second-generation antipsychotics and neuroleptic malignant
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S Y S T E M A T I C R E V I E W
Second-Generation Antipsychotics and Neuroleptic MalignantSyndrome: Systematic Review and Case Report Analysis
Martino Belvederi Murri • Argentina Guaglianone • Michele Bugliani •
Pietro Calcagno • Matteo Respino • Gianluca Serafini •
Marco Innamorati • Maurizio Pompili • Mario Amore
Published online: 13 January 2015
The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract
Background Neuroleptic malignant syndrome (NMS) is arare, severe, idiosyncratic adverse reaction to antipsychot-
ics. Second-generation antipsychotics (SGAs) were origi-
nally assumed to be free from the risk of causing NMS,
however several cases of NMS induced by SGAs (SGA-
NMS) have been reported.
Objectives The aim of this study was to systematically
review available studies and case reports on SGA-NMS
and compare the presentation of NMS induced by different
SGAs. Data Sources Citations were retrieved from PubMed up
to November 2013, and from reference lists of relevant
citations.
Study Eligibility Criteria Eligibility criteria included
(a) primary studies reporting data on NMS, with at least
50 % of the sample receiving SGAs; or (b) case reports
and case reviews reporting on NMS induced by SGA
monotherapy, excluding those due to antipsychotic
withdrawal.
Study Appraisal and Synthesis Methods A standardized
method for data extraction and coding was developed for
the analysis of eligible case reports.
Results Six primary studies and 186 individual cases
of NMS induced by SGAs were included. Primary
studies suggest that SGA-NMS is characterized by
lower incidence, lower clinical severity, and less fre-
quent lethal outcome than NMS induced by first-gen-
eration antipsychotics. Systematic analysis of case
reports suggests that even the most recently marketed
antipsychotics are not free from the risk of inducing
NMS. Furthermore, clozapine-, aripiprazole- and ami-
sulpride-induced NMS can present with atypical fea-
tures more frequently than other SGA-NMS, i.e.
displaying less intense extrapyramidal symptoms or
high fever.
Limitations Case reports report non-systematic data,
therefore analyses may be subject to bias.
Conclusions and Implications of Key Findings Clinicians
should be aware that NMS is virtually associated with all
antipsychotics, including those most recently marketed.
Although apparently less severe than NMS induced by
older antipsychotics, SGA-NMS still represent a relevant
clinical issue.
Electronic supplementary material The online version of thisarticle (doi:10.1007/s40268-014-0078-0 ) contains supplementarymaterial, which is available to authorized users.
M. Belvederi Murri (&) A. Guaglianone M. Bugliani
P. Calcagno M. Respino G. Serafini M. Amore
Section of Psychiatry, Department of Neuroscience,
Rehabilitation, Ophthalmology, Genetics, Maternal and ChildHealth, University of Genoa, Largo Rosanna Benzi, 10,
16132 Genoa, Italy
e-mail: martino.belvederi@gmail.com
M. Belvederi Murri
Department of Psychological Medicine, Institute of Psychiatry,
King’s College London, London, UK
M. Innamorati M. Pompili
Department of Neurosciences, Mental Health and Sensory
Organs, Suicide Prevention Center, Sant’Andrea Hospital,
Sapienza University of Rome, Rome, Italy
Drugs R D (2015) 15:45–62
DOI 10.1007/s40268-014-0078-0
http://dx.doi.org/10.1007/s40268-014-0078-0http://dx.doi.org/10.1007/s40268-014-0078-0
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Key Points
Neuroleptic malignant syndrome (NMS) induced by
second-generation antipsychotics is characterized by
lower incidence, lower clinical severity, and less
frequent lethal outcome than NMS induced by first-
generation antipsychotics.
Even the most recently marketed antipsychotics are
not free from the risk of inducing NMS.
Clozapine-, aripiprazole- and amisulpride-induced
NMS can present with atypical features more
frequently than other SGA-NMS, i.e. displaying less
intense extrapyramidal symptoms or high fever.
1 Introduction
Neuroleptic malignant syndrome (NMS) is a rare, unpre-
dictable adverse reaction associated with antipsychotic use.
It is generally characterized by rigidity, tremor, fever,
dysregulated sympathetic nervous system hyperactivity,
alterations of mental status, leukocytosis, and creatine
kinase (CK) elevation [1]. If not promptly recognized and
treated, NMS can lead to patient death or permanent
damages, such as neurological sequelae [2, 3]. Second-
generation antipsychotics (SGAs) were initially assumed to
be free from the risk of inducing NMS because of theirmore favorable pharmacodynamic profile [4]; however,
after they had been marketed, cases of NMS induced by
SGAs (SGA-NMS) began to be reported, with the first case
implicating clozapine [5]. Notably, several cases of NMS
induced by clozapine (CLZ-NMS) presented with different
clinical features than those of NMS induced by first-gen-
eration antipsychotics (FGA-NMS), i.e. lacking cardinal
signs or symptoms. These observations led to the hypoth-
esis that ‘atypical’ antipsychotics might determine ‘atypi-
cal’ forms of NMS on the basis of different
pharmacological properties [6]. Furthermore, newer SGAs
such as aripiprazole [7] and amisulpride [8] possesspeculiar pharmacodynamic profiles [9, 10] which might be
associated with different NMS presentation. At present,
while it is commonly accepted that no antipsychotic is free
from the risk of inducing NMS, there is still uncertainty on
the clinical profile of SGA-NMS [6, 11].
