657553

review-article2016
AOPXXX10.1177/1060028016657553Annals of PharmacotherapyPileggi and Cook

Review Article
Annals of Pharmacotherapy

Neuroleptic Malignant Syndrome Review:

1­–9
© The Author(s) 2016
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DOI: 10.1177/1060028016657553
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Dominic J. Pileggi, PharmD1, and Aaron M. Cook, PharmD, BCPS1,2

Abstract
Objective: To review evidence for the treatment of neuroleptic malignant syndrome (NMS) and to discuss how to
rechallenge patients with neuroleptics when continued pharmacotherapy for chronic psychological illness is required.
Data Sources: A PubMed search was conducted through March 2016 using available medical subject heading (MeSH)
terms and keywords that included neuroleptic malignant syndrome, treatment, dantrolene, and bromocriptine. A manual search
of article reference sections followed. Study Selection and Data Extraction: Case reports and case series in English
that discussed NMS and atypical NMS treatment as well as neuroleptic rechallenge were included for review. Data
Synthesis: The reported incidence of NMS was 0.02% to 0.03%, with a mortality rate of 5.6%. Current literature on NMS
is primarily retrospective and emphasizes diagnostic criteria, causative agents, and potential pharmacotherapy. Details
regarding timing of administration, dose, and duration of pharmacotherapy are inconsistently reported. Reported dosing
strategies and outcomes have been summarized. Instances of rechallenge were infrequently reported but demonstrate
that recurrence may happen at any time after NMS resolution. Recommendations regarding safe rechallenge are provided.
Conclusion: NMS is a rare adverse drug reaction, with a complex pathophysiology and presentation. Timely diagnosis
and discontinuation of antipsychotic therapy is the first-line treatment, followed by supportive care and pharmacotherapy.
Antipsychotic rechallenge is often required and should be attempted only after a drug-free period and with a different
agent, slowly titrated with close monitoring.

Keywords
neuroleptics, neuropharmacology, withdrawal, management, critical care, adverse drug reactions

Background known. A prospective study completed over 18 months esti-

Neuroleptic malignant syndrome (NMS), first recognized
in the 1960s, is a rare and potentially fatal adverse drug
reaction (ADR).1 The etymology of NMS, and the syn-
drome itself, begins with the term neuroleptic, which first
differentiated between medications with antidepressant or
anxiolytic properties and those with antagonistic effects on
dopamine-2 (D2) receptors—that is, antipsychotics. Now,
neuroleptics are synonymous with antipsychotics, but the
syndrome retains its name to be more encompassing of
causative agents.
The characteristic symptoms of NMS include hyperther-
mia, “lead-pipe” muscle rigidity, altered mental status
(AMS), and autonomic instability. However, clinicians are
often challenged with differentiating NMS from other diag-
noses such as malignant hyperthermia, serotonin syndrome,
and malignant catatonia, among others (Table 1). The cardi-
nal laboratory finding in NMS is often an elevation in cre-
atine kinase (CK), typically above 1000 µg/L.2
NMS is an ADR that is uncommon and challenging to
diagnose, and therefore, an accurate incidence cannot be
mated the incidence at 0.9% (n = 679), which was repro-
duced in another institution (n = 559).3,4 Later a pooled
analysis of 16 studies estimated NMS to occur at a rate of
0.2%.5 A more recent estimate that reflects the use of sec-
ond-generation antipsychotic (SGA) medications puts NMS
rates at 0.02% to 0.03%.6,7 Because SGAs cause fewer
extrapyramidal symptoms because of decreased D2-receptor
antagonism (pKi = 7.18 vs 8.89, P = 0.001), they were also
thought to not cause NMS.8,9 However, many new atypical
agents have been cited as causative agents in the develop-
ment of NMS.10 It is unlikely that a newly developed agent
with an overlapping mechanism of action with first-genera-
tion antipsychotics and SGAs would not cause NMS.
1
University of Kentucky Chandler Medical Center, Lexington, KY, USA
2
University of Kentucky College of Pharmacy, Department of Pharmacy
Practice and Science, Lexington, KY, USA
Corresponding Author:
Aaron M. Cook, University of Kentucky Chandler Medical Center, 800
Rose St H110, Lexington, KY 40536-0293, USA.
Email: amcook0@uky.edu

