urine, and may ultimately lead to renal failure.
Assessment of the serum CK level is especially frequently used in psychiatric practice for
diagnostic evaluation of rhabdomyolysis in patients with possible neuroleptic malignant
syndrome. Other causes of CK elevation may include prescription drugs, alcohol, acute coronary
syndrome, and other medical conditions.
Other causes of fever should be investigated, depending on the clinical scenario. This may
include urinary tract, respiratory, and central nervous system (CNS) infections. Cultures from
various sites may be indicated.
A summary of the laboratory abnormalities that may be found in neuroleptic malignant syndrome
includes the following:

Increased LDH

Increased CK (50-100% of cases)

Increased AST and ALT

Increased alkaline phosphatase

Hyperuricemia

Hyperphosphatemia

Hyperkalemia

Myoglobinemia

Leukocytosis (70-98% of cases)

Thrombocytosis

Proteinuria

Decreased serum iron

[1]

Increased CSF protein

Hypocalcemia

Myoglobinuria

Metabolic acidosis

If thromboembolic phenomenon or disseminated intravascular coagulation (DIC) is suspected,

the following coagulation studies may be performed:

Platelet count

Prothrombin time (PT) and international normalized ratio (INR)

Activated partial thromboplastin time (aPTT)

Imaging studies do not yield any diagnostic information for neuroleptic malignant syndrome per
se. However, computed tomography (CT) or magnetic resonance imaging of the brain may be
performed to rule out other conditions, such as intracranial hemorrhage (ICH), trauma, or
structural lesions. Chest radiography is indicated for suspected aspiration pneumonia.
A lumbar puncture (LP) is indicated to rule out meningitis as a cause of fever and altered mental
status. No universal agreement exists on the absolute need for a head CT scan before performing
an LP in patients without clinical evidence of a structural lesion of the brain; the decision is left
to the individual practitioner.
TREATMENT

Approach Considerations
Treatment of neuroleptic malignant syndrome (NMS) is mainly supportive; it is directed toward
controlling the rigidity and hyperthermia and preventing complications (eg, respiratory failure,
renal failure). Other interventions, such as dantrolene, bromocriptine, amantadine, lorazepam,
and electroconvulsive therapy, have been advocated, but their value is controversial.[2, 39]
Monitoring and management in an intensive care unit (ICU) is recommended.
The most important intervention is to discontinue all antipsychotics. Signs and symptoms should
improve after the antipsychotic is stopped. No new focal neurologic deficits should develop,
although cases of neurologic sequelae have been reported rarely. In most cases, symptoms will
resolve in 1-2 weeks. Episodes precipitated by long-acting depot injections of antipsychotics can
last as long as a month.

Patients should receive circulatory and ventilatory support as needed. Antipyretics, evaporative
cooling, ice packs, and cooled intravenous (IV) fluids can be used to reduce hyperthermia.
Consider prophylactic intubation for patients with excessive salivation, swallowing dysfunction,
coma, hypoxemia, acidosis, and severe rigidity with hyperthermia. Aggressive fluid resuscitation
and alkalization of urine can help prevent acute renal failure and enhance excretion of muscle
breakdown products.

Prehospital Care
Any patient being evaluated by prehospital personnel requires assessment of the airway,
breathing, and circulation (ABCs). Any patient with altered mental status should receive
thiamine, dextrose (or rapid glucose determination), and naloxone, to exclude alcohol
withdrawal, hypoglycemia, and opioid overdose, respectively.
Prehospital personnel must assess the patient's safety and, if necessary, restrain the patient.
Restraint use in agitated, hyperthermic patients can increase the risk of significant morbidity and
mortality in neuroleptic malignant syndrome and other disease states (eg, cocaine intoxication,
amphetamine abuse). Chemical restraints (eg, benzodiazepines), if available, may be preferable
in such situations.
To identify possible precipitants of neuroleptic malignant syndrome, prehospital personnel
should try to obtain an accurate medication list. If that is impossible, they should bring all the
medication bottles found with the patient.

