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Meta-analysis
Second-generation antipsychotic effect on
cognition in patients with schizophrenia—
a meta-analysis of randomized clinical trials
Nielsen RE, Levander S, Kjaersdam Tell
eus G, Jensen SOW,
Østergaard Christensen T, Leucht S. Second-generation antipsychotic
effect on cognition in patients with schizophrenia—a meta-analysis of
randomized clinical trials.
Objective: To investigate the effect of second-generation antipsychotics
on cognitive function in patients diagnosed with schizophrenia or
schizoaffective disorder.
Method: Multiple-treatments meta-analysis model.
Results: On cognitive composite score, sertindole was superior to
clozapine, effect size (ES) 0.87; 95% CI: 0.12–1.63, quetiapine, ES 0.75;
95% CI: 0.00–1.49, and first-generation antipsychotics (FGAs), ES
0.89; 95% CI: 0.14–1.64. Analyses on each cognitive domain showed
clozapine, ES 0.37; 95% CI: 0.00–0.74, olanzapine, ES 0.31; 95%CI:
0.02–0.59, quetiapine, ES 0.34; 95% CI: 0.03–0.64, and FGAs, ES 0.51;
95% CI: 0.18–0.83 performing poorer on verbal working memory than
ziprasidone, as well as FGAs performing poorer than risperidone, ES
0.31; 95% CI: 0.04–0.58. On executive function, sertindole performed
better than clozapine, ES 0.82; 95% CI: 0.06–1.58, olanzapine, ES 0.81;
95% CI: 0.07–1.55, quetiapine, ES 0.76; 95% CI: 0.02–1.51,
ziprasidone, ES 0.90; 95% CI: 0.14–1.67, and FGAs, ES 0.83; 95% CI:
0.08–1.58. On processing speed, FGAs performed poorer than
sertindole, ES 0.97; 95% CI: 0.02–1.91, and quetiapine, ES 0.36; 95%
CI: 0.01–0.72. On long-term verbal working memory, clozapine
performed poorer than olanzapine, ES 0.41; 95% CI: 0.06–0.76. On
verbal fluency, FGAs performed poorer than olanzapine, ES 0.26; 95%
CI: 0.01–0.50, and clozapine, ES 0.44; 95% CI: 0.06–0.81. Lastly,
FGAs, ES 0.41; 95% CI: 0.04–0.78, and clozapine, ES 0.44; 95% CI:
0.05–0.83, performed poorer on visuospatial skill compared to
olanzapine.
Conclusion: The meta-analysis was able to detect some trends in the
data analyzed, but did not show any drug having a uniform positive
cognitive profile.
R. E. Nielsen
1
, S. Levander
2
,
G. Kjaersdam Tell
eus
1
,S.O.W.
Jensen
1
, T. Østergaard
Christensen
3
, S. Leucht
4
1
Aalborg University Hospital, Psychiatry, Aalborg,
Denmark,
2
Department of Criminology, Malmo
University, Malmo, Sweden,
3
Public Health and Quality
Improvement, Aarhus, Denmark and
4
Department of
Psychiatry and Psychotherapy, Technische Universit€
at
M€
unchen, Munich, Germany
Key words: schizophrenia; meta-analysis; antipsychotics;
cognition
Ren
e Ernst Nielsen, Unit for Psychiatric Research,
Aalborg University Hospital, Psychiatry, Mølleparkvej 10,
9000 Aalborg, Denmark. E-mail: ren@rn.dk
Accepted for publication November 7, 2014
Summations
•The meta-analysis showed decreased verbal working memory in patients treated with clozapine, ola-
nzapine, quetiapine, and FGAs compared to ziprasidone.
•Sertindole had a positive effect on executive function compared to clozapine, olanzapine, ziprasidone,
and FGAs.
•Clozapine and olanzapine had positive effects on verbal fluency.
1
Acta Psychiatr Scand 2015: 1–12 ©2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
All rights reserved
DOI: 10.1111/acps.12374 ACTA PSYCHIATRICA SCANDINAVICA
Considerations
•The results regarding sertindole were only based on a single direct comparison and all of the indirect
comparisons with haloperidol.
•No conclusions can be drawn regarding the specific effects of drug dosage in the individual patients.
Introduction
Cognitive deficits are a core feature of schizophre-
nia (1, 2). Several studies have shown deficits of
one to more than three standard deviations com-
pared to healthy controls (2). The deficits are sta-
ble over time and modestly correlated to negative
symptoms, with more severe negative symptoms
being correlated to more severe cognitive deficits;
and positive symptoms only being correlated to
cognitive deficits to a minor degree (3–5). Neuro-
cognitive deficits are linked to family disposition
and predict longitudinal functional outcome (6–8).
Data on the general effect of first-generation anti-
psychotics (FGAs) on cognition in patients with
schizophrenia are sparse, as most studies have
used haloperidol as the comparator. FGAs are
generally associated with deficits in working mem-
ory, processing speed, and motor skills, perhaps
due to a higher affinity for the dopamine D2
receptor or because anticholinergics are often used
in combination with these drugs (9). A high affin-
ity for the cholinergic and the histaminergic recep-
tors is also seen in low-potency FGAs (10), with
antagonistic cholinergic effects being correlated
with decreases in attention, memory, and execu-
tive functions (9, 11). Second-generation antipsy-
chotics (SGAs) receptor profiles are more diverse,
and the group is more heterogeneous than FGAs
(12). Early, smaller, clinical studies suggested that
SGAs could reduce cognitive impairment in
patients with schizophrenia, but newer, larger,
clinical studies have only shown modest to negligi-
ble effects in both chronic and first-episode
patients (9, 13, 14).
