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The Primacy of Cognition in Schizophrenia.

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 The Primacy of Cognition in Schizophrenia
R. Walter Heinrichs
York University
Cognitive tasks and concepts are used increasingly in
schizophrenia science and treatment. Recent meta-analyses
show that across a spectrum of research domains only
cognitive measures distinguish a majority of schizophrenia
patients from healthy people. Average effect sizes derived
from common clinical tests of attention, memory, language,
and reasoning are twice as large as those obtained in
structural magnetic resonance imaging and positron emis-
sion tomography studies. Chronic stress, genes, brain dis-
turbances, task structure, gender, and sociocultural back-
ground may all enhance the sensitivity of cognitive
performance to schizophrenia. At the same time, disease
heterogeneity and the presence of endophenotypes and
subtypes within the patient population may place upper
limits on the strength of any specific cognitive finding.
Schizophrenia is a complex biobehavioral disorder that
manifests itself primarily in cognition.
A
t the turn of the 20th century, a form of madness
that came to be called schizophrenia was de-
scribed and distinguished from mood disorders
like mania and melancholia (Kraepelin, 1896, 1919).
Schizophrenia was observed in young people and persisted
for years, working its way deeply and intimately into mind
and behavior. People with the illness might hear the roars
of Satan or the whispers of children. They might move
armies with their thoughts and receive instructions from
other worlds. They might feel penetrated by scheming
parasites, stalked by enemies, or praised by guardian an-
gels. People with schizophrenia might also speak nonsen-
sically, their language at once intricate and impenetrable.
And many would push, or be pushed, to the edge of the
social landscape, overcome by solitude.
Yet there was more to this illness than dramatic de-
lusions and hallucinations, disorganized language, bizarre
behavior, and profound withdrawal. Early psychopatholo-
gists noted subtle disturbances in attention, memory, rea-
soning, and judgment. Indeed, Bleuler (1943, 1911/1950)
argued for impaired associative thinking, rather than delu-
sions or hallucinations, as a fundamental defect of the
disorder. The diagnosis and study of schizophrenia were
founded on its characteristic symptoms. But there were
hints of another and perhaps more basic dimension, a
cognitive dimension that coexisted with psychotic and so-
cial aspects of the illness.
Impaired cognition is now seen as a feature of schizo-
phrenia that precedes, accompanies, and then outlasts a
patient’s symptoms and medical regimen. Measurable de-
April 2005 ● American Psychologist
Copyright 2005 by the American Psychological Association 0003-066X/05/$12.00
Vol. 60, No. 3, 229 –242 DOI: 10.1037/0003-066X.60.3.229
fects in thought and language, perception, memory, and
attention appear in vulnerable children long before psycho-
sis erupts into their lives (Erlenmeyer-Kimling et al.,
2000). Patients experiencing their first psychotic episodes
are cognitively impaired, and this impairment is relatively
stable over time (Albus et al., 2002). Recent studies suggest
little or no relation between symptoms and cognitive per-
formance early in the illness, and cognitive deficits remain
when symptoms remit in response to medication (Hughes
et al., 2003; Rund et al., 2004). It is recognized that
cognitive abilities influence quality of life and long-term
adjustment and underpin learning and skills-based thera-
pies and interventions (Green, Kern, Braff, & Mintz, 2000).
Hence, cognitive remediation programs have been devel-
oped to modify the deficits observed in schizophrenia pa-
tients (Reeder, Newton, Frangou, & Wykes, 2004). Fur-
thermore, interest in psychotherapy, especially cognitive
approaches, has gradually rekindled (Bellack, 2004; Karon
& VandenBos, 1981; Trower et al., 2004). Cognitive func-
tion is also considered increasingly as a target for new
forms of medication (Harvey & Keefe, 2001). Finally,
hypotheses about the neurobiology and etiology of the
illness use cognitive theory, methods, and findings (An-
dreasen et al., 1999).
Thus, cognitive tasks and theory have come to play a
role in many fields of schizophrenia research and clinical
practice. However, although cognitive impairment is
viewed as an integral part of the illness, the magnitude and
implications of this impairment relative to other findings
have received little discussion. Cognitive deficits are not
only part of the schizophrenia syndrome; they are the
primary expression of the schizophrenic brain. In this arti-
cle, I will draw from quantified evidence (meta-analysis)
and document the magnitude of cognitive impairment
within a broad context of neuroscience findings. I will then
discuss influences that may enhance and limit these mag-
nitudes and argue for the importance of cognition in un-
derstanding the nature of schizophrenia.
