Wk 9 Assignment 1
Amblerchick
schiz.pdf
Neurocognitive Functions in Schizophrenia: A Systematic Review of the Effects of Typical and Atypical Antipsychotic Drugs
Cyntia Diógenes Ferreira, Maria Genecleide Dias de Souza, and Bernardino Fernández-Calvo
Federal University of Paraíba
João Paulo Machado-de-Sousa and Jaime Eduardo Cecilio Hallak
University of São Paulo
Nelson Torro-Alves Federal University of Paraíba
Schizophrenia is characterized by, in addition to positive and negative symptoms, impaired cognitive functioning. In this article, we conducted a systematic review of studies that directly compared the effects of typical and atypical antipsychotics on neurocognitive functions. Twenty-three articles published between 2000 and 2015 were included in the review. In general, atypical antipsychotics had a broader range of effects on neurocognitive functions, with improvements in working memory, executive func- tions, memory, and verbal fluency. Few articles reported no differences between typical and atypical medication or an advantage of typical medication. However, it is important to highlight that differences between the 2 classes of medication may not be attributable solely to the antipsychotics but to confounding factors including, for example, the concurrent use of anticholinergics to alleviate extrapyramidal symptoms, which can impair cognition. This review may help provide a better understanding of treatments addressing the maintenance or recovery of neurocognitive functions in patients with schizophrenia, which may have important benefits to the patients’ quality of life.
Keywords: schizophrenia, cognition, antipsychotics
Impaired neurocognitive functioning is com- mon in schizophrenia (Keefe & Fenton, 2007), with reported deficits in attention (Coleman et al., 2009), processing speed (Dickinson, Ram- sey, & Gold, 2007; Knowles, David, & Reichenberg, 2010), working memory (Levaux et al., 2009), intelligence (Kremen, Seidman, Faraone, & Tsuang, 2001), verbal fluency (Bho-
jraj et al., 2009), and executive functions (Wo- brock et al., 2009). Some studies have sug- gested that neurocognitive dysfunction is present even before the first psychotic episode (Albus et al., 2006), lasting throughout the dis- ease independently from the evolution of psy- chotic symptoms (O’Leary et al., 2000). The neurocognitive decline has impacts on patients’ quality of life, affecting their autonomy, psy- chosocial skills, and employment prospects (Lam, Raine, & Lee, 2014).
The history of antipsychotic drugs began in the 1950s with the discovery of the effects of chlorpromazine, which belongs to the chemical class of phenothiazines. Chlorpromazine was initially used to tranquilize patients in the pre- operatory period, and then some clinical studies revealed its effects in restoring the quality of life of psychiatric patients. Later on, a new class of drugs was introduced, the butyrophenones, mainly represented by the haloperidol. These antipsychotic drugs were known as neuroleptics
Cyntia Diógenes Ferreira, Maria Genecleide Dias de Souza, and Bernardino Fernández-Calvo, Department of Psychology, Federal University of Paraíba, João Pessoa, Paraíba, Brazil; João Paulo Machado-de-Sousa and Jaime Eduardo Cecilio Hallak, Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Nelson Torro- Alves, Department of Psychology, Federal University of Paraíba, João Pessoa, Paraíba, Brazil.
Correspondence concerning this article should be ad- dressed to Cyntia Diógenes Ferreira, Department of Psy- chology–Bloc IV, Federal University of Paraíba–Campus I, Cidade Universitária–João Pessoa–PB, Brazil CEP 58059- 900. E-mail: [email protected]
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Psychology & Neuroscience © 2016 American Psychological Association 2016, Vol. 9, No. 1, 12–31 1983-3288/16/$12.00 http://dx.doi.org/10.1037/pne0000045
12
because of their neurologic side effects, the so-called extrapyramidal effects (Lehmann & Ban, 1997; Miyamoto, Duncan, Marx, & Lieberman, 2005).
In the following decades, many advances re- vealed the mechanisms of antipsychotic drugs, which mainly acted on the dopaminergic sys- tem, more specifically on the D2 receptors of dopamine (Kapur & Mamo, 2003). According to the dopaminergic theory of schizophrenia, the excessive activation of D2 receptors in the nucleus accumbens would produce positive symptoms (e.g., delusions and hallucinations), whereas the negative symptoms (e.g., blunted affect and cognitive deficits) would result from a reduced activity in dopaminergic receptors in the prefrontal cortex. Therefore, the ideal anti- psychotic would reduce dopaminergic activity in the nucleus accumbens and enhance the ac- tivity in the prefrontal cortex, acting on both positive and negative symptoms (Kapur, 2004).
The antagonistic action on dopamine recep- tors is responsible for the therapeutic effect of antipsychotic drugs, a mechanism with impor- tant side effects, for example, on the dopami- nergic pathway from substantia nigra to dorsal striatum (caudate-putamen in the basal nuclei), which is part of the extrapyramidal system. The extrapyramidal effects are responsible for motor deficits such as bradykinesia and acathisia, characterizing the parkinsonian syndrome (Johnstone, Frith, Crow, Carney, & Price, 1978). The induction of extrapyramidal effects is a key feature of typical antipsychotics (“neu- roleptics”); however, an atypical profile was observed after the advent of clozapine. In par- ticular, it was observed that clozapine reduced both positive and negative symptoms without producing extrapyramidal side effects (Maia- de-Oliveira et al., 2012). This difference estab- lished two classes of antipsychotics—typical (first generation) and atypical (second genera- tion).
The complex relationship between alterations in dopaminergic transmission and some mental disorders, such as schizophrenia, indicate that more research in necessary to understand the mechanisms of action of dopamine in primary cognitive domains. According to some studies, the action of dopamine in the prefrontal cortex follows an inverted U dose–response curve, in which an increase or decrease in relation to an
optimum level results in cognitive impairments (Veselinović et al., 2013).
Atypical antipsychotics may, in addition to acting on the dopaminergic system, act on se- rotonergic pathways (Meltzer & Massey, 2011). When administered in clinically effective doses, these drugs may block serotonin (5-HT) 2A; directly or indirectly stimulate 5-HT1A recep- tors; and, to a lesser extent, reduce the neu- rotransmission mediated by the dopamine re- ceptor D2. This is in contrast to the effects of typical antipsychotics, which are mainly antag- onists of D2 and D3 dopamine receptors, with little antagonism over 5-HT2A receptors. This different effect on 5-HT receptors may contrib- ute to significant differences in efficacy and tolerance between typical and atypical antipsy- chotics (Meltzer, 2013; Meltzer & Massey, 2011).
Currently, there is evidence that atypical antipsychotics have greater benefits for neu- rocognitive function compared with typical antipsychotics (Bilder et al., 2002). Such re- sults have been observed with the administra- tion of olanzapine (Sharma, Hughes, Soni, & Kumari, 2003), clozapine (Keefe, Silva, Per- kins, & Lieberman, 1999), risperidone (Lee, Chou, Li, Wan, & Yen, 2007), and quetiapine and ziprasidone (Johnsen, Jørgensen, Kroken, & Løberg, 2013). However, despite the wide- spread use of these drugs in clinical practice, there are limited data comparing their overall efficacy in reducing the different symptoms of schizophrenia. Nevertheless, some studies have found contradictory results (Crespo- Facorro et al., 2009; Thornton, Van Snellen- berg, Sepehry, & Honer, 2006).
The quality of schizophrenia treatment with antipsychotics may be evidenced by improve- ment in symptoms and cognitive functioning. Estimates of the dose–response relationship for its effectiveness and adverse events requires careful study of the drug, mainly by conducting randomized controlled trials (Owen et al., 2002). The compilation of different research results contributes to defining schizophrenia treatment guidelines in psychiatric clinical prac- tice, with the specification of antipsychotics, dose intervals, efficacy of pharmacological treatment, and other therapeutic interventions (Dixon, Perkins, & Calmes, 2009; Lehman et al., 2004).
13ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA
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The World Federation of Societies of Biolog- ical Psychiatry (WFSBP) task force has sought to establish a consensus on key recommenda- tions for the treatment of schizophrenia in psy- chiatric practice through a systematic review of the available evidence (Falkai et al., 2005). It has found that the doses must be adjusted ac- cording to antipsychotic tolerability in order to rapidly achieve the therapeutic range (Falkai et al., 2005). Several studies of the diverse atypi- cal antipsychotics have sought to identify the minimum effective dose for each, but discrep- ancies still exist (e.g., Citrome & Volavka, 2002; Leucht et al., 2014). Davis and Chen (2004) reviewed studies comparing two or more doses of antipsychotics in patients with schizo- phrenia or schizoaffective disorder, with the purpose of calculating the dose–response curve for both typical and atypical medications. For haloperidol, they found that the effective dose was close to the maximum dose (3.3–10 mg). For olanzapine, the maximum effective dose can be greater than 16 mg, with 6 mg being 33% less effective compared with higher doses. It was also found that 4 mg of risperidone was the most efficient dose, whereas a dosage of 2 mg daily was 50% less effective than were higher doses. These results demonstrate the importance of evaluating doses used in the studies.
In summary, there is general agreement in the literature on the cognitive impairments related to schizophrenia, but there are conflicting re- sults concerning the effects of different antipsy- chotic drugs on cognition. Here, we review studies that directly compared the effects of typical and atypical antipsychotics on neuro- cognitive functions in patients with schizophre- nia.
Method
Using the terms typical and atypical antipsy- chotic and cognition and schizophrenia, we conducted a systematic search for empirical re- search articles published between 2000 and 2015 and indexed in PubMed, LILACS, Sci- ELO, and Science Direct. As a complementary strategy, we also screened the reference lists of the articles found for further relevant publica- tions. The inclusion criteria for the review were (a) comparison of the effects of typical and atypical antipsychotic drugs on neurocognitive functions in schizophrenia through empirical studies, (b) admin-
istration of neuropsychological tests, and (c) use of human participants. Literature reviews, meta- analysis studies, theses, dissertations, and neuroim- aging studies were not included. The systematic re- view employed the guidelines of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses; http://www.prisma-statement .org/) initiative for literature searches and data reporting in quantitative and qualitative system- atic reviews. The initial selection was based on the articles’ titles and abstracts and followed by reading and evaluating the full articles accord- ing to the inclusion criteria. We found a total of 23 studies that compared the effects of typical and atypical antipsychotics on neurocognitive functions.
Results
Figure 1 is a flow diagram of our systematic review. In general, most articles were published from 2003 to 2009. In comparison with typical antipsychotics, atypical drugs were associated with better performances in neuropsychological tests, with only four studies reporting no differ- ences between typical and atypical antipsychot- ics (Davidson et al., 2009; Keefe et al., 2007; Rémillard, Pourcher, & Cohen, 2008; Wittorf, Sickinger, Wiedemann, & Klingberg, 2008). These findings suggest that atypical antipsy- chotics are more efficient in maintaining or im- proving neurocognitive functions in schizophre- nia patients. The most frequently investigated atypical drugs were risperidone (n � 16), olan- zapine (n � 13), quetiapine (n � 7), and clo- zapine (n � 6).
Across studies, there was broad diversity in the methods employed to assess the neurocog- nitive functions in schizophrenia. However, the main neuropsychological instruments used were the Wisconsin Card Sorting Test (n � 13), Wechsler Adult Intelligence Scale (n � 12), Trail Making Test (n � 11) and the Wechsler Memory Scale—Revised (n � 9), all of which are involved in the assessment of executive functions, intelligence, visual attention and task switching, and memory.
The findings by Han et al. (2015) suggest that long-term treatment with antipsychotic cloza- pine caused worse performance in immediate memory (composed of list learning and story memory tasks) and delayed memory (composed of list recall, story recall, figure recall and list
14 FERREIRA ET AL.
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recognition tasks) than for those individuals taking typical drugs. However, individuals tak- ing clozapine showed better language perfor- mance than did those taking risperidone. Mül- ler, Werheid, Hammerstein, Jungmann, and Becker (2005) observed an advantage of indi- viduals taking atypical drugs in the task of or- dering digits, which requires working memory. Also, Morrens, Hulstijn, and Sabbe (2008) in- vestigated the effects of antipsychotics on psy- chomotor speed and found that of individuals taking typical drugs induced higher psychomo- tor deceleration in a copy task. Krakowski and Czobor (2011) found that general cognitive in- dex was greater for patients taking olanzapine than for those taking clozapine or haloperidol. Beninger et al. (2003) observed that individuals taking typical and atypical antipsychotics had distinct effects on nondeclarative memory and that patients taking typical medication had a better performance in decision-making (as mea- sured by the Iowa Gambling Task), whereas patients taking atypical medication were better at probabilistic classification learning.
Treatment with atypical antipsychotics, in comparison to typical antipsychotics, was gen- erally associated with gains in cognitive func-
tioning, as observed by Harvey, Rabinowitz, Eerdekens, and Davidson (2005) with risperi- done. In a similar way, Keefe et al. (2004) reported improvements in cognitive perfor- mance after 12 weeks of treatment with atypical antipsychotics in schizophrenia, whereas the re- sults were modest with the administration of haloperidol. In a subsequent study, Purdon et al. (2000) showed that, in the initial stages of schizophrenia, olanzapine and quetiapine led to benefits in processing speed. In addition, Keefe, Young, et al. (2006) observed that patients able to remain in treatment for the entire 52 weeks benefited more from olanzapine or risperidone treatment than haloperidol treatment.
Guo et al. (2011) observed neurocognitive benefits with the use of olanzapine and haloper- idol after 12, 24, 52, and 104 weeks of treat- ment, with an advantage of olanzapine in the 12th and 24th weeks; even so, they found no significant differences between groups of pa- tients treated with haloperidol, olanzapine, and risperidone with regard to the composite score of the neurocognitive tests. However, when in- dividual scores were analyzed, they verified that olanzapine and risperidone improved perfor- mance on the domains of executive function,
Figure 1. Flow diagram of the surveyed studies investigating the effects of typical and atypical antipsychotic drugs.
15ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA
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learning/memory, processing speed, attention/ vigilance, verbal working memory, and motor functions, whereas haloperidol-treated patients improved only on the domain of learning/ memory compared to the baseline. Risperidone improved the performance in all those domains in addition to visuospatial memory.
In studies assessing the use of combined drugs, Hori et al. (2006) observed that “nonstan- dard” use of antipsychotics (defined as antipsy- chotic polypharmacy or dosage �1,000 mg/day of chlorpromazine equivalents) is associated with cognitive function. Patients taking atypical antipsychotics showed better performance on visual memory, delayed recall, and executive function than did those taking typical drugs.
The antipsychotic olanzapine demonstrates a large improvement in cognitive functions eval- uated in some studies. Purdon et al. (2000) found that patients produced better procedural learning measures when treated with olanzapine than with haloperidol or risperidone, especially after 6 months of treatment. Cuesta, Peralta, and Zarzuela (2001) found a small advantage of olanzapine over risperidone in attentional func- tions, verbal memory, and executive functions in patients with chronic schizophrenia.
Lee et al. (2007) highlighted the good results obtained with risperidone compared to haloper- idol in verbal learning and working memory. Harvey et al. (2004) described an improvement in cognitive functions in patients who switched from typical or atypical drugs (olanzapine or risperidone) to ziprasidone.
Purdon, Malla, Labelle, and Lit (2001) ob- served that quetiapine, in comparison with hal- operidol, was associated with improvements in verbal fluency, reasoning, immediate memory, executive functions, and visuomotor tracking. Similarly, Velligan et al. (2002) found an ad- vantage of quetiapine over haloperidol on exec- utive functions, attention, and verbal memory.
On the other hand, some studies showed sim- ilar effects for the two classes of antipsychotics. Davidson et al. (2009) found no differences between haloperidol and second-generation an- tipsychotic drugs (amisulpride, olanzapine, que- tiapine, and ziprazidone) on the cognitive per- formance of patients with schizophreniform disorder or first-episode schizophrenia. Keefe et al. (2007) found no significant differences be- tween typical (i.e., perphenazine) and atypical (i.e., olanzapine, quetiapine, and risperidone)
antipsychotics administered. Wittorf et al. (2008) observed improvements in memory, at- tention, and executive functions in both patients using typical antipsychotics and those using atypical antipsychotics, with no differences be- tween the drug classes. In addition, Rémillard et al. (2008) found no improvement in neurocog- nitive performance in groups treated with ris- peridone and haloperidol over a 12-month fol- low-up. However, risperidone was more effective than haloperidol to reduce psychiatric symptoms.
