Journal of Clinical and Experimental Neuropsychology

ISSN: 1380-3395 (Print) 1744-411X (Online) Journal homepage: http://www.tandfonline.com/loi/ncen20

Comparing the effect of the subcategories of

atypical antipsychotic medications on cognition in
schizophrenia using a meta-analytic approach

Maverick Clissold & Simon F. Crowe

To cite this article: Maverick Clissold & Simon F. Crowe (2018): Comparing the effect of
the subcategories of atypical antipsychotic medications on cognition in schizophrenia using
a meta-analytic approach, Journal of Clinical and Experimental Neuropsychology, DOI:
10.1080/13803395.2018.1488952

To link to this article: https://doi.org/10.1080/13803395.2018.1488952

Published online: 20 Jul 2018.

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JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY
https://doi.org/10.1080/13803395.2018.1488952

Comparing the effect of the subcategories of atypical antipsychotic medications

on cognition in schizophrenia using a meta-analytic approach
Maverick Clissold and Simon F. Crowe
School of Psychology and Public Health, La Trobe University, Bundoora, VIC, Australia

ABSTRACT ARTICLE HISTORY

Objectives: The aim of this study was to compare the two most commonly prescribed classes of Received 25 September 2016
Accepted 9 June 2018
atypical antipsychotic medications (i.e., -pines and -dones) with regard to their effects on cogni-
tion in patients with schizophrenia. KEYWORDS
Data sources: Ovid Technologies web-based software was used to search the Medline and Antipsychotics; atypical;
PsycINFO computerized databases to identify articles that met the inclusion criteria. cognition; executive;
Review methods: The search was limited to papers published after 1990, written in English, memory; schizophrenia
employing human subjects, using atypical antipsychotics, using a within-subjects design or
control group of patients with schizophrenia for comparisons, using participants aged from
18–65, and employing standardized neuropsychological measures.
Results: A total of 996 eligible studies were identified, and of these 19 were finally analyzed. Nine
domains of cognitive functioning were assessed. The two groups of agents produced equivalent
overall effects (-dones = .254 versus -pines = .202). The -pines were found to improve the domains
of attention/working memory, executive functioning, fluency, nonverbal memory, processing
speed, and verbal memory, each with a significant, small effect size. The -dones were found to
improve attention/working memory, executive functioning, motor function, nonverbal memory,
processing speed, and verbal memory, each with a significant, small effect size. Failsafe N was
robust for all of the domains for the -pines, but only for the verbal memory domain for the -dones,
suggesting that the significant findings for the other domains with the -dones are more tenuous.
Conclusion: The results indicate that the agents were largely equivalent and that there was no
clear evidence that the pattern of cognitive effects differed as a result of the agent applied. The
effects themselves, while statistically significant, were small, indicating that some or all of the
differences may be attributable to practice effects on the instruments employed.

The clinical spectrum of schizophrenia features posi- “Processing speed” refers to an individual’s speed
tive (e.g., hallucinations and delusions), negative (e.g., in completing a variety of cognitive operations
avolition and anhedonia), and cognitive symptoms (K. (Reichenberg, 2010). Meta-analyses have indicated
Patel, Cherian, Gohil, & Atkinson, 2014). The cogni- that processing-speed deficits are a core cognitive
tive changes include compromise of general intelli- deficit experienced by individuals with schizophre-
gence (Aylward, Walker, & Bettes, 1984; Hedman, nia (Dickinson et al., 2007; Fioravanti, Carlone,
Haren, Baal, Kahn, & Hulshoff Pol, 2013), attention Vitale, Cinti, & Clare, 2005; Henry & Crawford,
(Galaverna, Morra, & Bueno, 2012; Reichenberg, 2005). While some cognitive functions can be
2010), language (Covington et al., 2005), memory more directly related to neurotransmitter dysregula-
(Aleman, Hijman, de Haan, & Kahn, 1999; tion in a single area or structure, research suggests
Reichenberg, 2010), and executive functioning that reductions in processing speed are more likely
(Dickinson, Ramsey, & Gold, 2007; Orellana & due to a lack of integrity of the white matter tracts,
Slachevsky, 2013). Deficits in both working memory culminating in reduced speed of interneuronal com-
(Forbes, Carrick, McIntosh, & Lawrie, 2009; Gold, munication (Antonova et al., 2005; Kochunov et al.,
Carpenter, Randolph, Goldberg, & Weinberger, 1997; 2016; Magistro et al., 2015; Turken et al., 2008;
Goldman-Rakic, 1994; Lee & Park, 2005) and proces- Woodward, Duffy, & Karbasforoushan, 2013).
sing speed (Bachman et al., 2010; Dickinson et al., While there has been limited research focusing
2007; Knowles, David, & Reichenberg, 2010) have on specific neurochemical irregularities causing slo-
also commonly been noted. wed processing, individuals receiving atypical

CONTACT Simon F. Crowe s.crowe@latrobe.edu.au School of Psychology and Public Health, La Trobe University, Bundoora, VIC 3086, Australia
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 M. CLISSOLD AND S. F. CROWE