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2 Annals of Pharmacotherapy 

Table 1.  Differential Diagnosis of NMS.6,19,52 Data Sources

Infectious A PubMed search was conducted through March 2016. The
  Brain abscess search utilized the medical subject heading (MeSH) terms
 Encephalitis in the following search strategies: Neuroleptic malignant
 Meningitis syndrome AND treatment = 612 results; neuroleptic malig-
 Rabies nant syndrome AND dantrolene OR bromocriptine OR
  Septic shock amantadine OR biperiden = 12 308 results. Limits included
 Tetanus
those available in English. In addition, the reference lists for
Neuropsychiatric
each article were investigated for relevant citations that
 Delirium
addressed rechallenge or recent/novel treatment methods.
  Lethal catatonia
Cases of “atypical” NMS were not excluded, and in some
  Nonconvulsive status epilepticus
Pharmacological
cases, accurate classification of atypical NMS was not pos-
  Anticholinergic delirium sible based on the data provided in the case reports.
  Drug-drug interaction
  Drug withdrawal Results
  Extrapyramidal side effects
  Malignant hyperthermia The Importance of Diagnosis
  Serotonin syndrome
Early diagnosis of NMS is essential to prevent disease pro-
Toxic
  Heavy metals (lead, arsenic)
gression, sequelae, and death. This has proven challenging
 Lithium because NMS shares symptoms with multiple possible eti-
 Salicylates ologies (Table 1) and often becomes a diagnosis of exclu-
  Substances of abuse sion. The varied presentation has not allowed for universal
Endocrine diagnostic criteria. At least 14 unique criteria exist, includ-
 Pheochromocytoma ing the Diagnostic and Statistical Manual of Mental
 Thyrotoxicosis Disorders, 5th edition, criteria by Levenson as well as a
Environmental staging and treatment protocol that utilizes criteria from
 Heatstroke Woodbury and Woodbury.6,12-15 A majority of the cases pub-
  Spider envenomation lished did not cite the criteria used to diagnose NMS. For
clinicians, a low threshold for suspicion of NMS allows for
rapid discontinuation of the offending agent, which may
Whereas some cases of NMS are self-limiting, it can prevent complications.16 This is especially true in the case
become a severe ADR, with increased morbidity and mor- of patients receiving antipsychotics off-label (such as for
tality. A recent study by Modi et al11 utilized a national chemotherapy-induced nausea and vomiting) or who have a
US database to examine outcomes in 1346 cases of NMS concomitant condition that might mask diagnosis. For
between the years 2002 and 2011. The crude rate of mor- example, muscle rigidity in a trauma patient receiving anti-
tality was 5.6%. This rate decreased from 8.3% in 2002 to psychotics might not be apparent in the presence of persis-
5.1% in 2011, attributed primarily to improved diagnosis. tent fever.16 Further complicating diagnosis is a lack of
In a multivariate analysis, the most potent predictor of characteristic sequence of symptoms presentation. For
mortality was acute respiratory failure, with an adjusted example, classic symptoms associated with NMS such as
odds ratio (OR) of 7.1. Age is also an important indepen- fever and autonomic instability may actually present after
dent predictor of mortality; each 10-year increase in age rigidity and AMS.10,17 Some investigators have proposed
is associated with a 40% increased odds of mortality.11 the concept of atypical NMS, a form of NMS stemming
The most common complication was rhabdomyolysis from SGAs that may not have all the cardinal symptoms.
(30.1%), and of those patients, 30% developed acute kid- An argument against this subclassification is that early
ney injury (AKI). Of the patients with AKI who had no diagnosis actually prevents the development of some com-
previous history of kidney disease, 5.9% underwent mon symptoms of NMS and that it is not atypical NMS
hemodialysis. Other complications included respiratory simply early NMS.2,7,18
failure requiring ventilator support, pneumonia, and sep-
sis. The relatively poor outcomes associated with NMS
Proposed Pathophysiology
are also reflective of the lack of definitive treatment
options. The intent of this review is to discuss the avail- The precise cause of NMS is not well elucidated. The most
able literature associated with treatment options for NMS enduring proposal for the mechanism underlying the symp-
and after NMS resolution. toms observed during NMS is an excessive dopamine