Suzuki and Gen (2012), in a study conducted with long-acting antipsychotics, found that switching from haloperidol decanoate depot to risperidone long-acting injection improved cog- nitive functions including memory, executive function, motor processing function, and atten- tion. This is an important finding considering that risperidone is less likely than haloperidol to cause extrapyramidal symptoms and that in their study it allowed them to reduce the anti- parkinsonian medication. Main findings and characteristics of the studies included in the systematic review are presented in Table 1.
With regard to the study design and conduct of the clinical trials, we found that 10 studies used the double-blind randomization procedure to investigate the treatment with typical and atypical antipsychotics. Ten studies defined groups on the basis of the medication already taken by the participants or that would be pre- scribed by the professionals. In four studies, participants were randomly distributed between groups, but the double-blind procedure was not used (see Table 1).
Discussion
We reviewed empirical studies comparing the effects of typical and atypical antipsychotics on neurocognitive functions in patients with schizophrenia. In general terms, we observed that atypical antipsychotics have a broader range of effects on neurocognition in compari- son with typical drugs, which in turn were as- sociated with improvements in executive func- tions, as revealed by some studies (Cuesta et al., 2001; Keefe, Young, et al., 2006; Purdon et al., 2001).
Atypical antipsychotics were generally more efficient than was haloperidol (Guo et al., 2011; Harvey et al., 2004) or combined use (polyp-
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as el
in e,
6 an
d 12
m on
th s)
A tt
en ti
on ,
pr oc
es si
ng sp
ee d,
le ar
ni ng
an d
m em
or y,
ex ec
ut iv
e fu
nc ti
on s
W M
S -R
–v is
ua l
re pr
od uc
ti on
te s,
W A
IS -
R –d
ig it
sy m
bo l
te st
an d
di gi
t sp
an te
st ,
W C
S T
, T
M T
(A an
d B
)
O la
nz ap
in e
an d
qu et
ia pi
ne :
P ro
ce ss
in g
sp ee
d sc
or es
(D ig
it S
ym bo
l, T
M A
–P ar
t A
)
(t a b le
co n ti
n u es
)
17ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA
T hi
s do
cu m
en t
is co
py ri
gh te
d by
th e
A m
er ic
an P
sy ch
ol og
ic al
A ss
oc ia
ti on
or on
e of
it s
al li
ed pu
bl is
he rs
. T
hi s
ar ti
cl e
is in
te nd
ed so
le ly
fo r
th e
pe rs
on al
us e
of th
e in
di vi
du al
us er
an d
is no
t to
be di
ss em
in at
ed br
oa dl
y.
T ab
le 1
(c o n ti
n u ed
)
S tu
dy S
am pl
e
C ha
ra ct
er is
ti cs
of th
e m
ai n
sa m
pl e
T yp
ic al
dr ug
s A
ty pi
ca l
dr ug
s S
tu dy
de si
gn N
eu ro
co gn
it iv
e fu
nc ti
on s
A ss
es sm
en t
to ol
s
R es
ul ts
T yp
ic al
� at
yp ic
al A
ty pi
ca l
� ty
pi ca
l
H an
et al
. (2
01 5)
N �
57 7
(n �
41 8
pa ti
en ts
w it
h sc
hi zo
ph re
ni a,
n �
15 9
he al
th y
co nt
ro ls
).
C hr
on ic
pa ti
en ts
N ot
sp ec
ifi ed
(n �
11 2)
C lo
za pi
ne (n
� 21
5) ,
ri sp
er id
on e
(n �
91 )
T ra
ns ve
rs al
Im m
ed ia
te m
em or
y, vi
su os
pa ti
al -
co ns
tr uc
ti on
al ,
la ng
ua ge
, at
te nt
io n,
de la
ye d
m em
or y
R B
A N
S Im
m ed
ia te
an d
de la
ye d
m em
or y
pe rf
or m
an ce
th an
th os
e ta
ki ng
cl oz
ap in
e
C lo
za pi
ne sh
ow ed
be tt
er la
ng ua
ge pe
rf or
m an
ce th
an th
os e
ta ki
ng ri
sp er
id on
e
H ar
ve y
et al
. (2
00 4)
n �
27 0
(p at
ie nt
s w
it h
sc hi
zo ph
re ni
a or
sc hi
zo af
fe ct
iv e
di so
rd er
th at
ch an
ge d
th e
m ed
ic at
io n
to zi
pr as
id on
e)
N on
cr it
ic al
pa ti
en ts
N ot
sp ec
ifi ed
(n �
10 8)
. Z
ip ra
si do
ne ,
ol an
za pi
ne (n
� 10
4) ,
ri sp
er id
on e
(n �
58 )
T ra
ns ve
rs al
L ea
rn in
g an
d m
em or
y, at
te nt
io n
an d
vi gi
la nc
e, ex
ec ut
iv e
fu nc
ti on
, ve
rb al
fl ue
nc y,
vi su
om ot
or sp
ee d
R A
V L
T ,
S pa
ti al
W or
ki ng
M em
or y
te st
, C
P T
-I P
, D
S D
T ,
T M
T (A
an d
B ),
F A
S (a
ni m
al s,
ve ge
ta bl
es ,
fr ui
ts ),
W C
S T
S ig
ni fi
ca nt
im pr
ov em
en ts
w it
h bo
th ty
pe s
of m
ed ic
at io
n in
ex ec
ut iv
e fu
nc ti
on (W
C S
T )
Z ip
ra si
do ne
: L
ea rn
in g
an d
m em
or y
(R A
V L
T ),
at te
nt io
n (d
is tr
ac ti
on co
nd it
io n–
D S
D T
), vi
su om
ot or
sp ee
d (T
M T
), ve
rb al
fl ue
nc y
H ar
ve y
et al
. (2
00 5)
n �
53 3
(p at
ie nt
s w
it h
sc hi
zo ph
re ni
a) F
ir st
-e pi
so de
sc hi
zo ph
re ni
a H
al op
er id
ol (n
� 25
0) R
is pe
ri do
ne (n
� 25
6) L
on gi
tu di
na l
(b as
el in
e an
d 3
m on
th )
V is
uo m
ot or
sp ee
d, m
em or
y, vi
gi la
nc e,
ex ec
ut iv
e fu
nc ti
on ,
ve rb
al fl
ue nc
y, ps
yc ho
m ot
or sp
ee d
an d
at te
nt io
n
W M
S -R
–v is
ua l
re pr
od uc
ti on
su bt
es t,
R A
V L
T ,
C P
T -
IP –d
ig it
ve rs
io n,
ve rb
al fl
ue nc
y ex
am in
at io
ns ,
W A
IS -R
, W
C S
T
S ig
ni fi
ca nt
im pr
ov em
en ts
w it
h bo
th ty
pe s
of m
ed ic
at io
n in
V is
uo m
ot or
sp ee
d (W
M S
-R )
an d
vi gi
la nc
e (C
on ti
nu ou
s P
er fo
rm an
ce T
es t)
M em
or y
an d
ve rb
al le
ar ni
ng (R
A V
L T
), ex
ec ut
iv e
fu nc
ti on
(W C
S T
)
H or
i et
al .
(2 00
6) n
� 15
9 (n
� 67
pa ti
en ts
w it
h ch
ro ni
c sc
hi zo
ph re
ni a,
n �
92 co
nt ro
ls )
C hr
on ic
an d
no nc
ri ti
ca l
pa ti
en ts
C hl
or pr
om az
in e
an d
si m
il ar
(n �
23 )
N ot
sp ec
ifi ed
(n �
22 )
T ra
ns ve
rs al
M em
or y,
in te
ll ig
en ce
(I Q
), ex
ec ut
iv e
fu nc
ti on
, sp
at ia
l ab
il it
y, ps
yc ho
m ot
or sp
ee d
W M
S -R
, W
A IS
- R
, W
C S
T ,
T M
T –A
dv an
ce d
V is
ua l
m em
or y
(W M
S -R
), de
la ye
d re
ca ll
(W M
S -R
), ex
ec ut
iv e
fu nc
ti on
(W C
S T
)
18 FERREIRA ET AL.
T hi
s do
cu m
en t
is co
py ri
gh te
d by
th e
A m
er ic
an P
sy ch
ol og
ic al
A ss
oc ia
ti on
or on
e of
it s
al li
ed pu
bl is
he rs
. T
hi s
ar ti
cl e
is in
te nd
ed so
le ly
fo r
th e
pe rs
on al
us e
of th
e in
di vi
du al
us er
an d
is no
t to
be di
ss em
in at
ed br
oa dl
y.