A Panorama of Quantified Evidence
Evaluating the diverse and burgeoning knowledge base of
schizophrenia science has been a major challenge over the
last two decades, giving rise to increased application of
meta-analysis and research synthesis. Meta-analysis statis-
tically integrates the results of previous studies and cali-
Correspondence concerning this article should be addressed to R. Walter
Heinrichs, Department of Psychology, York University, Toronto, Ontario
M3J 1P3, Canada. E-mail: walterh@yorku.ca
229

R. Walter
Heinrichs
brates the average magnitude of difference (effect size
[ES]) in the dependent variable between groups or condi-
tions. Confidence intervals placed around the average ES
provide a quasi-inferential estimate of stability and error. In
addition, methodology and sample characteristics can be
coded as moderator variables and analyzed for relation-
ships with study outcomes. For example, a meta-analyst
may suspect that the use of more or less medicated clinical
samples accounts for a portion of ES variability between
studies. Correlating each study’s ES and proportion of
patients on medication can assess such possibilities. How-
ever, moderator analysis is only feasible if large numbers
of reports include the relevant information. Still, in theory
and often in practice, meta-analysis offers a useful toolbox
for estimating the strength and attributes of evidence in
psychological and medical science. As such, it represents a
major advance over the traditional, and often highly selec-
tive and impressionistic, literature review (Lipsey & Wil-
son, 2001, pp. 5–9).
Average ESs are available for schizophrenia-control
differences in cognition (Aleman, Hijman, de Haan, &
Kahn, 1999; Bokat & Goldberg, 2003; Johnson-Selfridge
& Zalewski, 2001), evoked potentials (Jeon & Polich,
2001, 2003), regional brain volumes (Konick & Friedman,
2001; Lawrie & Abukmeil, 1998; Nelson, Saykin, Flash-
man, & Riordan, 1998; Wright et al., 2000), cerebral me-
tabolism and blood flow (Zakzanis, Poulin, Hansen, &
Jolic, 2000), dopamine receptor densities (Kestler, Walker,
& Vega, 2001; Zakzanis & Hansen, 1998), and obstetrical
events (Cannon, Jones, & Murray, 2002; Geddes et al.,
1999).
The most inclusive and systematic synthesis is a series
of meta-analyses ranging across two decades of research
and 82 quantified differences between healthy people and
230
schizophrenia patients (Davidson & Heinrichs, 2003; Hei-
nrichs, 2001; Heinrichs & Zakzanis, 1998; Zakzanis &
Heinrichs, 1999). This synthesis is especially informative
because, in addition to quantifying a wide range of findings
from attention to cell counts, it used uniform study selec-
tion standards and statistical methods. Articles were in-
cluded if they compared healthy people and patients who
met criteria for schizophrenia based on the Diagnostic and
Statistical Manual of Mental Disorders (American Psychi-
atric Association, 1980, 1987, 1994 [DSM–IV]) or the
International Classification of Diseases (World Health Or-
ganization, 1978, 1992). In addition, articles had to report
descriptive or inferential statistics that were convertible to
Cohen’s d (Cohen, 1988), a common measure of ES. ES in
these meta-analyses was calculated as (Mc – Ms)/SDp,
where Mc is the control group mean, Ms is the schizophre-
nia group mean, and SDp is the pooled standard deviation.
The PsycINFO and MEDLINE databases were searched
back to 1980 along with reference sections from published
reviews in order to minimize the omission of relevant
studies. Altogether, the synthesis quantified the results of
639 articles reporting schizophrenia-healthy control differ-
ences in cognition, psychophysiology, and neurobiology.
This synthesis will be used to illustrate several points about
the strength of cognitive evidence and the wider spectrum
of schizophrenia science.
First consider the overview of research domains pre-
sented in Figure 1. Studies were compiled into a cognitive
performance domain if they involved an information-pro-
cessing task and reported response times, accuracy scores
and errors, or verbal behavior. This yielded results primar-
ily from easily administered and commonly used clinical
and neuropsychological tests of digit span, verbal recall,
word generation, spatial ability, attention, and reasoning
(Heinrichs, 2001, pp. 256 –260; Heinrichs & Zakzanis,
1998). Results derived from laboratory and experimental
tasks and paradigms like perceptual masking (Green,
Nuechterlein, Breitmeyer, & Mintz, 1999) and shadowing
or dichotic listening (Wielgus & Harvey, 1988) were also
included. The grand mean ES in cognitive performance
studies of schizophrenia patients and healthy people came
to 0.92 pooled standard deviation units. In other words, on
average, healthy comparison groups scored almost one
standard deviation unit higher or better on the average
performance measure than did the average group of schizo-
phrenia patients.
