CASE REPORTS

Neuroleptic Malignant Syndrome Versus Serotonin Syndrome:

The Search for a Diagnostic Tool
AbdulRazaq AH Sokoro, Joel Zivot, and Robert E Ariano

euroleptic malignant syndrome

(NMS) is a severe and potentially
life-threatening idiosyncratic reaction to
antipsychotic drugs. It is characterized
by the sudden onset of autonomic and
extrapyramidal dysfunction manifesting
as fever, hypotension or hypertension,
tachycardia, dystonias, and altered mental status.1 Diagnosis of NMS is made by
excluding other central nervous syndrome (CNS) toxodromes.2 At present, a
definitive diagnostic test is lacking. Reported laboratory findings have been
nonspecific.3-7 Another commonly described disorder that may occur as a consequence of exposure to psychotropic
medication is serotonin syndrome. Serotonin syndrome is a clinical triad (but all
3 are not consistently present in all patients) of autonomic hyperactivity, altered mental status, and neuromuscular
abnormalities. Thus, signs and symptoms of serotonin syndrome can range
from tremors and diarrhea in mild cases
to delirium, rigidity, and hyperthermia in
severe cases.2,8,9 It is evident that the presentation of serotonin syndrome is similar
to that of NMS and can initially confound
the clinician.2,8,9 These 2 conditions require very different pharmacologic interventions for their management.

OBJECTIVE:

To evaluate the use of urine dopamine and catecholamine concentrations as diagnostic aids in a patient with neuroleptic malignant syndrome
(NMS) in the emergency department setting.

CASE SUMMARY: A 61-year-old female on multiple medications, including several

antipsychotics, rapidly deteriorated, with fever, lead-pipe rigidity, and decreased
level of consciousness. The patient died 20 days after initial presentation to an
emergency department. The Naranjo probability scale indicated probable
causality for NMS due to quetiapine, haloperidol, and risperidone in this patient,
whereas the Naranjo scale assigned only possible causality for serotonin
syndrome developing with serotonergic agents. Laboratory investigations of
blood and urine revealed elevations in dopamine, metanephrines, and
epinephrines, as well as trazodone and risperidone. Serotonin metabolites were
not elevated.
DISCUSSION:

NMS is a rare and potentially severe adverse effect associated with

the use of antipsychotic medications. It is mainly characterized by hyperthermia,
altered mental state, hemodynamic dysregulation, elevated serum creatine
kinase, and rigors. It has been associated with multisystem organ failure
potentially leading to rhabdomyolysis, acute respiratory distress syndrome, and
disseminated intravascular coagulation. The prevalence of this syndrome is
associated with the use of neuroleptics. Serotonin syndrome is another adverse
drug reaction leading to NMS associated with elevated serotonin. It occurs when
multiple serotonergic medications are ingested and is associated with rapid onset
of altered mental status, myoclonus, and autonomic instability. Differentiating
between NMS and serotonin syndrome can be challenging because of their
similar clinical presentation. This case highlights the importance of a diagnostic
aid being available to help distinguish between the 2 syndromes.

CONCLUSIONS:

We propose that laboratory findings that include dopamine and

serotonin metabolites can be used as adjuncts to clinical and prescription
histories in the diagnosis of NMS. The use of urinary catecholamine as a
diagnostic aid in NMS needs further evaluation.

KEY WORDS: dopamine metabolites, malignant hyperthermia, neuroleptic

malignant syndrome, serotonin syndrome, SSRIs.

Ann Pharmacother 2011;45:e50.

Published Online, 30 Aug 2011, theannals.com, DOI 10.1345/aph.1P787

Author information provided at end of text.

theannals.com

The Annals of Pharmacotherapy

Downloaded from aop.sagepub.com at Linkoping University Library on August 23, 2014

2011 September, Volume 45

e50

ARAH Sokoro et al.