T ab
le 1
(c o n ti
n u ed
)
S tu
dy S
am pl
e
C ha
ra ct
er is
ti cs
of th
e m
ai n
sa m
pl e
T yp
ic al
dr ug
s A
ty pi
ca l
dr ug
s S
tu dy
de si
gn N
eu ro
co gn
it iv
e fu
nc ti
on s
A ss
es sm
en t
to ol
s
R es
ul ts
T yp
ic al
� at
yp ic
al A
ty pi
ca l
� ty
pi ca
l
K ee
fe et
al .
(2 00
7) n
� 14
60 (p
at ie
nt s
w it
h sc
hi zo
ph re
ni a)
C hr
on ic
pa ti
en ts
P er
ph en
az in
e (n
� 25
7) O
la nz
ap in
e (n
� 33
0) ,
qu et
ia pi
ne (n
� 32
9) ,
ri sp
er id
on e
(n �
33 3)
, zi
pr as
id on
e (n
� 18
3)
L on
gi tu
di na
l (b
as el
in e
an d
12 m
ot hs
)
P ro
ce ss
in g
sp ee
d, re
as on
in g,
w or
ki ng
m em
or y,
ve rb
al m
em or
y, vi
gi la
nc e
C O
W A
T ,
C P
T -
IP ,
W A
IS -R
– di
gi t
sy m
bo l
te st
, W
C S
T ,
W A
IS .
N o
si gn
ifi ca
nt di
ff er
en ce
s be
tw ee
n tr
ea tm
en ts
K ee
fe et
al .
(2 00
4) N
� 16
7 (p
at ie
nt s
w it
h fi
rs t
ep is
od e
of sc
hi zo
ph re
ni a,
sc hi
zo af
fe ct
iv e
di so
rd er
, an
d sc
hi zo
ph re
ni fo
rm di
so rd
er )
F ir
st -e
pi so
de sc
hi zo
ph re
ni a
H al
op er
id ol
(n �
78 )
O la
nz ap
in e
(n �
89 )
L on
gi tu
di na
l (b
as el
in e
an d
12 w
ee ks
)
V er
ba l
fl ue
nc y,
at te
nt io
n, m
em or
y an
d le
ar ni
ng ,
vi su
om ot
or sp
ee d,
w or
ki ng
m em
or y,
m ot
or sp
ee d,
ex ec
ut iv
e fu
nc ti
on s,
di si
nh ib
it io
n, de
si gn
fl ue
nc y,
m em
or y
an d
vi su
al or
ie nt
at io
n, la
te ra
li ty
C P
T -I
P ,
C V
L T
, W
A IS
-R di
gi t-
sy m
bo l
te st
, D
ot T
es t
of V
is uo
sp at
ia l
W or
ki ng
M em
or y,
L et
te r-
N um
be r
S eq
ue nc
in g
T es
t, F
in ge
r O
sc il
la ti
on T
es t,
W C
S T
– 64
-c ar
d, T
M T
(A an
d B
), va
ri ab
le -
in te
rv al
de la
ye d
al te
rn at
io n
ta sk
, ob
je ct
al te
rn at
io n
ta sk
, S
C W
T ,
R uf
f F
ig ur
al F
lu en
cy T
es t,
W M
S R
S ig
ni fi
ca nt
im pr
ov em
en ts
(n on
w ei
gh te
d sc
or es
) w
it h
bo th
ty pe
s of
m ed
ic at
io n
in ve
rb al
fl ue
nc y,
m ot
or fu
nc ti
on ,
w or
ki ng
m em
or y,
ve rb
al m
em or
y, an
d vi
gi la
nc e
C om
po si
te sc
or es
of ve
rb al
fl ue
nc y,
m ot
or fu
nc ti
on ,
w or
ki ng
m em
or y,
ve rb
al m
em or
y, an
d vi
gi la
nc e
(t a b le
co n ti
n u es
)
19ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA
T hi
s do
cu m
en t
is co
py ri
gh te
d by
th e
A m
er ic
an P
sy ch
ol og
ic al
A ss
oc ia
ti on
or on
e of
it s
al li
ed pu
bl is
he rs
. T
hi s
ar ti
cl e
is in
te nd
ed so
le ly
fo r
th e
pe rs
on al
us e
of th
e in
di vi
du al
us er
an d
is no
t to
be di
ss em
in at
ed br
oa dl
y.
T ab
le 1
(c o n ti
n u ed
)
S tu
dy S
am pl
e
C ha
ra ct
er is
ti cs
of th
e m
ai n
sa m
pl e
T yp
ic al
dr ug
s A
ty pi
ca l
dr ug
s S
tu dy
de si
gn N
eu ro
co gn
it iv
e fu
nc ti
on s
A ss
es sm
en t
to ol
s
R es
ul ts
T yp
ic al
� at
yp ic
al A
ty pi
ca l
� ty
pi ca
l
K ee
fe ,
S ei
dm an
, et
al .
(2 00
6) N
� 26
3 (p
at ie
nt s
w it
h fi
rs t
ep is
od e
of sc
hi zo
ph re
ni a,
sc hi
zo af
fe ct
iv e
di so
rd er
, an
d sc
hi zo
ph re
ni fo
rm di
so rd
er )
F ir
st -e
pi so
de sc
hi zo
ph re
ni a
H al
op er
id ol
O la
nz ap
in e
L on
gi tu
di na
l (b
as el
in e
an d
12 ,
24 ,
52 ,
10 4
w ee
ks )
A tt
en ti
on an
d vi
gi la
nc e,
pr oc
es si
ng sp
ee d,
m ot
or fu
nc ti
on ,
ve rb
al m
em or
y an
d le
ar ni
ng ,
ve rb
al fl
ue nc
y, w
or ki
ng m
em or
y, an
d vi
su os
pa ti
al w
or ki
ng m
em or
y
C P
T -I
P ,
W A
IS -
R –d
ig it
sy m
bo l
te st
, fi
ng er
ta pp
in g,
C V
L T
, C
at eg
or y
In st
an ce
s an
d C
on tr
ol le
d O
ra l
A ss
oc ia
ti on
, L
et te
r- N
um be
r S
pa n,
W C
S T
– 64
-c ar
d, T
M T
(A an
d B
), va
ri ab
le -
in te
rv al
de la
ye d
al te
rn at
io n,
ob je
ct al
te rn
at io
n, S
C W
T ,
R uf
f de
si gn
fl ue
nc y
te st
, W
M S
R ,
B en
to n
L in
e O
ri en
ta ti
on T
es t
S ig
ni fi
ca nt
im pr
ov em
en ts
w it
h bo
th ty
pe s
of m
ed ic
at io
n in
th e
co m
po si
te sc
or e
of ne
ur oc
og ni
ti ve
te st
s D
ig it
S ym
bo l
an d
C on
ti nu
ou s
P er
fo rm
an ce
T es
t in
th e
12 th
w ee
k of
tr ea
tm en
t, w
ei gh
te d
sc or
e in
th e
12 th
an d
24 th
w ee
ks
K ee
fe ,
Y ou
ng ,
et al
. (2
00 6)
N �
41 4
(p at
ie nt
s w
it h
sc hi
zo ph
re ni
a) P
at ie
nt s
in ea
rl y-
st ag
e sc
hi zo
ph re
ni a
H al
op er
id ol
(n �
97 )
O la
nz ap
in e
(n �
15 9)
, ri
sp er
id on
e (n
� 15
8)
L on
gi tu
di na
l (b
as el
in e
an d
12 m
ot hs
)
E xe
cu ti
ve fu
nc ti
on ,
le ar
ni ng
an d
m em
or y,
pr oc
es si
ng sp
ee d,
at te
nt io
n- vi
gi la
nc e,
ve rb
al w
or ki
ng m
em or
y, ve
rb al
fl ue
nc y,
m ot
or fu
nc ti
on ,
an d
vi su
os pa
ti al
ab il
it y
R A
V L
T ,
W C
S T
– 64
-c ar
d, R
C F
T ,
W A
IS ,
C P
T -D
S ,
V er
ba l
F lu
en cy
, C
O W
A T
, G
ro ov
ed P
eg bo
ar d
(t ot
al nu
m be
r of
pe gs
)