Current studies have not shown a uniform pat-
tern of cognitive effects of antipsychotic drug, for
patients diagnosed with schizophrenia. Several
meta-analyses, all but one, conducted as simple
pairwise meta-analyses, have tried to investigate
the effects of antipsychotic drugs on cognition in
patients diagnosed with schizophrenia (15–18).
One meta-analysis has used multiple-treatment
meta-analysis methodology, but has chosen only
to include studies with a duration of more than
6 months (19). Several large studies have been con-
ducted and results published as the latest large
meta-analysis on this topic was conducted and
published (15), making more data available for the
current analysis. In the recent years, multiple-treat-
ment meta-analysis (MTMA), also termed a net-
work meta-analysis, have increasingly been used to
investigate the effects of psychotropic drugs (20,
21), as the statistical model allows for investigation
of not only all directly compared drug—drug com-
binations, for example, head-to-head studies, but
also to investigate the effects of all indirect drug—
drug comparisons; for example, if drug A vs. B
and drug B vs. drug C have been directly com-
pared, this model can investigate the effects of drug
A vs. drug C, even when no head-to-head study
has been conducted (22).
Aims of the study
In this meta-analysis, we aim to evaluate available
data on second-generation antipsychotic drugs
published between January 1, 1980 and April 15,
2013.
Material and methods
Search strategy
We searched for relevant primary studies and/or
secondary publications (systematic reviews) in
MEDLINE, EMBASE, PsycINFO, and the Coch-
rane Central Register of Controlled Trials (CEN-
TRAL) using the keywords schizophrenia or
schizophrenic AND cognition or cognitive or neu-
rocognition or neurocognitive AND amisulpride
or aripiprazole or asenapine or blonanserin or
clozapine or iloperidone or lurasidone or mosapr-
amine or olanzapine or paliperidone or perospi-
rone or quetiapine or remoxipride or risperidone
or sertindole or ziprasidone or zotepine. In addi-
tion, the Cochrane Database of Systematic
Reviews (CDSR), the Database of Abstracts of
Reviews of Effects (DARE), and the Cochrane
Health Technology Assessment (HTA) Database
were searched for relevant secondary publications.
A handsearch of primary and secondary publica-
tion reference lists was conducted to identify fur-
ther studies.
2
Nielsen et al.
Only randomized controlled trials on humans,
diagnosed with schizophrenia or schizoaffective
disorders, published between January 1, 1980 and
April 15, 2013 were included. Studies with a dura-
tion of <8 weeks were excluded, as well as studies
on depot formulations of antipsychotics. The 8-
week minimum duration was chosen to minimize
the risk of carryover effects from previous treat-
ment and to allow for cognitive effects of the inves-
tigated drug to occur. Longer study durations have
been proposed by the MATRICS group (23). Par-
ticipants in included studies should be between the
ages of 18 and 65 years. Only head-to-head studies
of a SGA vs. another antipsychotic drug or pla-
cebo were included. Studies on combinations of
antipsychotic drugs vs. a single antipsychotic drug
or placebo were analyzed separately from the oth-
ers studies. Conference abstracts were not
included. Only studies with a neurocognitive test
were included in the meta-analysis.
Meta-analysis
Drugs were divided into FGAs or SGAs. All SGAs
were included in the meta-analysis as individual
drugs, whereas FGAs were grouped. A MTMA
was conducted with individual neurocognitive tests
being categorized as mainly measuring 1) atten-
tion, 2) executive function, 3) long-term non-verbal
memory, 4) long-term verbal memory, 5) motor
function, 6) non-verbal working memory, 7) verbal
working memory, 8) processing speed, 9) reason-
ing, 10) verbal fluency, 11) verbal IQ, 12) vigilance,
13) visuospatial skill, or none of the domains
listed. A composite score was calculated from the
listed cognitive domains, with each domain
weighted equally. The allocation of neurocognitive
tests to domains was conducted by authors GKT,
SL, and TOC, in a blinded fashion initially. Dis-
crepancies were discussed openly, in line with the
domain allocations specified in Lezak et al. (24).
The cognitive domain preferred by the majority of
the authors listed was chosen, if consensus could
not be reached. We preferred this approach, in
contrast to the MATRICS suggestions (25), for
two reasons: many studies were performed before
2004, and the Lezak approach is more general
being based on all kinds of tests and data from the
1930s and forward.
The chosen measure of effect was Cohen’s d
using the pooled standard deviation as a denomi-
nator. Effect sizes and the corresponding standard
errors were calculated for all the included studies.
We furthermore adjusted the effect size due to Co-
hen’s d being upwardly biased when based on
small samples.
To ensure a unidirectional interpretation of the
effect sizes, we recoded those measures where an
increasing score equaled worsening such that a
positive value of Cohen’s d indicated improve-
ment.
When studies reported multiple measures of the
same cognitive domain, an average effect size was
computed to ensure that the studies were given the
same weight in the subsequent analyses.
The meta-analyses were then performed for each
of the two groups using a random effects regres-
sion model where effect size was entered as the
dependent variable and the drug categories as
explanatory variables. The standard error of effect
size was also entered into the model as the estimate
of within study variance. In addition to the
MTMA, a simple pairwise meta-analysis of all
studies was conducted, which is available upon
request from the corresponding author.
