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Ni Hms 509207
Author Manuscript
Schizophr Res. Author manuscript; available in PMC 2014 October 14.
Published in final edited form as:
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Abstract
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Method—Relevant publications from 2006 to 2011 were identified through keyword searches in
Pubmed and an examination of reference lists. Studies were included if they (1) compared the
cognitive performance of adult schizophrenia patients and healthy controls, (2) based
schizophrenia diagnoses on contemporary diagnostic criteria, (3) reported information sufficient to
permit effect size calculation, (4) were reported in English, and (5) reported data for
neuropsychological tests falling into at least 3 distinct cognitive domains. A set of 100 non-
overlapping studies was identified, and effect sizes (Hedge’s g) were calculated for each cognitive
variable.
Results—Consistent with earlier analyses, patients with schizophrenia scored significantly lower
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than controls across all cognitive tests and domains (grand mean effect size, g = −1.03). Patients
showed somewhat larger impairments in the domains of processing speed (g = −1.25) and episodic
memory (g = −1.23). Our results also showed few inconsistencies when grouped by geographic
region.
Correspondence: Dwight Dickinson, Clinical Brain Disorders Branch, NIMH, NIH, 10 Center Drive, MSC 1379, Bethesda, Maryland
20892, [email protected], Telephone: (301) 451-2123, Fax: (301) 480-7795.
Contributors
JS, EG, and DD collected and analyzed the data and prepared the first draft of the manuscript. All authors contributed to manuscript
revisions.
Conflict of Interest
The authors declare that they have no conflict of interest.
The authors of this manuscript report no competing interests.
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Schaefer et al. Page 2
manifests similarly in different regions of the world despite linguistic and cultural differences.
Keywords
schizophrenia; cognition; neuropsychology; meta-analysis; processing speed; memory
1. Introduction
Schizophrenia is a “global” condition in many respects. It impacts widely-acting
neurotransmitter systems (e.g. dopamine, glutatmate, GABA) through subtle changes in
brain microstructure, physiology, and connectivity, and these neurobiological differences
give rise to a variety of affective, cognitive, and psychotic symptoms. Epidemiologically,
the disorder cuts across cultures, regions, and genders, with an estimated lifetime prevalence
of about 1% of the world’s population. Functionally, schizophrenia is associated with
considerable generalized disability, as affected individuals experience low rates of
employment and marriage, decreased somatic health and quality of life, lower levels of
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The effect that schizophrenia exerts on cognition can fairly be described as “global” as well.
Resting on evidence from hundreds of studies and thousands of individuals, the finding that
schizophrenia is associated with impairment across a wide range of higher-order cognitive
performance domains is now well-established. Although some reviews highlight particularly
large cognitive deficits in the domains of verbal episodic memory (Heinrichs and Zakzanis,
1998; Reichenberg and Harvey, 2007), executive functioning (Reichenberg and Harvey,
2007), or processing speed (Dickinson et al., 2007), the most consistent finding across
studies has been an overall, generalized impairment across neuropsychological measures
that persists in every clinical state and across patients’ lifespans (Hughes et al., 2003; Albus
et al., 2002; Hill et al., 2004; Hyde et al., 1994). The relationship of cognitive impairment in
schizophrenia to symptom severity is modest (Hughes et al., 2003; Dominguez et al., 2009;
Rund et al., 2004; Ventura et al., 2010). However, cognitive impairment shows consistent
association with indexes of everyday functional capacity. Several studies using a variety of
cognitive assessment strategies have shown consistent associations between cogition and the
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In 1998, Heinrichs and Zakzanis published the first large-scale meta-analysis of cognitive
deficit findings in schizophrenia, drawing on more than 200 studies conducted between 1980
and 1997 (Heinrichs and Zakzanis, 1998) and documenting an overall mean impairment of
0.92 standard deviations relative to community comparison groups (Heinrichs, 2005).
Various smaller reviews followed, generally focused on a particular cognitive domain
(Aleman et al., 1999) or set of measures (Bokat and Goldberg, 2003). Although narrower in
focus than the Heinrichs review, our 2007 meta-analysis (Dickinson et al., 2007) offered a
general update for studies completed in the decade following Heinrichs & Zakzanis (1998)
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and reported a similar outcome. Across measures and samples, this later analysis found a
grand mean effect size of schizophrenia on cognitive performance of 0.98 standard
deviations.