P at
ie nt
s ab
le to
re m
ai n
in tr
ea tm
en t
fo r
th e
en ti
re 52
w ee
ks be
ne fi
te d
m or
e fr
om ol
an za
pi ne
or ri
sp er
id on
e th
an ha
lo pe
ri do
l
20 FERREIRA ET AL.
T hi
s do
cu m
en t
is co
py ri
gh te
d by
th e
A m
er ic
an P
sy ch
ol og
ic al
A ss
oc ia
ti on
or on
e of
it s
al li
ed pu
bl is
he rs
. T
hi s
ar ti
cl e
is in
te nd
ed so
le ly
fo r
th e
pe rs
on al
us e
of th
e in
di vi
du al
us er
an d
is no
t to
be di
ss em
in at
ed br
oa dl
y.
T ab
le 1
(c o n ti
n u ed
)
S tu
dy S
am pl
e
C ha
ra ct
er is
ti cs
of th
e m
ai n
sa m
pl e
T yp
ic al
dr ug
s A
ty pi
ca l
dr ug
s S
tu dy
de si
gn N
eu ro
co gn
it iv
e fu
nc ti
on s
A ss
es sm
en t
to ol
s
R es
ul ts
T yp
ic al
� at
yp ic
al A
ty pi
ca l
� ty
pi ca
l
K ra
ko w
sk i
& C
zo bo
r (2
01 1)
.
N �
82 (p
at ie
nt s
w it
h sc
hi zo
ph re
ni a
or sc
hi zo
af fe
ct iv
e di
so rd
er )
N on
cr it
ic al
pa ti
en ts
H al
op er
id ol
(n �
22 )
C lo
za pi
ne (n
� 30
), ol
an za
pi ne
(n �
30 )
L on
gi tu
di na
l (b
as el
in e
an d
12 w
ee ks
)
P sy
ch om
ot or
fu nc
ti on
, ge
ne ra
l ex
ec ut
iv e
fu nc
ti on
, vi
su al
an d
ve rb
al m
em or
y, vi
su os
pa ti
al ab
il it
y
W C
S T
– ca
te go
ri es
co m
pl et
ed ,
T M
T -B
, W
M S
-R –l
og ic
al m
em or
y an
d fi
gu ra
l m
em or
y, M
M S
E
G en
er al
co gn
it iv
e in
de x
w as
gr ea
te r
w it
h ol
an za
pi ne
th an
w it
h cl
oz ap
in e
or ha
lo pe
ri do
l. C
lo za
pi ne
: la
ng ua
ge pe
rf or
m an
ce th
an ri
sp er
id on
e L
ee et
al .
(2 00
7) N
� 16
3 (n
� 68
pa ti
en ts
w it
h sc
hi zo
ph re
ni a
an d
n �
95 co
nt ro
ls )
N on
cr it
ic al
pa ti
en ts
H al
op er
id ol
(n �
10 )
R is
pe ri
do ne
(n �
10 )
L on
gi tu
di na
l (b
as el
in e
an d
1, 2,
4, an
d 8
w ee
ks )
E xe
cu ti
ve fu
nc ti
on ,
w or
ki ng
m em
or y,
an d
vi su
os pa
ti al
sp ee
d
W C
S T
, M
az e
pa ra
di gm
s fo
r co
gn it
iv e
fu nc
ti on
pe rf
or m
an ce
W or
ki ng
m em
or y
an d
vi su
os pa
ti al
sp ee
d (M
az e
pa ra
di gm
s)
M or
re ns
et al
. (2
00 8)
N �
12 1
(n �
96 pa
ti en
ts w
it h
sc hi
zo ph
re ni
a, n
� 25
co nt
ro ls
)
C hr
on ic
pa ti
en ts
B ro
m pe
ri do
l (n
� 2)
, fl
up en
ti xo
l (n
� 1)
, ha
lo pe
ri do
l (n
� 11
), pi
m oz
id e
(n �
2) ,
zu cl
op en
th ix
ol (n
� 5)
R is
pe ri
do ne
(n �
26 ),
ol an
za pi
ne (n
� 24
), ar
ip ip
ra zo
le (n
� 1)
, am
is ul
pr id
e (n
� 8)
, qu
et ia
pi ne
(n �
5) ,
cl oz
ap in
e (n
� 11
).
T ra
ns ve
rs al
P ro
ce ss
in g
sp ee
d, ve
rb al
m em
or y,
w or
ki ng
m em
or y,
ex ec
ut iv
e fu
nc ti
on ,
an d
ps yc
ho m
ot ri
ci ty
S D
S T
, C
V L
T ,
L et
te r-
N um
be r
S eq
ue nc
in g
ta sk
, W
C S
T ,
C P
T -I
P ,
fi gu
re -c
op yi
ng ta
sk s
P sy
ch om
ot or
m ea
su re
s (fi
gu re
- co
py in
g ta
sk s)
M ül
le r
et al
. (2
00 5)
. N
� 70
(n �
43 pa
ti en
ts w
it h
sc hi
zo ph
re ni
a, n
� 27
co nt
ro ls
)
N on
cr it
ic al
pa ti
en ts
F lu
pe nt
ix ol
(n �
14 ),
ha lo
pe ri
do l
(n �
7) ,
pi m
oz id
e (n
� 1)
, le
vo m
ep ro
m az
in e
(n �
1)
C lo
za pi
ne (n
� 10
), ol
an za
pi ne
(n �
8) ,
ri sp
er id
on e
(n �
4) ,
am is
ul pr
id e
(n �
3) ,
qu et
ia pi
ne (n
� 2)
.
T ra
ns ve
rs al
W or
ki ng
m em
or y
an d
ex ec
ut iv
e fu
nc ti
on s
M C
S T
, M
W T
-A ,
ve rb
al fl
ue nc
y, di
gi t
or de
ri ng
sp an
ta sk
W or
ki ng
m em
or y
(d ig
it or
de ri
ng sp
an ta
sk )
(t a b le
co n ti
n u es
)
21ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA
T hi
s do
cu m
en t
is co
py ri
gh te
d by
th e
A m
er ic
an P
sy ch
ol og
ic al
A ss
oc ia
ti on
or on
e of
it s
al li
ed pu
bl is
he rs
. T
hi s
ar ti
cl e
is in
te nd
ed so
le ly
fo r
th e
pe rs
on al
us e
of th
e in
di vi
du al
us er
an d
is no
t to
be di
ss em
in at
ed br
oa dl
y.