antipsychotic agents have demonstrated improved (Hedges' g > 0.60) were noted for all 22 of the neurocog-
performance on neuropsychological measures of nitive tests categorized into the 10 cognitive domains.
this construct after treatment (Wang et al., 2013; This body of evidence clearly indicates that there are
Woodward, Purdon, Melzer, & Zald, 2005), and pervasive deficits across a broad range of cognitive
reduction in processing speed has been regarded domains in schizophrenia.
as the best predictor of functional outcome in the Developing a better understanding of the mechanism
condition (Woodward et al., 2013). of these deficits is worthwhile as they have been found to
Reduced psychomotor processing is also often linked correlate with patients’ functional outcome (Bowie &
with the negative symptoms of the condition (Fuller & Harvey, 2006; Harvey, 2007). Dysfunctional neurotrans-
Jahanshahi, 1999; Jogems-Kosterman, Zitman, Van mitter regulation of each of the dopamine, serotonin,
Hoof, & Hulstijn, 2001). However, some studies have and glutamate systems have each been implicated in the
found that after controlling for the other cognitive def- condition (De Bartolomeis, Buonaguro, & Iasevoli,
icits noted with the condition (i.e., memory, attention, 2013). Within the frontal lobe, dysregulation of the
and executive functioning), these deficits may no longer activity of serotonin (Abi-Dargham & Moore, 2003;
be noted (Morrens, Hulstijn, & Sabbe, 2007). Matsumoto, Inoue, Iwazaki, Pavey, & Dean, 2005;
Studies examining visuospatial deficits have found Rasmussen et al., 2016; Selvaraj, Arnone, Cappai, &
significant impairment in patients with schizophrenia Howes, 2014), dopamine (Brisch et al., 2014; Howes &
(Butler, Silverstein, & Dakin, 2008; Leiderman & Kapur, 2009), and glutamate (Marsman et al., 2014;
Strejilevich, 2008), but it is possible that these deficits Marsman, Van Den Heuvel, Klomp Kahn, Luijten, &
may also be moderated by core deficits in more basic Hulshoff Pol, 2012; Pitman et al., 2014; Poels et al., 2014)
processes such as visual working memory (Leiderman has been consistently observed.
& Strejilevich, 2008). Dysregulation of these neurotransmitter systems has
Heinrichs and Zakzanis (1998) undertook a quanti- also been observed in the hippocampus, although this
tative review of 204 studies comparing patients with evidence is not as definitive as that for the frontal lobes.
schizophrenia and controls on tests of global and selec- The hippocampus is a structure crucial to memory
tive verbal memory, nonverbal memory, bilateral and processing (Bird & Burgess, 2008; Burgess, Maquire,
unilateral motor performance, visual and auditory & O’Keefe, 2002; Kelley et al., 1998), as well as in the
attention, general intelligence, spatial ability, executive processing and storage of spatial information, although
function, language, and interhemispheric tactile-trans- other structures may also be implicated in these deficits
fer. They concluded that there were varying degrees of (Bose, Agarwal, Kalmady, & Venkatasubramanian,
deficit on standardized clinical tests in all of the sur- 2014). Impairments in the dorsal (knowing where)
veyed domains. stream have been consistently recorded, while impair-
Fioravanti et al. (2005) undertook a meta-analysis ments in the ventral (knowing what) stream are noted
focusing on five cognitive domains—IQ, memory, lan- less commonly (Doniger, Foxe, Murray, Higgins, &
guage, executive functioning, and attention—combin- Javitt, 2002; Kravitz, Saleem, Baker, & Mishkin, 2011;
ing 113 studies of 4,365 patients with schizophrenia Plomp et al., 2013).
and 3,429 controls. Significant impairments were A number of review papers have implicated dopami-
found across all five cognitive domains, and these nergic hyperactivation in the hippocampus (Grace, 2012,
findings were replicated seven years later in their 2016; N. Patel, Vyas, Puri, Nijran, & Al-Nahhas, 2010);
updated analysis, which included 247 papers of 18,300 however, studies examining serotonin dysregulation
patients (Fioravanti, Bianchi, & Cinti, 2012). within the hippocampus have reported conflicting results.
Similar results were found in the meta-analysis con- While some postmortem studies have noted no discre-
ducted by Mesholam-Gately, Giuliana, Goff, Faraone, pancies between patients and controls in the levels of
and Seidman (2009), which included 47 studies of serotonin in the hippocampus (Burnet, Eastwood, &
2,204 patients and 2,775 age- and gender-matched con- Harrison, 1997; Gurevich & Joyce, 1997; Hashimoto,
trols, on first-episode patients with schizophrenia. They Nishino, Nakai, & Tanaka, 1991; Scarr, Pavey, Copolov,
examined 10 cognitive domains: immediate verbal & Dean, 2004), other studies have identified changes in
memory, nonverbal memory, general cognitive ability, the serotonin transporter (Dean et al., 1995), with either
language functions, visuospatial abilities, delayed verbal increased (Joyce et al., 1993) or decreased (Burnet,
memory and learning strategies, executive functioning, Eastwood, & Harrison, 1996) levels noted. A recent in
social cognition, motor skills, and attention. Attention vivo study using magnetic resonance imaging and high-
was divided into three subdomains: vigilance, working resolution positron emission topography found that
memory, and processing speed. Medium-sized effects patients with schizophrenia have significantly lower
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 3