The newest cohort of neuropsychological studies, however, differs from those sampled in
previous meta-analyses in several ways. First, while Heinrichs & Zakzanis’s (1998) seminal
publication included samples of patients diagnosed according to DSM-III and DSM-III-R
criteria, studies conducted within the past decade have virtually all defined schizophrenia
according to criteria laid out in the DSM-IV and DSM-IV-TR. Second, since Heinrichs &
Zakzanis’s (1998) meta-analysis, several canonical neuropsychological measures have been
revised (e.g. WAIS, WMS, CPT), and expert judgment regarding the most appropriate
measures for the study of schizophrenia has evolved, resulting in the emergence of testing
arrays like the MATRICS Consensus Cognitive Battery (Kern et al., 2008; Nuechterlein et
al., 2008). Finally, driven in part by the power requirements of genetics analyses, the most
recent cohort of studies examining cognition in schizophrenia is uniquely international. The
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degree to which cognitive deficit findings in schizophrenia are similar across regions that
differ substantially in both language and culture is unknown, however, and some
performance differences have been reported across sites in different areas of the world
(Harvey et al., 2003). As cognitive impairment is considered for inclusion as a possible
specifier for psychotic disorders in ICD-11, the possibility of regional differences in
neuropsychological measurement and/or performance is especially relevant.
effect size, examining both clinical variables (e.g. medication, symptom ratings, chronicity
of illness) and demographic variables (e.g. participants’ sex, education).
literature. In total, nearly 4000 articles were identified in preliminary searches. We retained
a subset of these articles for examination in greater detail based on a review of their titles
and abstracts. Additional publications were also found by searching the reference lists of
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Studies were included in the present analysis if they (1) compared the cognitive performance
of adult schizophrenia patients and healthy controls (and mean ages of both samples were
between 18 and 50 yrs), (2) based schizophrenia diagnoses on contemporary diagnostic
criteria (e.g. DSM-IV, DSM-IV-TR, or ICD-9 or later), (3) reported information sufficient to
permit effect size calculation, (4) were reported in English, and (5) reported data for
neuropsychological tests falling into at least 3 distinct cognitive domains. Of the 376 studies,
we excluded 99 because of insufficient test batteries, 68 because of problems with the
presentation of values, 18 because they did not compare schizophrenia patients and healthy
controls, 17 because patients did not meet DSM-IV criteria for schizophrenia, 11 because
subjects were matched for IQ, 9 because subjects’ mean age fell outside of the acceptable
range, and 2 because of abnormalities in the data due to study methodology (e.g. extreme
flooring or ceiling effects). Where studies appeared to use the same (or overlapping)
samples, we used data from only one of the studies. Accordingly, an additional 52 studies
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were eliminated due to overlap concerns, leaving exactly 100 studies that met all meta-
analytic inclusion criteria.
Specific cognitive variables were included in our analysis if they appeared in at least 4 of the
included studies. Altogether, we collected data on 46 cognitive variables, and assembled
them into 10 familiar cognitive domains for presentation. In general, measures were
combined on an individual test by individual test basis, but we also combined very similar
measures in some instances. For example, we combined data across different list-learning
tasks and across different sets of prompts for letter and category fluency tasks. Similarly,
full-battery IQ scores and estimates based on IQ battery short forms were also combined, as
were word reading scores from the Wide Range Achievement and National Adult Reading
Tests.
These values were then weighted and combined using a conservative random effects model.
We also calculated 95% confidence intervals as well as a χ2 statistic, Q, an indicator of
variability across studies for a given effect size estimate. In our analysis of quantitative
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moderator variables, we also calculated the homogeneity statistics Qwithin and Qbetween. The
Qwithin statistic denotes the homogeneity or heterogeneity of studies within moderator
variable subgroups, whereas the Qbetween statistic tests the significance of differences in
effect size magnitude between moderator variable subgroups, similar to an F statistic.
To compare the current findings to past meta-analytic work, we compiled findings from two
other non-overlapping meta-analyses that have addressed the same or comparable cognitive
variables in this population (Heinrichs and Zakzanis, 1998; Dickinson et al., 2007), allowing
us to examine the extent to which cognitive impairment in schizophrenia has remained
stable across time and across changes in testing materials and diagnostic criteria.