If data for the meta-analysis were not readily
available in the published studies, the correspond-
ing author was contacted to request the missing
data.
Confounder analysis
We conducted linear regression analyses to investi-
gate the association between the effect size and
publication year, sample size, study duration,
duration of illness, sponsorship of study and blind-
ing. Univariate analyses were performed for each
of the mentioned variables, and subsequently, a
multivariate analysis was performed. In these
regression analyses, we excluded two studies as
they were deemed outliers. The assumptions
underlying the linear regression were investigated
by visual inspection of residual plots. These analy-
ses are available upon request from the corre-
sponding author.
Exploration of publication bias
Publication bias might occur in a meta-analytic
review. To investigate this, we obtained funnel
plots to detect publication bias in meta-analysis
(26). We assessed the symmetry of the funnel plots
and found two studies to be outliers. As variation
from the symmetric funnel can be sign of publica-
tion bias, these studies were excluded.
Consistency of meta-analyses
We conducted both simple pairwise meta-analyses,
analyses which are available if requested from the
corresponding author, and MTMA with similar
results. One of the main assumptions behind a
3
SGAs effect on cognition
MTMA is that the analyzed network is coherent
and that the direct and indirect comparisons do
not disagree beyond chance. Inconsistency was
evaluated by calculating and examining confidence
intervals of the difference between direct and indi-
rect estimates.
The analyses were carried out in Stata 11, and
the chosen level of significance was 5%.
Results
A total of 5854 possible studies were identified
through the initial search. By screening of study
title, a large portion of studies could be excluded
due to several reasons, for example, studies not
investigating cognition as an outcome measure,
studies on other patient groups, other age groups,
short study duration, studies with non-randomized
design, studies on animals, and studies on other
drugs than antipsychotics. A total of 229 studies
were read and evaluated for the meta-analyses,
and a total of 51 studies fulfilled all criteria for
inclusion in the meta-analyses. Not all studies
reported the necessary data to calculate effects
sizes, and first authors of these studies were con-
tacted regarding missing data, resulting in further
14 studies being excluded due to lack of data, as
shown in Fig. 1.
Thirty-seven studies with 3526 patients were
included in the two meta-analyses, with three stud-
ies investigating the effects of augmenting cloza-
pine with a second antipsychotic (146 patients).
The mean duration of all studies was 23.6 weeks,
95% CI (17.7–29.5) weeks. The average age for
patients included in the meta-analyses was
35.4 years, 95% CI (33.1–37.8) years, and the
mean duration of illness was 10.6 years, 95% CI
(8.0–13.3) years. The included studies are listed in
bold in Table 1.
The most investigated drug in the MTMA on
non-clozapine augmentation was olanzapine
(n=970), followed by risperidone (n=894), que-
tiapine (n=514), clozapine (n=238), ziprasidone
(n=206), amisulpride (n=92), perospirone (n=
18), and sertindole (n=17). FGAs were used
as comparator drugs in 354 patients. No studies
with asenapine, blonanserin, iloperidone, lurasi-
done, mosapramine, paliperidone, perospirone,
remoxipride, and zotepine were included in the
meta-analyses.
Initial allocation of cognitive tests to cognitive
domains resulted in total agreement on 38.0% of
neurocognitive tests, remaining tests were dis-
cussed openly, and consensus was reached on all
tests allocated to cognitive domains. The alloca-
tion of cognitive tests to domains can be requested
from the corresponding author.
We administered Begg’s plot and Egger’s test to
investigate potential publication bias in our data-
set, and the funnel plot found two outliers. These
were excluded from further analyses. Egger’s test
showed no significant publication bias, P=0.272,
after excluding outliers.
Second, we conducted a confounder analysis to
investigate the effects of publication year, duration
of illness, study duration, gender, sponsorship of
study, blinding, and number of patients and found
no significant influences on outcome. The analyses
can be requested from the corresponding author.
Our analyses on antipsychotic monotherapy did
not show any significant differences on the cogni-
tive composite score when comparing all SGA
drugs to each other and to a group of FGAs,
except for sertindole being superior to clozapine
with an effect size (ES) of 0.87; 95% CI: 0.12–1.63,
quetiapine, ES 0.75; 95% CI: 0.00–1.49, and
FGAs, ES -0.89; 95% CI: -1.64–(-0.14), as shown
in Table 2.
The analyses on each cognitive domain are
shown in Table 3, where we found clozapine, ES
0.37; 95% CI: 0.00–0.74, olanzapine, ES 0.31; 95%
CI: 0.02–0.59, quetiapine, ES 0.34; 95% CI: 0.03–
0.64, and FGAs, ES 0.51; 95% CI: 0.18–0.83 per-
forming poorer on verbal working memory than
ziprasidone, as well as FGAs performing poorer
on verbal working memory as compared to risperi-
done, ES 0.31, 95% CI: 0.04–0.58. Examination of
executive function showed sertindole performing
better than clozapine, ES 0.82; 95% CI: 0.06–1.58,
olanzapine, ES 0.81; 95% CI: 0.07–1.55, quetia-
pine, ES 0.76, 95% CI: 0.02–1.51, ziprasidone, ES
0.90; 95% CI: 0.14–1.67, and FGAs, ES 0.83; 95%
CI: 0.08–1.58. On processing speed, FGAs per-
formed poorer than sertindole, ES 0.97; 95% CI:
0.02–1.91, and quetiapine, ES 0.36; 95% CI: 0.01–
0.72. On long-term verbal working memory,
patients treated with clozapine performed poorer
than those treated with olanzapine, ES 0.41; 95%
CI: 0.06–0.76. On verbal fluency, FGAs performed
poorer than olanzapine, ES 0.26; 95% CI: 0.01–
0.50, and clozapine, ES 0.44; 95% CI: 0.06–0.81.