serotonin transporter availability in the anterior hippo- more conventional (typical) antipsychotic, culminating
campus than healthy controls (Kim et al., 2017). While in extrapyramidal side effects (Tarsy, Baldessarini, &
there are inconsistencies in this research, the importance Tarazi, 2002).
of 5-hydroxytryptamine (5-HT)-receptor-based mechan- In contrast to both clozapine and risperidone, aripi-
isms within the hippocampus is still considered as an prazole possesses greater D2 binding properties than
important site for the action of atypical antipsychotic 5HT2a binding properties (Stahl, 2013), but has the
agents (Meltzer, Li, Kaneda, & Ichikawa, 2003). same level of “other” binding properties as does risper-
Glutamatergic function within the hippocampus in idone. Furthermore, aripiprazole is a D2 receptor par-
patients with schizophrenia has not been as extensively tial agonist, a unique feature that distinguishes it from
examined as have dopamine and serotonin. A review the other SGAs (Stahl, 2013). It has been suggested that
paper by Heckers and Konradi (2015) noted that most aripiprazole should be considered the first agent in a
postmortem and animal studies throughout the 1990s third generation of atypical antipsychotics (Keltner &
found significant changes in glutamatergic receptors Johnson, 2002), although given the fact that it is a
within the hippocampus. In vivo research using relatively new drug, more research into its pharmacol-
voxel-based magnetic resonance spectroscopy noted ogy, treatment outcomes, and side effects is required.
increased levels of glutamate within the hippocampus The meta-analysis by Woodward et al. (2005) com-
as compared to healthy controls (Kraguljac, White, bined 14 studies and compared the effectiveness of clo-
Reid, & Lahti, 2013; Tebartz van Elst et al., 2005). zapine, olanzapine, quetiapine, and risperidone in
Heckers and Konradi (2015) suggest that this body of improving cognitive performance in patients with schizo-
evidence, coupled with neuroimaging studies finding phrenia. They examined a global cognitive index and the
hyperactivation of the hippocampus, explain some of cognitive domains of vigilance and selective attention,
the cognitive deficits noted with the illness, with the working memory, learning, processing speed, cognitive
majority of this research focusing on the frontal cortex. flexibility and abstraction, verbal fluency, visuospatial
Second-generation antipsychotic (SGA) medications processing, motor skills, and delayed recall of informa-
(i.e., atypical antipsychotics) are now the first-line tion. The results indicated that at an individual level,
treatment for both the positive and negative symptoms olanzapine improved the most cognitive domains (8/
of the condition; however, there is as yet no recom- 10), followed by clozapine (7/10), risperidone (5/10),
mended first-line pharmacological option for the cog- and lastly quetiapine (4/10). When grouped together,
nitive symptoms that these patients experience the SGAs resulted in mild significant improvements
(Morrison et al., 2012). across all cognitive domains.
Stahl (2013) has classified the SGAs into three dis- This study set out to provide an updated compar-
tinct categories based upon their chemical structure: ison of the -pines and -dones in their effectiveness in
the -pines (based upon the agent clozapine), the -dones treating the cognitive deficits experienced by patients
(based upon the agent risperidone), and the -pips with schizophrenia using meta-analytic techniques.
(based upon the agent aripiprazole). Stahl (2013) con- The -pips were not included as there is currently only
tends that clozapine’s binding properties are one of the limited research examining its cognitive efficacy as it is
most complex in all of psychopharmacology, with reg- a relatively new medication. Previous research has
ular updates and revisions being published. Clozapine found that atypical antipsychotics achieve mild reme-
possesses greater serotonin-2a receptor (5HT2a) bind- diation of the cognitive deficits noted in schizophrenia,
ing antagonism than dopamine-2 receptor (D2) antag- with olanzapine and clozapine being somewhat better
onism. However, unlike other SGAs, clozapine has in ameliorating the cognitive deficits than the other
considerably more “other” binding properties, includ- SGAs including risperidone (Woodward et al., 2005).
ing with the muscarinic, adrenergic, and histaminergic It was thus hypothesized that the -pines would improve
receptors. more cognitive domains than would the -dones.
Like clozapine, risperidone also features greater
5HT2a binding properties than D2 binding properties.
However, risperidone has more 5HT2a and D2 binding Method
properties and has considerably less “other” binding
Literature search
properties. Given its high 5HT2a and D2 binding,
only low to moderate doses of risperidone are required Ovid Technologies web-based software was used to
to produce positive therapeutic outcomes (Leysen, search the Medline and PsycINFO databases to iden-
Janssen, Megens, & Schotte, 1994; Li, Xia, & Wang, tify studies that examined the efficacy of atypical
2009). At higher doses, risperidone can operate as a antipsychotics in treating the cognitive deficits in
4 M. CLISSOLD AND S. F. CROWE

patients with schizophrenia. Studies published from 1 cognitive domains. This study employed the scheme devel-
January 1990 to 10 March 2017 (the date of last oped by Daffner et al. (2015) as the principal guide in
update) were included. This time frame was applied undertaking our approach as modified by both Lezak,
as most of the SGAs were not being employed before Howieson, Bigler, and Tranel (2012) and Strauss,
the early 1990s. Advanced Medical Subject Headings Sherman, and Spreen (2006), where appropriate. Final
(MeSH), Boolean search terms, and appropriate test allocation decisions were reviewed and agreed by
search-term limitations were used to identify relevant both authors.
articles. The MeSH headings included attention, pro- While it is acknowledged that other, more theoreti-
cessing speed, memory, language, fluency, motor, cal, approaches based upon the Cattell–Horn–Carroll
visuospatial, visual memory, verbal memory, execu- (CHC) theory of intelligence have been developed (e.g.,
tive function, clozapine, olanzapine, risperidone, and Jewsbury & Bowden, 2017; Jewsbury, Bowden, & Duff,
quetiapine. Boolean search terms included working 2016; Jewsbury, Bowden, & Strauss, 2016), this
memory, auditory memory, ziprasidone, iloperidone, approach was not applied in this study due to its
paliperidone, lurasidone, and asenapine. Appropriate relative novelty and the lack of more extensive confir-
search limitations included human studies and papers mation as yet by the field. The latter scheme produces
written in English. largely similar results to the scheme developed by
Daffner et al. (2015) with the exception of creating a
separate category for measures of fluency (Jewsbury &
Study selection
Bowden, 2017), which was implemented with this
The following criteria were required for an article to be meta-analysis.
included in the meta-analysis:

1. Published after 1990;

2. English language; Table 1. Neuropsychological tests meeting inclusion criteria
allocated to their respective cognitive domains.
3. Human subjects;
Cognitive domain Tests used
4. Include atypical antipsychotics within the inclu-
Attention Digit Span
sion criteria; STROOP
5. Within-subjects design or control comparisons used; ACT
TMT B
6. Participants had to be between 16 and 65 years old; WMS–R: LNS
7. Neuropsychological tests within inclusion criteria Executive function SOPT
TOL
employed; WCST
8. Results provided means and standard deviations Language PPVT
WAIS–R: Similarities
sufficient to calculate effect sizes; and, Motor function FTT
9. Original results or results not reported elsewhere. Grooved Pegboard
Nonverbal memory WMS–R: VR
Processing speed TMT A
Different types of antipsychotic medications can have DSS
varying effects on cognition (Wang et al., 2013). Verbal memory AVLT
BSDLT
Therefore, only articles that implemented a randomized CVLT
control method or within-groups design with schizo- RAVLT
WMS–R: LM
phrenic patients, who were drug naïve or had received WMS–R: VPA
a washout prior to the baseline neuropsychological tests, Visuospatial skills Hooper Visual Organisation
JOLO
were included within the analysis. The age range from 18 Fluency COWAT
to 65 years was employed as this is typically the age range Design Fluency
of most neuropsychological measures used with adults. Semantic Fluency
RFFT
Note. ACT = Auditory Consonant Trigram Test; AVLT = Auditory Verbal
Learning Test; BSDLT = Benton Serial Digit Learning Test;
Cognitive domains assessed COWAT = Controlled Oral Word Association Test; CVLT = California
Verbal Learning Test; DS = Digit Span; DSS = Digit Symbol Substitution;
Tests were categorized into nine cognitive domains (see FTT = Finger Tapping Test; JOLO = Judgement of Line Orientation;
Table 1): attention/working memory, executive function- LM = Logical Memory; LNS = Letter Number Sequencing;
PPVT = Peabody Picture Vocabulary Test; RAVLT = Rey Auditory Verbal
ing, fluency, language, motor functioning, nonverbal Learning Test; RFFT = Ruff Figural Fluency Task; SOPT = Self-Ordered
memory, processing speed, verbal memory, and visuospa- Pointing Task; TMT = Trail Making Test; TOL = Tower of London;
VPA = Verbal Paired Associates; VR = Visual Reproduction;
tial skills. As yet the field has not achieved a consensus that WCST = Wisconsin Card Sorting Task; WAIS–R = Wechsler Adult
concisely allocates specific cognitive tests to precise Intelligence Scale–Revised; WMS–R = Wechsler Memory Scales–Revised.
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 5