Studies were considered in the cognitive psychophys-
iology domain if they involved a mental or information-
processing task but measured outcome with surface and
electrophysiological recordings and responses. This inte-
grated studies of eye movements during visual tracking
tasks and reports on the amplitude and latency of electrical
brain potentials in response to novel or repeated events
(Iacono, 1998). Cognitive psychophysiology findings were
similar in magnitude to cognitive performance, averaging
about one ES standard deviation unit relative to healthy
people.
A large number of neurobiological fields were also
included. The results of postmortem techniques, which
April 2005 ● American Psychologist
Figure 1
Meta-Analytic Findings of Impairment in Different Domains of Schizophrenia Research

Note. This summary includes grand mean effect sizes and their 95% confidence intervals derived from clinical and experimental tests of cognitive performance
(Heinrichs, 2001; Heinrichs & Zakzanis, 1998); smooth pursuit eye tracking and evoked potential measures of cognitive psychophysiology (Heinrichs, 2001);
postmortem neuroanatomical and neurotransmitter receptor binding studies (Heinrichs, 2001); positron emission tomography (PET) and xenon inhalation studies of
regional metabolism and blood flow conducted with participants engaged in cognitive activation tasks (Davidson & Heinrichs, 2003); PET studies of regional
metabolism, blood flow, and receptor binding and xenon blood flow studies with participants in a resting state (Davidson & Heinrichs, 2003; Heinrichs, 2001); and
regional volumetric measurements of the frontal and temporal lobes based on structural magnetic resonance imaging (MRI; Davidson & Heinrichs, 2003).

provide unparalleled spatial resolution of brain tissue, in-
cluded findings in cytoarchitecture (e.g., neuronal cell dis-
array and disorientation; see Zaidel, Esiri, & Harrison,
1997) and neurotransmitter receptor densities (e.g., dopa-
mine; see Dean, Scarr, Bradbury, & Copolov, 1999). Taken
together they yielded a grand mean ES of 0.85.
Structural magnetic resonance imaging (MRI) offers
the highest resolution of neuroanatomical detail available
in living people. Moreover, structural MRI studies of re-
gional brain volumes are numerous. Davidson and Hein-
richs (2003) found 100 articles published between 1988
and 2002 reporting frontal and temporal lobe volumes in
schizophrenia patients and healthy people. These studies
produced a grand mean ES of 0.41.
A variety of imaging methods have been used to index
regional cerebral blood flow and metabolism. Early blood
flow methods like the xenon inhalation technique (Ingvar &
Franzen, 1974; Mathew, Duncan, Weinman, & Barr, 1982)
were superseded by positron emission tomography (PET)
scanning (e.g., Ragland et al., 1998) during the 1990s. Yet
Davidson and Heinrichs (2003) found no relationships be-
tween imaging method (i.e., PET vs. xenon) or physiolog-
ical index (i.e., glucose metabolism vs. blood flow) and the
ESs in 55 imaging studies. Hence, for summary purposes,
these studies were combined into one domain. However,
some articles used an information-processing task and re-
ported changes in regional brain metabolism or blood flow
in response to this task. Other studies reported only resting
state or baseline hemodynamic and metabolic or receptor
occupancy data. This methodological difference was of
theoretical interest and hence studies were compiled and
quantified into separate PET/xenon active (ES ⫽ 0.58) and
resting domains (ES ⫽ 0.41). Two very recent outgrowths
of existing technology, functional MRI (e.g., Salgado-
Pineda et al., 2004) and diffusion tensor imaging (e.g.,
Nestor et al., 2004), were not included because of the small
number of studies reporting data convertible to ESs.1
The evidential value of an ES is implied by a number
of quantitative rules of thumb as well as by theoretical
considerations. Thus, for example, ES ⫽ 0.78 separates
1
Paradoxically, the evolution of neuroimaging is making quantita-
tive synthesis and evaluation more difficult. Functional magnetic reso-

April 2005 ● American Psychologist 231

slightly less than half of patients and controls in a joint
distribution (Cohen, 1988). Hence, the average ESs of
neuroimaging literatures indicate very extensive overlap
between healthy people and patient groups in terms of the
biological variables measured in these fields. It is also
noteworthy that ESs for regional brain volume (MRI) are
very similar to those for physiology (PET/xenon), whereas
both contrast with the magnitudes of cognitive domains. In
fact, only cognitive studies yield average ESs large enough
to distinguish a clear majority of patients from healthy
people.