The current diagnostic tools for NMS involve nonspecific biochemical laboratory investigations. We present a
case of NMS believed to be due to psychotropic medications. With respect to NMS and serotonin syndrome, we
speculated that blood and urine analyses would reveal excessive catecholamines (including dopamine) or serotonin
and metabolite. We hypothesized further that the presence
of metabolites of dopamine or serotonin would direct the
diagnosis.
Case Report
A 61-year-old female (66 kg body weight) presented to
the emergency department of a community hospital, transported by emergency medical services (EMS) after having
collapsed on the floor of her apartment. Information obtained later revealed that the patient had been feeling unwell for 2 weeks prior to this admission. She had a history
of numerous falls, supported by evidence of bruises on her
arms and knees. The patient had a history of schizophrenia,
hypertension, dyslipidemia, hypothyroidism, congestive
heart failure, and osteoporosis. She had been prescribed
several medications (Table 1), all of which were discontinued upon admission. It was confirmed by records from the
Provincial Drug Information Network (DPIN) that she was
taking many concurrently prescribed psychotropic agents
(Table 1). She denied overmedicating, although her level
of alertness at the time of questioning was slightly impaired, and she had no known history of alcohol or drug
abuse. An interesting finding from the DPIN record was a
stable quetiapine prescription fill pattern (~142 mg/day)
from April to early September 2009, then a drastic increase
to 1800 mg/day for 4 days in mid-September. This was followed by an abrupt decrease in prescription refills to approximately 487 mg/day by early October. We acknowledge that this analysis is based on the patients prescription
fill pattern and not on reported consumption patterns or
daily pill counts. In any case, these later amounts are in
sharp contrast to her intended prescription of 400 mg/day.
On examination, pertinent findings were decreased level
of consciousness, hypotension (blood pressure 72/54
mm Hg), mottled skin with cool extremities, irregular heart
rhythm with tachycardia (135 beats/min), tachypnea, and
cyanosis. Auscultation of the chest revealed bilateral
coarse breath sounds in the lower lung fields. Further examination revealed a distended abdomen with the presence
of bowel sounds. Fluid resuscitation with normal saline
was begun en route to the hospital by EMS and continued
during initial evaluation in the emergency department.
The presumed diagnosis was septic shock, with possible
aspiration. Blood and urine samples were sent to the laboratory for culture and the patient then received piperacillin/tazobactam 2.25 g and intravenous hydrocortisone
100 mg. Norepinephrine and vasopressin infusions were
e50

The Annals of Pharmacotherapy

commenced for blood pressure support. She was transferred to the intensive care unit (ICU) for monitoring. Over
the next several hours, her respiratory condition deteriorated and she required endotracheal intubation and mechanical ventilation. She developed lead-pipe rigidity, fever
(temperature 41 C), and leukocytosis. With the patients
uncertain diagnosis and rapid clinical deterioration, the
physician ordered empiric treatment with dantrolene for
NMS and cyproheptadine for serotonin syndrome. The patient was placed in cooling blankets and transferred to our
tertiary care center for further management. Her serum creatinine remained stable despite a peak myoglobin level of
4842 g/L on day 3, indicative of rhabdomyolysis. However, over the course of her ICU stay, she developed electrolyte imbalance and renal failure.
In addition to intravenous dantrolene 75 mg every 6
hours and cooling blankets, treatment was mainly support-