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Pileggi and Cook 3
blockade, most prominently at the D2 receptor. Antagonizing
this receptor within the nigrostriatal, hypothalamic, and
mesolimbic/cortical pathways likely explains the rigidity,
hyperthermia, and AMS, respectively, commonly seen in
patients with NMS. Furthermore, this proposed mechanism
is supported by resolution of symptoms on discontinuation
of neuroleptics that cause dopamine blockade, specifically
those with potent D2 affinity.2,9,19 Moreover, removal of
dopamine agonists can induce NMS symptoms.20,21 Genetic
polymorphisms with the D2 receptor may also factor into the
risk for individual patients. For example, patients with a taqI
A, A1 allele may be up to 10 times more likely to experience
NMS than noncarriers.22
Atypical antipsychotics with less D2 antagonist activity
can also cause NMS, which suggests that dopamine block-
ade may not be the sole precipitator of NMS.7 Increased
catecholamines in the urine and plasma support the sympa-
thoadrenal hyperactivity hypothesis.22 Abnormalities in this
system would explain the lack of tonic inhibition as well as
autonomic instability, though downstream effects of dopa-
mine blockade may also explain the sympathoadrenal dys-
function. Unregulated sympathetic outflow can account for
nearly all the symptoms commonly seen in NMS.22,23
Another possible mechanism that could contribute to NMS
presentation could be predisposition of the patient’s musculo-
skeletal fiber, as seen in the pathophysiology of malignant
hyperthermia. Halothane anesthetics can induce muscle con-
traction and produce the symptoms of malignant hyperther-
mia, including muscle rigidity and high body temperature.
NMS shares these symptoms with malignant hyperthermia
along with symptom resolution with use of dantrolene, a
peripheral muscle relaxant. If not a predisposition, NMS
symptoms could be the result of a direct toxic effect by neuro-
leptics on musculoskeletal fiber. Antipsychotics have been
shown in vitro to affect calcium release from the sarcoplasmic
reticulum, which, if in excess, could lead to rigidity and
hyperthermia.24 It is important to understand the underlying
cause of NMS in order to guide treatment, but the complex
and varied presentation of NMS bespeaks the complexity of
the pathophysiology itself.
Risk Factors
Although the occurrence of NMS is typically unpredictable,
knowledge of risk factors can help guide treatment and pre-
vent recurrence. Risk factors may be environmental, patient
specific, or most classically, pharmacological. Any antipsy-
chotic at any typical dose via any route has the potential to
cause NMS. Rapid dose escalation and use of higher anti-
psychotic doses as well as depot formulation use (OR =
5.66) also appear to increase the likelihood of NMS.7
Intravenous (IV) routes of administration have also been
indicated as a contributing factor toward NMS development.
Polypharmacy with both antipsychotic and nonantipsychotic
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drugs, especially lithium, may potentiate an individual
drug’s risk for causing NMS.3 Although NMS is less likely
to appear when using moderate stable doses, reports of NMS
resulting from these circumstances do exist.25
Just as excessive dopamine blockade may lead to NMS, so
can withdrawal of prodopaminergic medications. Reports of
discontinuation of medications for Parkinson’s disease (PD)
or inadequate dose resulting from malabsorption that have led
to NMS have been published.20,26,27 Similarly, sudden discon-
tinuation of antipsychotics may produce a withdrawal NMS,
attributed not to dopamine blockade but a general dysregula-
tion of the central dopamine signal pathways.28
Environmental risk factors that may predispose the
patient to development of NMS include an elevated ambi-
ent room temperature or prolonged heat exposure, the use
of patient restraints, and dehydration. All environmental
factors that inhibit heat dissipation could contribute to the
development of NMS or exacerbate the condition.2 Stress
caused by surgical intervention, as well as necessary disrup-
tion of antipsychotic dosing preoperatively, may also raise
an individual’s risk for NMS.29
A previous history of NMS is an established patient-spe-
cific risk factor for recurrent NMS. Additionally, a family
history of NMS or other dystonic reactions should be obtained
because a genetic component has been suggested.24,30 Acute
vomiting or diarrhea can predispose patients to electrolyte
imbalance. In one patient with PD, acute hyponatremia from
vomiting as well as reduced levodopa absorption may have
affected central signaling pathways involving Na-dependent
catecholamine reuptake, leading to development of NMS.
Once it was appropriately corrected, symptoms of NMS
resolved within 24 hours.26 Other patient-specific factors for
recurrent NMS include increasing age and number of medi-
cal comorbidities.2,5
Management
Initial Management
It is clear that the initial treatment in patients with NMS is
to discontinue antipsychotics (or other potential offending
agents) as soon as NMS is suspected. This is recommended
even with an atypical presentation of NMS, without a con-
clusive diagnosis of NMS. The morbidity and mortality risk
associated with NMS outweighs the risk of untreated psy-
chosis and agitation resulting from sudden discontinuation
of antipsychotics. However, the opposite is true in the case
of discontinuation of prodopaminergic medications. If
NMS results from their discontinuation, they should be
restarted as quickly as possible.6,19
Supportive Care
Efforts should also be made to control and correct any mod-
ifiable factors that may contribute to NMS progression such
4 Annals of Pharmacotherapy 
as removal of restraints and reducing elevated room tem-