T ab
le 1
(c o n ti
n u ed
)
S tu
dy S
am pl
e
C ha
ra ct
er is
ti cs
of th
e m
ai n
sa m
pl e
T yp
ic al
dr ug
s A
ty pi
ca l
dr ug
s S
tu dy
de si
gn N
eu ro
co gn
it iv
e fu
nc ti
on s
A ss
es sm
en t
to ol
s
R es
ul ts
T yp
ic al
� at
yp ic
al A
ty pi
ca l
� ty
pi ca
l
P ur
do n
et al
. (2
00 0)
N �
65 (p
at ie
nt s
w it
h sc
hi zo
ph re
ni a–
in it
ia l
st ag
e)
P at
ie nt
s in
ea rl
y- st
ag e
sc hi
zo ph
re ni
a
H al
op er
id ol
(n �
23 )
R is
pe ri
do ne
(n �
21 ),
ol an
za pi
ne (n
� 21
) L
on gi
tu di
na l
(b as
el in
e an
d 6,
30 ,
an d
54 w
ee ks
)
M ot
or sk
il ls
, at
te nt
io n,
ve rb
al an
d no
nv er
ba l
fl ue
nc y,
re as
on in
g, ex
ec ut
iv e
fu nc
ti on
s, an
d im
m ed
ia te
re ca
ll
G ro
ov ed
P eg
bo ar
d T
es t
an d
th e
F in
ge r
T ap
pi ng
T es
t, V
er ba
l an
d N
on ve
rb al
S pa
n te
st s,
W M
S -R
, C
O W
A T
, W
A IS
-R ,
D es
ig n
F lu
en cy
T es
t, H
oo pe
r V
is ua
l O
rg an
iz at
io n
T es
t, R
C F
T
O la
nz ap
in e:
G en
er al
in de
x of
co gn
it iv
e do
m ai
ns ,
no nv
er ba
l fl
ue nc
y an
d re
as on
in g
(H oo
pe r
V is
ua l
O rg
an iz
at io
n T
es t)
P ur
do n
et al
. (2
00 1)
N �
25 (p
at ie
nt s
w it
h sc
hi zo
ph re
ni a)
N on
cr it
ic al
pa ti
en ts
H al
op er
id ol
(n �
12 )
Q ue
ti ap
in e
(n �
13 )
L on
gi tu
di na
l (b
as el
in e
an d
8 an
d 54
w ee
ks )
M ot
or ab
il it
y, at
te nt
io n,
ve rb
al fl
ue nc
y an
d re
as on
in g,
vi su
os pa
ti al
in te
ll ig
en ce
, ex
ec ut
iv e
fu nc
ti on
an d
vi su
om ot
or tr
ac ki
ng ,
im m
ed ia
te re
ca ll
F in
ge r
T ap
pi ng
T es
t, G
ro ov
ed P
eg bo
ar d
T es
t, W
M S
-R ,
C O
W A
T ,
de si
gn fl
ue nc
y, V
is ua
l O
rg an
iz at
io n
T es
t, C
om pl
ex F
ig ur
e C
op y
T es
t, T
M T
(B ),
W A
IS -R
– di
gi t
sy m
bo l
te st
, W
C S
T ,
R A
V L
T ,
W M
S -R
–v is
ua l
re pr
od uc
ti on
te st
, R
ey an
d T
ay lo
r C
om pl
ex F
ig ur
e Im
m ed
ia te
R ec
al l
T es
t
V er
ba l
fl ue
nc y
an d
re as
on in
g, im
m ed
ia te
re ca
ll ,
ex ec
ut iv
e fu
nc ti
on an
d vi
su om
ot or
tr ac
ki ng
22 FERREIRA ET AL.
T hi
s do
cu m
en t
is co
py ri
gh te
d by
th e
A m
er ic
an P
sy ch
ol og
ic al
A ss
oc ia
ti on
or on
e of
it s
al li
ed pu
bl is
he rs
. T
hi s
ar ti
cl e
is in
te nd
ed so
le ly
fo r
th e
pe rs
on al
us e
of th
e in
di vi
du al
us er
an d
is no
t to
be di
ss em
in at
ed br
oa dl
y.
T ab
le 1
(c o n ti
n u ed
)
S tu
dy S
am pl
e
C ha
ra ct
er is
ti cs
of th
e m
ai n
sa m
pl e
T yp
ic al
dr ug
s A
ty pi
ca l
dr ug
s S
tu dy
de si
gn N
eu ro
co gn
it iv
e fu
nc ti
on s
A ss
es sm
en t
to ol
s
R es
ul ts
T yp
ic al
� at
yp ic
al A
ty pi
ca l
� ty
pi ca
l
P ur
do n
et al
. (2
00 3)
n �
39 (p
at ie
nt s
w it
h sc
hi zo
ph re
ni a)
P at
ie nt
s in
ea rl
y- st
ag e
sc hi
zo ph
re ni
a
H al
op er
id ol
(n �
9) R
is pe
ri do
ne (n
� 13
), ol
an za
pi ne
(n �
11 )
L on
gi tu
di na
l (b
as el
in e
54 w
ee ks
)
P ro
ce du
ra l
le ar
ni ng
T ow
er of
T or
on to
te st
S ig
ni fi
ca nt
im pr
ov em
en ts
in pe
rf or
m an
ce w
it h
bo th
ty pe
s of
m ed
ic at
io n
af te
r 6
w ee
ks of
tr ea
tm en
t O
la nz
ap in
e (a
ft er
6 m
on th
s of
tr ea
tm en
t) R
ém il
la rd
et al
. (2
00 8)
N �
46 (n
� 28
pa ti
en ts
w it
h sc
hi zo
ph re
ni a,
n �
18 co
nt ro
ls )
N on
cr it
ic al
pa ti
en ts
H al
op er
id ol
(n �
14 )
R is
pe ri
do ne
(n �
14 )
L on
gi tu
di na
l (b
as el
in e,
3, 6,
an d
12 m on
th s)
V er
ba l
m em
or y,
pr oc
es si
ng sp
ee d
C V
L T
, d2
C an
ce ll
at io
n T
es t
N o
si gn
ifi ca
nt di
ff er
en ce
s be
tw ee
n tr
ea tm
en ts
S uz
uk i,
& G
en (2
01 2)
N �
20 (p
at ie
nt s
w it
h sc
hi zo
ph re
ni a)
N on
cr it
ic al
pa ti
en ts
H al
op er
id ol
de ca
no at
e de
po t
(n �
10 )
R is
pe ri
do ne
lo ng
- ac
ti ng
in je
ct io
n (n
� 10
)
L on
gi tu
di na
l (b
as el
in e
an d
24 w
ee ks
)
E xe
cu ti
ve fu
nc ti
on ,
ve rb
al m
em or
y fu
nc ti
on .
an d
at te
nt io
n
W C
S T
(K ei
o V
er si
on ),
S T
M -C
O M
E T
M em
or y,
ex ec
ut iv
e fu
nc ti
on ,
m ot
or pr
oc es
si ng
fu nc
ti on
, an
d at
te nt
io n.
V el
li ga
n et
al .
(2 00
2) n
� 58
(p at
ie nt
s w
it h
sc hi
zo ph
re ni
a) .
N on
cr it
ic al
pa ti
en ts
. H
al op
er id
ol (n
� 15
) Q
ue ti
ap in
e (3
00 m
g- n
� 17
, 60
0m g-
n �
26 )
L on
gi tu
di na
l (b
as el
in e
an d
24 w
ee ks
).
E xe
cu ti
ve fu
nc ti
on s,
m em
or y,
at te
nt io
n.
S C
W T
, H
op ki
ns V
er ba
l L
ea rn
in g,
S ym
bo l-
di gi
t su
bs ti
tu ti
on ,
T M
T (A
e B
), P
ar ag
ra ph
re ca
ll (v
er ba
l m
em or
y) ,
V er
ba l
fl ue
nc y,
P at
te rn
m em
or y.
Q ua
ti ap
in e
(6 00
m g)
: E
xe cu
ti ve
fu nc
ti on
(v er
ba l
fl ue
nc y)
, at
te nt
io n
(S tr
oo p
C ol
or -
W or
d) an
d ve
rb al
m em
or y
(p ar
ag ra
ph re
ca ll
)
23ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA
T hi
s do
cu m
en t
is co
py ri
gh te
d by
th e
A m
er ic
an P
sy ch
ol og
ic al
A ss
oc ia
ti on
or on
e of
it s
al li
ed pu
bl is
he rs
. T
hi s
ar ti
cl e
is in
te nd
ed so
le ly
fo r
th e
pe rs
on al
us e
of th
e in
di vi
du al
us er
an d
is no
t to
be di
ss em
in at
ed br
oa dl
y.