SGAs are the most commonly prescribed antipsychotics
[12] but our knowledge on SGA-NMS continues to be very
limited given the intrinsic difficulties of studying NMS
under experimental conditions. Of note, case reports
remain one of the main sources of information for clini-
cians. Hence, there is still great uncertainty regarding
SGA-NMS epidemiology [13, 14], diagnostic definition
[1], presentation, clinical course, and pathophysiology [15],
and possible influence of concomitant drugs [16]. Consid-
erable time has elapsed since this topic was examined in a
systematic fashion [6], hence our aim was to review the
available evidence on SGA-NMS, considering both pri-mary studies and case reports. In order to minimize the risk
of bias in the interpretation of available evidence, a stan-
dardized approach was used to analyze the available
information.
2 Methods
2.1 Search Strategy
The Pubmed database was searched using the followingsearch string:\Malignant AND (‘Antipsychotic Agents’
[Mesh] OR amisulpride OR aripiprazole OR asenapine OR
clozapine OR olanzapine OR paliperidone OR quetiapine
OR risperidone OR ziprasidone OR iloperidone OR zote-
pine OR sertindole OR lurasidone)[. Two independent
researchers screened and systematically assessed all
retrieved references to identify (1) primary studies on
SGA-NMS, i.e. those conducted on clinical samples; and
(3) case reports or case reviews of SGA-NMS. All works
published prior to November 2013 as well as relevant
citations obtained from bibliographies were screened. In
addition to citations in English, those written in Italian,Spanish, and French were included as two researchers were
fluent in these languages.
2.2 Inclusion and Exclusion Criteria
For the review of primary studies, any study that reported
data on NMS developed during a treatment course with any
SGA was included. If studies were conducted on samples
where NMS was developed during treatment with both
FGAs and SGAs, only those where at least 50 % of par-
ticipants were treated with SGAs were included.
For the review of case reports, the aim was to obtain themaximum degree of clinical homogeneity; hence, cases
(a) with an unclear diagnosis of NMS, meaning that the
reporting clinician did not explicitly state this diagnosis,
irrespective of the set of diagnostic criteria that were used
[1]; (b) where an SGA was given in association with
another antipsychotic (either FGA or SGA) in the week
preceding the diagnosis of NMS; and (c) where the NMS
was apparently induced by withdrawal of an antipsychotic
[15, 17], were excluded.
46 M. Belvederi Murri et al.
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2.3 Data Extraction
For the case review, researchers extracted, coded, and
analyzed relevant data available from case reports using a
standardized method (described in detail in the Methods
section of the Online Resource). Briefly, two researchers
(AG and MB), blinded to each other, coded for each case
detailed information on subject sociodemographic andclinical features, treatment with SGAs and other psycho-
tropic drugs, NMS clinical presentation, course and man-
agement. In order to provide a description of the time
course of NMS, all available data relative to the temporal
sequence of events were extracted. An adapted version of
the Francis–Yacoub NMS Rating Scale [18] was used to
improve the homogeneity for the ratings of NMS severity.
2.4 Statistical Analysis
For all cases of SGA-NMS, a summary of descriptive data
was reported, including demographic and clinical character-istics. Furthermore, to explore the presence of potential
intraclass differences between cases of NMS prompted by
different SGAs, exploratory statistical analyses were con-
ducted comparing the demographic and clinical characteris-
tics of cases by means of the Chi-square test and analysis of
variance (ANOVA). Since description of the case reports was
not conducted in a systematic fashion, a significant amountof
missing data was expected; to provide the reader with an
estimation of the representativity of results, the percentage of
cases with missing data for each comparison is reported.
Also, Pearson’s correlation index (R) and Student’s t test
were used to test whether sociodemographic and clinical
features of NMSshowed associations with theglobal severity
of NMS (expressed as the total severity score for each case).
Statistical analyses were conducted including only the SGA-
NMS groups where a sufficient number of NMS cases were
available (setting an arbitrary threshold of ten cases per
subgroup), using the Statistical Package for Social Sciences,
version 15.0 (SPSS Inc., Chicago, IL, USA).
3 Results
3.1 Search Results
The search yielded 918 citations (see Fig. S1 in the Online
Resource). Of these, six primary studies were included in
the review [11, 14, 19–22], while 247 case reports were
potentially eligible for inclusion. After full-text review,
105 more citations were excluded, leading to the inclusion
of 142 citations (case reports or case series). These
accounted for 186 individual case reports of SGA-NMS.
References for included case reports are included in the
References section of the Online Resource. Table 1 reports
the description of the included primary studies.
3.2 Case Report Analysis
Tables 2, 3 and 4 report data on cases of SGA-NMS that
were considered for statistical analysis (n = 155): 42 cases
of NMS were induced by olanzapine (OLA, mean dose12 ± 5.8 mg), 44 by risperidone (RSP, mean dose
3.7 ± 3.2 mg), 19 by quetiapine (QUE, 335 ± 270 mg),
36 by clozapine (CLZ, 332 ± 263 mg), and 14 by aripip-
razole (ARP, 18.9 ± 9.2 mg). Table 5 reports descriptive
data of those cases of SGA-NMS for which only descrip-
tive analyses are provided. These were induced by ami-
sulpride (AMI, n = 7; mean dose 480 ± 179 mg),
ziprasidone (ZPR, n = 6; 86.7 ± 46.8 mg), paliperidone
(PAL, n = 4; 7.5 ± 1.7 mg), and zotepine (ZOT, n = 4;
325 ± 247 mg). Lastly, because of a low number of cases,
ten cases of NMS induced by other antipsychotics (pero-
spirone, clotiapine, tiapride, iloperidone, asenapine, rem-oxipride) were excluded from the review.
The majority of case reports did not specify which
diagnostic criteria set was used for the diagnosis of NMS
(n = 131, 70.1 %), whereas in the remainder of cases the
Diagnostic and Statistical Manual of Mental Disorders, 4th
edition, text revision (DSM-IV-TR) criteria were used most
commonly (n = 35,18.7 %) [23], followed by the criteria
of Levenson (n = 13, 7 %) [24], Sachdev (n = 3, 1.6 %)
[25], Pope et al. (n = 2, 1.1 %) [26], and Caroff and Mann
(n = 2, 1.1 %) [27].
