Case Reports

DOI: 10.5455/bcp.20130613121019

Neuroleptic Malignant Syndrome Induced by Clozapine:

A Case Report and Discussion
Wei-Wei Wang1, Yu Wang1, Ping Xiao2, Pan Zhang1

ABSTRACT:

Neuroleptic malignant syndrome induced by clozapine: a case report and discussion

Objective: Neuroleptic malignant syndrome (NMS) is a rare, but life-threatening condition associated with the use
of antipsychotics. Although NMS is mainly associated with typical antipsychotics, it can also be induced by atypical
antipsychotics. In this paper, we report a case of NMS associated with clozapine use and describe the classic and
atypical manifestations of NMS. The case and discussion highlight the importance of considering NMS as part of
the differential diagnosis for any patient using neuroleptics.
Case: This case was about a 52-year-old female suffering from pneumonia, who was diagnosed as having NMS after
a dosage increase of clozapine. NMS is a rare but serious adverse reaction to an antipsychotic drug. It is essentially
characterized by hyperthermia, and muscle rigidity, which may be accompanied by other extra pyramidal effects
(EPS), autonomic instability and mental status changes. Laboratory examinations showed significantly higher
creatine kinase. A typical treatment usually involves supportive medication and an immediate withdrawal of the
antipsychotic drug.
Conclusion: Incomplete or extraordinary NMS cases have been reported due to clozapine. However, this case was
remarkably associated with the complete and typical presentation of NMS. Given the routine and regular writing
of prescriptions of neuroleptics by physicians in a variety of medical disciplines, physicians need to recognize and
appropriately manage NMS.

1
M.D., Tianjin First Central Hospital,
Department of Emergency, Tianjin,
China
2
M.D., Tianjin First Central Hospital,
Emergency Laboratory Centre, Tianjin,
China

Address reprint requests to:

Dr. Wei-Wei Wang
Tianjin First Central Hospital,
Department of Emergency 300192,
Tianjin, China
E-mail address:
wang_weiwei1980@163.com
Date of submission:
April 2, 2013
Date of acceptance:
June 13, 2013

Keywords: neuroleptic malignant syndrome, clozapine, diagnosis

Bulletin of Clinical Psychopharmacology 2014;24(2):172-5

INTRODUCTION
NMS is a rare, but severe clinical syndrome
usually caused by antipsychotic drugs. According to
the DSM-IV1, an essential feature of NMS is the
development of severe muscle rigidity and elevated
temperature associated with the use of antipsychotic
medication. These features must be accompanied
by two or more of the following symptoms:
diaphoresis, dysphagia, tremor and incontinence,
changes in the level of consciousness, mutism,
tachycardia, elevated or labile blood pressure,
leukocytosis or laboratory evidence of muscle injury
(e.g., elevated CK). A common theory for the
development of NMS is that it results from the

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Declaration of interest:
W.W.W., Y.W., P.X., P.Z.: The author
reported no conflict of interest related to
this article.

hypodopaminergic state caused by antipsychotic

blockade 2 . Other neurotransmitters, such as
serotonin, -aminobutyric acid, acetylcholine and
norepinephrine may be involved in the occurrence
of the syndrome3.
NMS has been mainly related to the inappropriate
use of dopamine antagonists (especially typical
antipsychotics, such as haloperidol) and with the
withdrawal of anti-parkinsonian medications. NMS
is thought to occur in fewer instances with atypical
neuroleptics than with typical antipsychotic drugs.
Although clozapine-associated NMS cases have
been observed with different clinical manifestations
compared with other atypical antipsychoticinduced NMS cases, physicians need to recognize

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Wang WW, Wang Y, Xiao P, Zhang P

and accurately diagnose NMS4.

The following case of clozapine-associated NMS
describes a patient who exhibited all classical forms
and persistent intestinal flatulence.

CASE REPORT
A 52-year-old female, with a history of severe
depression, was taken to the emergency room with
the main complaint of disorientation and high fever
for two days. Two days before being admitted to the
hospital, she developed hypermyotonia, tremor
and lapsed into unconsciousness. She had a body
temperature of 41C accompanied by diaphoresis.
Physical examination: Blood pressure was
125/85 mmHg, heart rate was at 120-130 beats/min.
Other signs included: disorientation, normal pupil
size, normal reflection of light; normal lung and
heart, bulging abdomen, drum percussion sounds,
weak bowel sounds. The muscle tension was high
with tremor and the dual Babinski sign was negative.
Laboratory investigation revealed leukocytosis

Figure 1: An abdominal X-ray of the patient showed extensive

intestinal dilatation

(leukocyte count 15.29109/L), with a shift to the left

(neutrophil count 12.6010 9/L). Her PCT was
normal (0.03ng/ml). Arterial blood acidity and gas
analyses results included: pH, 7.373; PO2, 78torr;
PCO 2, 45torr; FiO 2, 25%; and HCO 3, 33mmol/L.
Electrolyte level test along with liver and renal
function tests all yielded normal results. A head CT
scan did not show any acute abnormalities, but a
chest X-ray showed pneumonia and an abdominal
X-ray showed extensive intestinal dilatation (Figure
1).
The patient was given the antibiotic cefuroxime
for symptomatic treatment for two days but the
symptoms did not display any significant
improvement. On day 3 of hospitalization, she
continued to suffer from hyperthermia, muscle
rigidity and persistent changes in the level of
consciousness. We asked about the patient history
again in detail. Her anti-psychotic medications
included clozapine 200 mg daily, estazolam 2 mg
daily and trihexyphenidyl 8 mg daily. About 10 days
prior to this event, due to worsening depression, she
had taken clozapine (25 mg/tablet) from 100 mg
every 12-hours to 800 mg every 8-hours.
Furthermore, a toxicology screen was conducted,
which showed the patients clozapine serum
concentration to be 0.45 mg% (toxic dose >0.2
mg%). Further laboratory analysis showed a
markedly elevated creatine kinase (CK) level (927
U/L) and her urine myoglobin test was positive.
According to positive symptoms, signs and
laboratory examinations, a firm diagnosis of NMS
was made. Clozapine was withheld and therapy
with supportive medication was started. To deal
with flatulence, decompression and cathartic
treatment were carried out. After a few days, the
patients NMS symptoms improved and her
biochemical parameters returned to normal but the
intestinal flatulence remained abnormal. However,
due to aggravated complications of pneumonia, the
patient was put into ICU with continued treatment.
She was discharged one month later and six months
after discharge she remained stable and was able to
engage in regular activities. Table 1 shows the
changes in the patients vital signs and clinical
indicators.