Table 1. Patients Home Oral Medicationsa

Tricyclic antidepressant
desipramine 25 mg twice daily
Benzodiazepine
lorazepam 2 mg at bedtime
Antipsychotics
haloperidol 20 mg at bedtime
quetiapine 400 mg at bedtime
risperidone 2 mg in the morning, 3 mg at bedtime
SSRIs/NSSRIs
trazodone 200 mg at bedtime
venlafaxine 75 mg twice daily
Corticosteroids
prednisone 7.5 mg once daily
budesonide 200 g (inhaler) 2 inhalations daily
mometasone furoate 0.05% 2 sprays twice daily
Other
fluconazole 150 mg 1 (5-6 times in past 6 mo)
alendronate 70 mg weekly
atorvastatin 10 mg daily
celecoxib 200 mg twice daily
conjugated estrogen 1.3 mg daily
furosemide 40 mg daily
hydroxyzine 25 mg twice daily
levothyroxine 50 g daily
loperamide 2 mg (100 tablets/mo) as needed
omeprazole 20 mg twice daily
sumatriptan 50 mg as needed
salbutamol 100 g as needed
trimethoprim/sulfamethoxazole 160/800 g daily for the past 3 mo
cyclobenzaprine 10 mg as needed
hydroxychloroquinine 200 mg twice daily
NSSRI = nonselective serotonin reuptake inhibitor; SSRI = selective
serotonin reuptake inhibitor.
a
Confirmed with the Provincial Prescription Drug Network database.

2011 September, Volume 45

Downloaded from aop.sagepub.com at Linkoping University Library on August 23, 2014

theannals.com

NMS Versus Serotonin Syndrome

ive, with pressor agents and lactated Ringers administered for blood pressure support, as well as fentanyl for
pain and midazolam for anxiety. Rhabdomyolysis, fever,
and electrolyte imbalance started to improve by day 5.
However, hemodynamic imbalance, decreased mental status, and respiratory failure could not be resolved. She continued to be ventilator-dependent and in a vegetative state,
despite discontinuance of sedatives. She died on hospital
day 20.
Initial laboratory results (on presentation to emergency
department; Table 2) showed elevated dopamine metabolites, low serotonin metabolites, elevated serum creatinine and urea, and elevated white blood cell count. We
found no evidence of myocardial infarction or microbial
growth on cultures of blood and urine. There were also
elevated concentrations of trazodone (ie, 1.5 times the
upper predicted value) and risperidone (ie, 1.2 times the
upper predicted value), based on measured plasma concentrations versus predicted steady-state concentrations
(Css),10,11 a given dosing regimen,10,11 a body weight of 66
kg, and the following formula: Css (ng/mL) = [dose

(mg/day) / 24 h] / *1000 clearance (L/h) (Table 3). Other

drugs could not be analyzed because of an insufficient
volume of primary admission blood samples. Unfortunately, no cerebrospinal fluid was collected.
Discussion
NMS is a rare and potentially fatal complication associated with the use of neuroleptics. Manifestation of NMS
includes changes in mental status, extrapyramidal symptoms (eg, dystonia, akinesia, and Parkinsonian features
such as rigidity and tremor), and signs of autonomic dysfunction (eg, hyperthermia, tachycardia, diaphoresis, labile
blood pressure). The syndrome was first described by Delay and colleagues.12 It occurs in all age groups treated with
neuroleptic drugs, with higher prevalence in individuals
with organic brain disease such as mental challenges,
Huntington chorea, opiate addiction, and alcohol-induced
psychosis.13
The clinical course of NMS can occur as soon as 45
minutes14 or as late as 2 months following administration

Table 2. Laboratory Test Results on Specimens Collected on Presentation

Specimen

Test

Result

Reference Range

Urine
Creatinine,a mg/dL

0.18

0.09-0.18

Metanephrine, mg/24 h

1.45

0.51

Normetanephrine, mg/24 h

8.21

1.19

5-Hydroxyindoleacetic acid,b mg/24 h

0.38

0.96-6.69

Homovanillic acid, mg/24 h

0.36

<22.27

Vanillylmandelic acid, mg/24 h

1.29

<9.37

Epinephrine,c pg/mL

247

20

Norepinephrine,d pg/mL

528

15-80

Dopamine,e pg/mL

1454

65-400

Urea, mg/dl

31.09

7.84-19.89

Creatinine, mg/dL

2.16

0.40-1.10

Urea to creatinine ratio

58

<70

Plasma/serum

Creatine kinase, U/L

26

28-110

Troponin T, ng/mL

<0.01

<0.01 (negative for myocardial infarct)