3.3 Intraclass Comparison of Cases of Second-
Generation Antipsychotic-Induced Neuroleptic
Malignant Syndrome (SGA-NMS)
3.3.1 Sociodemographic, Clinical Features and Treatment
with SGAs
Table 1 reports the comparison of subjects’ sociodemo-
graphic and clinical features by each SGA-NMS. In the
overall sample, the mean age was 41.5 ± 20.2. The
majority were males (62.6 %), and the diagnoses were
psychotic disorders (58.3 %), mood disorders (23.2 %),
dementia (9.3 %), or other disorders (9.3 %). Half of the
subjects receiving CLZ (50 %) and one-third of those
treated with olanzapine (34.8 %) had already suffered from
NMS in the past, whereas none of the subjects in the ari-
piprazole group ( p = 0.04) had developed NMS.
Among those patients receiving risperidone and aripip-
razole, more were antipsychotic-naı̈ve than in the clozapine
subgroup (41.2 and 38.5 vs. 4.0 %; p = 0.01). The mean
reported doses of SGAs on the day of NMS insurgence
were very similar between the five subgroups ( p = 0.89).
Second-Generation Antipsychotics and NMS 47
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T a b l e 1
S t u d i e s o n n e u r o l e p t i c m a
l i g n a n t s y n d r o m e i n d u c e d b y s e c o n d - g e n e r a t i o n a n t i p s y c h o t i c s
R e f e r e n c e s
S a m p l e
S t u d y d e s i g n a n d d a t a s o u r c e s
T r e a t m e n t
N M S c r i t e r i a ;
n o . o f c a s e s a n d
e s t i m a t e o f
i n c i d e n c e
D e a t h s
[ n ( % ) ]
M a i n fi n d
i n g s a n d l i m i t a t i o n s
B i s w a s l
e t a l .
[ 1 4 ]
1 C a s e o f N M S ; 8 , 8 5 8 s u b j e c t s ;
3 8 % F ; m e a n a g e 4
3 ±
1 7
y e a r s ; w i t h S C Z , 3 9
% ; P S Y ,
1 3 % ; o t h e r s 1 1 % ;
N S 3 3 %
O b s e r v a t i o n a l c o h o r t s t u d y .
D a t a
o n o l a n z a p i n e p r e s c r i p t i o n
s
o b t a i n e d f r o m t h e N H S d a t a b a s e
t h r o u g h p r e s c r i p t i o n - e v e n t
m o n i t o r i n g m e t h o d o v e r a
p e r i o d
o f 2 y e a r s . D a t a o n A E s
c o l l e c t e d t h r o u g h q u e s t i o n
n a i r e s
s e n t t o t h e G P s t r e a t i n g t h
e
s u b j e c t s
O L A ( 1 0 0 % )
N S ; 1 / 8 . 8 5 8
( 0 . 0 5 6 /
1 , 0 0 0 9
y e a r )
N o n e
O n l y o n e
c a s e o f N M S r e p o r t e d ,
n o t l e t h a l . E P S r e p o r t e d i n 1 3
c a s e s , m
o r e o f t e n a m o n g t h o s e
a g e d 7 0
y e a r s a n d o l d e r t h a n i n
y o u n g e r s u b j e c t s
C h e n e t a l .
[ 1 9 ]
5 0 S u b j e c t s w i t h N M S ; 4 4 % F ;
m e a n a g e 4 1 ±
1 4 y e a r s ; w i t h
B D , 1 0 0 % . 8 0 0 c o n
t r o l s w i t h o u t
N M S m a t c h e d f o r d i a g n o s i s , a g e ,
a n d d a t e o f B D i n s u
r g e n c e
C a s e – c o n t r o l s t u d y . D a t a f r o m
m e d i c a l c l a i m s d a t a b a s e o
v e r a
5 - y e a r p e r i o d . C a s e s w i t h
N M S
i d e n t i fi e d f r o m 1 5 4 , 4 7 4 s u
b j e c t s
w i t h B D , t h r o u g h s p o n t a n e o u s
r e p o r t s b y t r e a t i n g p h y s i c i a n s .
C a s e s : A P 3 4 % , o f w h i c h
7 2 % w e r e S G A s ( O L A ,
1 8 % ; Q U E , 2 8 % ; R S P :
1 2 % ; Z P R : 1 2 % ; C L Z :
2 % ) ; F G A s : 8 % ; L I T :
1 0 % ; B D Z : 1 6 % ; A P K :
8 % ; A D : 3 0 %
I C D - 9 ;
5 0 / 1 5 4 . 4 7 4
( 0 . 0 6 4 /
1 0 0 0 * y e a r ) )
N o n e
N M S w a s a s s o c i a t e d w i t h t h e u s e
o f A P ( a O R 2 . 4 ) , m a l e g e n d e r
( a O R 2 . 1 ) , c o n f u s i o n ( a O R 2 . 9 ) ,
d e h y d r a
t i o n ( a O R 4 . 0 ) , d e l i r i u m
( a O R 4 . 9 ) , a n d E P S ( a O R 3 . 5 ) .
N o t a b l y
, o n l y 3 4 % o f N M S
c a s e s h a d b e e n c l a s s i fi e d a s
c u r r e n t l y r e c e i v i n g A P ; a u t h o r s
c o m m e n t e d t h a t m o s t A P
t r e a t m e n t l i k e l y h a d n o t b e e n
r e g i s t e r e d ( p a i d o u t - o f - p o c k e t b y
p a t i e n t s )
N a k a m u r a
e t a l .