T ab
le 1
(c o n ti
n u ed
)
S tu
dy S
am pl
e
C ha
ra ct
er is
ti cs
of th
e m
ai n
sa m
pl e
T yp
ic al
dr ug
s A
ty pi
ca l
dr ug
s S
tu dy
de si
gn N
eu ro
co gn
it iv
e fu
nc ti
on s
A ss
es sm
en t
to ol
s
R es
ul ts
T yp
ic al
� at
yp ic
al A
ty pi
ca l
� ty
pi ca
l
W it
to rf
et al
. (2
00 8)
N �
12 2
(n �
82 pa
ti en
ts w
it h
sc hi
zo ph
re ni
a, n
� 40
co nt
ro ls
)
N on
cr it
ic al
pa ti
en ts
P er
ph en
az in
e (n
� 6)
, pe
ra zi
ne (n
� 6)
, fl
up he
na zi
ne (n
� 1)
, fl
up en
ti xo
l �
cl or
pr ot
hi xe
n (n
� 1)
, ha
lo pe
ri do
l �
fl up
he na
zi ne
(n �
1) ,
pe ra
zi ne
� pr
om et
ha zi
ne �
br om
pe ri
do l
(n �
1)
O la
nz ap
in e
(n �
14 ),
cl oz
ap in
e (n
� 12
), ri
sp er
id on
e �
cl oz
ap in
e (n
� 2)
, ri
sp er
id on
e (n
� 1)
, am
is ul
pr id
e (n
� 1)
, su
lp ir
id e
(n �
1) ,
ol an
za pi
ne �
am is
ul pr
id e
(n �
1) ,
cl oz
ap in
e �
ri sp
er id
on e
� ol
an za
pi ne
(n �
1)
L on
gi tu
di na
l (b
as el
in e
an d
6 m
on th
s)
M em
or y,
at te
nt io
n, ex
ec ut
iv e
fu nc
ti on
W C
S T
, C
P T
-D S
, T
M T
(A an
d B
), W
A IS
-R –
di gi
t sy
m bo
l an
d di
gi t
sp an
, ve
rb al
fl ue
nc y,
R A
V L
T
N o
si gn
ifi ca
nt di
ff er
en ce
s be
tw ee
n tr
ea tm
en ts
N o te
. C
P T
-D S
� C
on ti
nu ou
s P
er fo
rm an
ce T
es t–
D eg
ra de
d- S
ti m
ul us
; C
P T
-I P
� C
on ti
nu ou
s P
er fo
rm an
ce T
es t–
Id en
ti ca
l P
ai rs
ve rs
io n;
C O
W A
T �
C on
tr ol
le d
O ra
l W
or d
A ss
oc ia
ti on
T es
t; C
V L
T �
C al
if or
ni a
V er
ba l
L ea
rn in
g T
es t;
D S
D T
� D
ig it
S pa
n D
is tr
ac ti
on T
es t;
M C
S T
� M
od ifi
ed ca
rd so
rt in
g te
st ;
M M
S E
� M
in i
M en
ta l
S ta
te E
xa m
in at
io n
(M in
i E
xa m
e do
E st
ad o
M en
ta l)
; M
W T
-A �
M eh
rf ac
hw or
ts ch
at zt
es t,
V er
si on
A (G
er m
an N
A R
T eq
ui va
le nt
); P
C L
� P
ro ba
bi li
st ic
C la
ss ifi
ca ti
on L
ea rn
in g;
R A
V L
T �
R ey
A ud
it or
y V
er ba
l L
ea rn
in g
T es
t; R
B A
N S
� R
ep ea
ta bl
e B
at te
ry fo
r th
e A
ss es
sm en
t of
N eu
ro ps
yc ho
lo gi
ca l
S ta
tu s;
R C
F T
� R
ey C
om pl
ex F
ig ur
e te
st ;
S C
W T
� S
tr oo
p C
ol or
W or
d T
es t;
S D
S T
� S
ym bo
l- D
ig it
S ub
st it
ut io
n T
es t;
S T
M -C
O M
E T
� S
t. M
ar ia
nn a
U ni
ve rs
it y
S ch
oo l
of M
ed ic
in e’
s C
om pu
te ri
ze d
M em
or y
T es
t; T
M T
� T
ra il
M ak
in g
T es
t; W
A IS
� W
ec hs
le r
A du
lt In
te ll
ig en
ce S
ca le
; W
C S
T �
W is
co ns
in C
ar d
S or
ti ng
T es
t; W
M S
-R �
W ec
hs le
r M
em or
y S
ca le
R ev
is ed
.
24 FERREIRA ET AL.
T hi
s do
cu m
en t
is co
py ri
gh te
d by
th e
A m
er ic
an P
sy ch
ol og
ic al
A ss
oc ia
ti on
or on
e of
it s
al li
ed pu
bl is
he rs
. T
hi s
ar ti
cl e
is in
te nd
ed so
le ly
fo r
th e
pe rs
on al
us e
of th
e in
di vi
du al
us er
an d
is no
t to
be di
ss em
in at
ed br
oa dl
y.
harmacy) of typical drugs (Hori et al., 2006) in the remediation of cognitive deficits in schizo- phrenia. However, in some cases such an ad- vantage was not evident. Keefe, Seidman, et al. (2006) found that lower doses of haloperidol produced better effects on cognitive symptoms than did the administration of olanzapine. Thornton et al. (2006), in a review article, re- ported no significant differences between typi- cal and atypical antipsychotics on long-term memory, whereas Crespo-Facorro et al. (2009) found no differences between the effects of haloperidol and those of atypical drugs (olan- zapine and risperidone) on neurocognition.
We observed that the studies reviewed had huge differences in sample size, ranging from 20 to 1,432 participants. When it came to larger samples (above 100 participants), we identified a relatively consistent pattern of the effects of typical and atypical antipsychotics on cognition. In general, both classes of antipsychotics pro- duced positive effects on visuomotor processing speed and vigilance (Harvey et al., 2005), ex- ecutive functions (Harvey et al., 2004; Suzuki & Gen, 2012), and other neurocognitive functions (Davidson et al., 2009; Guo et al., 2011; Purdon et al., 2000). In addition, atypical antipsychotics had a tendency to produce better effects on cognitive functions. Harvey et al. (2005) con- ducted a study with 506 patients and verified that patients under typical (haloperidol) and atypical (risperidone) treatment presented better episodic memory, vigilance, and visuomotor speed. However, only the group under atypical treatment presented a better performance in ex- ecutive functions and verbal fluency. In con- trast, Han et al. (2015) found that individuals taking clozapine showed worse immediate and delayed memory performance than did those taking typical antipsychotics.
Among the studies with large samples, Keefe et al. (2007) and Davidson et al. (2009) found no differences between first- and second- generation antipsychotics. Keefe et al. (2007) showed that both typical (perphenazine) and atypical (olanzapine, quetiapine, risperidone, and ziprasidone) antipsychotics produced simi- lar positive effects on neurocognitive functions. According to the authors, this result may be related to the fact that perphenazine is a mod- erate typical antipsychotic, producing minor sedative effects and extrapyramidal symptoms, a different pattern than observed with first-
generation antipsychotics such as haloperidol. Anticholinergic drugs are usually employed to attenuate extrapyramidal symptoms, but they also impair cognitive functions. Considering this fact, it is reasonable to suppose that small quantities of anticholinergic were administered concurrently with perphenazine, which may ex- plain the better cognitive performance obtained with typical treatment. Although perphenazine is not considered an atypical antipsychotic, one of its metabolites has relatively high affinity with serotonin 2A receptors, which may confer some atypical properties. Furthermore, Keefe et al. (2007) adopted inclusion criteria (e.g., al- lowing comorbidity, use of other medications, and substance abuse) that made the comparison with more-controlled studies difficult. Despite the fact that groups were not homogeneous, the study has some aspects similar to “real-world” conditions, and their results may be broadly applied. Similarly, Davidson et al. (2009) found no differences between the treatment with low doses of haloperidol and second-generation an- tipsychotics. In accordance with the previous point, the authors argued that lower doses of haloperidol are probably associated with the decrease of extrapyramidal symptoms and the use of anticholinergic medications.