White blood cells, 103/L

21.5

4.5-11

Hemoglobin, g/dL

16.2

12.0-16.0

Platelets, 103/L

350

140-440

Blood

No growth

Urine

No growth

Whole blood

Microbiology

Predicted from a creatinine result of 0.18 mg/dL, a projected urine output of 1 L/day, and reference range, in the absence of clinical evidence of hyperfiltration (due to pregnancy, diabetic nephropathy, and increased protein intake).
b
Predicted from 5-hydroxyindoleacetic acid result of 0.38 g/mL, creatinine result of 0.18 mg/dL, and a projected urine output of 1 L/day.
c
Predicted from epinephrine result of 0.25 g/mL, creatinine result of 0.18 mg/dL, and a projected urine output of 1 L/day.
d
Predicted from norepinephrine result of 0.53 g/mL, creatinine result of 0.18 mg/dL, and a projected urine output of 1 L/day.
e
Predicted from dopamine result of 1.45 g/mL, creatinine result of 0.18 mg/dL, and a projected urine output of 1 L/day.

theannals.com

The Annals of Pharmacotherapy

Downloaded from aop.sagepub.com at Linkoping University Library on August 23, 2014

2011 September, Volume 45

e50

ARAH Sokoro et al.

of neuroleptic medication.15 Shalev and Munitz13 found the

average time to onset of symptoms in 65 cases of NMS
was 4.8 days. They also found that, once the offending
agent was stopped, NMS regressed within a period ranging
from 4 days to 40 days (mean 14.7 9.8 days) under conservative management. Case reviews have found that neuroleptic drugs with a longer half-life tend to exhibit longer
times to resolution of NMS; the difference, however, did
not reach statistical significance.13 Caroff and Mann16 reported onset of NMS within 24 hours after initiation of antipsychotic drugs in about 16% of cases, within a week in
66% of cases, and within 30 days in virtually all cases.
Serotonin syndrome, like NMS, is a potentially lifethreatening condition resulting from an adverse drug reaction to serotonergic drugs. Three features are important in
understanding serotonin syndrome: it is a predictable consequence of excess serotonergic agonism of the serotonin
receptors; it is not an idiopathic drug reaction; and its clinical manifestations can range from barely perceptible to
lethal. Similar to that of NMS, serotonin syndrome presentation involves autonomic hyperactivity, altered mental status, and neuromuscular abnormalities. Thus, signs and
symptoms can range from tremors and diarrhea in mild
cases to delirium, rigidity, and hyperthermia in severe cases.2,8,9 The management of serotonin syndrome is similar to
that of NMS to a certain extent (ie, control of autonomic
instability, agitation, and hyperthermia; removal of precipitating medication; and provision of supportive care). The
difference, however, lies in the pharmacologic treatment:
administration of serotonin 5-HT2a antagonists for serotonin syndrome and dopaminergic agents (ie, bromocriptine and amantadine) and dantrolene for NMS.2,9 It is clear

Table 3. Plasma and Predicted Blood Drug Concentrationsa

Drug

Predicted
Blood
Daily
Measured
SteadyDose
Plasma
State
(mg) (as
Concentration
Range
prescribed)
(ng/mL)
(ng/mL)

Quetiapine

400

382

Trazodone

200

1610b

23b

Risperidone

O-desmethylvenlafaxine

6-20

35b,c

9-OH-risperidone
Venlafaxine

468
915-1108

150

159

38-947

409

Css = steady-state concentration.

a
Predicted steady-state blood concentrations based on given dosing
regimens and clearance.
b
Concentrations are elevated compared with the predicted steady-state
blood concentrations.
c
Total active drug (risperidone + 9-OH-risperidone) measured in this
patient was 58 ng/mL; mean steady-state trough concentration of total active drug in patients with schizophrenia, following a 3-mg oral
dose given twice daily, is 45 ng/mL.10,11

