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Clinical Review Lesson of the week

Clomipramine induced neuroleptic malignant syndrome and pyrexia of unknown origin

BMJ 2004; 329 doi: (Published 02 December 2004) Cite this as: BMJ 2004;329:1333

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Neuroleptic malignant syndrome!


Previously, we have highlighted multiple risk factors of neuroleptic
malignant syndrome (NMS) [1] and also have reviewed extensively relevant
literature in particular its prevalence, phenomenology, diagnostic
criteria, pathophysiological mechanisms, diagnostic conundrum,
differential diagnosis, therapeutic modalities, and early and delayed
complications. In addition, subsequently updates of NMS and report of 14
cases were also published[2-6]. About 0.7-1.4% of neuropsychiatric
patients treated with neuroleptics and non-neuroleptics tend to manifest
unpredictably hyperpyrexia (>380C), changes in consciousness,
extrapyramidal symptoms (EPS), autonomic dysfunctions, leukocytosis with
or without left shift, and elevated creatine phosphokinase [CPK], which
are relatively the salient features of NMS. The syndrome caused by non-
neuroleptics is also referred to as non-neuroleptic malignant syndrome
(NNMS). It is prudent that physicians should suspect or diagnose NMS/NNMS
early and also manage it by aggressive supportive measures, i.e., cold
sponging, correction of eletrolytes and dehydration, discontinuation of
offending drugs and use of specific drug interventions, otherwise a
proportion of patients tend to develop several delayed complications and
up to 20% of them eventually die. Though the incidence of NMS among
psychiatric patients exposed to neuroleptics is still high, this dose-
independent idiosyncratic reaction is on the decrease globally due to its
early recognition and immediate management.

Unfortunately, even the introduction of second generation of
antipsychotics such as clozapine, risperidone, olanzapine, quetiapine,
ziprasidone, and aripiprazole and others in the therapeutic armamentarium
of neuropsychiatric disorders has not solved radically the problem of NMS,
rather all these drugs are linked with this rare but devastating
complication. Possibly like other atypicals, quetiapine is less likely to
cause NMS as it has low affinity and fast dissociation from post-synaptic
dopamine-2 receptors, located specifically in limbic system. Notably,
novel antipsychotics when combined with one of selective serotonin re-
uptake inhibitors (SSRIs) for treating obsessive-compulsive symptoms
associated with psychosis may produce neurotoxic syndrome simulating NMS
or serotonin syndrome.

From multiple perspectives, NMS needs constant surveillance globally.
Moreover, NMS is a psychomedical emergency and has been conceptualized as
a spectrum disorder with varying severity, presentations, and clinical
course. Hence, there is a persistent need to know more about NMS, in
particular how to early diagnose NMS/NNMS and rapidly treat this order in
order to decrease its high morbidity and mortality. To meet these goals,
it is wise to highlight global new research developments in NMS/NNMS.