Additionally, as the vast majority of samples used in this analysis (N = 92) were from one of
three distinct geographic clusters (closely approximating North America, Europe, and Asia),
we divided these studies into three separate geographic regions to examine the consistency
of generalized cognitive impairment across different cultures and areas of the world, again
calculating Qwithin and Qbetween statistics as measures of within-region and between-region
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variability, respectively.
3. Results
3.1 Main meta-analysis
The results of the main meta-analysis are presented in Table 1. Across these studies, data
were analyzed from 9048 patients with schizophrenia and 8814 healthy comparison subjects.
Of our 100 studies, 96 reported the mean ages of both patients and controls. The sample
weighted mean age for the schizophrenia group was 35.1 years (range of study means: 20.1
to 48.5) years, compared with 35.6 years for controls (range: 19.0 to 48.7 years). In the set
of 91 studies reporting participant sex, 49.9% of control participants and 66.8% of probands
were male. The sample-weighted average of years of education across the 70 studies that
provided this information was 12.1 years for patients (range: 9.0 to 14.3) and 13.9 for
controls (range: 10.3 to 16.9). Finally, the average duration of illness for patients according
to the 55 studies reporting this information was 13.2 years (range: 0.8 to 25.0), indicating
considerable chronicity across the study sample as a whole.
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Negative effect sizes in Table 1 indicate impairment in the schizophrenia group relative to
healthy controls. As shown in this table, neuropsychological performance was significantly
impaired in the schizophrenia group across all measures tested and all domains, with a grand
mean weighted effect size of g = −1.03. The range of effect sizes for individual variables
grouped by domain is illustrated in Figure 1. In line with our earlier meta-analysis (3), the
largest effect size observed was for the Digit-Symbol Coding test (g = −1.55). The smallest
effect size observed was for the WAIS Information subtest (g = −0.43).
Table 1 also provides weighted average effect sizes for each cognitive domain. Although
different investigators may group cognitive variables differently, such summaries provide an
approximate index of domain specificity. Across domains, impairment among schizophrenia
patients was substantial and fairly consistent, with most measure-by-measure and domain-
level effect sizes falling in the medium to large range (−0.63 to −1.11). Inconsistency from
study to study in terms of which variables and domains were available prevented a formal
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Regarding the current analysis, significant Q-values in Table 1 signify greater variation in
cognitive performance from study to study than would be expected by chance for 38 of the
46 individual effect sizes. We performed a series of analyses to examine the influence of
moderator variables on effect size variability within the schizophrenia sample. Our first
analysis examined the effect of geographic region on neuropsychological functioning (Table
3). Results indicated that the grand mean effect size, reflecting overall impairment, was
strikingly consistent across the three regions examined (Qbetween = 0.21, p = 0.98), a finding
that also extended to the measure-by-measure analyses, with the exception of Vocabulary
(Qbetween = 8.94, p = 0.01) and Trails B (Qbetween = 21.54, p = 8.13 × 10−5) tests.
Meta-regressions for age and education effects on impairment effect size were confounded
in these data. Across studies, as the schizophrenia sample mean age increased, so did the
degree to which the schizophrenia sample was relatively older than the control sample (K =
96, r = .376, p = 8.02 × 10−5), making it difficult to separate within group age effects from
between groups age-disparity effects. Similarly, across studies, the mean years of education
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achieved by controls was highly correlated with the magnitude of the difference in years of
education between controls and patients (K = 70, r = .686, p < 1 × 10−5). In regard to sex,
the effect sizes derived from a given study tended to be larger in studies reporting a greater
percentage of male patients (K = 92; z = 2.45, p = 0.01).
Among clinical variables, we found that neither schizophrenia age of onset (K = 39; z =
−0.36, p = 0.72), duration of illness (K = 55; z = 0.42, p = 0.68), nor CPZE (K = 28; z =
−0.11, p = 0.91) were significantly related to the magnitude of impairment observed.