e50

The Annals of Pharmacotherapy

that, in an acute care setting, both of these conditions could

provide a diagnostic dilemma for the clinician.
Given our patients clinical history of chronic use of antipsychotic drugs and feeling unwell prior to presentation,
we believe that the progression of NMS symptoms was insidious rather than fulminant. This is supported by the numerous cuts and bruises sustained from falls, suggesting
early onset of parkinsonian symptoms (although it is possible that her falls prior to admission were related to an adverse effect from other medications). This concurs with observations by others that many patients with NMS present
with extrapyramidal signs, such as dystonias leading to frequent falls, long before other symptoms manifest.13,17-20 On
presentation to the emergency department, our patient also
had symptoms of autonomic dysfunction (tachycardia, diaphoresis, and labile blood pressure). Fully expressed
NMS signs, such as rigidity, fever, and autonomic dysfunction manifesting as hypotension, were noted within hours
of admission. Once the diagnosis was suspected in the
emergency department, antipsychotic drugs were discontinued.
Several drugs can cause NMS. Shalev and Munitz,13 in a
review of NMS literature, found as many as 25 different
compounds associated with NMS. The atypical antipsychotic drugs clozapine, olanzapine, risperidone, aripiprazole, ziprasidone, amisulpride, and quetiapine have been
implicated, alone or as part of combination therapy, as
have first-generation antipsychotics such as haloperidol.21
Several other classes of drugs with dopamine-blocking
pharmacologic effects (eg, amoxapine, prochlorperazine,
metoclopramide) may cause NMS symptoms. In addition,
withdrawal of dopaminergic agents (eg, L-dopa and amantadine) and the GABAergic (-aminobutyric acid) medication baclofen may cause symptoms of NMS.2 There is no
unique method of dosing (ie, high vs low dose, rapid increase, drug withdrawal) that would more likely herald
NMS associated with a neuroleptic drug.13
Our patient had been prescribed several antipsychotic
medications (ie, haloperidol, quetiapine, risperidone) as evidenced by the prescription history and refill pattern in the
DPIN record (Table 1). The Naranjo probability scale indicated a probable causality association between NMS and
quetiapine, haloperidol, and risperidone in our patient,
whereas it assigned only a possible causality association
for serotonergic agents and development of serotonin syndrome.22 We attempted to measure plasma concentrations
of the drugs from specimens taken during her first presentation to the emergency department. Despite the limited
amount of blood, we were able to quantitate some of the
drugs and predict steady-state plasma concentrations based
on published daily dose and clearance rates as determined
in the equation presented in the Case Report section (Table
3), assuming standard oral absorption. Concentrations of
trazodone were elevated compared with the predicted

2011 September, Volume 45

Downloaded from aop.sagepub.com at Linkoping University Library on August 23, 2014