[ 2 0 ]
2 1 0 C a s e s w i t h S G A - N M S ; I N P T ,
1 0 0 % ; 4 2 % F ; w i t h p s y c h i a t r i c
d i a g n o s e s a n d n e u r o
l o g i c a l
d i a g n o s e s ; 2 1 0 c o n t r o l s w i t h
F G A - N M S m a t c h e d
b y A P
e x p o s u r e
C a s e – c o n t r o l s t u d y . D a t a f r o m
a d m i n i s t r a t i v e c l a i m s d a t a
b a s e
( J a p a n e s e D i a g n o s i s P r o c e
d u r e
C o m b i n a t i o n ) r e g i s t e r i n g
a d m i s s i o n s t o g e n e r a l h o s p i - t a l s
o v e r a p e r i o d o f 4 y e a r s
( n = 1 2 m i l l i o n ) . C a s e s a n d
c o n t r o l s w e r e s e l e c t e d f r o m
1 , 5 8 5 a d m i s s i o n s f o r N M S
C a s e s : S G A s , 1 0 0 %
C o n t r o l s : F G A s , 1 0 0 %
I C D - 1 0 ; N A
S G A s : 7
( 3 . 3 )
F G A s : 1 6
( 7 . 6 )
C o m p a r e d w i t h F G A - N M S , S G A -
N M S w e r e a s s o c i a t e d w i t h f e w e r
a d m i s s i o n s t o I C U ( 2 1 v s . 3 1 % ;
p = 0 . 0 2 ) a n d w i t h l o w e r
m o r t a l i t y ( a O R 0 , 4 4 ; p = 0 . 0 8 )
a f t e r a d j u s t i n g f o r g e n d e r , a g e ,
a n d C V
D
C V D w a s a s s o c i a t e d w i t h
i n c r e a s e
d N M S - r e l a t e d m o r t a l i t y
48 M. Belvederi Murri et al.
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T a b l e 1
c o n t i n u e d
R e f e r e n c e s
S a m p l e
S t u d y d e s i g n a n d d a t a s o u r c e s
T r e a t m e n t
N M S c r i t e r i a ;
n o . o f c a s e s a n d
e s t i m a t e o f
i n c i d e n c e
D e a t h s
[ n ( % ) ]
M a i n fi n d
i n g s a n d l i m i t a t i o n s
N i e l s e n
e t a l .
[ 2 1 ]
8 3 S u b j e c t s w i t h N M S ; 4 8 % F ;
m e a n a g e 5 1 y e a r s ;
w i t h P S Y ,
4 8 % ; O R G , 3 1 % ;
M D , 1 6 % ;
N E U R , 5 %
4 1 5 C o n t r o l s m a t c h e d
b y s e x , a g e ,
a n d d i a g n o s i s ; P S Y ,
4 8 % ; O R G ,
3 1 % ; M D , 1 6 % ; N
E U R , 5 %
R e t r o s p e c t i v e a n d c a s e – c o n t r o l
s t u d y . D a t a f r o m t h e D P C
R R
o v e r a p e r i o d o f 1 2 y e a r s
( 2 2 4 , 0 0 0 s u b j e c t s )
C a s e s a n d c o n t r o l s w e r e f o l l o w e d
f o r 3 m o n t h s b e f o r e a n d a
f t e r
N M S d i a g n o s i s
C a s e s : S G A s , 3 7 % ; F G A s ,
6 9 % ( h i g h p o t e n c y , 1 7 % ;
m e d i u m p o t e n c y , 2 3 % ; l o w
p o t e n c y , 2 8 % ; d e p o t , 1 3 % ) ;
B D Z , 6 5 % ; L I T , 1 2 %
C o n t r o l s : S G A s , 1 9 % ; F G A s ,
2 7 % ( h i g h p o t e n c y , 4 % ;
m e d i u m p o t e n c y , 1 0 % ; l o w
p o t e n c y , 1 3 % ; d e p o t , 6 % ) ;
B D Z , 3 2 % ; L I T , 4 %
I C D - 1 0 ;
8 3 / 2 2 4 . 3 7 2
( 0 . 0 3 1 /
1 0 0 0 * y e a r )
7 ( 8 . 4 )
I n t h e g e n
e r a l s a m p l e ( n = 8 3 ) , t h e
r i s k o f d e v e l o p i n g N M S w a s
h i g h e r w i t h l i t h i u m u s e ( a O R
5 . 9 ; p \
0 . 0 5 ) , d e p o t ( a O R 5 . 7 ;
p = 0 . 0 0 5 ) , S G A s ( a O R 3 . 0 ; p \
0 . 0 1 ) , b
e n z o d i a z e p i n e u s e ( a O R
2 . 7 ; p \
0 . 0 0 5 ) , a n d d o s e o f A P
( a O R 1 . 0 0 2 ; p \
0 . 0 5 )
I n t h e g r o
u p o f p a t i e n t s t r e a t e d
w i t h A P
f o r 3 m o n t h s b e f o r e
h o s p i t a l i z a t i o n ( n = 6 2 ) , t h e r i s k
o f d e v e l o p i n g N M S w a s h i g h e r
w i t h h i g h - p o t e n c y F G A s ( a O R
2 3 . 4 ; p \
0 . 0 0 1 ) , S G A s ( a O R
4 . 7 ; p =
0 . 0 0 1 ) , a n d d e p o t A P
( a O R 4 . 5 ; p \
0 . 0 0 5 )
M o r t a l i t y
w i t h i n t h e fi r s t 3 0 d a y s
a f t e r N M S w a s h i g h e r a m o n g
c a s e s ( H
R 1 . 9 ; p \
0 . 0 1 ) ,
e s p e c i a l l y f e m a l e s . C a s e s a n d
c o n t r o l s
w e r e n o t m a t c h e d b y A P
u s e , b u t f o r s e x , a g e , a n d
d i a g n o s i s
T r o l l o r
e t a l .
