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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.

Keywords: neuroleptic malignant syndrome, clozapine, diagnosis

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

1M.D., Tianjin First Central Hospital,Department of Emergency, Tianjin,

China2M.D., Tianjin First Central Hospital,Emergency Laboratory Centre, Tianjin,China

Address reprint requests to:Dr. Wei-Wei WangTianjin 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

Declaration of interest:

W.W.W., Y.W., P.X., P.Z.: The authorreported no conflict of interest related tothis article.

Case Reports DOI: 10.5455/bcp.20130613121019

  INTRODUCTION

  NMS is a rare, but severe clinical syndrome

usually caused by antipsychotic drugs. According to

the DSM-IV 1, an essential feature of NMS is the

“development of severe muscle rigidity and elevatedtemperature 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

hypodopaminergic state caused by antipsychotic

blockade2. Other neurotransmitters, such as

serotonin, γ-aminobutyric acid, acetylcholine and

norepinephrine may be involved in the occurrence

of the syndrome3.

  NMS has been mainly related to the inappropriateuse 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 antipsychotic-

induced 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 41°C 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

(leukocyte count 15.29×109/L), with a shift to the left

(neutrophil count 12.60×109/L). Her PCT was

normal (0.03ng/ml). Arterial blood acidity and gas

analyses results included: pH, 7.373; PO2, 78torr;

PCO2, 45torr; FiO2, 25%; and HCO3, 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, musclerigidity 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 patient’s clozapine serumconcentration 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.

 Acco rd ing to po si tive symp to ms, sign s an d

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

patient’s 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 patient’s vital signs and clinical

indicators.

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

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

  DISCUSSION

  NMS was originally described in 1968 by the

French psychiatrist Delay 5. 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, thecomplete 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

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 multiplereceptor antagonistic activity. Therefore, the

pathophysiology of NMS is complex, involving a

c a s c a de o f dys r e gu l a t i o n s i n m u l t i p l e

neurochemical and neuroendocrine systems10.

However, unlike other reports of clozapine-

associated 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 patient’s 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 ofpoisoning 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 receptor-

binding characteristics. The usual dose of clozapine

is 300 to 450 mg daily, and the maximum dose is 900

Table 1: Clinical indicators of changes over time

Clinical indicators 1 day 3 days 5 days 7 days

Highest temperature(°C) 41.0 39.1 37.5 37.2

Muscle rigidity ++++ +++ ++ +

GCS score 10 12 15 15

Blood pressure (mm hg) 125/85 120/75 115/70 120/80Heart beat (beats /min) 120-130 110-120 90-100 85-95

CK level (U/L) Not checked 927.4 425.0 163.5

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

Table 2: Antipsychotic drugs associated with neuroleptic

malignant syndrome

Typical antipsychotic drugs Atypical antipsychotic drugs

Haloperidol (+++) Clozapine (+)

Chlorpromazine (++) Olanzapine (+)

Fluphenazine (++) Quetiapine (+)

Note: +rarely associated with NMS, +++more commonly associated with NMS.

Data from Adnet.7

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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 diagnoses11. 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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