theannals.com

NMS Versus Serotonin Syndrome

model. It appears that venlafaxine may have competitively

inhibited the metabolism of trazodone through CYP3A4,
thus increasing trazodone serum concentrations. As venlafaxine has multiple CYP pathways of elimination its
serum concentrations would not be anticipated to be affected as significantly. Although it is possible for serotonin
syndrome to develop with concomitant use of sumatriptan
and selective serotonin reuptake inhibitors (SSRIs)23 (our
patient was on both at one time), we believe that serotonin
syndrome is less likely given the absence of a sumatriptan
refill for the period immediately preceding the development of NMS (based on the prescription refill pattern). It
had been more than 6 weeks past any refill date.
Most consistent laboratory findings in reported cases of
NMS are leukocytosis with or without left shift, metabolic
acidosis, hypoxia, elevated serum catecholamines, increased creatine kinase, electrolyte imbalance, signs of
dehydration, elevated liver enzymes, and myoglobinemia
when rhabdomyolysis is present, leading to renal failure.2,5,13,21,24,25 Our patient developed all of these abnormalities during her stay in the ICU. In addition, we found elevated urine concentrations of dopamine (>3 fold),
epinephrine (>12 fold), and norepinephrine (>6 fold) and
their metabolites, metanephrine (2.5 fold) and normetanephrine (>6 fold), before administration of exogenous
norepinephrine. All of these are products in the dopamine
metabolic pathway. Serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) was not elevated as one would
predict/hypothesize in serotonin syndrome. Serotonin is
metabolized to 5-HIAA by the monoamine oxidase subtype A in the CNS, liver, gastrointestinal tract, and placenta.26-29 The low level of 5-HIAA encountered in this patient
and the absence of monoamine oxidase inhibitor from the
medication history may be used to rule out serotonin syndrome.
The elevated concentrations of urinary dopamine, epinephrine, norepinephrine, metanephrine, and normetanephrine were seen at hospital presentation. Such elevations can be explained by the antipsychotic-induced dopamine blockade theory.2,30 According to this theory, there is
a massive and sudden reduction in dopaminergic activity in
the brain secondary to antipsychotic-induced dopamine
blockade, thereby mediating the symptoms of NMS. This
theory underscores the reduction in dopaminergic activity
in the brain (resulting in dysregulated sympathetic nervous
system hyperactivity) as the pathologic basis of NMS.2,30
Feibel and Schiffer reported elevated catecholamines in the
plasma and urine of a patient with NMS.31 In this patient,
the elevated levels returned to near normal after the resolution of NMS. Other studies have shown dopamine depletion in the CNS of NMS patients2,5,7 and elevations in peripheral catecholamine levels.5,30 Haloperidol (our patient
was prescribed 20 mg at bedtime) is a selective D2 receptor
theannals.com

blocker and, thereby, can cause extrapyramidal symptoms

and possibly elevations in dopamine concentrations.32,33
The actions of desipramine (as norepinephrine uptake
pump inhibitor) and -1 antagonists (risperidone, quetiapine, trazodone) would explain the elevations seen in these
catecholamine levels.32 Absence of serotonin syndrome,
despite elevated trazodone concentrations, can be explained by the fact that the pharmacologically active metabolite of trazodone is 1-(m-chlorophenyl)-piperazine
(CPP). This metabolic pathway may not have been active
due to the inhibition of CYP2D6 by haloperidol. Catecholamine measurement is available in most tertiary care
hospitals. Knowledge of urinary catecholamine levels
would be useful in the diagnosis of NMS. Consistent with
NMS-precipitating risk factors (sudden withdrawal of
dopamine antagonists) from our patients medication history is the abrupt drop in the use of quetiapine (from ~1800
mg/day to ~487 mg/day). We have no explanation as to
how she was able to obtain enough quetiapine to take 1800
mg/day. This abnormal prescription refill pattern was not
seen with any of her other medications.
Clinical approaches to the management of NMS in our
patient involved cessation of antipsychotic medications,
nonpharmacologic intervention (cooling blankets to correct hyperthermia), and pharmacologic interventions
aimed at reducing muscle rigidity (dantrolene), controlling
agitation and pain (midazolam and fentanyl), as well as
correcting homeostatic imbalance. Our patient had unremarkable results of a computed tomography (CT) scan of
the brain, although she never regained consciousness.
There is evidence in the literature of support for a normal
CT in patients with NMS.13 Despite aggressive supportive
therapy, our patient died on hospital day 20. Mortality rates
for NMS are approximately 22%, with an absence of an
age or sex predisposition.16 NMS can be acute or chronic
and may include CNS, peripheral neurologic, and psychological impairment.34 Any chronic neurologic sequelae
suggest a prior history of organic brain insult.13,34,35 The sequelae could be due to severe secondary complications
from CNS hypoxia and ischemia.13,34,36-38 We believe that
our patient experienced anoxic brain insult during active
NMS, which resulted in a vegetative state. Unfortunately,
she died a few days prior to a scheduled magnetic resonance imaging scan of her brain, results of which may
have supported a finding of anoxic injury.
NMS warrants special attention in the panoply of adverse reactions to neuroleptic drugs because of its potential
severity, unpredictable occurrence, and high mortality rate.
It is often challenging to diagnose NMS. One must rule out
CNS infections, especially viral meningitis (although
meningitis could have been present, the clinical presentation was not indicative of a CNS infection, as evidenced by
the negative results of blood and urine cultures), advanced