[ 1 1 ]
1 6 5 S u b j e c t s w i t h S G
A - N M S ;
2 7 % F ; m e a n a g e 4 9 y e a r s ; w i t h
P S Y , 4 9 % ; O R G , 2
% ; M D ,
3 % ; A N X , 1 % ; N S , 4 6 % . 4 3
c o n t r o l s w i t h F G A - N M S ; 3 0 %
F ; m e a n a g e 6 2 y e a r s ; w i t h P S Y ,
3 0 % ; M D , 7 % ; O R G , 2 % ;
o t h e r , 9 % ; N S , 5 1 %
R e t r o s p e c t i v e s t u d y . D a t a f r o m
s p o n t a n e o u s N M S r e p o r t i n g i n
A u s t r a l i a n A D R A C d a t a b a s e
o v e r a p e r i o d o f 1 6 y e a r s
S u b j e c t s i n p o l y t h e r a p y w e r e
e x c l u d e d ( n = 8 5 )
S G A - N M S : C L Z , 3 7 % ; R S P ,
1 6 % ; O L A , 1 4 % ; Q U E ,
7 % ; A M I , 3 % ; A R P , 2 % ;
P A L , 1 %
D e l p h i
c o n s e n s u s ;
N A
S G A s : 3 % ;
F G A s :
1 6 %
M o r t a l i t y
r a t e i n i n d i v i d u a l s w i t h
S G A - N M S w a s s i g n i fi c a n t l y
l o w e r t h a n t h a t o f F G A - N M S ,
b u t t h e
d i f f e r e n c e w a s r e d u c e d
a f t e r a d j u s t i n g f o r a g e . N o o t h e r
s i g n i fi c a n t d i f f e r e n c e s w e r e
f o u n d b
e t w e e n t h e c l i n i c a l
p r e s e n t a t i o n o f S G A - N M S a n d
t h a t o f F G A - N M S , e x c e p t f o r
c l o z a p i n e - i n d u c e d N M S t h a t w a s
c h a r a c t e r i z e d b y a l o w e r
p r e s e n c e o f r i g i d i t y a n d o t h e r
E P S c o m p a r e d w i t h o t h e r S G A -
N M S
Second-Generation Antipsychotics and NMS 49
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T a b l e 1
c o n t i n u e d
R e f e r e n c e s
S a m p l e
S t u d y d e s i g n a n d d a t a s o u r c e s
T r e a t m e n t
N M S c r i t e r i a ;
n o . o f c a s e s a n d
e s t i m a t e o f
i n c i d e n c e
D e a t h s
[ n ( % ) ]
M a i n fi n d
i n g s a n d l i m i t a t i o n s
S u e t a l .
[ 2 2 ]
6 7 S u b j e c t s w i t h N M S ; 3 6 % F ;
m e a n a g e 4 3 ±
1 8 y e a r s ; w i t h
P S Y , 4 6 % ; B D , 2 7
% ;
S C Z A F F , 1 2 % ; D E P , 4 % ;
o t h e r s , 1 0 % ; 2 5 4 c o n t r o l s
m a t c h e d ( 1 : 4 ) b y a g
e , g e n d e r ,
a n d d i a g n o s i s : P S Y , 4 6 % ; B D ,
2 7 % ; S C Z A F F , 1 3 ; D E P , 5 % ;
o t h e r s , 9 %
C a s e – c o n t r o l s t u d y . D a t a f r o m t h e
S o u t h L o n d o n a n d M a u d s l e y
N H S F o u n d a t i o n T r u s t C a
s e
R e g i s t e r o v e r a p e r i o d o f 9
y e a r s .
A t l e a s t o n e c r i t e r i a f o r N
M S
d i a g n o s i s . D r u g s w e r e
a d m i n i s t e r e d 5 ( o r a l A P ) o r 1 5
( d e p o t A P ) d a y s b e f o r e t h e i n d e x
d a t e
4 8 % S G A s o n l y , 1 8 % F G A s
o n l y , 4 % A R P o n l y , 4 5 %
p o l y t h e r a p y , 1 0 % d e p o t o n l y
L e v e n s o n ,
A d d o n i z i o ,
P o p e ( d e fi n i t e
o r p r o b a b l e ) ,
C a r o f f ,
A d i t y a n j e e ,
D S M - I V
D e a t h s : N A
I n u n i v a r i a t e a n a l y s e s , F G A s w e r e
a s s o c i a t e d w i t h a n O R o f N M S
o f 3 . 9 ( p \
0 . 0 0 1 ) , w h e r e a s
S G A s w
e r e n o t a s s o c i a t e d w i t h
s i g n i fi c a n t l y h i g h e r r i s k o f N M S ,
w i t h t h e e x c e p t i o n o f A R P ( O R
2 . 5 ; p =
0 . 0 4 ) . I n m u l t i v a r i a t e
a n a l y s e s , c o m p a r e d w i t h S G A s ,
t h e O R
f o r N M S w a s s i g n i fi c a n t
f o r F G A
s ( 2 . 8 1 ; p = 0 . 0 1 ) , S G A /
F G A a s
s o c i a t e d ( 5 . 5 2 ;
p \
0 . 0 0 1 ) , b u t n o t f o r A R P
( p = 2 . 4 3 ) . F l u c t u a n t d o s e s a n d
n o n - W h
i t e e t h n i c i t y w e r e a l s o
s i g n i fi c a n t r i s k f a c t o r s f o r N M S
N M S c a s e d e fi n i t i o n w a s b a s e d o n
f u l fi l l i n g a t l e a s t o n e o f t h e s i x
c r i t e r i a
s e t , r e s u l t i n g i n a h i g h
d e g r e e o f d i a g n o s t i c
h e t e r o g e n e i t y . O n l y o n e c a s e
f u l fi l l e d
a l l s i x c r i t e r i a
A E s a d v e r s e e v e n t s ,
A D a n t i d e p r e s s a n t s , A D R A C A d v e r s e D r u g R e a c t i o n A d v i s o r y C o m m i t e e ,