In the literature, many studies have indi- cated that higher doses of first-generation an- tipsychotics can impair cognition. For exam- ple, Knowles et al. (2010), in a meta-analysis study, examined the influence of potential variables on processing speed and other spe- cific cognitive functions in schizophrenia. They found that processing speed is signifi- cantly affected by several moderating factors, such as IQ differences between case and compar- ison subjects concerning the dosage of the anti- psychotic medication. For the case of chlorprom- azine, they found a strong relationship between dosage and performance in the symbol-coding task, in which the smaller the daily doses of chlor- promazine, the lower the coding-task effect size. When they grouped the four studies with the high- est and the lowest doses values, they found an effect size of �2.04 and �1.24, respectively, in comparison with healthy controls. In such a case, one cannot rule out the possibility that, for the patients who received more chlorpromazine, the concurrent-use higher dosages of anticho- linergic medication may have contributed to the worse cognitive performance. Cognitive bene-
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fits of the atypical antipsychotic may be supe- rior for some domains of cognition and require less use of anticholinergic drugs, which impair memory, for treatment of extrapyramidal side effects (Meltzer, 2013), but even in studies showing an advantage of atypical over typical antipsychotics one cannot be sure of the mag- nitude of the impairment produced by the con- current use of antiparkinsonian medication. For example, Suzuki and Gen (2012) found that the switching from haloperidol decanoate depot to risperidone long-acting injection (RLAI) im- proved cognitive function, including memory, executive function, motor processing function, and attention. In the study, they also observed a significant reduction in the antiparkinsonian medication (biperiden) taken by the group sub- mitted to RLAI compared to the control group. Therefore, the authors concluded that “it is im- possible to rule out the possibility that the con- comitant use of anti-Parkinson’s medication may have masked changes in cognitive func- tions” (p. 475). In fact, this problem has been related in many works in literature (Leucht et al., 2009).
An important characteristic to be stressed in the selected studies is the variation in the morbidity time of schizophrenia. Some stud- ies involve assessments from the first episode of schizophrenia (Davidson et al., 2009; Har- vey et al., 2005; Keefe et al., 2004 and Keefe, Seidman, et al., 2006), which provide impor- tant information on neurocognitive deficits not associated with side effects of treatment with antipsychotics. Among such studies, only Davidson et al. (2009) reported no dif- ferences between treatment with haloperidol and atypical antipsychotics in the symptom- atic improvement of patients with schizophre- nia. Some of these studies reported that both typical and atypical antipsychotics promote improvements in neurocognitive function, with atypical antipsychotics tending to favor some specific cognitive functions, such as memory, verbal learning, and executive func- tion (Harvey et al., 2005); verbal fluency, motor function, and vigilance (Keefe et al., 2004); and processing speed and attention (Keefe, Seidman, et al., 2006).
In a different manner, other studies have evaluated chronic schizophrenia patients (Cuesta et al., 2001; Han et al., 2015; Hori et al., 2006; Keefe et al., 2007; Morrens et al., 2008).
Most of these studies indicated an advantage for atypical antipsychotics on neurocognitive func- tion (Cuesta et al., 2001; Han et al., 2015; Hori et al., 2006; Morrens et al., 2008). Only Keefe et al. (2007) found no differences among classes of antipsychotics on neurocognitive function in patients with chronic schizophrenia, which may be associated with the use of a typical antipsy- chotic (perphenazine) with characteristics simi- lar to those for atypical drugs (see earlier). Lieberman et al. (2005) reported variations in efficacy and tolerability of antipsychotic medi- cations in chronic patients, and they also found substantial limitations in the effectiveness of typical and atypical antipsychotics. Olanzapine appeared to be more effective than the other drugs studied; however, there were no signifi- cant differences between perphenazine and other atypical drugs. This variation in duration of illness chronicity makes a direct comparison between studies difficult, because there is no well-established evidence on the progression pattern of impairment in schizophrenia, which can be caused by the use of long-term medica- tion and/or by the underlying disease process (Keefe, 2008).
In order to understand the effect of different antipsychotics on cognition, recent studies have been conducted with healthy participants. For example, Veselinović et al. (2013), in a single- blind, randomized, placebo-controlled study, analyzed the subchronic effect of antidopamin- ergic treatment. They found that after a 7-day intervention, young healthy participants pre- sented impairments in processing speed, atten- tion, and learning when compared to healthy controls receiving the placebo. Differences be- tween first- (haloperidol and reserpine) and sec- ond-generation (aripiprazole) antipsychotics were not observed, but seven of the 18 patients (38.9%) submitted to the haloperidol group in- terrupted the study ahead of schedule, probably due to the side effects associated with the med- ication.
In the present review, when we analyzed the studies with smaller sample sizes, only Wittorf et al. (2008) and Rémillard et al. (2008) did not find significant differences be- tween typical and atypical drugs. According to Wittorf et al. (2008), this may be due to factors related to the sample, because they tested patients in the stabilization phase and excluded those who had to withdraw before
26 FERREIRA ET AL.
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follow-up. Thus, their results may apply only to patients who were able to recover from the disease. In addition, the sample comprised only first-episode cases.
Concerning the design of the clinical trials, we observed that most of the studies with large samples used the randomized double-blind pro- cedure (Harvey et al., 2005; Guo et al., 2011; Keefe et al., 2007, 2004), which contributes to making the study more reliable and reducing research bias.
Finally, it is important to indicate some limitations of the present review. The first one concerns the heterogeneity of the neuropsy- chological tests used and the cognitive func- tions investigated. Some studies addressed broad neurocognitive domains such as intel- ligence, whereas others focused on specific functions such as working memory. Such characteristics of the review make difficult or prevent an adequate analysis of the same cog- nitive function throughout the studies. A sug- gestion for future works is to carry out a review on the same cognitive function as- sessed by similar neurocognitive tests. Like- wise, a meta-analysis may focus on the effect size concerning the impairment of a certain cognitive function, similar to the studies by Dickinson et al. (2007) and Knowles et al. (2010) in regard to the analysis of processing speed and other specific cognitive functions in schizophrenia.
Another limitation concerns the exclusion of neuroimaging studies that could contain rele- vant evidence about the effects of different an- tipsychotics on cognition. The inclusion of those studies, however, would have made any synthesis still more complicated by the inclu- sion of additional variables, and it is our opinion that this should be the subject of another review. It is worth noting, however, that the keywords chosen allowed us to gather representative works in the literature that have directly com- pared the effects of typical and atypical antip- sychotics on neurocognitive functions in pa- tients with schizophrenia.
Our review showed that most empirical stud- ies indicated advantages of atypical over typical antipsychotics, especially regarding cognitive functions such as working memory, reasoning, attention, and verbal fluency. However, it is important to highlight that many studies indi- cated that the decrease in the dosage or an
adjustment in the type of first-generation anti- psychotic (e.g., perphenazine) may reduce ex- trapyramidal symptoms and the subsequent use of anticholinergics, thereby attenuating the cog- nitive impairments associated with their admin- istration. Those findings indicate that more re- search is needed to disentangle the negative effect produced on cognition by anticholin- ergics from other variables, such as the kind of antipsychotic prescribed.
Another important variable that may hinder comparison studies is the duration of antipsy- chotic treatment along with the follow-up eval- uation time. In some longitudinal studies, pa- tients were evaluated a few weeks after starting treatment with certain medications, for exam- ple, between 1 and 8 weeks (Lee et al., 2007). In other cases, patients were followed up for a longer time interval, such as in Keefe, Seidman, et al. (2006), where patients were evaluated at 12, 24, 52, and 104 weeks after the beginning of treatment.
Table 1 shows that the majority of studies (73.9%) used a longitudinal design for evaluat- ing neurocognitive function. The advantages and disadvantages of transverse or longitudinal designs must be considered in each case. In longitudinal studies, there is a higher dropout rate of patients and learning can influence the results during short retest intervals (Rund, 1998). Cross-sectional studies may have greater sample heterogeneity regarding the stages of the disease, chronicity, medications used, and their association with neuroleptics and anticholin- ergics, representing potential confounding vari- ables.
Despite the promising results, future re- search is required to assess the advantages and disadvantages of atypical drugs in the long term. Further systematic reviews should investigate specific cognitive functions such as working memory, attention, or verbal flu- ency, which would contribute to more- accurate results. Similarly, additional empir- ical analyses may focus on the effects of antipsychotics on specific neurocognitive functions or social cognition, for example. This line of investigation is of great impor- tance because of its potential contributions to establishing effective pharmacological treat- ments that allow the maintenance or recovery of neurocognitive functions in schizophrenia, increasing the quality of life of patients.
27ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA
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Received July 13, 2015 Revision received February 8, 2016
Accepted February 12, 2016 �
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31ANTIPSYCHOTIC DRUGS IN SCHIZOPHRENIA
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- Neurocognitive Functions in Schizophrenia: A Systematic Review of the Effects of Typical and Aty ...
- Method
- Results
- Discussion
- References