perature. Cooling blankets and antipyretics may both be
used to reduce fever, but the latter are regarded as less effec-
tive because the nature of the hyperthermia is likely a result
of the anticholinergic and dopaminergic effects of the anti-
psychotics versus prostaglandins.24 Fluid resuscitation and
electrolyte correction may be required because patients
with NMS typically develop dehydration and are prone to
electrolyte imbalances. Maintaining a slightly alkalotic pH
may prevent rhabdomyolysis and AKI. For labile hyperten-
sion, calcium channel blockers have been suggested because
they may also reverse toxicity at the musculoskeletal level.2
If immobilized from rigidity, prophylaxis for deep-vein
thrombosis should be initiated. In severe cases, intubation
may be required in patients with muscle rigidity extending
to their airway. There are reports of successfully treating
NMS with supportive care alone.6,19,31,32 However, in cases
of severe rigidity or persistent hyperthermia, pharmacother-
apy is required for symptom resolution.
Pharmacological Interventions
Many claims for efficacy in treating NMS have been made
for a variety of medications. Based on their proposed mech-
anisms of action, agents such as dantrolene sodium, bro-
mocriptine, and benzodiazepines have the most compelling
evidence for NMS resolution. The majority of the literature
published in this area suffers from small sample size and
lack of prospective studies. Dose, route of administration,
and duration of treatment are also inconsistently reported in
the literature (Table 2). A stepwise approach based on NMS
severity has been adapted from Strawn et al6 and Woodbury
and Woodbury12 to guide treatment with the most studied
agents (Table 3). Anticholinergic agents, such as biperiden,
have limited published data and are thought to potentially
worsen hyperthermia through a reduction in heat dissipa-
tion and have little to no effect on NMS rigidity.24 These
agents, therefore, are not recommended for treatment of
NMS symptoms.
Dantrolene. Dantrolene sodium is a direct skeletal muscle
relaxant that disrupts excitation-contraction coupling by
blocking calcium efflux from the sarcoplasmic reticulum.33 It
is the drug of choice for treatment of malignant hyperther-
mia, and since its first mention in 1981, has been routinely
used for NMS treatment (Table 2). An analysis of 271 cases
by Reulbach et al34 evaluating the efficacy of dantrolene in
NMS argued that dantrolene used as monotherapy may actu-
ally be associated with an increase in mortality. However,
timing of drug administration could not be ascertained from
their analysis, and dantrolene tended to be reserved for
severely ill patients. If IV access can be obtained and the
patient is demonstrating mild to moderate symptoms of rigid-
ity and fever, dantrolene may be efficacious earlier in NMS
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presentation. For severe cases, there has long been support
for the use of a combination of dantrolene with other medica-
tions such as bromocriptine.2,35
Adverse effects with dantrolene use are rare and not
reported when used for short-term treatment of NMS.
Hepatitis is the most reported adverse effect but is primarily
associated with prolonged use.33 Although incompletely
described, the dose of dantrolene is typically weaned over
several days to avoid recurrence of NMS rather than with-
drawal to the drug itself.6
Bromocriptine.  Bromocriptine is an ergot derivative with
potent agonist activity in the postsynaptic D2-receptor and
is used primarily in the treatment of PD. In NMS, bro-
mocriptine may counteract dopamine blockade attributed
to antipsychotics. It is available only as an oral formula-
tion that can also be administered via feeding tube.
Because of its ability to cause hypotension, initial dosing
tends to begin in the lower end of the dosing range, and
upward titration as tolerated is done over a period of sev-
eral days (Table 2). Symptom recrudescence has been
reported with rapid discontinuation of bromocriptine, so it
is typically weaned.36
Panagariya et al37 reported use of bromocriptine (5-20
mg/d) plus supportive care to manage 14 patients with mild
to moderate NMS, with complete resolution of symptoms in
79% of patients and signs of Parkinsonian features in the
remaining 21%.37 Bromocriptine has recently been used
successfully as monotherapy in a critically ill patient with
myxedema coma and NMS requiring ventilator support.38
Use of the combination of bromocriptine + dantrolene may
be efficacious for severe cases, but complete symptom reso-
lution may still take 2 weeks or more of therapy.34,39
However, early relief of some symptoms such as hyperther-
mia and rigidity are reported with the combination The
algorithm proposed by Strawn et al6 supports use of bro-
mocriptine in moderate to severe cases of NMS, with addi-
tion of IV dantrolene in the severest cases.
Benzodiazepines. Of the benzodiazepines, literature sup-
ports use of lorazepam, diazepam, and clonazepam as treat-
ments for NMS.6,40 The mechanism behind their efficacy is
through reversal of the hypofunctioning GABAergic sys-
tem that contributes to NMS symptoms. Though benzodiaz-
epines carry the potential for delirium, one manic and
delirious patient with NMS from intramuscular (IM) halo-
peridol was successfully treated with lorazepam and diaze-
pam without the use of dantrolene or bromocriptine.41
Benzodiazepines can be administered by several different
routes (IV, IM, oral, buccal, intranasal, and rectal), so the
route and dose can be individualized based on the clinical
scenario. Benzodiazepines can potentially delay wakeful-
ness and typically require a dose taper.
 Table 2.  Reported Dosing Strategies for Treatment and Subsequent Rechallenge.