A M I a m i s u l p r i d e , A N X A
n x i e t y D i s o r d e r s , a O R a d j u s t e d o d d s r a t i o
, A P a n t i p s y c h o t i c , A P K
a n t i p a r k i n s o n a g e n t s ,
A R P a r i p i p r a z
o l e , B D b i p o l a r d i s o r d e r ,
B D Z b e n z o d i a z e p i n e s ,
C L Z c l o z a p i n e , C V D c a r d i o v a s c u l a r d i s e a s e ,
D E P u n i p o l a r d e p r e s s i o n ,
D P C R R D
a n i s h P s y c h i a t r i c C e n t r a l
R e s e a r c h R e g i s t e r , D S M - I V D i a g n o s t i c a n d S t a t i s t i c a l M a n u a l o f M e n t a l D i s o r d e r s , 4 t h e d i t i o n , E P S e x t r a p y r a m i d a l s y m p t o m s , F f e m a l e , F G A fi r s t - g e n e r a t i o n a n t i p s y c h o t i c , F G A - N M S F G A -
i n d u c e d N M S ,
G P s g e n e r a l p r a c t i t i o n e r s ,
H R h a z a r d r a t i o , I C D - 9 I n t e r n a t i o n a l C l a s s i fi c a t i o n o f D i s e a s e s , 9 t h r e v i s i o n ,
I C D - 1 0 I n t e r n a t i o n a l C l a s s i fi c a t i o n o f D i s e a s e s , 1 0 t h r e v i s i o n ,
I C U
i n t e n s i v e c a r e u n i t ,
I N P T i n p a t i e n t s ,
L I T l i t h i u m ,
M D m o o d d i s o r d e r ,
N A n o t a p
p l i c a b l e , N E U R n e u r o t i c d i s o r d e r s , N
H S N a t i o n a l H e a l t h S e r v i c e , N
M S n e u r o l e p t i c m a l i g n a n t s y n d r o m e , N S n o t
s p e c i fi e d ,
O L A o l a n z a p i n e ,
O R o d d s r a t i o , O R G o r g a n i c d i s o r d e r s , P A L p a l i p e r i d o n e ,
P S Y p s y c h o t i c d i s o r d e r s , Q U E q
u e t i a p i n e , R S P r i s p e r i d o n e ,
S C Z A F F s c h i z
o a f f e c t i v e d i s o r d e r ,
S C Z
s c h i z o p h r e n i a , S G A s e c o n d - g e n e r a t i o n a n t i p s y c h o t i c , S G A - N M S S G A - i n d u c e d
N M S ,
Z P R z i p r a s i d o n e
50 M. Belvederi Murri et al.
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Instead, a steep dose titration before NMS was found morefrequently in the aripiprazole group than in the quetiapine
group (50 vs. 10.5 %; p = 0.04). Olanzapine, quetiapine,
and risperidone were more often associated with antide-
pressant use than clozapine and aripiprazole. Lithium was
prescribed to 5.3 % of participants using quetiapine and up
to 13.9 % of those taking clozapine.
3.3.2 NMS Clinical Features
The comparisons of the prevalence, duration, and
severity of NMS symptoms are reported in Table 3. The
clinical presentation of NMS showed significant differ-ences according to the SGA used; rigidity and tremor
were less frequent in CLZ-NMS than in other subgroups
( p\ 0.01 and p = 0.03, respectively). While a degree of
hyperpyrexia was almost ubiquitary, higher temperatures
were less commonly observed for aripiprazole (58.3 %)
than other SGAs, but this difference did not reach sta-
tistical significance ( p = 0.10). Diaphoresis was constant
or very frequent in olanzapine, quetiapine, and clozapine
(100, 100, and 94 %, respectively), less frequent in
risperidone (75 %), and in cases of aripiprazole-inducedNMS (ARP-NMS) [42.9 %; p = 0.001]. Considering
laboratory tests, both CK elevation and leukocyto-
sis were very frequent without showing intra-class
differences.
Global severity was significantly lower for CLZ–NMS
than risperidone-induced NMS (RSP-NMS) [ p = 0.02] or
olanzapine-induced NMS (OLA-NMS) [ p = 0.03]. There
was no significant association between global severity and
age (r = 0.07, p = 0.48), gender (t = 1.37, p = 0.17),
diagnoses (F = 0.18, p = 0.91), antipsychotic dose
(r = 0.08, p = 0.44) or percentage of dose increase in the
preceding week (r = 0.13, p = 0.48), use of mood stabi-lizers (t = 0.49, p = 0.69) or benzodiazepines (t = 0.76,
p = 0.45) in the preceding week. There was a statistical
trend for an association between antidepressant use in the
past week and a higher global severity (37.0 ± 9.6 vs.
32.4 ± 8.7; p = 0.08) but this disappeared after adjusting
for the type of antipsychotic.