The Annals of Pharmacotherapy

Downloaded from aop.sagepub.com at Linkoping University Library on August 23, 2014

2011 September, Volume 45

e50

ARAH Sokoro et al.

stages of psychotic disorders associated with excited or

stuporous catatonia, and serotonin syndrome. The management of each is unique.
In this case, urine catecholamine levels, serotonin metabolite levels, and plasma drug concentrations assisted in
the diagnosis of NMS. We believe these laboratory investigations have a key role in identifying NMS. Further research needs to be conducted into the clinical utility of
these tests in atypical presentation of NMS (formes
frustes).
AbdulRazaq AH Sokoro PhD, Assistant Professor, Department
of Pathology, Faculty of Medicine, University of Manitoba; Clinical
Biochemist, Diagnostic Services of Manitoba, Health Sciences Centre, Winnipeg, Manitoba, Canada
Joel Zivot MD FRCP, Assistant Professor, Anesthesiology, The
Emory Clinic, Emory University Hospital, Atlanta, GA
Robert E Ariano PharmD BCPS FCCM, Associate Professor, Faculty of Pharmacy, University of Manitoba; Critical Care Pharmacist,
Department of Pharmacy, St. Boniface General Hospital, Winnipeg
Correspondence: Dr. Sokoro, asokoro@hsc.mb.ca
Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1P787
Conflict of interest: Authors reported none

References
1. Caroff SN. Neuroleptic malignant syndrome. J Clin Psychiatry 1980;41:
79-83.
2. Strawn JR, Keck PE, Caroff SN. Neuroleptic malignant syndrome. Am J
Psychiatry 2007;164:870-6.
3. Gomez-Esteban JC, Barcena J, Forcadas M, et al. Neuroleptic malignant
syndrome and serotonin syndrome in a female patient: a clinicopathologic case. Clin Neuropharmacol 2009;32:299-300.
DOI 10.1097/WNF.0b013e3181a939b9
4. Kish SJ, Kleinert R, Minauf M, et al. Brain neurotransmitter changes in
three patients who had a fatal hyperthermia syndrome. Am J Psychiatry
1990;147:1358-62.
5. Nisijima K, Ishiguro T. Cerebrospinal-fluid levels of monoamine
metabolites and gamma-aminobutyric-acid in neuroleptic malignant syndrome. J Psychiatr Res 1995;29:233-44.
6. Ueda M, Hamamoto M, Nagayama H, Okubo S, Amemiya S, Katayama
Y. Biochemical alterations during medication withdrawal in Parkinsons
disease with and without neuroleptic malignantlike syndrome. J Neurol
Neurosurg Psychiatry 2001;71:111-3.
7. Wait SD, Ponce FA, Killory BD, Wallace D, Rekate HL. Neuroleptic
malignant syndrome from central nervous system insult: 4 cases and a
novel treatment strategy. Clinical article. J Neurosurg Pediatr 2009;4:
217-21.
8. Adityanjee, Aderibigbe YA, Mathews T. Epidemiology of neuroleptic
malignant syndrome. Clin Neuropharmacol 1999;22:151-8.
9. Boyer EW, Shannon M. The serotonin syndrome N Engl J Med 2005;
352:1112-20.
10. Cohen LJ. Risperidone. Pharmacotherapy 1994;14:253-65.
11. Heykants J, Huang ML, Mannens G, et al. The pharmacokinetics of
risperidone in humans: a summary. J Clin Psychiatry 1994;55(suppl):13-7.
12. Delay J, Pichot P, Lemperiere T, Elissalde B, Peigne F. [A non-phenothiazine and non-reserpine major neuroleptic, haloperidol, in the treatment
of psychoses.]. Ann Med Psychol (Paris) 1960;118:145-52.