Reference Treatment Dose Reported Success Follow-up Described

Al Danaf et al39 Dantrolene 120 mg IV ×1, 100 mg per NG tube every 8 Both drugs used for 10 days; Not described
hours symptoms improved by day 9
Bromocriptine 5-10 mg per NG tube
Arnaout et al51 Dantrolene 60 mg IV infusion Fever control Not described
Bromocriptine 15 mg/d No
Chandran et al52 Dantrolene 70 mg IV ×1 Yes Changed to olanzapine and sertraline with
Bromocriptine 2.5 mg 3 Times daily, then tapered 5-week follow-up
Strawn et al6 Lorazepam 1-2 mg IM or IV every 4-6 hours n/a Low-dose SGA titrated slowly starting 2 weeks
Amantadine 100 mg po or by NG every 8 hours after NMS resolutiona
Bromocriptine 2.5-5 mg po or by NG every 8 hours
Dantrolene 1-2.5 mg/kg of actual body weight IV every 6
hours for 48 hours, then tapered
Patel et al45 Dantrolene 50 mg 3 Times daily Fever improved, but rigidity and Not described
Bromocriptine 5 mg po 4 Times daily sensorium did not improve over
4 weeks
Gortney et al53 Dantrolene 1 mg/kg IV ×1 Yes Not rechallenged
Bromocriptine 2.5 mg Every 8 hours as needed; increased
to 5 mg every 8 hours as needed
Morris et al54 Bromocriptine 2.5 mg 4 Times daily; increased to 5 mg No Not described
every 4 hours by NG
Stoner and Berry56 Dantrolene 25 mg IV ×1 Yes Started risperidone 30 days after
Bromocriptine 2.5 mg Twice daily discontinuation of all antipsychotic
medications. Discharged on olanzapine 10 mg
twice daily
Kouparanis et al25 Dantrolene 2.5 mg/kg IV bolus, followed by 0.25 mg/kg Yes Patient expired