There were differences in the timing of the onset of
some symptoms between the SGA-NMS subgroups (see
Table 5), although no comparison reached statistical
Table 2 Cases of neuroleptic malignant syndrome induced by olanzapine, quetiapine, risperidone, aripiprazole, and clozapine
OLA
(n = 42)
QUE
(n = 19)
RSP
(n = 44)
ARP
(n = 14)
CLZ
(n = 36)
Missing
[n (%)]
Statistics
Gender [female; %] 33.3 42.1 50 42.9 22.2 – v2 = 7.18, df = 4, p = 0.13
Age [years; mean ± SD] 46.2 ± 22.4 45.3 ± 18.8 39.6 ± 21.2 32.1 ± 18.2 39.9 ± 16.3 – F = 1.68, df = 4, p = 0.16
Ethnicity [Caucasian; %] 41.2 42.9 55 60 87.5 93 (60) v2 = 9.74, df = 12, p = 0.64c
Diagnosis [%] 4 (2.6) v2
= 13.99, df = 12, p = 0.3Psychotic disorders 52.5 44.4 50 71.4 77.1
Mood disorders 25 27.8 25 21.4 17.1
Dementia 15 15 9.1 – 2.9
Other 7.5 7.5 15.9 7.1 2.9
Previous NMS [%] 34.8 12.5 12.5 0 50 119 (76) v2 = 9.74, df = 4, p = 0.04*c
AP naive [%] 26.7 15.4 41.2 38.5 4.0 40 (26) v2 = 12.15, df = 4, p = 0.02*,c
Dose [mg; mean ± SD] 12.1 ± 5.9 335 ± 270 3.7 ± 3.2 18.9 ± 9.2 332 ± 263 23 (15) –
CPZ eq [mean ± SD] 253 ± 124 236 ± 190 279 ± 240 295 ± 144 308 ± 243 23 (15) F = 0.48, df = 4, p = 0.75
Dose increase [%]a 33.3 15.8 25 50 36.1 – v2 = 5.71, df = 4, p = 0.22
Dose increase C50 [%]b 30.0 10.5 25 50 33.3 – v2 = 6.87, df = 4, p = 0.14
Other treatments [%]
SSRI 11.9 10.5 11.4 7.1 2.8 31 (20) v2 = 2.54, df = 4, p = 0.64
Other AD 4.8 5.3 6.8 0 2.8 31 (20) v2 = 1.49, df = 4, p = 0.83
LIT 11.9 5.3 13.6 7.1 13.9 31 (20) v2 = 1.38, df = 4, p = 0.85
Other MS 21.4 10.5 13.6 7.1 8.3 31 (20) v2 = 3.7, df = 4, p = 0.45
AD antidepressant, AP antipsychotic, ARP aripiprazole, CLZ clozapine, CPZ eq chlorpromazine equivalents, df degrees of freedom, LIT lithium,
NMS neuroleptic malignant syndrome, OLA olanzapine, QUE quetiapine, RSP risperidone, SSRI selective serotonin reuptake inhibitor, MS mood
stabilizers, SD standard deviation
* p\ 0.05a Any dose increase of AP in the 5 days preceding NMS onsetb Percentage of dose increase was calculated as 100 % when the APs were newly introduced in the 5 days before NMS diagnosisc Missing values over 25 %
Second-Generation Antipsychotics and NMS 51
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T a b l e 3
C l i n i c a l f e a t u r e s o f n e u r o l e p t i c m a l i g n a n t s y n d r o m e i n d u c e d b y o l a n
z a p i n e , q u e t i a p i n e , r i s p e r i d o n e , a r i p i p r a z o l e , a n d c l o z a p i n e
O L A ( n = 4 2 )
Q U E ( n = 1 9 )
R S P ( n = 4 4 )
A R P ( n = 1 4 )
C L Z
( n = 3 6 )
M i s s i n g [ n ( % ) ]
S t a t i s t i c s
S y m p t o m s [ % ]
M e n t a l s t a t u s c h a n g e
1 0 0
8 5 . 7
8 8 . 2
1 0 0
9 6 . 6
3 3 ( 2 1 )
v 2
=
7 . 1 9 5 ,
d f =
4 , p = 0 . 1 3
R i g i d i t y
9 1 . 4
9 2 . 3
9 4 . 1
1 0 0
6 7 . 6
2 7 ( 1 7 )
v 2
=
1 5 . 4 7 2 ,
d f =
4 , p \
0 . 0 1 *
T r e m o r
9 2 . 3
1 0 0
9 1 . 7
8 1 . 8
4 4 . 4
1 0 7 ( 6 9 )
v 2
=
1 0 . 5 9 6 ,
d f =
4 , p = 0 . 0 3 * d
O t h e r E P S
8 4 . 6
7 1 . 4
6 6 . 7
8 3 . 3
5 8 . 3
1 0 5 ( 6 8 )
v 2
=
2 . 6 9 1 ,
d f =
4 , p = 0 . 6 1 d
H y p e r p y r e x i a
8 8 . 9
9 2 . 3
9 7 . 3
8 4 . 6
9 1 . 4
2 1 ( 1 4 )
v 2
=
2 . 7 9 , d f =
4 , p = 0 . 5 9