Lastly, FGAs performed poorer on visuospatial
skill compared to olanzapine, ES 0.41; 95% CI:
0.04–0.78, as well as olanzapine patients perform-
ing better as compared to clozapine, ES 0.44; 95%
CI: 0.05–0.83. We did not find any other significant
differences between any of the investigated drugs
as shown in Table 3.
Our analyses showed no significant effect of
adjunctive treatment with SGAs to clozapine
4
Nielsen et al.
utilizing a cognitive composite score as shown in
Table 2.
The simple pairwise meta-analysis with only
direct comparisons did not show any significant
differences between any of the drugs investigated
on the composite score. On attention, motor func-
tion, reasoning, processing speed, and long-term
verbal memory, results were similar between the
simple pairwise and MTMA. The simple pairwise
meta-analysis found no differences between any of
the drugs compared directly on verbal fluency, but
the MTMA found clozapine and olanzapine to be
superior as compared to FGAs. On verbal working
memory, the simple pairwise analysis showed a
superior effect of risperidone compared to quetia-
pine, but with confidence intervals close to zero.
On the visuospatial domain, both analyses showed
a superior effect of olanzapine as compared to
clozapine, but the MTMA was the only one to find
a superior effect of olanzapine as compared to
FGAs. Finally, both analyses found olanzapine to
be superior to clozapine in long-term verbal mem-
ory, but only the simple pairwise meta-analysis
found risperidone to be superior to clozapine on
the same cognitive domain. Forest plots are avail-
able by request from the corresponding author,
and a network plot of all direct comparisons is
shown in Fig. 2. To estimate differences between
the direct comparisons in the simple pairwise
meta-analysis and the both direct and indirect
comparisons in the MTMA, we conducted an
analysis of consistency showing our data to be con-
sistent. All analyses regarding consistency are
available by request from the corresponding
author.
Discussion
The meta-analyses on composite cognitive score
did not show any general differences between
Citations retrieved from
bibliographic databases:
n= 5,854
Non-relevant citations:
n = 5,625
Excluded with reasons: n= 178
Excluded due to:
Published abstract: n= 32
Age: n= 12
Data published before: n= 6
Design: n= 99
Diagnosis: n= 5
Duration: n= 23
Non-human: n= 1
Full-text publication
retrieved for more detailed
evaluation:
n= 229
Overall number of meeting
inclusion criteria:
n= 51
Relevant articles identified
by handsearch:
n= 0
Overall number of studies
included in meta-analyses:
n= 35
Excluded due to missing data:
n= 14
Excluded due to bias analysis:
n= 2
Fig. 1. Flowchart: Study selection.
5
SGAs effect on cognition
SGAs and FGAs, except for the findings of sertin-
dole’s superior effects compared to clozapine, que-
tiapine, and FGAs, which were primarily driven by
a single smaller study (76), but due to the MTMA
model also driven by indirect comparisons from
studies with haloperidol as a comparator.
On the verbal working memory domain cloza-
pine, olanzapine, quetiapine, and FGAs did
poorer than ziprasidone, and FGAs did poorer
than risperidone. The main features shared by
clozapine, olanzapine, and quetiapine are a low
affinity for the dopaminergic receptor, as well as a
Table 1. Studies full-filling criteria to be included in the meta-analyses
Author Year Drug Duration (weeks) N
included
N
baseline
N
in meta-analysis
Abdolahian et al.* (27) 2008 Risperidone, haloperidol 8 65 65 65
Bellack et al. (28) 2004 Clozapine, risperidone 29 107 65 22
Bender et al. (29) 2006 Clozapine, olanzapine 26 54 54 31
Bilder et al. (30) 2002 Clozapine, olanzapine, risperidone, haloperidol 14 101 101 101
Boulay et al. (31) 2007 Olanzapine, haloperidol 8 27 27
Buchanan et al. (32) 1994 Clozapine, haloperidol 10 38 38 38
Davidson et al. (14) 2009 Amisulpride, quetiapine, ziprasidone, haloperidol 26 498 286 320
Fagerlund et al. (33) 2004 Risperidone, zuclopenthixol 13 31 25
Gallhofer et al. (34) 2007 Sertindole, haloperidol 12 40 34 32
Goldberg et al. (35) 2007 Olanzapine, risperidone 16 104 104
Green et al. (36) 1997 Risperidone, haloperidol 8 59 59
Green et al. (37) 2002 Risperidone, haloperidol 26 62 62
Grootens et al. (38) 2010 Olanzapine, ziprasidone 24 74 74
Gurpegui et al. (39) 2007 Olanzapine, risperidone 48 235 235 163
Harvey et al. (40) 2008 Clozapine, ziprasidone 12 130 130 100
Harvey et al. (41) 2003 Olanzapine, risperidone 8 377 377 267
Harvey et al. (42) 2006 Olanzapine, ziprasidone 26 133 72 72
Harvey et al. (43) 2006 Quetiapine, risperidone 8 673 289 289
Honer et al. (44) 2006 Clozapine + risperidone or clozapine + placebo 8 68 68 65
Jerrell et al. (45) 2008 Olanzapine, risperidone, typical antipsychotic drugs 52 108 108 108