Coding of study characteristics Effect sizes for each cognitive domain were then
categorized into their respective SGA classification.
Each of the 21 studies that met the inclusion criteria
Each effect size was then pooled to calculate an overall
were coded according to the following study attributes:
effect size (Hedges' g ) and p-value for each of the
cognitive domains across each class of SGA
1. Publication month and year;
(Anderson-Hanley, Sherman, Riggs, Agocha, &
2. Authors;
Compas, 2003; Harvey & Taylor, 2010; Hutchinson &
3. Name of study;
Mathias, 2007; Stewart, Bielajew, Collins, Parkinson, &
4. The diagnostic manual used;
Tomiak, 2006; Wilson, 2001). Hedges' g was employed
5. Number of participants;
for the pooled effect size as it provides a more unbiased
6. Gender of participants;
effect size estimate that accounts for sample size bias
7. Age of participants (mean and standard deviation);
(Cumming, 2013). As the distribution of effect sizes
8. Average year of education completed;
across studies was heterogeneous as each used different
9. Mean age of first psychotic episode;
participants, designs, and measures, a random effects
10. Duration of illness;
model was employed (Wilson, 2001). The statistics
11. Source of population (e.g., inpatients, outpati-
were calculated using the Comprehensive Meta-
ents, history );
Analysis software, Version 3.3.070 (2014; CMA). The
12. Type of atypical antipsychotic used;
pooled effect sizes from the CMA software provided a
13. Minimum and maximum doses of atypical
standardized overall effect for the respective cognitive
antipsychotic;
domains. Effect sizes were interpreted as small (0.2 to
14. Average dose of atypical antipsychotic;
0.4), medium (0.4 to 0.6), or large (>0.6), in line with
15. If there was a need for washout, and if so, the
previous meta-analyses (Cohen, 1990; Gabay,
length of the washout period;
Kempton, & Mehta, 2015; Woodward et al., 2005),
16. Any additional medications being taken (e.g.,
although it should be noted that small effect sizes
benzodiazepines for sedation);
may not directly translate into clinical importance
17. Tests used;
(Kelley & Preacher, 2012). Results were considered
18. Cognitive domain assigned;
significant at the p < .05 level.
19. Relevant statistics related to performance on cog-
nitive tasks (i.e., means and standard deviation).
Results
Trial flow
A total of 996 papers were examined, of which 975 were
Statistical analyses
deemed ineligible for inclusion for the following reasons:
Effect sizes for test performances within each study
were calculated using the means and standard devia- – 269 either did not examine cognition or did not
tions from the control/baseline group and the post- include neuropsychological tests within the inclu-
treatment group. The effect size represents the sion criteria;
difference between the baseline group and the experi- – 180 had no appropriate baseline comparison
mental group divided by the pooled standard deviation group that included patients who received wash-
(Cohen, 1990). The effect sizes were calculated using out from their prior antipsychotic medications
the Practical Meta-Analysis Effect Size Calculator that could have affected their cognitive abilities;
(Rosenthal, 1995). – 145 were review studies;
Individual effect sizes for each cognitive test within – 81 studies taken from meta-analyses bibliogra-
each study were calculated. Some studies used multiple phies had already been examined in the initial
test outcomes for a single test (e.g., some studies would search of PsychINFO and Medline;
include total correct responses and percentage of per- – 63 included patients outside of the age limits;
severative errors for the Wisconsin Card Sorting Task). – 52 were nonexperimental articles (i.e., comment,
Individual effect sizes for single outcomes within the letter, response, or opinion piece);
same test were collated to calculate an overall effect size – 43 did not provide the required statistics necessary
(Hedges' g ) for that test. A residual analysis was then to make appropriate comparisons for analysis;
conducted to remove any influential data that exceeded – 41 included participants that had not met diag-
±1.96 standard deviations. nostic criteria for schizophrenia;
6 M. CLISSOLD AND S. F. CROWE