Another important aspect of research outcomes is the
stability or reproducibility of findings. This can be indexed
by the 95% confidence interval for the average ES, which
is analogous to a margin of error within which the mean is
most likely to occur. When this interval is large and in-
cludes 0, then, by definition, the average difference be-
tween patients and healthy people may also be 0. Similarly,
mean effects with overlapping confidence intervals are
statistically indistinguishable, whereas completely sepa-
rated intervals imply significant differences.
In light of these considerations, all of the research
domains in Figure 1 consistently generate findings well
removed from 0. However, the PET/xenon and MRI do-
mains yield findings that occur in minorities of schizophre-
nia patients. These neuroimaging domains also represent a
statistical dead heat situation in terms of their relative mean
ESs. In other words, they are equivalent in their ability to
discriminate patients and healthy people. Structural MRI
findings are remarkably stable if modest in magnitude. The
confidence intervals for the cognitive and postmortem do-
mains also overlap, implying equality of the respective
mean ESs. At the same time, these intervals suggest that
cognitive performance yields significantly larger average
ESs and hence more powerful findings than the neuroim-
aging domains.
Comparison of evidential strength across research do-
mains is vulnerable to the apples-and-oranges criticism
sometimes leveled at meta-analysis. In other words, it is
questionable to compare qualitatively different data derived
from different sources. Thus, what does it mean to say that,
in general, postmortem brain tissue data yield larger ESs
than those produced by MRI data from relatively young
living people? It may be meaningful to compare the dis-
criminating power of different research methods when they
are applied to the same kinds of samples. But when qual-
itatively different methods are applied to qualitatively dif-
ferent samples, then the meaning of the comparison is less
clear.
nance studies often report only p values or statistically significant z scores
instead of group means and standard deviations. In addition, results are
frequently provided only for those spatial coordinates that yield significant
contrasts. These attributes make conversion of study outcomes into ESs
questionable and render cross-study comparisons problematic (see Lipsey
& Wilson, 2001, pp. 34 –72). Hence, none of the published meta-analyses
cited in the present article included functional MRI studies. Special
meta-analytic techniques or changes in reporting practices will be required
as the functional MRI literature expands.
232
Nevertheless, this criticism does not apply in the same
way to comparisons of cognitive and neuroimaging do-
mains. True, these domains comprise literatures that use
qualitatively different kinds of measures. However, the
patient populations involved are essentially the same. The
descriptive data presented in Table 1 suggest that the pri-
mary difference between the 155 neuroimaging and 204
cognitive studies underlying the findings in Figure 1 is the
average sample size. Otherwise, the clinical samples that
give rise to cognitive and neuroimaging evidence are very
similar. It seems unlikely that commonly reported patient
characteristics confound the ES comparisons in these
broad research domains. Therefore, it is important to
note the sensitivity and discriminating power of cogni-
tive measures when contrasted with the results of neu-
roimaging methods.
Of course, grand mean ESs paint a picture of cognitive
evidence in extremely broad strokes, generalizing and col-
lapsing across many specific tasks and measures. However,
the strength of this evidence is even more apparent when
literatures relevant to specific hypotheses are examined.
For example, studies of left frontal lobe cognition, anat-
omy, and physiology have a long history in schizophrenia
science. Average ESs from three cognitive performance
literatures (Heinrichs, 2001; Heinrichs & Zakzanis, 1998)
associated with the frontal region and three neuroimaging
literatures (Davidson & Heinrichs, 2003) are presented in
Figure 2. Across all left frontal brain research domains, the
largest average findings involve cognitive performance.
Relevant abilities and measures include generating words
that begin with specified letters (Controlled Oral Word
Association Test [COWAT]; Benton & Hamsher, 1989),
abstract reasoning and mental flexibility indexed by the
Wisconsin Card Sorting Test (Heaton, Chelune, Talley,
Kay, & Curtiss, 1993), and working memory and attention-
related deficiency on the Continuous Performance Test
(Adler et al., 2001; Barch et al., 2001; Cornblatt & Erlen-
meyer-Kimling, 1985; Nuechterlein, 1983).
Associated confidence intervals for the cognitive per-
formance domains in Figure 2 indicate that the three mean
ESs are equivalent in magnitude and approximate 1.00.