e50

The Annals of Pharmacotherapy

13. Shalev A, Munitz H. The neuroleptic malignant syndromeagent and

host interaction. Acta Psychiatr Scand 1986;73:337- 47.
14. Moyes DG. Malignant hyperpyrexia caused by trimeprazine. Case report. Br J Anaesth 1973;45:1163- 4.
15. Boles JM, Lecam B, Mialon P, Pennec Y, Garre M. [Malignant hyperthermia induced by neuroleptics. Rapid cure with dantrolene]. Nouv
Presse Med 1982;11:674.
16. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Psychopharmacol Bull 1988;24:25-9
17. Coons DJ, Hillman FJ, Marshall RW. Treatment of neuroleptic malignant
syndrome with dantrolene sodiuma case-report. Am J Psychiatry
1982;139:944-5.
18. Goulon M, Rohan-Chabot P, Elkharrat D, Gajdos P, Bismuth C, Conso F.
Beneficial effects of dantrolene in the treatment of neuroleptic malignant
syndrome: a report of two cases. Neurology 1983;33:516-8.
19. Misiaszek JJ, Potter RL. Atypical neuroleptic malignant syndrome responsive to conservative management. Psychosomatics 1985;26:62-3, 66.
20. Weinberg S, Twersky RS. Neuroleptic malignant syndrome. Anesth
Analg 1983;62:848-50.
21. Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs 2009;23:477-92.
22. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.
23. Gardner DM, Lynd LD. Sumatriptan contraindications and the serotonin
syndrome. Ann Pharmacother 1998;32:33-38. DOI 10.1345/aph.17204
24. Adityanjee, Mathews T, Aderibigbe YA. Proposed research diagnostic
criteria for neuroleptic malignant syndrome. Int J Neuropsychopharmacol 1999;2:129- 44.
25. Rosenberg MR, Green M. Neuroleptic malignant syndrome. Review of
response to therapy. Arch Intern Med 1989;149:1927-31.
26. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2009;
361:1714.
27. Meyer JH, Ginovart N, Boovariwala A, et al. Elevated monoamine oxidase A levels in the brainan explanation for the monoamine imbalance
of major depression. Arch Gen Psychiatry 2006;63:1209-16.
28. Sabol SZ, Hu S, Hamer D. A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998;103:273-9.
29. Weyler W, Salach JI. Purification and properties of mitochondrial
monoamine oxidase type A from human placenta. J Biol Chem 1985;
260:13199-207.
30. Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry 1999;156:169-80.
31. Feibel JH, Schiffer RB. Sympathoadrenomedullary hyperactivity in the
neuroleptic malignant syndromea case-report. Am J Psychiatry 1981;
138:1115-6.
32. Preskorn SH. Classification of neuropsychiatric medications by principal
mechanism of action: a meaningful way to anticipate pharmacodynamically mediated drug interactions. J Psychiatr Pract 2003;9:376-84.
33. Preskorn SH. Classification of neuropsychiatric medications by principal
mechanism of action: a meaningful way to anticipate pharmacodynamically mediated drug interactions (part II). J Psychiatr Pract 2004;10:177-81.
34. Adityanjee, Sajatovic M, Munshi KR. Neuropsychiatric sequelae of neuroleptic malignant syndrome. Clin Neuropharmacol 2005;28:197-204.
35. Keck PE, Pope HG, Cohen BM, McElroy SL, Nierenberg AA. Risk-factors for neuroleptic malignant syndromea case-control study. Arch
Gen Psychiatry 1989;46:914-8.
36. Horn E, Lach B, Lapierre Y, Hrdina P. Hypothalamic pathology in the
neuroleptic malignant syndrome. Am J Psychiatry 1988;145:617-20.
37. Koponen H, Repo E, Lepola U. Long-term outcome after neuroleptic
malignant syndrome. Acta Psychiatr Scand 1991;84:550-1.
38. Levenson JL, Fisher JG. Long-term outcome after neuroleptic malignant
syndrome. J Clin Psychiatry 1988;49:154-6.

2011 September, Volume 45

Downloaded from aop.sagepub.com at Linkoping University Library on August 23, 2014

theannals.com