Keefe et al. (46) 2006 Olanzapine, risperidone, haloperidol 52 414 414
Keefe et al. (47) 2007 Olanzapine, quetiapine, risperidone 52 400 400 81
Keefe et al. (13) 2007 Olanzapine, quetiapine, risperidone, ziprasidone, perphenazine 78 1460 1460 128
Kern et al. (48) 2006 Aripiprazole, olanzapine 26 169 169
Krakowski et al. (49) 2008 Clozapine, olanzapine, haloperidol 12 100 101 100
Lee et al. (50) 1994 Clozapine, typical antipsychotic drugs 52 59 47
Lee et al. (51) 1999 Clozapine, typical antipsychotic drugs 52 64 64 52
Lee et al. (52) 2007 Risperidone, haloperidol 8 20 20 20
Lindenmayer et al. (53) 2007 Olanzapine, haloperidol 12 35 35 33
Ljubin et al. (54) 2000 Olanzapine, fluphenazine 22 18 18 18
McGurk et al. (55) 2005 Clozapine, risperidone 29 97 97 35
Meltzer et al. (56) 2008 Clozapine, olanzapine 26 40 40 24
Mori et al. (57) 2004 Olanzapine, perospirone, quetiapine, risperidone 12 77 77 77
Mortimer et al. (58) 2007 Amisulpride, olanzapine 26 26 26 18
Muscatello et al. (59) 2011 Aripiprazole + clozapine or placebo + clozapine 24 40 31 31
Nielsen et al. (60) 2012 Clozapine + sertindole or clozapine + placebo 12 50 50 50
Purdon et al. (61) 2000 Olanzapine, risperidone, haloperidol 54 65 65 65
Purdon et al. (62) 2001 Quetiapine, haloperidol 26 25 25 25
Remillard et al. (63) 2005 Risperidone, haloperidol 52 31 31
Remillard et al. (64) 2008 Risperidone. Haloperidol 52 28 28
Remillard et al. (65) 2010 Risperidone, haloperidol 52 26 26
Riedel et al. (66) 2007 Olanzapine, quetiapine 8 52 33 33
Riedel et al. (67) 2006 Quetiapine, risperidone 12 44 44 34
Rosenheck et al. (68) 2003 Olanzapine, haloperidol 52 309 309
Sergi et al. (69) 2007 Olanzapine, risperidone, haloperidol 8 100 77 73
Smith et al. (70) 2001 Olanzapine, haloperidol 21 45 45 29
Van Veelen et al. (71) 2010 Olanzapine, ziprasidone 8 74 74 56
Velligan et al. (72) 2002 Quetiapine, haloperidol 24 58 58 34
Velligan et al. (73) 2003 Quetiapine, typical antipsychotic drugs 26 40 40
Voruganti et al.* (74) 2007 Olanzapine, quetiapine 52 86 85 85
Wagner et al. (75) 2005 Amisulpride, olanzapine 8 52 36 36
Studies highlighted in bold are included in the first meta-analysis of the effects of atypical antipsychotic treatment. Studies highlighted with bold and underlined are included in
the second meta-analysis on the effects of using atypical antipsychotic drugs as adjunctive treatment to clozapine.
Year, year of publication.
*Studies excluded from the meta-analyses, as funnel plots found results were outliers.
6
Nielsen et al.
relatively high affinity for the cholinergic receptor
(12). The FGAs used as comparator drugs are
primarily haloperidol and perphenazine, with a
moderate to high affinity for the dopaminergic
receptor system and a low to moderate affinity for
the muscarinergic receptor system (10). Many of
the studies included allowed treatment with anti-
cholinergics in patients treated with FGAs, if EPS
occurred, thereby exposing patients to a high
degree of antagonism on the muscarinergic recep-
tors. The use of anticholinergic drugs was not
described in all studies. Studies have shown the
muscarinergic receptor system being implicated
with cognitive function (11, 13, 77–79), with
antagonizing drugs worsening symptoms and
drugs with agonizing effects improving function in
attention and working memory domains (11, 80–
83). By comparison, ziprasidone is characterized
by a relatively low affinity for the muscarinergic
receptor system. Finally, the superior effect of ris-
peridone to FGAs could perhaps be explained by
a greater use of anticholinergics in patients treated
with FGAs, a hypothesis we cannot investigate, as
all direct comparisons between risperidone and
FGAs do not report the use of anticholinergic
drugs.
Sertindole showed superiority compared to
clozapine, olanzapine, ziprasidone, and FGAs on
executive functions, primarily driven by the results
of a single study (76), but also indirectly by all
studies using haloperidol as a comparator drug via
the MTMA. Animal studies have shown remitting
effects of sertindole on phencyclidine (PCP)-
induced executive function deficits, as well as sug-
gested the 5-HT
6
affinity of sertindole as a possible
mechanism of action (84–86), possibly explaining
our findings.
In regard to processing speed, both sertindole
and quetiapine performed better than FGAs. The
receptor profiles of sertindole and quetiapine are
not similar, as quetiapine is characterized by a low
affinity for the dopamine D2 receptor and a high
affinity for both the muscarinergic and histaminer-
gic receptors as opposed to sertindole (12). They
do share the same high affinity for the adrenergic
receptor, but this receptor affinity is also seen in
especially clozapine, which does not improve pro-
cessing speed (12).