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continuous infusion for 72 hours
Zhao et al29 Dantrolene 70 mg IVb Yes At 6-month follow-up, patient stable on
Bromocriptine 2.5 mg 3 Times daily clozapine 400 mg twice daily
Dixit et al38 Bromocriptine 2.5 mg 3 Times daily; increased to 10 mg po Yes Started on 2.5 mg of aripiprazole 12 days after
daily NMS resolution. Stable on 10 mg/d
Wilkinson et al42 Amantadine 100 mg Twice daily Yes Not applicable
Tsai and Huang41 Lorazepam 8 mg Lorazepam IM and po daily, scheduled Yes Started olanzapine 5 mg 5 days after NMS
and as needed resolved
Diazepam 10 mg IV every 8 hours
Biperiden 5 mg IVc
Nielsen and Bruhn40 Clonazepam 1 mg every 3 hours Yes Not rechallenged
Tadke and Suryavanshi55 Valproic acid 250 mg IV ×1, 250 mg po every 12 hours Yes Maintained on po valproic acid

Abbreviations: IM, intramuscular; IV, intravenous; NG, nasogastric; NMS, neuroleptic malignant syndrome; SGA, second-generation antipsychotic.
a
Article outlines a treatment algorithm based on NMS severity.
b
Unclear if given as a single dose, daily, or continuous infusion.
c

5
Unclear frequency of dose; prescribed on fifth day for muscle rigidity.
 6
Table 3.  Treatment Algorithm Based on NMS Severity.12

Woodbury Stage Clinical Presentation Supportive Care Pharmacotherapy

Stage I: drug-induced Rigidity and/or tremor •• Discontinue neuroleptics Lorazepam 1-2 mg IM/IV every 4-6 hours
parkinsonism •• Reduce or change antipsychotic regimen
Stage II: drug-induced catatonia •• Rigidity •• Discontinue neuroleptics Lorazepam 1-2 mg IM/IV every 4-6 hours
•• AMS •• Reduce or change antipsychotic regimen
•• Mutism •• Correct risk factors
Stage III: mild, early NMS •• Mild rigidity •• Discontinue antipsychotics •• Lorazepam 1-2 mg IM/IV every 4-6 hours, or
•• Catatonia or confusion •• Correct risk factors •• Diazepam 10 mg IV every 8 hours
•• Temperature < 38°C •• Monitor closely
•• Heart rate ≤ 100 bpm
Stage IV: moderate NMS •• Moderate rigidity; catatonia or •• Discontinue neuroleptics •• Lorazepam 1-2 mg IM/IV every 4-6 hours, or
confusion •• Hydration and electrolyte replacement •• Diazepam 10 mg IV every 8 hours, plus
•• Temperature 38°C-40°C •• Cooling blankets •• Bromocriptine 2.5 to 5 mg enterally, or
•• Heart rate 100-120 bpm •• Correct risk factors •• Amantadine 100 mg enterally every 8 hours
Stage V: severe NMS •• Severe rigidity •• Discontinue neuroleptics •• Dantrolene 1-2.5 mg/kg IV every 6 hours or
•• Catatonia or confusion •• Hydration and electrolyte replacement continuously for 48 hours, tapered off, plus