Consistent with the literature (e.g. 8), after excluding an outlying, medication-naïve, first
episode sample from the analysis (115), we found no significant relationship between
patient’s scores on the PANSS positive symptom scale and cognition (K = 40, z = −0.01, p =
0.99). Somewhat surprisingly, we also observed no significant relationship between
impairment effect size and patient’s scores on both the PANSS negative symptom scale (K =
41; z = 0.44, p = 0.66) and measures of total symptomatology, such as patient’s PANSS
Total Scores (K = 24; z = −1.04, p = 0.30), or scores on the BPRS (K = 15; z = −0.02, p =
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0.98). In a small selection of studies reporting the data, cognitive impairment was not
significantly associated with patients’ global functioning (GAF) scores (K = 11; z = −0.72, p
= 0.47).
4. Discussion
The current analysis updates the evidence of broad cognitive impairment in schizophrenia,
again revealing moderate to severe impairment in people with schizophrenia relative to
controls across all neuropsychological measures studied, and somewhat larger cognitive
differences in the domains of processing speed and episodic memory (see Figure 1). These
findings are quite consistent with earlier reviews. Remarkably, despite significant changes in
diagnostic criteria, assessment materials and practice, and sample ascertainment, the
observed variation in the overall, grand mean effect size of cognitive impairment in
schizophrenia over three decades of research is about 0.1 standard deviations, less than 10%
of the total impairment observed.
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Geographic variation in the pattern of cognitive impairment in schizophrenia has not been
examined in previous reviews. Our analyses indicate that the region of the world in which a
cognition study is conducted has little impact on the effect sizes reported. The average grand
means across groups of studies from Asia, Europe, and the United States are strikingly
consistent (ranging from 1.02 to 1.08), despite substantial geographic, cultural, and
linguistic differences across groups. Similar consistency can also be observed at the level of
individual measures, with the exception of Vocabulary and Trails B tests. The reason for the
differences by region in Vocabulary and Trails B performance is unclear, but variation in
Vocabulary performance might relate in part to varying levels of multilingualism among the
samples studied (Paez et al., 2006; Windsor and Kohnert, 2006). Variation in Trails B, on
the other hand, may be partially attributable to differences in testing stimuli used in different
countries (e.g. some Chinese versions of the test replace the letters with corresponding
Chinese characters).
In an attempt to explain the substantial effect size heterogeneity observed in our main meta-
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analysis (see Table 1), we also examined several other moderator variables. Consistent with
studies that report poorer cognitive functioning in male schizophrenia patients relative to
females (Vaskinn et al., 2011), we found that studies with larger percentages of male
patients tended to report larger effect sizes. In addition, we found that cognitive impairment
was relatively unrelated to most measures of symptomatology, somewhat in contrast to
studies highlighting modest but statistically reliable associations between cognition and
negative or disorganized symptoms, including a recent meta-analysis on the topic
(Dominguez et al., 2009).
degree of cognitive change over time tends to be similar in cases and controls (Bozikas and
Andreou, 2011). Although other studies have shown an association between cognition and
indexes of everyday functioning (Green et al., 2000, 2004, 2006), including the Global
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As with all meta-analyses, the findings reported in this paper are shaped by study selection
methods, analytical methods, and the information made available to researchers in the
studies selected for review. One difference between this review and some previous analyses
is that we elected to include only studies that included at least one cognitive measure across
at least three distinct domains. This resulted in a high representation in our study sample of
“full neuropsychological battery” studies. We imposed this limitation because we judged
such studies most likely to yield consistent, unbiased information about cognitive
performance across measures. Despite this limitation, the present analysis is, as measured by
combined sample size, the largest of its kind and results show a remarkable degree of
consistency with past reviews.
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Acknowledgments
The authors would like to extend their heartfelt thanks to Jody Mozersky for her hard work on the meta-analysis
article database.
Funding
This work was supported by the Division of Intramural Research Programs, National Institute of Mental Health,
National Institutes of Health (NIH), through funding to the Weinberger Lab, and the Lieber Institute for Brain
Development, Baltimore, Maryland (http://www.libd.org).
Support for this research was provided by the National Institute of Mental Health Intramural Research Program via
direct funding to the Weinberger Lab.
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relatives and controls. Aust N Z J Psychiatry. 2010; 44(2):109–119. [PubMed: 20113299]
NIH-PA Author Manuscript
Figure 1.
Selected effect sizes for impairment in schizophrenia relative to control performance.