Our finding of verbal fluency improvement in
patients treated with clozapine or olanzapine as
compared to FGAs could be suggestive of low
dopaminergic affinity being correlated to verbal
fluency, especially as quetiapine shows a trend
toward similar findings. No studies have examined
this in patients diagnosed with schizophrenia, but
low dopaminergic states have been associated with
decreased verbal fluency in patients diagnosed with
Parkinson’s disease (87).
Table 2. Effect sizes and confidence intervals for cognitive composite scores
Amis Arip
(Cloz)
-0.14 Cloz 0.07 Placebo
-0.49; 0.21 -1.58; 1.72 (Cloz)
0.02 0.16 Olan -0.25 -0.32 Risp
-0.29; 0.33 -
0.05; 0.37 -2.09; 1.59 -
1.59; 0.95 (Cloz)
0.07 0.21 0.05 Pero -0.14 -0.22 0.11 Sert
-0.66; 0.80 -0.48; 0.90 -0.62; 0. 73 -2.08; 1.79 -1.62; 1.19 -1.51; 1.72 (Cloz)
-0.01 0.13 -0.03 -
0.08 Quet
-0.34; 0.32 -0.11; 0.37 -0.21; 0.15 -0.77; 0.60
0.01 0.15 -0.01 -0.06 0.02 Risp
-0.30; 0.33 -0.06; 0.36 -0.16; 0.14 -0.74; 0.61 -
0.16; 0.21
0.74 0.87 0.72 0.66 0.75 0.72 Sert
-0.05; 1.52 0.12; 1.63 -0.02; 1.45 -0.33; 1.65 0.00; 1.49 -0 .01; 1.46
0.00 0.13 -0.02 -0.08 0.01 -0.02 -0.74 Zipr
-0.36; 0.36 -0.14; 0.41 -0.25; 0.20 -0.78; 0.62 -
0.25; 0.26 -0.25; 0.21 -1.50 ; 0.02
-0.16 -0.02 -0.18 -0.23 -0.15 -0.17 -0.89 -0.15 FGA
-0.49; 0.18 -0.26; 0.23 -0.36; 0.01 -0.92; 0.46 -
0.36; 0.07 -0.36; 0.03 -1.64; -0. 14 -0.41; 0.11
Adjunctive treatment to clozapine is shown on the right. The column headings correspond to the respective reference group. Significant values are in white font color and black fill
in.
Amis, amisulpride; Cloz, clozapine; Olan, olanzapine; Pero, perospirone; Quet, quetiapine; Risp, risperidone; Sert, sertindole; Zipr, ziprasidone; FGA, first-generation antipsychotic.
7
SGAs effect on cognition
The findings on long-term verbal memory and
visuospatial skill seem less uniform, and no obvi-
ous explanation is apparent for these findings.
Contrary to our expectations, we did not find
any significant differences on motor function
between any of the FGAs and SGAs investigated,
probably as a consequence of comedication with
anticholinergic drugs, and some studies using low
dose FGA treatment.
Newer studies suggest an association between
antipsychotic high dosage or polypharmaceutical
treatment and cognitive impairment, with
improved cognitive function after dose reduction
(88, 89). In the meta-analysis of adjunctive treat-
ment to clozapine with another antipsychotic drug,
we are unable to show any differential effect on
cognition between the groups treated with two
antipsychotic drugs compared to the groups only
treated with clozapine, but the study population is
small and highly selected due to the primary treat-
ment with clozapine. In the main meta-analysis of
non-adjunctively treated patients, most studies
have been conducted with a variable dosage para-
digm, with patients being treated with the optimum
dosage defined by effects and side-effects, making
an investigation of possible drug dose-dependent
cognitive effects impossible. Mean drug dosages
and drug ranges can available by request from the
corresponding author.
Several meta-analyses have previously been con-
ducted on the effects of FGAs and SGAs on cogni-
tion in patients diagnosed with schizophrenia (15–
19). However, the current meta-analysis is the larg-
est conducted to date on the cognitive effects anti-
psychotic drugs, including 18 studies published in
2007 and onwards. Furthermore, the current meta-
analysis is the first to include all SGAs and to com-
pare them directly and indirectly to each other uti-
lizing a MTMA (22). Other meta-analyses have
used predefined cognitive domains with accompa-
nying cognitive tests, thereby excluding a portion
of the cognitive tests utilized in the studies (15, 16),
contrary to this meta-analysis where all cognitive
tests have been included and categorized under
specific predefined domains, as also done by Keefe
et al. and Mishara et al. (17, 18).