Emergency Department Care

Treatment of patients with neuroleptic malignant syndrome may include the following:

Benzodiazepines for restraint may be useful

Stop all neuroleptics

Correct volume depletion and hypotension with intravenous fluids

Reduce hyperthermia

Methods to reduce the temperature include the following:

Cooling blankets

Antipyretics

Cooled intravenous fluids

Ice packs

Evaporative cooling

Pharmacologic therapies to reduce rigidity (see below)

When rhabdomyolysis occurs, maintain vigorous hydration and alkalinize the urine with
intravenous sodium bicarbonate to prevent renal failure.
Additional evaluation and treatment should be in an inpatient setting, preferably an ICU.

Electroconvulsive Therapy
In patients with neuroleptic malignant syndrome, electroconvulsive therapy (ECT) can help with
the alteration of temperature, level of consciousness, and diaphoresis. It may also be useful in
treating the underlying psychiatric disease in patients who are unable to take neuroleptics.[40, 41]
ECT with anesthesia has generally been safe, with no increased incidence of malignant
hyperthermia from succinylcholine administration.[42, 43] However, serious treatment-related
complications have occurred. Specifically, patients with neuroleptic malignant syndrome have
developed cardiac arrest and ventricular fibrillation after ECT.

Pharmacologic Therapy
A variety of medications have been used to provide symptomatic treatment of neuroleptic
malignant syndrome. Dantrolene sodium directly relaxes muscles by inhibiting calcium release
from the sarcoplasmic reticulum. Most patients respond to 400 mg/day or less.
Dantrolene therapy alone appears to shorten the duration of illness, but use is controversial.
Reduction of fever and rigidity is not immediate but occurs over a mean of 1.7 days. A review of
case reports concluded that combining dantrolene with other drugs prolongs the recovery period,
and that using dantrolene as monotherapy seemed to be associated with increased mortality. The
only benefit from dantrolene was in patients who had been on neuroleptic monotherapy.[44]
Bromocriptine is a dopamine agonist that overcomes neuroleptic-induced dopaminergic
blockade. It has also been used in combination with dantrolene, but studies have questioned the
benefit of this approach.[45, 44]
Other agents that have been tried include amantadine, which enhances presynaptic release of
dopamine, and levodopa/carbidopa, which increase presynaptic dopamine stores. Dopaminergic
medications can be especially useful if the NMS was caused by withdrawal of anti-Parkinson
medication.[45, 46, 39]
Use of nondepolarizing neuromuscular blocking agents (eg, pancuronium, other newer agents)
may be considered. These may achieve rapid, predictable, and effective control of rigidity and

hyperthermia. However, such medications can be used only in patients who have been intubated
and sedated and are receiving mechanical ventilation.
Antimuscarinic agents are not recommended. They are not only ineffective but also may worsen
hyperthermia.

Deterrence/Prevention
Clinicians should take a careful history before starting a new neuroleptic medication, to uncover
any previous instances of neuroleptic malignant syndrome, as those patients are at risk for
recurrence. Because neuroleptic malignant syndrome usually develops while the dose is being
increased, the clinician, patient, and family members must be alert to this possibility until a
steady dose is achieved.
Patient education should be provided regarding avoidance of factors that may increase the risk
for development of neuroleptic malignant syndrome. These include dehydration, agitation,
exhaustion, and malnutrition (see Patient Education).

Consultations
Consultation with a neurologist may be needed if the diagnosis is in question. Consultation with
a nephrologist is needed if the patient develops rhabdomyolysis and renal failure.
Consultation with a psychiatrist can be helpful to manage the underlying psychiatric disease once
the neuroleptics have been withdrawn. On the other hand, if neuroleptic malignant syndrome is
diagnosed in a psychiatric facility, the patient should be transferred to an acute care medical
facility where intensive monitoring and treatment is available.