– 36 did not include SGAs within the inclusion nonverbal memory (g = 0.342, p < .0005), verbal
criteria; memory (g = 0.308, p < .0005), processing speed
– 20 were animal studies; (g = 0.286, p < .0005), attention/working memory
– 18 included adjunctive treatments with multiple (g = 0.251, p < .0005), executive functioning
types of antipsychotics; (g = 0.224, p = .001), and fluency (g = 0.163,
– 17 were meta-analyses; 4 of these meta-analyses p = .0286). Each of these was a small effect size
were related to the current study, and the biblio- using Cohen’s (1990) classification. A nonstatistically
graphies were examined for additional sources; significant result was found for language (g = 0.049,
– 5 articles were not accessible; p = .871) and motor functioning (g = 0.195,
– 4 articles included overlapping data from the p = .131). Six of the nine cognitive categories showed
CATIE trials; statistically significant but small effect sizes, and with
– 4 were conducted after 1990; and a small effect size overall.
– 2 were postmortem studies. Table 5 represents Hedges' g for the -dones across
the cognitive domains examined. A statistically sig-
A total of 21 studies were finally identified. These nificant overall effect size was noted (g = 0.202,
studies included the agents clozapine, olanzapine, and p < .0005), producing a small significant effect size
quetiapine (-pines), and ziprasidone and risperidone using Cohen’s (1990) classification. Specific effect
(-dones). All the studies used a within-groups design sizes (in decreasing order) were found for the
with a washout of the antipsychotics prior to baseline domain of verbal memory (g = 0.397, p < .0005),
neuropsychological testing. A flow chart of studies nonverbal memory (g = 0.256, p = .005), fluency
meeting inclusion criteria is provided in Figure 1. (g = 0.191, p = .104; however, this was not statisti-
cally significant), executive functioning (g = 0.170,
p = .037), processing speed (g = 0.168, p = .028),
Quantitative data synthesis
motor function (g = 0.168, p = .498; however, this
Data cleaning using residual analysis was conducted to effect was not statistically significant), and attention/
remove any results that could have unduly influenced the working memory (g = 0.146, p = .046). No significant
analysis (see Table 2). Residual analysis identified two effects was found for visuospatial skills (g = 0.212,
results that exceeded ±1.96 standard deviations: p = .392) language (g = 0.065, p = .831). Five of the
Abdolahian, Mohareri, and Bordbar’s (2008) results for nine cognitive categories showing statistically signifi-
risperidone and executive functioning, and Zhou, Zhu, cant but small effect sizes, and with a small effect
Wang, and Zhu’s (2009) results for olanzapine and execu- size overall.
tive functioning. As executive functioning was the only Publication bias was assessed by the calculation
domain that each study examined, they were removed of fail-safe Ns, which indicate the number of
from the final analysis. The information extracted from unpublished studies with nonsignificant results
the remaining 19 studies are summarized in Table 3. that would need to exist in order to call the
The 19 studies employed 26 different neuropsycho- observed significant findings into question. The for-
logical tests. One test, the continuous performance mula developed by Orwin (1983) was used to calcu-
task, was used in a number of studies; however, the late these values.
manner in which this test was applied varied across As different tests were used with varying frequency,
studies (X. Chen et al., 2015; Goldberg, Goldman, & it was decided that the fail-safe Ns should be greater
Burdick, 2007; Harvey, Green, McGurk, & Meltzer, than the number of published studies that had used the
2003), hence these data were not included in the final test (Hutchinson & Mathias, 2007). The fail-safe N
analysis to avoid issues with reliability, internal consis- values for the cognitive domain of verbal memory
tency, and construct validity. was greater than the number of studies that measured
Table 4 presents Hedges' g for the -pines across this cognitive domain for both groups of agents, and
the cognitive domains examined. A significant over- thus it was determined that relative confidence could
all effect size was noted (g = 0.254, p < .0005), pro- be placed in the obtained results. This observation also
ducing a small effect size using Cohen’s (1990) applied to the effects of attention/working memory,
classification. Specific effect sizes (in decreasing executive, nonverbal memory processing speed, and
order) were found for the domain of visuospatial verbal memory with the -pines. Less confidence should
skills (g = 0.419, p = .128); however, this effect was be placed on the effects noted with the remaining
not statistically significant due to variability and the domains in the studies that explored the effects of the
small number of studies included. Next in effect were -dones.
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 7

Figure 1. Summary of studies meeting inclusion criteria for the systematic review.

Discussion statistically significant, small effect sizes. The -dones

This meta-analysis compared two subcategories of aty- improved the domains of attention/working memory,
pical antipsychotics (-pines and -dones) with respect to executive functioning, nonverbal memory, processing
their effect on the cognitive deficits noted in patients speed, and verbal memory with a statistically signifi-
with schizophrenia. The results indicated that the cant small effect size. In fact the only difference
-pines improved the domains of attention/working between the two agents was that the fluency effect
memory, executive functioning, fluency, nonverbal with the -dones was not significant but did, however,
memory, processing speed, and verbal memory with produce a comparable effect size (i.e., -pines = 0.163
8 M. CLISSOLD AND S. F. CROWE

Table 2. Individual effect sizes calculated for each cognitive test within each study prior to residual analysis.
Effect size
Study Drug Neuropsychological test (Cohen’s d)
Abdolahian et al. (2008) Risperidone WCST 2.866
Clozapine STROOP 0.357
TOL 0.346
WCST 0.780
Bender et al. (2006) Olanzapine STROOP 0.129
TOL 0.580
WCST 0.419
Ertugral et al. (2007) Clozapine ACT 0.311
COWAT 0.387
DS 0.225
RAVLT 0.231
SEMANTIC 0.338
WCST 0.102
WMS–R: VR 0.150
Ertugral et al. (2009) Clozapine ACT 0.406
COWAT 0.326
DS 0.182
RAVLT 0.200
SEMANTIC 0.347
WCST 0.129
WMS–R: VR 0.260
Harvey et al. (2003) Olanzapine COWAT 0.198
CVLT 0.352
SEMANTIC 0.102
TMT A 0.315
TMT B 0.194
WCST 0.107
Risperidone COWAT 0.075
CVLT 0.310
SEMANTIC −0.113
TMT A 0.089
TMT B 0.074
WCST 0.132
Harvey et al. (2004) Olanzapine COWAT 0.089
RAVLT 0.499
SEMANTIC 0.213
TMT A 0.266
TMT B 0.369
WCST 0.147
Ziprasidone COWAT 0.080
RAVLT 0.404
SEMANTIC 0.022
TMT A 0.331
TMT B 0.143
WCST 0.165
Harvey et al. (2008) Clozapine RAVLT 0.243
STROOP 0.263
TMT A 0.154
TMT B 0.128
Ziprasidone RAVLT 0.347
STROOP 0.091
TMT A 0.071
TMT B 0.299
Keefe et al. (2004) Olanzapine COWAT 0.032
CVLT 0.179
DSS 0.316
FTT 0.120
JOLO 0.201
RFFT −0.030
SEMANTIC 0.017
STROOP 0.152
TMT A 0.142
TMT B 0.183
WCST −0.018
WMS–R: VR 0.369
WMS–R: LNS 0.083
Lee, Chou, Li, Wan, and Yen (2007) Risperidone WCST 0.969
Malhotra, Burdick, Razi, Sanders, and Kane (2006) Ziprasidone COWAT 0.627
CVLT 0.477
DS 0.051
(Continued )
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 9