Generally, in meta-analyses, a high degree of
homogeneity is needed, as data are pooled from
several different studies into a single analysis. In
MTMA, this is even more so needed, as both direct
and indirect comparisons are conducted. In a
meta-analysis, there is a risk of the included studies
Table 3. Effect sizes and confidence intervals for cognitive domain scores
VERBAL WORKING MEMORYLONGTERMVERBALWORKINGMEMORY
ATTENTION
Amis -0.04 0.02 0.02 -0.01 0.13 0.33 -0.18
VERBAL FLUENCY
Amis
-0.48; 0.39 -0.35; 0.39 -
0.76; 0.80 -
0.39; 0.37 -0.25; 0.51 -0.09; 0.74 -0.57; 0.22
Cloz 0.06 0.06 0.03 0.17 0.37 -0.14 0.19 Cloz 0. 41 0.32 0.32 0.20 0.34
-0.25; 0.37 -
0.69; 0.81 -0.29; 0.36 -0.14; 0.49 0.00; 0.74 -0.48; 0.21 -0.46; 0.83 0.06; 0.76 -0. 10; 0.74 -0.04; 0.69 -0.31; 0.71 -0.05; 0.73
0.13 Olan 0.00 -0.03 0.11 0.31 -0.20 0.00 -0.18 Olan -0.09 -0.09 -0.21 -0.07
-0.63; 0.90 -0.71; 0.72 -0.26; 0.20 -0.11; 0.34 0.02; 0.59 -0.45; 0.06 -0.57; 0.58 -0.52; 0.16 -0. 40; 0.22 -0.32; 0.15 -0.63; 0.21 -0.35; 0.20
Pero -0.03 0.11 0.31 -0.20 0.00 -0.19 -0.01 Quet 0.00 -0.12 0.02
-0.75; 0.69 -0.61; 0.83 -0.43; 1.05 -0.93; 0.53 -0.60; 0.59 -0.55; 0.17 -0.24 ; 0.23 -0.32; 0.33 -0.60; 0. 36 -0.34; 0.38
-0.01 -0.14 Quet 0.14 0.34 -0.17 -0.07 -0.25 -0.07 -0.06 Risp -0.12 0.01
-0.79; 0.78 -0.45;0.17 -0.10; 0.39 0.03; 0.6 4 -0 .44; 0.11 -0.64; 0.51 -0.59; 0.08 -0.26; 0.12 -0.29; 0.17 -0.56; 0.31 -0.27; 0.30
0.10 -0.03 0.11 Risp 0.20 -0.31 0.04 -0.14 0.04 0.04 0.11 Zipr 0.14
-0.66; 0.86 -0.27; 0.21 -0.19; 0.41 -0.10; 0.49 -0.58; -0.04 -0.62; 0.71 -0.62; 0.33 -0.34; 0.42 -0.36; 0.44 -0.27; 0.48 -0.32 ; 0.60
0.16 0.03 0.17 0.06 Zipr -0.51 -0.25 -0.44 -0.26 -0.25 -0.19 -
0.29 FGA
-0.80; 1.13 -0.61; 0.67 -0.50; 0.83 -0.58; 0.70 -0.83; -0.18 -0.85; 0.35 -0.81; -0.06 -0.50 ; -0.01 -0.53; 0.03 -0.43; 0.06 -0.70; 0.12
-0.03 -0.16 -0.02 -0.13 -0.19 FGA
-1.00; 0.95 -0.82; 0.49 -0.70; 0.66 -0.78; 0.52 -1.07;0.69 VISUO - SPATIAL SKILL
MOTOR FUNCTION
Amis -0.26 0.18 0.03 0.01 -0.23
PROCESSING SPEED -1.02;0.50 -0.58; 0. 94 -1.07; 1.13 -0.83; 0.85 -0.99; 0.52
EXECUTIVE FUNCTION
Amis -0.24 -0.07 0.05 -0.16 0.65 -0.31 -0.32 0.48 Cloz 0.44 0.29 0.27 0.03
-0.81; 0.34 -0.56; 0.43 -0.49; 0.58 -0.67; 0.36 -0.38; 1.67 -0.86; 0.25 -0.84; 0.20 -0.25;1.21 0.05; 0.83 -0.59 ; 1.17 -0.25; 0.79 -0.34;0.40
-0.14 Cloz 0.17 0.28 0.08 0. 88 -0.07 -0.08 0.04 -0.44 Olan -0.15 -0.17 -0.41
-0.50; 0.23 -0.21; 0.54 -0.15; 0.71 -0.32; 0.48 -0.09;1.86 -0.53; 0.39 -0.50; 0.33 -0.39;0.47 -1.10; 0.22 -1.03; 0.73 -0.69 ; 0.35 -0.78; -0.04
-0.13 0.01 Olan 0.11 -
0.09 0.72 -0.24 -0.25 -0.02 -0.49 -0.06 Quet -0.02 -0.26
-0.44; 0.19 -
0.23; 0.25 -0.20; 0.43 -0.36; 0.19 -0.21; 1.65 -0.59;0.12 -0.54;0.04 -0.48; 0.45 -1.18;0.19 -0.40; 0.29 -0.97;0.93 -1.14; 0.61
-0.08 0.05 0.04 Quet -0.20 0.60 -
0.35 -0.03 -0.50 -0.07 -0.01 Risp -0.24
-0.42; 0.25 -0.21; 0.32 -
0.15; 0.24 -0.54; 0.14 -0.35; 1.55 -0.76; 0.06 -0.49; 0.44 -
1.19; 0.18 -0.41; 0.27 -0.40; 0.38 -0.75; 0.26
-0.06 0.08 0.07 0.03 Risp 0.80 -0. 15 -0.16 -0.04 -0.52 -0.08 -0.02 -0.01 Zipr
-0.38; 0.26 -0.16; 0.32 -0.09; 0.23 -0.17;0.22 -0. 13; 1.74 -0.53; 0.23 -0.48; 0.16 -0.62; 0.54 -1.28; 0.25 -0.57; 0.41 -0.55; 0.50 -0.53; 0.51
0.68 0.82 0.81 0.76 0.74 Sert -0.96 0.00 -0.47 -0.04 0.02 0.03 0.04 FGA
-0.11; 1.47 0.06; 1.58 0.07; 1.55 0.02; 1.51 -0. 00; 1.48 -1.92; 0.01 -0.45; 0.45 -1.15; 0.20 -0.36;0. 28 -0.35; 0.39 -0.34; 0.40 -0.47;0.55
-0.22 -0.09 -0.10 -0.14 -0.17 -0.90 Zipr -0.01
-0.59; 0.15 -0.39; 0.22 -0.34; 0.15 -0.41; 0.13 -0.42; 0.08 -1.67; -0.14 -0.41; 0. 38 LONG TERM NON -VERBAL
-0.15 -0.01 -0.02 -0.06 -0.09 -0.83 0.08 FGA
REASONING
Cloz 0.10 0.41 0.03 -0.12
-0.49; 0.20 -0.28; 0.26 -
0.22; 0.18 -0.30; 0.17 -
0.30; 0.12 -1.58; -0.08 -0. 20; 0.36 -0.49;0.68 -0. 26; 1.08 -0.60; 0.66 -0.73;0.48
Olan 0.32 -0.07 -0.22
-0.25; 0.89 -0.59; 0.46 -0.71; 0.27
0.20 Quet -0.38 -0.54
-0.50;0.90 -1.00 ; 0.23 -1.12; 0.05
0.10 -0.10 Ri sp -0.15
-0.53;0. 73 -0.8 5; 0.64 -0.69; 0.39
0.25 0.04 0.15 Zipr
-0.50;0.99 -0.80; 0.89 -0.64; 0.94
0.25 0.05 0.15 0.00 FGA
-0.43;0.92 -0.73; 0.83 -0.57; 0.87 -0.82; 0.82
-0.36
-0.72; -0.01
-0.97
-1.91; -0.02
The column headings correspond to the respective reference group. Significant values are in white font color and black fill in.