Neuropsychological domain names are labeled in capital letters with black diamonds as
effect size markers. Selected individual variables in each domain are marked with small
black circles.
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Table 1
Summary of meta-analytic results based on selected neuropsychological measures from 100 studies and 9048 people with schizophrenia.
Heterogeneity Test
Cognitive domain/measure Number of Studies Total Sample Size Effect Size Standard Error 95% Confidence Interval Z-value P-value Q Statistic P-value
Schaefer et al.
Grand mean 100 17146 −1.03 0.03 −1.09 to −0.96 30.26 <1 × 10−8 329.98 <1 × 10−8
Processing speed (ES = −1.25)
Digit symbol coding 22 7861 −1.55 0.11 −1.75 to −1.34 14.67 <1 × 10−8 271.79 <1 × 10−8
Trail Making Test part A 31 6388 −0.90 0.06 −1.02 to −0.78 15.05 <1 × 10−8 137.73 <1 × 10−8
Stroop color-reading condition 9 1117 −1.16 0.13 −1.42 to −0.90 8.75 <1 × 10−8 25.21 0.0014
IQ (ES = −1.13)
General IQ 31 6661 −1.11 0.08 − 1.26 to −0.96 14.54 <1 × 10−8 183.65 <1 × 10−8
Verbal IQ 8 2091 −1.09 0.20 −1.48 to −0.70 5.49 4.0 × 10−8 92.71 <1 × 10−8
Performance IQ 8 2096 −1.26 0.14 −1.54 to −0.99 8.87 <1 × 10−8 44.43 1.7 × 10−7
Verbal ability (ES = −0.68)
Word Reading 23 4579 −0.72 0.07 −0.86 to −0.58 10.30 <1 × 10−8 85.30 <1 × 10−8
Vocabulary 21 4008 −0.76 0.08 −0.90 to −0.61 10.01 <1 × 10−8 81.72 <1 × 10−8
Information 10 3524 −0.43 0.07 −0.56 to −0.29 6.02 <1 × 10−8 20.72 0.0140
Similarities 11 3811 −0.79 0.09 −0.97 to −0.62 8.80 <1 × 10−8 46.54 <1 × 10−8
Comprehension 6 684 −1.08 0.18 −1.43 to −0.74 6.11 <1 × 10−8 18.84 0.0021
Fluency (ES = −1.11)
Category fluency 41 6853 −1.21 0.07 −1.35 to −1.07 17.012 <1 × 10−8 229.66 <1 × 10−8
Letter fluency 36 4845 −0.98 0.06 −1.09 to −0.86 16.87 <1 × 10−8 95.25 1.7 × 10−7
Heterogeneity Test
Cognitive domain/measure Number of Studies Total Sample Size Effect Size Standard Error 95% Confidence Interval Z-value P-value Q Statistic P-value
Spatial span total 5 657 −0.81 0.22 −1.24 to −0.39 3.77 1.6 × 10−4 26.32 2.7 × 105
Motor speed (ES = −1.00)
Schaefer et al.