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•• Temperature ≥ 40°C •• Cooling blankets •• Bromocriptine 2.5-5 mg enterally, or
•• Heart rate ≥ 120 bpm •• Correct risk factors •• Amantadine 100 mg enterally every 8 hours
•• Intensive care measures
Pileggi and Cook 7
Amantadine.  Amantadine has been described as adjunctive
treatment in NMS for moderate to severe cases.6 In a patient
receiving amantadine for PD, abrupt discontinuation of
amantadine led to withdrawal NMS.28 Its mechanism of
action, though not clearly understood, is likely a result of
both direct increase in dopamine release and reduction in
reuptake.20,42 It also has anticholinergic-like activity that
could shift D2-receptors to high-affinity states; this would
also explain its anticholinergic adverse effect profile (ie, dry
mouth, urinary retention, and constipation).20,43 It also func-
tions as a weak NMDA (N-methyl-d-aspartic acid) receptor
antagonist and has shown to improve dyskinesias associ-
ated with levodopa.44 Though similar to bromocriptine in
activity with less risk of hypotensive episodes, only 1 report
could be found where amantadine was used as the sole
treatment for NMS in a patient who had suffered a traumatic
brain injury.42
Electroconvulsive Therapy (ECT)
Pharmacotherapy has not been successful in all reported
cases of NMS. When multiple medications have failed,
ECT has been used successfully. One female patient with
NMS for 4 weeks despite the use of high doses of bro-
mocriptine and dantrolene was started on ECT. She received
bilateral ECT for a total of 9 cycles, at a frequency of 3
cycles per week. Her muscle rigidity had completely
resolved by the ninth cycle, and she was discharged without
any residual symptoms.45 It has also been suggested that
patients with only a partial response to pharmacotherapy
could receive a course of ECT to ameliorate the remaining
symptoms.6,46 It is unclear how this method improves symp-
toms, but it has been shown to be effective in a variety of
other refractory psychological illnesses.
Rechallenge and Follow-up Care
The population most at risk for developing NMS from anti-
psychotic administration is also the population requiring
chronic antipsychotic therapy for management of their
underlying disorder. Case reports of NMS often fail to
describe follow-up care and rechallenge. Reported rates of
recurrence vary and may be as high as 30%.47 A report by
Wells et al48 of 40 cases suggests that the recurrence rate is
between 13% (confirmed) and 37% (likely) cases. The the-
orized genetic component to NMS may predispose patients
to the condition, but it seems that other cofactors must still
be present because several reports show successful rechal-
lenge after NMS resolution.36,49
After resolution of NMS, the patient should be evalu-
ated for rechallenge with neuroleptics or for management
with an alternative agent. If it is necessary to continue
antipsychotic therapy, it is unequivocally prudent to select
an agent that has low D2 affinity (eg, quetiapine) and to
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begin at a low initial dose.24,49 When rechallenge is
reported, typically, a different agent was chosen. This may
be a result of caution on the clinician’s part as well as
patient preference. However, according to 1 case series,
recurrence is similar regardless of whether a new antipsy-
chotic is used.50 Acute recurrence of NMS may depend
more on the time between NMS resolution and rechal-
lenge than on the antipsychotic agent chosen for rechal-
lenge.32,36 Analysis of more than 40 rechallenges have
suggested success if the washout period from symptom
resolution to rechallenge is at least 5 days.48 Another
report of 20 rechallenges recommends a period of at least
14 days.36 A patient-specific approach toward rechallenge
requires consideration of the patient’s overall health after
NMS resolution (eg, presence of sequelae) and the sever-
ity of his or her underlying psychiatric disorder. In certain
patients, it may be reasonable to rechallenge as early as 5
days after NMS resolves if they experience intolerable
effects from discontinuation of their neuroleptic therapy.
A longer period may be safer to prevent recurrence, but
recurrence may still occur years later.48 Careful monitor-
ing and slow titration are required regardless of the period
selected between NMS resolution and rechallenge. For
patients who may not be candidates for rechallenge, or
who have severe sequelae, ECT may be a possible treat-
ment option for their underlying illness.46
Conclusion
NMS is a rare ADR, which precludes it from study in
large prospective trials. Although all antipsychotics have
potential to cause NMS at any time during therapy, it
most frequently results from administration of a new
agent, use of high doses, or during rapid dose titration.
Because of its life-threatening potential, causative agents
should be discontinued as soon as NMS or atypical NMS
are suspected. Stepwise pharmacotherapy based on sever-
ity has the potential to alleviate symptoms and prevent
complications. Rechallenge with antipsychotics will be
required for many patients who develop NMS.
Rechallenge should begin only after NMS symptom reso-
lution, with a washout period of at least 2 weeks. A 5-day
period may be considered if the benefits outweigh the
risks. A low-potency antipsychotic agent different from
the causative antipsychotic should be chosen, started at a
low dose, and titrated slowly with careful monitoring for
life. Future case reports of agents causing NMS should be
meticulous in documenting the precipitating cause(s),
agents (including dosing and duration) used to treat NMS
symptoms, and the precise method of rechallenging when
applicable. Postmarketing surveillance by the pharma-
ceutical industry for new agents should also include anal-
ysis of cases of NMS as they arise.
8 Annals of Pharmacotherapy 
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
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