Amis, amisulpride; Cloz, clozapine; Olan, olanzapine; Pero, perospirone; Quet, quetiapine; Risp, risperidone; Sert, sertindole; Zipr, ziprasidone; FGA, first-generation antipsychotic.
8
Nielsen et al.
being too heterogeneous, making the interpreta-
tion of results hard or even impossible. With the
criteria used for inclusion of studies, we have tried
to diminish the heterogeneousity, without being
too restrictive, and thereby excluding too many
studies. In the current meta-analysis, the inclusion
criteria used have ensured inclusion of well-
designed studies only, for example, randomization,
diagnosis, and duration of study, thereby increas-
ing homogeneity of the studies. We have chosen to
include newly diagnosed, more chronically ill, and
even treatment-resistant patients diagnosed with
schizophrenia or schizoaffective disorder and
investigated the effects in the sensitivity analyses.
Optimally, investigation of, for example, duration
of untreated psychosis, previous treatment, and
effects of low- or high-dose treatment would have
been included in the sensitivity analyses, but most
of the included studies have not reported these
data, and we have only been able to investigate the
effects of associations between the effect size and
publication year, sample size, study duration,
duration of illness, sponsorship of study and
blinding.
The allocation of cognitive tests to cognitive
domains was carried out by three experienced clini-
cians with both clinical and research experience
with cognitive testing. The initial allocation of tests
to domains was carried out blinded and resulted in
a 38% agreement on tests to domains between the
raters, which could seem low. The reason for these
results is that cognitive tests do not measure a sin-
gle cognitive domain, but always measures several
domains, with a single domain dominating the test.
After the initial blinded allocation of cognitive
tests to domains, the remaining tests were dis-
cussed openly, and total agreement was reached by
the three raters.
The meta-analysis was able to detect some
trends in the data analyzed, suggesting a decreased
verbal working memory in patients treated with
clozapine, olanzapine, quetiapine, and FGAs com-
pared to ziprasidone and a positive effect of sertin-
dole on executive function compared to clozapine,
olanzapine, ziprasidone, and FGAs, as well as a
possible positive effect of clozapine and olanzapine
on verbal fluency.
Acknowledgements
None.
Declaration of interest
All expenses toward the authors’ salaries were paid by the
affiliated institutions. Expenses for retrieval of manuscripts
were covered by the Unit of Psychiatric Research, Aalborg
Psychiatric Hospital, Aalborg University Hospital, Aalborg,
Denmark.
Amisulpride
Clozapine
Quetiapine
Sertindole
Ziprasidone
FGA
Risperidone Olanzapine
Perospirone
Fig. 2. Network plot of direct comparisons between non-augmented studies. Thicknesses of lines symbolize number of studies on
each direct comparison, and size of node symbolizes number of participants for each drug.
9
SGAs effect on cognition
R. E. Nielsen has received research grants from H. Lund-
beck for clinical trials, received speaking fees from Bristol-
Myers Squibb, Astra Zeneca, Janssen & Cilag, Lundbeck,
Servier, Otsuka Pharmaceuticals, and Eli Lilly and has acted
as advisor to Astra Zeneca, Eli Lilly, Lundbeck, Otsuka Phar-
maceuticals, Takeda, and Medivir.
S. Leucht has received honoraria for consulting/advisory
boards from Alkermes, Bristol-Myers Squibb, Eli Lilly, Jans-
sen & Cilag, Johnson & Johnson, Lundbeck, MedAvante,
Roche; has received lecture honoraria from Astra Zeneca, Bris-
tol-Myers Squibb, Eli Lilly, Essex Pharma, Janssen & Cilag,
Johnson & Johnson, Lundbeck, Pfizer, Sanofi-Aventis, and Eli
Lilly; and has provided medication for a trial with SL as the
primary investigator.
S. Levander, G. Kjærsdam Tell
eus, S. Olrik Wallenstein
Jensen, and T. Østergaard Christensen have nothing to
declare.
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