Grooved pegboard dominant 5 530 −0.86 0.17 −1.19 to −0.53 5.11 3.1 × 10−7 10.71 0.0300
Grooved pegboard nondominant 4 478 −0.94 0.22 −1.37 to −0.50 4.24 2.2 × 10−5 12.01 0.0073
Token Motor Task (BACS) 4 459 −1.23 0.17 −1.55 to −0.90 7.37 <1 × 10−8 6.89 0.0756
Episodic memory (ES = −1.23)
Word list learning 42 8906 −1.30 0.06 −1.42 to −1.19 21.83 <1 × 10−8 202.18 <1 × 10−8
Word list learning delayed 32 4601 −1.27 0.06 −1.38 to −1.15 21.24 <1 × 10−8 85.26 5.8 × 10−7
Word list recognition 10 2858 −0.68 0.06 −0.80 to −0.56 11.07 <1 × 10−8 13.25 0.1517
Story memory 16 5053 −1.41 0.09 −1.59 to −1.24 15.74 <1 × 10−8 92.90 <1 × 10−8
Story memory delayed 14 4681 −1.40 0.11 −1.60 to −1.19 13.09 <1 × 10−8 104.16 <1 × 10−8
Figure learning 14 4345 −1.10 0.14 −1.37 to −0.84 8.18 <1 × 10−8 171.98 <1 × 10−8
Figure learning delayed 16 4528 −1.21 0.14 −1.48 to −0.94 8.78 <1 × 10−8 209.49 <1 × 10−8
Visuospatial/problem solving (ES = −0.73)
Block design 11 4930 −0.71 0.09 −0.89 to −0.52 7.60 <1 × 10−8 69.21 <1 × 10−8
Matrix Reasoning 12 1813 −0.90 0.07 −1.03 to −0.78 14.00 <1 × 10−8 14.65 0.1989
Figure copy 7 943 −0.64 0.17 −0.97 to −0.31 3.84 1.2 × 10−4 31.49 2.0 × 10−5
Picture completion 5 505 −0.64 0.12 −0.87 to −0.41 5.41 6× 10−8 6.14 0.1891
Executive functioning (ES = −0.94)
Trail Making Test part B 37 7267 −1.08 0.06 −1.18 to −0.97 19.72 <1 × 10−8 128.24 <1 × 10−8
Stroop color-word condition 11 2764 −1.11 0.13 −1.36 to −0.85 8.55 <1 × 10−8 76.24 <1 × 10−8
Heterogeneity Test
Cognitive domain/measure Number of Studies Total Sample Size Effect Size Standard Error 95% Confidence Interval Z-value P-value Q Statistic P-value
Identical pairs CPT (d′) 9 1257 −1.10 0.09 −1.28 to −0.91 11.72 <1 × 10−8 15.67 0.0474
Degraded stimulus CPT (rt) 5 750 −1.04 0.15 −1.33 to −0.75 6.97 <1 × 10−8 10.88 0.0279
Schaefer et al.
Table 2
Side by side comparison of results from three meta-analysis samples comparing schizophrenia cognitive performance to controls, covering the years 1980
to 2012.
Heinrichs & Zakzanis (1998); Zakzanis et al. (1999) Dickinson et al. (2007) Current analysis
Schaefer et al.
Effect Size Schizophrenia Sample Size Effect Size Schizophrenia Sample Size Effect Size Schizophrenia Sample Size
Meta-analysis Grand Mean 0.92 7420 0.98 1961 1.02 8617
Full Scale or Estimated IQ 1.1 1018 1.19 863 1.11 3273
Word Reading (“Premorbid IQ”) 0.42 1069 0.59 450 0.72 2087
Heinrichs & Zakzanis (1998); Zakzanis et al. (1999) Dickinson et al. (2007) Current analysis
WAIS Digit Span Forward 0.69 440 0.73 175 0.63 1970
WAIS Digit Span Backward 0.82 440 0.86 155 1.01 2026
Table 3
Results of a test-by-test comparative analysis investigating the extent to which effect sizes obtained from the main meta-analysis are robust to differences
in geographic location. Measures used in fewer than 3 studies from a given region were excluded from this analysis.
Processing speed
Digit symbol coding N Schizophrenics 772 2250 548 0.150 0.928
Effect Size 1.45 1.58 1.56
Qwithin 86.86** 69.50** 104.63**
Trail Making Test part A N Schizophrenics 963 1576 365 2.043 0.564
Effect Size 1.04 0.89 0.87
Qwithin 25.28* 38.99* 30.76**
Intellectual/verbal ability
General IQ N Schizophrenics 275 2446 552 1.844 0.605
Effect Size 1.26 1.09 1.01
Qwithin 8.24 115.95** 55.15**
Word Reading N Schizophrenics 1247 309 330 3.172 0.205
Effect Size 0.78 0.51 1.05
Qwithin 32.85** 20.03* 22.42**
Fluency
Category fluency N Schizophrenics 712 1482 673 1.802 0.615
Effect Size 1.02 1.29 1.22
Qwithin 43.25** 62.17** 79.75**
Letter fluency N Schizophrenics 691 1120 285 6.546 0.088
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Episodic memory
Schaefer et al.
Perceptual/problem solving
Block design N Schizophrenics 166 1445 568 4.119 0.128
Effect Size 0.83 0.53 0.85
Qwithin 0.94 20.62** 20.69**
Executive functioning
*
p < .05,
**
p ≤ 0.01