T e m p e r a t u r e C 3 8 C
7 9 . 4
7 8 . 9
9 4 . 3
5 8 . 3
7 9 . 2
3 1 ( 2 0 )
v 2
=
1 3 . 3 8 6 ,
d f =
8 , p = 0 . 1 0
D i a p h o r e s i s
1 0 0
1 0 0
7 5
4 2 . 9
9 5
9 0 ( 5 8 )
v 2
=
1 9 . 4 6 7 ,
d f =
4 , p = 0 . 0 0 1 * d
B P a l t e r a t i o n
8 8 . 2
9 0
7 3 . 7
7 6 . 9
8 1
5 8 ( 3 7 )
v 2
=
2 . 4 9 9 ,
d f =
4 , p = 0 . 6 4 d
T a c h y c a r d i a
1 0 0
1 0 0
9 5 . 7
9 1 . 7
1 0 0
4 5 ( 2 9 )
v 2
=
5 . 0 6 7 ,
d f =
4 , p = 0 . 2 8 d
T a c h y p n e a
7 0
1 0 0
7 0
6 0
1 0 0
1 1 3 ( 7 3 )
v 2
=
5 . 1 6 3 ,
d f =
4 , p = 0 . 2 7 d
D y s p h a g i a
1 3 . 2
8 . 7
1 7 . 6
1 5 . 4
1 1 . 1
5 1 ( 2 7 )
v 2
=
1 . 1 3 9 ,
d f =
4 , p = 0 . 8 9 d
O t h e r a u t o n o m i c s y m p t o m s
1 4 . 3
1 5 . 8
2 5
3 5 . 7
2 5
–
v 2
=
3 . 8 4 5 ,
d f =
4 , p = 0 . 4 3
L a b o r a t o r y t e s t s
C K e l e v a t i o n [ % ]
9 7 . 4
9 1 . 7
9 7 . 1
9 2 . 3
8 5 . 2
1 8 ( 1 1 )
v 2
=
4 . 8 8 5 ,
d f =
4 , p = 0 . 3 0
C K [ 1 0 0 U I / l ; m e a n ±
S D ]
2 2 . 8 ±
5 5 . 0
2 9 . 1 ±
4 7 . 8
5 7 . 3 ±
1 5 . 5
2 4 . 8 ±
6 3 . 6
1 1 . 2
±
4 1 . 9
3 3 ( 2 1 )
F =
1 . 3 4
7 , d f =
4 , p = 0 . 3 3
C K p e a k [ 1 0 0 U I / l ; m e a n ±
S D ]
4 8 . 1 ±
6 5 . 5
5 4 . 8 ±
5 7 . 1
8 5 . 0 ±
1 7 8 . 9
3 5 . 9 ±
6 5 . 6
5 4 . 6
±
1 2 1 . 7
3 3 ( 2 1 )
F =
0 . 5 6
9 , d f =
4 , p = 0 . 6 9
L e u k o c y t o s i s [ % ] a
8 0 . 0
8 0
7 0 . 8
7 0 . 0
7 5
5 4 ( 3 5 )
v 2
=
0 . 8 2 4 ,
d f =
4 , p = 0 . 9 4 d
W B C [ 1 , 0 0 0 U / l ; m e a n ±
S D ]
1 4 . 3 ±
7 . 6
1 1 . 9 ±
4 . 8
1 5 . 3 ±
5 . 2
1 5 . 5 ±
5 . 4
1 3 . 9
±
6 . 0
7 8 ( 5 0 )
F =
0 . 4 4
3 , d f =
4 , p = 0 . 7 8 d
S y m p t o m d u r a t i o n [ d a y s ; m e a n ±
S D ]
8 ±
5 . 4
1 3 . 7 ±
8 . 4
9 . 7 ±
9 . 8
7 . 5 ±
3 . 0
1 0 . 4
±
9 . 9
6 5 ( 4 2 )
F =
1 . 1 7
4 , d f =
4 , p = 0 . 3 3 d
N M S s e v e r i t y [ p o i n t s ; m e a n ±
S D ] b
3 5 . 3 ±
8 . 3
3 1 . 1 ±
8
3 6 . 3 ±
8 . 3
3 1 . 6 ±
1 0 . 1
2 8 . 8
±
8 . 3
5 7 ( 3 6 )
F =
3 . 3 ,
d f =
4 , p = 0 . 0 1 * d
T i m i n g o f N M S s y m p t o m s c
M e n t a l s t a t u s c h a n g e
1 . 0
0 . 5
1 . 5
0 . 8
1 . 0
5 7 ( 3 6 )
F =
0 . 3 1
9 , d f =
4 , p = 0 . 8 6 d
R i g i d i t y
1 . 2
0 . 3
1 . 5
1 . 1
- 1 . 2
4 8 ( 3 0 )
F =
1 . 1 6
3 , d f =
4 , p = 0 . 3 3 d
T r e m o r
1
0 . 7
1 . 7
1 . 1
0 . 0
1 1 5 ( 7 4 )
F =
0 . 1 8
3 , d f =
4 , p = 0 . 9 4 d
O t h e r E P S
1 . 9
0 . 3
3 . 4
1 . 6
2 . 0
–
F =
0 . 0 4
0 , d f =
4 , p = 0 . 9 9
D i a p h o r e s i s
0 . 7
0 . 8
- 0 . 1
0 . 0
1 . 4
1 0 3 ( 6 6 )
F =
0 . 2 1
2 , d f =
4 , p = 0 . 9 3 d
H y p e r p y r e x i a
0 . 7
0 . 1
0 . 7
- 2 . 2
2 . 2
4 3 ( 2 7 )
F =
1 . 3 6
3 , d f =
4 , p = 0 . 2 5 d
T a c h y c a r d i a
- 0 . 4
0 . 3
- 0 . 2
- 3 . 3
1 . 4
6 1 ( 3 9 )
F =
1 . 9 9
2 , d f =
4 , p = 0 . 1 0 d
T a c h y p n e a
- 1 . 1
0 . 2
- 0 . 5
0 . 0
- 0 . 5
1 1 3 ( 7 2 )
F =
0 . 3 7
3 , d f =
4 , p = 0 . 8 3 d
B P a l t e r a t i o n
- 0 . 1
0 . 1
- 0 . 1
0 . 2
0 . 4
7 4 ( 4 7 )
F =
0 . 2 8
2 , d f =
4 , p = 0 . 8 9 d
O t h e r a u t o n o m i c d i s o r d e r s
5 . 3
0 . 0
2 . 7
0 . 0
3 . 0
–
F =
0 . 5 3
9 , d f =
4 , p = 0 . 7 1
C K
- 0 . 7
0 . 0
0 . 0
- 3 . 6
- 0 . 4
4 2 ( 2 7 )
F =
1 . 9
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