Long-Term Monitoring
Neuroleptic malignant syndrome may be prolonged. If the patient is discharged, close follow-up
care should be given to monitor residual symptoms. The patient's psychiatric disease must be
evaluated and treated during withdrawal of the neuroleptic medication.
If neuroleptics are to be reinstituted, they should be administered at relatively low initial doses.
Challenge with an atypical antipsychotic may be appropriate, since these drugs have a lower
incidence of neuroleptic malignant syndrome.

Medication Summary
Specific drug therapies, such as dantrolene, amantadine, and bromocriptine, have an uncertain
role in the treatment of neuroleptic malignant syndrome. Recommendations for the use of these
drugs are from noncontrolled prospective and retrospective studies and case reports; no
controlled studies exist. While the drugs generally are felt to be helpful, they have been found to
have deleterious effects in some studies.

Skeletal Muscle Relaxants

Class Summary

These agents stimulate muscle relaxation by modulating skeletal muscle contractions at sites
beyond the myoneural junction and by acting directly on muscle itself. Benzodiazepines are used
in a small number of patients with neuroleptic malignant syndrome unresponsive to other
measures. In most cases, a continuous IV infusion of diazepam or lorazepam has been utilized.
View full drug information
Dantrolene (Dantrium, Revonto)

Dantrolene interferes with the release of calcium from sarcoplasmic reticulum, thus directly
inhibiting muscle contraction. It also prevents or reduces the increase in myoplasmic calcium ion
concentration that activates acute catabolic process associated with malignant hyperthermia. It is
used to treat muscular rigidity and hyperthermia associated with neuroleptic malignant
syndrome.
Dantrolene is available as a sodium salt in 25-mg, 50-mg, and 100-mg capsules and in 20-mg
vial for intravenous (IV) administration. The IV form is much more expensive and should be
reserved for patients unable to take oral medications.

Benzodiazepine-Antispasmodic Agents
Class Summary

By binding to specific receptor sites, benzodiazepines appear to potentiate the effects of gammaaminobutyric acid (GABA) and facilitate inhibitory GABA neurotransmission and the action of
other inhibitory transmitters.
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Diazepam

Diazepam modulates postsynaptic effects of gamma amino-butyric acid A (GABA-A)

transmission, resulting in an increase in presynaptic inhibition. It appears to act on part of the
limbic system, as well as on the thalamus and hypothalamus, to induce a calming effect.
Individualize dosage and increase cautiously to avoid adverse effects.
View full drug information
Lorazepam (Ativan)

Lorazepam is a benzodiazepine with short onset of effects and intermediate-long half-life.

By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it
might depress all levels of CNS, including the limbic and reticular formation.

Dopamine Agonists
Class Summary

A dopamine agonist must stimulate D2 receptors if it is to offer clinical benefit in neuroleptic

malignant syndrome. D2 receptor blockade might cause neuroleptic malignant syndrome by
removing tonic inhibition from the sympathetic nervous system or more directly by neuroleptic
agents (eg, phenothiazines).
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Bromocriptine (Parlodel)

Bromocriptine is a semisynthetic, ergot alkaloid derivative that is a strong dopamine D2-receptor

agonist and a partial dopamine, D1-receptor agonist. It stimulates dopamine receptors in the
corpus striatum. Bromocriptine may relieve akinesia, rigidity, and tremor associated with
Parkinson disease. Initiate at low dosage. Slowly increase dosage to individualize therapy. Assess
dosage titration every 2 weeks. Gradually reduce dose in 2.5-mg decrements if severe adverse
reactions occur.
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Amantadine

Amantadine has been used to treat Parkinson disease and has been tried in neuroleptic malignant
syndrome because it increases synaptic dopamine activity. Its antiparkinsonian activity results
from blocking reuptake of dopamine into presynaptic neurons and causing direct stimulation of
postsynaptic receptors.