Table 2. (Continued).
Effect size
Study Drug Neuropsychological test (Cohen’s d)
FTT 0.522
JOLO 0.141
SEMANTIC 0.369
TMT A 0.870
TMT B 0.638
WMS–R: LM 0.693
McGurk et al. (1997) Risperidone TMT A −0.143
TMT B 0.281
Milas, Golub, Mimica, Folnegović-Šmalc, and Makaric (1999) Olanzapine AVLT −0.007
BSDLT −0.043
FTT 0.332
Mortimer, Joyce, Balasubramaniam, Choudhary and Saleem (2007) Olanzapine COWAT 0.077
SEMANTIC −0.112
Purdon et al. (2000) Olanzapine Design Fluency 0.703
DS 0.388
DSS 0.397
FTT 0.230
Grooved Pegboard 0.652
Hooper Visual Organisation 0.766
PPVT 0.025
TMT B 0.491
WAIS–R: Similarities 0.075
WCST 0.599
WMS–R: VR 0.282
Risperidone Design Fluency 0.580
DS 0.098
DSS −0.016
FTT −0.021
Grooved Pegboard 0.016
Hooper Visual Organisation 0.248
PPVT −0.130
TMT B 0.054
WAIS–R: Similarities 0.261
WCST 0.215
WMS–R: VR −0.232
Quinones et al. (2011) Quetiapine TMT A 0.174
TMT B 0.303
Riedel, Müller, et al. (2007) Olanzapine COWAT AND SEMANTIC 0.176
RAVLT 0.410
SOPT 0.644
TMT A 0.303
TMT B 0.446
WMS–R: VR 0.476
WMS–R: LNS 0.289
Quetiapine COWAT AND SEMANTIC 0.005
RAVLT 0.507
SOPT 0.532
TMT A 0.538
TMT B 0.675
WMS–R: VR 0.730
WMS–R: LNS 0.287
Riedel, Spellmann, et al. (2007) Quetiapine COWAT 0.375
RAVLT 0.871
SEMANTIC 0.108
SOPT 0.490
TMT A 0.562
TMT B 0.417
WMS–R: VR 0.365
WMS–R: LNS 0.288
Risperidone COWAT 0.073
RAVLT 0.417
SEMANTIC −0.127
SOPT −0.191
TMT A 0.435
TMT B 0.313
WMS–R: VR 0.270
WMS–R: LNS 0.288
Tybura et al. (2013) Olanzapine WCST 0.093
Ziprasidone WCST 0.131
Van Veelen et al. (2010) Olanzapine COWAT 0.275
(Continued )
10 M. CLISSOLD AND S. F. CROWE

Table 2. (Continued).
Effect size
Study Drug Neuropsychological test (Cohen’s d)
CVLT 0.421
SEMANTIC 0.265
STROOP 0.176
TMT A 0.303
TMT B 0.273
WCST 0.459
WMS–R: VPA 0.286
WMS–R: VR 0.163
Ziprasidone COWAT 0.301
CVLT 0.286
SEMANTIC 0.174
STROOP 0.098
TMT A 0.437
TMT B 0.319
WCST 0.313
WMS–R: VPA 0.483
WMS–R: VR 0.278
Wagner et al. (2004) Olanzapine COWAT AND SEMANTIC −0.020
RAVLT −0.231
TMT A 0.362
TMT B 0.313
WMS–R: LNS 0.000
Zhou et al. (2009) Risperidone WCST 0.970
Note. ACT = Auditory Consonant Trigram Test; AVLT = Auditory Verbal Learning Test; BSDLT = Benton Serial Digit Learning Test; COWAT = Controlled Oral
Word Association Test; CVLT = California Verbal Learning Test; DS = Digit Span; DSS = Digit Symbol Substitution; FTT = Finger Tapping Test; JOLO =
Judgement of Line Orientation; LM = Logical Memory; LNS = Letter Number Sequencing; PPVT = Peabody Picture Vocabulary Test; RAVLT = Rey Auditory
Verbal Learning Test; RFFT = Ruff Figural Fluency Test; SOPT = Self-Ordered Pointing Task; TMT = Trail Making Test; TOL = Tower of London; VPA = Verbal
Paired Associates; VR = Visual Reproduction; WCST = Wisconsin Card Sorting Task; WAIS–R = Wechsler Adult Intelligence Scale–Revised; WMS–
R = Wechsler Memory Scales–Revised.