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Neuroleptic malignant syndrome induced by clozapine: a case report and discussion

Table 1: Clinical indicators of changes over time

Clinical indicators

1 day

3 days

5 days

7 days

Highest temperature(C)
Muscle rigidity
GCS score
Blood pressure (mm hg)
Heart beat (beats /min)
CK level (U/L)

41.0
39.1
37.5
37.2
++++
+++
++
+
10 12 15 15
125/85
120/75
115/70
120/80
120-130
110-120
90-100
85-95
Not checked
927.4
425.0
163.5

Note: +light extent of muscle rigidity, ++++more severe extent of muscle rigidity

Tab
le 2: Antipsychotic drugs associated with neuroleptic
malignant syndrome
Typical antipsychotic drugs
Haloperidol (+++)
Chlorpromazine (++)
Fluphenazine (++)

Atypical antipsychotic drugs

Clozapine (+)
Olanzapine (+)
Quetiapine (+)

Note: +rarely associated with NMS, +++more commonly associated with NMS.
Data from Adnet.7

DISCUSSION
NMS was originally described in 1968 by the
French psychiatrist Delay5. Almost all antipsychotic
drugs have some level of risk of NMS6. The frequency
of the syndrome ranges from 0.07 to 2.2% and the
mortality is 10-30%7.
Typical antipsychotic drugs have greater
antagonistic effects on dopamine receptors as
compared to atypical ones. Consequently, NMS is
thought to occur in fewer instances with atypical
neuroleptics than with typical antipsychotic drugs
due to their mechanism of action (Table 2) 7.
Therefore, NMS cases induced by clozapine are not
prevalent as reported in the literature. Atypical NMS
associated with atypical antipsychotics has been
defined as rare small increases in CK, minor muscle
rigidity and mild fever8. In the presented case, the
complete NMS presentation with severe muscle
rigidity and unusually elevated CK differentiated
this condition from most other clozapine-induced
cases, which have been rarely reported in the
literature. Furthermore, abnormalities in
dopaminergic activity and dopamine receptor
functions have been associated with genetic factors9.
Therefore, we concluded that the potential
mechanism might be that the patient was
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extraordinarily sensitive to the blockade of

dopamine, which led us to think that she might have
had an individual predisposition for NMS.
Clozapine is an atypical antipsychotic drug with
a broad range of receptor affinity (dopamine, 5HT,
muscarinic and adrenergic receptor) and multiple
receptor antagonistic activity. Therefore, the
pathophysiology of NMS is complex, involving a
c a s c a d e o f d y s r e g u l a t i o n s i n mu l t i p l e
neurochemical and neuroendocrine systems 10.
However, unlike other reports of clozapineassociated NMS, our patient had some signs of
significant abdominal distension and her
abdominal X-ray showed extensive intestinal
dilatation, which might have been related to a
greater antagonistic effect on muscarinic receptors.
Clozapine is a tricyclic dibenzodiazepine
derivative mainly used in various subtypes of both
acute and chronic schizophrenia to treat the
associated emotional symptoms. It is also used to
treat mania or other psychotic disorders, such as
agitation, hallucinations, and delusions. According
to the patients medical history, depression was
diagnosed at another hospital, and the psychiatrist
did prescribe clozapine. This situation is common
in some rural areas, where health care infrastructure
is very underdeveloped. The main feature of
poisoning with this class of drugs is consciousness
disturbance and cardiovascular dysfunction.
Clozapine poisoning usually manifests as impaired
consciousness, ranging from somnolence to coma
or agitation, and delirium, tachycardia, abnormal
blood pressure, and seizures. The symptoms of
clozapine toxicity are due to its complex receptorbinding characteristics. The usual dose of clozapine
is 300 to 450 mg daily, and the maximum dose is 900

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Wang WW, Wang Y, Xiao P, Zhang P

mg. After ingestion of 2400 mg clozapine daily for

about 10 days, intoxication was observed that was
ultimately secondary to NMS.
Hyperthermia and unconsciousness are the
most important manifestations of NMS. Therefore,
infections, lethal catatonia, malignant hyperthermia
and serotonin syndrome were considered to be the
main differential diagnoses 11. In this case, we
initially gave the patient an anti-infective treatment
but it did not work. We conducted a thorough
analysis and our case was in an active phase of a
chronic mental illness in the presence of a relatively

rapid increase in the dose of clozapine. Furthermore,

the accompanying pneumonia might have
contributed to the development of NMS.

CONCLUSION
NMS is a known but potentially lethal
idiosyncratic disorder. NMS is easy to misdiagnose
and the performance of patients may initially
appear to be atypical or with complications. As
such, early identification is the key to patient
wellness and recovery.

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