With special reference to its epidemiology, risk factor, etiologies,
phenomenology, differential diagnosis, therapeutic modalities,
complications, clinical course, outcome and recovery, and drug
rechallenge, a brief review of pertinent literature (38 references are
available upon request) revealed certain newer findings; the prevalence of
NMS, a medication-induced movement disorder and possibly a neurogenic form
of malignant hyperthermia is now decreasing globally; all second
generation of antipsychotics are reported to cause NMS and relatively most
cases were reported from western world; a variety of nonneuroleptics such
as tetrabenazine, carbidopa/levodopa, alpha-methyl-tyrosine,
metoclopramide, promethazine, lithium, amphetamines and its derivatives,
cocaine, fenfluramine, phencyclidine, lysergic acid diethylamide,
traditional antidepressants as well as SSRIs, monoamine oxidase
inhibitors, and anticholinergics interfering with CNS dopamine
neurotransmission also cause NM-like syndromes; NMS should be suspected in
primary care patients with mental health problems who are often prescribed
psychotropics including antipsychotics and antidepressants by general
practitioners (GPs); GPs should have basic information about NMS; other
than CNS underpinnings, peripheral mechanisms such as neuroleptics’ direct
effect on skeletal muscles are identified to contribute to the
pathophysiology of NMS; involvement of biopterin metabolism in malignant
syndrome is emphasized; similarly calcium–mediated signal transduction
mechanisms and regulatory proteins in the etiology of NMS are speculated
and explored; unlike dopamine, epinephrine and serotonin are reported to
be overactive in NMS; muscles from patients with NMS may show positive
muscle contracture tests and alterations similar to those patients with
anaesthetic malignant hyperthermia; as regards atypical antipsychotics,
dopamine 2 receptor blocking potential does not have direct correlation
with the occurrence of NMS; the phenomenology of NMS caused by atypical
and traditional antipsychotics did differ across studies; unlike other
differential diagnoses, serotonin syndrome in particular is reported to
have highly overlapping features with NMS and hence it posits a diagnostic
as well as a therapeutic challenge; the mainstay of treatment of serotonin
syndrome are cyproheptadine (8-30 mg) and/or chlorpromazine (50 to 100 mg
IMI); physicians now tend to early recognize NMS and moreover prompt
treatment of NMS tends to abort its full-fledged clinical manifestations;
hence physicians will encounter more mild cases of NMS, i.e., “formes
frustes” ; rapid and full recovery in 90% to 94% of cases is contingent on
early recognition and proper management; atypicals possibly cause less
mortality than traditional antipsychotics; immunostaining of skeletal
muscle by antibodies for muscle-associated proteins and mitochondria-
actin, myoglobin, and desmin-is useful to support the diagnosis of NMS;
patients with NMS and autonomic dysfunctions in particular blood pressure
unstability respond effectively to clonidine therapy and finally
rechallenge with different atypical or traditional antipsychotics either
on out-or in-patient basis is reported to cause less likely the recurrence
of NMS.

Like in children and adolescents, NMS is also reported in elderly
population. Patients with Parkinson’s disease, a switch from bromocriptine
to pergolide, both dopamine agonists, may result in NM-like disorder,
which is attributed to differences in dopamine receptor affinities between
bromocriptine and pergolide. Patients with presenile dementia, mostly
dementia Lew body when exposed to neuroleptics tend to develop neuroleptic
hypersensitivity, EPSs and NMS attibuted to depleted nigrostriatal
dopaminergic neurons and acetylcholinergic receptors. Approximately 50% of
patients with dementia with Lewy body (DLB), second commonest dementia
after Alzheimer dmentia, are affected by NMS. Unlike other atypicals,
quetiapine is well tolerated by DLB patients without causing any EPSs or
NMS and therefore it is recommended for the treatment of psychotic
manifestations coupled with LBD. Indeed, elderly patients with
adrenocorticotropin deficiency are found to manifest signs-high grade
fever, altered consciousness, EPS, and muscle enzyme elevations-of NM-like
syndrome which responds to corticosteroid supplement therapy and in such
cases adrenal and pituitary functions including hyponatremia should be
investigated. Patients with Huntington’s disease [HD] exposed to
neuroleptics are reported to develop hyperthermia compatible with NMS or
serotonin syndrome. Notably, donepezil recommended in early mild dementia
is noted to cause NMS.

A knowledge of risk factors of NMS/NNMS probably help in prevention
of this syndrome. Acute withdrawal of anticholinergics is one of the
acquired risk factors of NMS. Other reported risk factors-clinical as well
as pharmacological are; male gender; young adults; rapid escalation of
antipsychotics; pareneteral use of high potency antipsychotics; mood
disorders; acute catatonia and disorganization; nonschizophrenic psychotic
and nonpsychotic states; external excessive heat load; electrolyte
imbalance; psychosis associated CKemia; microclimate of hospital wards or
seclusion rooms; quick switch of one antipsychotic to another; use of
potent antipsychotics; exercise in warm climate; primary hypothyroidism;
neurological diseases; previous history of NMS; exhaustion and
dehydration; psychomotor excitement; constant agitation; post-partum
period; stress of psychiatric disorders; metabolic dysregulation;
uncontrolled diabetes mellitus; resistant extrapyramidalsResistant EPS;
acute withdrawal of dopamine agonists and benzodiazepines; use of dopamine
depleting drugs; poor neuroleptic metabolizers; and genetic
vulnerability,i.e, -141 C Ins/Del polymorphism. Certainly, a knowledge of
these risk factors will guide physicians to use neuroleptics or like drugs
judiciously in vulnerable neuropsychiatric population, which by extension
will result in reduction in the incidence of NMS.