and -dones = 0.191). Neither the -pines nor the -dones et al., 2003, 2004; Tybura et al., 2013; Van Veelan
produced effects on language, motor functioning, or et al., 2010), two found the -pines to be superior in
visuospatial skill. These findings clearly do not support some domains (Purdon et al., 2000; Riedel, Spellmann,
the hypothesis that the -pines improve more cognitive et al., 2007), and one study found that treatment with
domains than the -dones, or that -pines could be con- the -dones resulted in greater cognitive improvement
sidered as first-line treatment by practitioners for schi- than that with the -pines (Harvey et al., 2008). The
zophrenia with cognitive deficits. current study adds to the developing consensus view
The overall levels of effect are similar to those pre- that there is no substantial difference between the two
viously noted by Woodward et al. (2005; i.e., atypicals categories of agent with respect to their effects on
improving cognitive functioning with an effect size of cognition.
0.24), and the observation that specific atypicals have The results did not support the results of the pre-
different effects within certain cognitive domains was vious meta-analysis of Woodward et al. (2005), which
not supported by the analysis with the two groups of have found that the -pines (clozapine, olanzapine, and
agents producing similar outcomes, perhaps with the quetiapine) were superior to the -dones (risperidone)
exception of the -pines yielding more robust effects as for the domains of vigilance and selective attention.
assessed by the fail-safe N analysis; however, this obser- While different cognitive domains were examined in
vation needs to be mediated by the fact that there were the current meta-analysis compared to the meta-analy-
fewer papers that examined the -dones than those that sis by Woodward et al. (2005), overall, the current
examined the -pines. results and the previous literature do not comprehen-
As yet, seven studies have made direct comparisons sively validate the -pines being a superior treatment
between the -pines and -dones (Harvey et al., 2003; option over the -dones with regard to their cognitive
Harvey et al., 2008; Harvey, Siu, & Romano, 2004; effects.
Purdon et al., 2000; Riedel, Spellmann, et al., 2007; The basis of the cognitive deficits in schizophrenia
Tybura et al., 2013; Van Veelan et al., 2007). While are still vigorously debated (Carlsson, 2006), and while
these studies each examined different cognitive some investigators contend that these are a predisposi-
domains to those in the current study, four found no tional trait marker (i.e., a behavioral or biological pro-
significant differences between the -pines and the cess that may play a causal role in developing the
-dones across multiple cognitive domains (Harvey illness), others suggest that they are state dependent
Table 3. Information from the studies that met inclusion criteria after residual analysis.
First
Education psychotic Duration
Diagnostics Participants: (years episode: of illness Duration
manual Participants: Age (years) completed) Age (in years) (years) of study
Authors used SGA used N (% males) M (SD) M (SD) M (SD) M (SD) (weeks) Neuropsychological measures used
Bender et al. (2006) DSM 4 Olanzapine 30 (45) 31.60 (9.90) NP 25.10 (7.90) NP 26 STROOP, TOL, and WCST
Clozapine 24 (71) 34.5 (11.00) 25.30 (7.70)
Ertugral et al. (2007) DSM 4 Clozapine 20 (55) 29.75 (5.55) NP NP NP 8 ACT, COWAT, DS, RAVLT, Semantic Fluency, WCST, and WMS–R: VR.
Ertugral et al. (2009) DSM 4 Clozapine 22 (50) 30.82 (9.86) NP 22.73 (6.4) 8.14 (6.6) 8 ACT, COWAT, DS, RAVLT, Semantic Fluency, WCST, and WMS–R: VR.
Harvey et al. (2003) DSM 4 Risperidone 188 (72) 41.00 NP 24.50 (6.70) NP 8 COWAT, CVLT, Semantic Fluency, TMT A and B, and WCST
(11.00)
Olanzapine 189 (73) 38.90
(10.50)
Harvey et al. (2004) DSM 4 Ziprasidone 136 (62) 37.70 (9.70) NP 23.80 (6.95) NP 6 COWAT, RAVLT, Semantic Fluency, TMT A and B, and WCST
Harvey et al. (2008) DSM 3R Ziprasidone 61 (70) 41.80 NP NP 1.08 (NP) 12 RAVLT, STROOP, and TMT A and B
(10.20)
Clozapine 69 (67) 37.90
(10.70)
Keefe et al. (2004) DSM 4 Olanzapine 89 (79) 23.7 (4.6) NP NP NP 12 COWAT, CVLT, FTT, JOLO, RFFT, Semantic Fluency, STROOP, TMT A and B, WAIS–
R: DSS, WCST, and WMS–R: LNS and VR.
Lee et al. (2007) DSM 4 Risperidone 10 (100) 25.90 (2.30) 12.10 NP NP 8 WCST
(1.30)
Malhotra et al. (2006) DSM 4 Ziprasidone 10 (80) 40.10 12.40 20.70 (4.50) 1.53 (0.97) 12 COWAT, CVLT, DS, FTT, JOLO, Semantic Fluency, TMT A and B, and WMS–R: LM
(12.80) (3.00)
McGurk et al. (1997) DSM 3R Risperidone 28 (71) 42.13 12.39 23.00 (6.16) 19.13 4 TMT A and B
(10.83) (3.06) (11.12)
Milas et al. (1999) DSM 4 Olanzapine 10 (NP) 37.00 (NP) NP NP NP 22 AVLT, BSDLT, and FTT
Mortimer et al. (2007) DSM 4 Olanzapine 10 (80) 38.07 NP NP NP 26 COWAT and Semantic Fluency
(10.40)
Purdon et al. (2000) DSM 4 Olanzapine 21 (81) 26.01 (5.76) 12.76 23.37 (5.99) 2.79 (1.87) 54 Design fluency, DS, FTT, Grooved Pegboard, Hooper Visual Organisation Test,
(2.62) PPVT, TMT B, WAIS–R: Similarities, WCST, and WMS–R: DSS
Risperidone 21 (67) 31.77 12.67 28.86 (11.39) 2.67
(11.24) (2.33) (1.96)
Quinones et al. (2011) DSM 4 Quetiapine 33 (55) 35.36 (9.58) 12.27 25.74 (9.00) 8.90 (8.76) 12 TMT A and B
(2.56)
Riedel, Müller, et al. DSM 4 Quetiapine 16 (63) 36.69 NP 28.25 (7.10) 8.44 8 COWAT, RAVLT, Semantic Fluency, SOPT, TMT A and B, WMS–R: LNS and VR.
(2007) (11.71) (10.11)
Olanzapine 17 (65) 34.47 29.76 (9.00) 4.71 (6.22)
(11.60)
Riedel, Spellmann, et al. DSM 4 Quetiapine 19 (68) 29.20 NP 3.3 (3.8) 3.3 (3.8) 12 COWAT, RAVLT, Semantic Fluency, SOPT, TMT A and B, and WMS–R: LNS and VR
(2007) (10.70)
Risperidone 15 (53) 39.60 2.3 (15.1) 2.3 (15.1)
(12.40)
Tybura et al. (2013) ICD-10 Olanzapine 19 (NP) 35.50 NP 26.90 (6.90) NP 8 WCST
(13.50)
Ziprasidone 20 (NP) 37.10
(10.90)
Van Veelan et al. (2010) DSM 4 Olanzapine 29 (90) 23.38 (4.67) NP NP 1.15 (1.36) 8 COWAT, CVLT, Semantic Fluency, STROOP, TMT A and B, WCST, and WMS–R:
Ziprasidone 27 (74) 24.48 (4.15) 1.22 VPA and VR
(1.33)
Wagner et al. (2004) DSM 4 Olanzapine 18 (72) 34.30 (7.30) 14.30 27.30 (7.00) 7.00 (6.70) 8 COWAT, RAVLT, Semantic Fluency, TMT A and B, and WMS–R: LNS
JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY

(3.70)
Note. DSM = Diagnostic and Statistical Manual of Mental Disorders; ICD = International Classification of Disease; NP = not provided; ACT = Auditory Consonant Trigram Test; AVLT = Auditory Verbal Learning Test; BSDLT = Benton Serial
Digit Learning Test; COWAT = Controlled Oral Word Association Test; CVLT = California Verbal Learning Test; DS = Digit Span; DSS = Digit Symbol Substitution; FTT = Finger Tapping Test; JOLO = Judgement of Line Orientation;
11

LM = Logical Memory; LNS = Letter Number Sequencing; PPVT = Peabody Picture Vocabulary Test; RAVLT = Rey Auditory Verbal Learning Test; RFFT = Ruff Figural Fluency Test; SGA = second-generation antipsychotic; SOPT = Self-
Ordered Pointing Task; TMT = Trail Making Test; TOL = Tower of London; VPA = Verbal Paired Associates; VR = Visual Reproduction; WCST = Wisconsin Card Sorting Task; WAIS–R = Wechsler Adult Intelligence Scale–Revised; WMS–
R = Wechsler Memory Scales–Revised.
12 M. CLISSOLD AND S. F. CROWE