Patients with NMS are reported to improve rapidly with aggressive
supportive measures and relatively specific interventions, i.e.,
bromocriptine, benzodiazepine, and benztropine. Early recognition of NMS
with administration both of supportive and relatively specific drugs also
abort its severe course with complete recovery. Besides dantrolene and
clonidine, subcutaneous apomorphine is also found to be effective in NMS.
Modified ECT is reported to be effective in controlling persistent
psychosis when patient is in or recovering from NMS. On rechallenge with
different typical/atypical antipsychotics especially after 2-week hiatus
therapy, approximately 75% of patients don't redevelop NMS. Conversely, in
25% of patients, rechallenge with neuroleptics after ECT may succeed.
Notably, premature rechallenge with offending neuroleptics tend to cause
recurrence of NMS. Certain drugs such as nifedipine, bromocriptine, and
dantrolene are used prophylactically in the prevention of recurrence of
NMS in vulnerable individuals.

Finally, treatment both of NMS and its complications simultaneously
by aggressive measures is essential as these complications enhance
mortality, long-term morbidity and adverse consequences among patients
with NMS. Notably, the reported complications of NMS are; respiratory
infection; disseminated intravascular coagulation; thrombocytopenia;
eletrolyte imbalance including hypernatremia; acute respiratory distress
syndrome [ARDS]; pulmonary embolism; myocardial infarction; acute cardiac
failure; severe liver failure; rhabdomyolysis; renal failure; stroke;
hypovolumic shock; skin eruptions; contractures; myoneuropathies; anterior
tibial compartment syndromes; intestinal bleeding; necrotizing
entercolitis; and short-term memory deficits. Neuroleptic drugs may cause
ARDS independent of NMS manifestations. Clinical wisdom suggests that
physicians should observe carefully patients with NMS for emerging
complications so that they can intervene quickly and effectively.

In summary, NMS, potentially a fatal complication of neuroleptic and
nonneuroleptic drugs (7) prescribed by physicians to a wide variety of
vulnerable patients in all health delivery settings, needs early
recognition and prompt treatment that includes supportive measures and
specific drugs for circumventing associated high morbidity and mortality.


1. Qureshi N A. Neuroleptic malignant syndrome- risk factors. Annals
of Saudi Medicine 1993; 13: 106-107.

2. Qureshi N A, Al-Amri AH, Abdelgadir MH, Al-Habeeb TA. Neuroleptic
malignant syndrome: a comprehensive review and update. Saudi
Pharmaceutical J 1996; 4: 138-148.

3. Qureshi N A, Al-Amri AH, Abdelgadir MH, Al-Habeeb TA. Neuroleptic
malignant syndrome: a report of 9 suspected cases. Saudi Pharmaceutical J
1996; 4: 179-189.

4. Qureshi NA, Al-Habeeb TA, Al-Ghamdy YS. Neuroleptic malignant
syndrome: clinical update and report of additional four cases. Saudi
Pharmaceutical J 2001; 9:

5. Qureshi N A , Al-Habeeb TA. Sympathoadrenal hyperactivity and
neuroleptic malignant Syndrome. American J Psychiatry 2000; 157: 310-311.

6. Qureshi NA. Neuroleptic malignant syndrome revisited. Saudi Med J
2002; 23: 1147.

7. Alison M Haddow, Dawn Harris, Martin Wilson, and Hannah Logie.
Clomipramine induced neuroleptic malignant syndrome and pyrexia of unknown
origin.BMJ 2004; 329: 1333-1335.

Competing interests:
None declared

Competing interests: No competing interests

08 December 2004
Dr. Naseem A. Qureshi MD, IMAPA, LMIPS
Director, CME&R
POBox.2292, Buraidah Ment. Halth. Hosp., Saudi Arabia.