Table 4. Summary statistics for the effects of -pines on each between these deficits (Lesh, Niendam, Minzenberg, &
domain of cognitive functioning. Carter, 2011), the direct effect of both the positive and
Studies Hedges' the negative symptoms on cognition symptoms cannot
Cognitive domain (N) g 95% CI p Nfs
Attention/working 15 0.251 0.142 0.360 .000 64
be ignored (Aleman, 2014).
memory Whether the marginal improvements in test perfor-
Executive functioning 13 0.224 0.103 0.344 .000 50 mance noted in our study directly translate to improve-
Fluency 12 0.163 0.040 0.286 .009 10
Language 1 0.049 −0.544 0.643 .871 NA ment in functional outcomes was not examined in the
Motor functioning 3 0.195 −0.058 0.447 .131 0 analysis, and quantitative comparative analyses were
Nonverbal memory 9 0.342 0.197 0.488 .000 34
Processing speed 11 0.286 0.167 0.406 .000 50 not conducted between the two classifications of
Verbal memory 11 0.308 0.166 0.449 .000 34 SGAs. Many of the effects observed were small, indi-
Visuospatial skills 2 0.419 −0.120 0.958 .128 NA
Overall 0.254 0.204 0.303 .000 cating that they may not directly translate into sub-
Note. CI = confidence interval; Nfs = fail-safe N value. For domains that stantial levels of clinical improvement. These effects
examined ≤2 studies, Nfs could not be calculated.

Table 5. Summary statistics for the effects of -dones on each domain of cognitive functioning.
Studies Hedges'
Cognitive domain (N) g 95% CI p Nfs
Attention/working memory 8 0.146 0.002 0.290 .046 2
Executive functioning 7 0.170 0.010 0.330 .037 2
Fluency 5 0.191 −0.039 0.420 .104 0
Language 1 0.065 −0.529 0.658 .831 NA
Motor functioning 2 0.168 −0.319 0.656 .498 NA
Nonverbal memory 4 0.256 0.079 0.433 .005 1
Processing speed 8 0.168 0.018 0.318 .028 6
Verbal memory 5 0.397 0.187 0.608 .000 13
Visuospatial skills 2 0.212 −0.274 0.698 .392 NA
Overall 0.202 0.134 0.270 .000
Note. CI = confidence interval; Nfs = fail-safe N value. For domains that examined ≤2 studies, Nfs could not be calculated.

(i.e., the clinical outcomes from the illness itself; Y. occur in the context of the fact that each of the studies
Chen, Bidwell, & Norton, 2006). While it was originally undertaken was a within-subjects design without any
believed that the cognitive deficits in schizophrenia control for learning, most likely culminating in practice
only developed in aging populations (O’Carrol, 2000), effects. The study by Goldberg et al. (2007) noted no
research gathered over the last 30 years indicates that difference between olanzapine and risperidone over
these deficits predate the first episode of psychosis and multiple cognitive domains and yielded a similar level
are apparent across the entire course of the illness of effect. There was also no significant difference in
(Bowie & Harvey, 2006; Kitchen, Rofali, Heron, & practice effects for the respective treatment groups,
Sacco, 2012). indicating that the small effect sizes noted for both
There is strong evidence to suggest that cognitive groups of agents may well be due to practice effects
deficits on neuropsychological measures have a strong alone.
relationship with day-to-day functional outcomes A limitation of this meta-analysis was the lack of
(Bowie & Harvey, 2006; Harvey, 2007). Lepage, studies examining the -pips as this is a relatively
Bodnar, and Bowie (2014) note that verbal memory, newly developed class. From the limited available
for example, consistently exhibits a strong association research that has compared the -pips to the other
with clinical status and showed the largest deficits in SGAs, it appears that aripiprazole improves cognition
their group of poor outcome patients. While this asso- at a similar level to that from olanzapine (Kern et al.,
ciation is well established, our understanding of the 2006). As compared to the -pines, which have the
direct improvements on cognitive tasks from antipsy- highest risk of potential side-effects with over 30% of
chotics causing improvements on functional outcomes clients experiencing sedation, weight gain, hypergly-
is yet to be explored. There is also the broad question cemia, and anticholinergic effects, the -pips have not
as to whether neuropsychological impairments directly as yet been found to be associated with any of these
affect an individual’s ability to think. While studies negative side effects (Dowden, 2008), so clearly war-
have started to hypothesize different theoretical neuro- rant further study and application for these potential
logical mechanisms that would help explain the link benefits.
 JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 13

Another limitation of the study is the disproportionate Conclusion

distribution in the variety of tests used to examine the
This study indicates that both the -pines and the
respective cognitive domains. Impairment in attention
-dones produced an equivalent level of improvement
(Galaverna et al., 2012; Reichenberg, 2010), executive
in cognition across most domains examined. The data
functioning (Reichenberg, 2010), language (Covington
indicate that the search for a specific class of antipsy-
et al., 2005), and memory (Aleman et al., 1999;
chotic agent that improves cognitive functioning
Reichenberg, 2010) are the most extensively researched
remains elusive. The main limitation of this study was
areas of cognitive deficits in schizophrenia. This is
that there has been limited research examining the
reflected in the number of studies that examined these
effect that the -pips have on cognition; thus all three
cognitive domains in the current analysis; six studies
classifications of atypical antipsychotics could not be
examined attention, six examined verbal memory, four
comprehensively explored. Hopefully in the not-too-
examined fluency, and three examined executive func-
distant future these data will become available allowing
tioning. Combined, these four domains encompassed 19
for a more robust and comprehensive examination.
of the total 27 tests meeting inclusion criteria.
These observations should, however, be mediated by
To date there has been limited research examin-
the fact that the -pines have a higher risk of side effects
ing the longitudinal effect of the atypical antipsy-
(Dowden, 2008), and thus the findings should be
chotics on cognition with only two studies assessing
viewed with caution.
the effects of the SGAs over periods longer than
26 weeks. This clearly constrains the conclusions
that can be drawn regarding the long-term effects Disclosure statement
of SGAs in improving cognitive performance.
No potential conflict of interest was reported by the authors.
Future research should follow up patients after pro-
longed treatment, to determine whether these ben-
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