This means that at least half and perhaps as many as two
thirds of schizophrenia patients score below the range of
healthy participants on these performance tasks. In con-
trast, the neuroimaging domains all yield less discriminat-
ing power, with average effects approximately half the size
of the cognitive findings. Hence, PET/xenon studies of left
frontal brain activation, resting metabolism, and blood flow
as well as structural MRI-based studies of left frontal
volumes distinguish a minority of patients from healthy
people. It is also informative to consider the close similar-
ity between active (ES ⫽ 0.54) and resting (ES ⫽ 0.48)
PET/xenon literatures. It appears that using activation tasks
does not necessarily yield patient-control differences larger
than those obtained with only resting or baseline conditions
(Davidson & Heinrichs, 2003). However, the confidence
intervals for these domains are large, implying the exis-
tence of considerable variability and instability in study
outcomes. The structural MRI domain again seems to yield
April 2005 ● American Psychologist
 lation. The PET/xenon studies of this region yield fairly
Table 1 small and highly variable ESs. Indeed, consideration of the
Descriptive Statistics for Schizophrenia Samples Used confidence intervals for the mean effects shows that they
in Neuroimaging and Cognitive Performance Studies include 0. Therefore, it could be argued that on average,
Neuroimaging Cognitive
patients and healthy people are essentially identical in
literature literature temporal lobe blood flow and metabolism. However, the
variability in outcomes implies that technical, design, and
Variable M SD M SD
sample composition differences between studies may con-
Sample size 26.1 18.6 36.1 30.2 tribute to effect magnitudes within these domains (see
Age (years) 31.9 5.4 34.4 10.0 Davidson & Heinrichs, 2003; Heinrichs, 2004). Overall,
Proportion of men (%) 78.6 18.3 82.4 63.0 nonetheless, it is clear that schizophrenia manifests itself
First hospitalization (age) 22.5 2.0 22.2 3.2 strongly in cognitive performance and more moderately
Length of illness (years) 10.0 4.9 12.7 7.6 and often inconsistently in neuroimaging measures of as-
Number of admissions 5.5 5.0 3.9 7.4 sociated brain systems.
Education (years) 12.6 0.9 12.0 1.1 The point of these overviews and comparisons is not
Antipsychotic medication to maintain that cognitive performance measures are some-
(%) 79.6 34.6 77.6 36.6
CPZ equivalent daily
how better than neuroimaging measures. Different ques-
dose (mg) 555.7 281.1 582.1 340.3 tions are being asked and answered with different instru-
ments in these fields, and they yield different categories of
Note. Sample data for neuroimaging studies were obtained from Davidson data. Yet there is one evaluation that can be applied across
and Heinrichs (2003) and for cognitive performance studies, from Heinrichs
and Zakzanis (1998). CPZ ⫽ chlorpromazine.
these diverse methods—their relative ability to discrimi-
nate healthy people from those with schizophrenia. And in
this respect, the discrepancy between neuroimaging tech-
niques, which have driven the neuroscience approach to
psychiatric disorders over the last two decades, and cogni-
stable average findings. This domain suggests that a mi- tive techniques is striking. The strength of cognitive find-
nority of schizophrenia patients, perhaps only a quarter, has ings is perhaps especially noteworthy because most of the
reduced left frontal lobe brain volumes relative to healthy techniques used to generate these findings are decidedly
people. low tech in nature. Orally administered and paper-and-
Another case in point is the left temporal lobe system, pencil tests— everyday tools to many clinical psycholo-
which has been considered along with the frontal lobes as gists—rather than sophisticated high-tech brain-imaging
part of a dysfunctional network in schizophrenia. In addi- instruments, distinguish people with schizophrenia most
tion to the neocortex, more medial regions of the temporal clearly.
lobe, like the hippocampus, which underpins aspects of
verbal memory, are of interest. Two cognitive (Heinrichs, Why Are Cognitive Measures So
2001; Heinrichs & Zakzanis, 1998) and four neuroimaging Sensitive to Schizophrenia?
(Davidson & Heinrichs, 2003) literatures are presented in
Figure 3. Here again there is a pattern wherein cognitive Instead of trying to explain, or explain away, modest neu-
performance yields large average ESs and neuroimaging roimaging findings, it makes sense to consider reasons for
measures of associated cerebral regions yield modest and the apparent strength of cognitive performance as an indi-
sometimes small and unstable effects. Verbal learning and cator of schizophrenia. Several possibilities are presented
recall of word lists and stories (verbal memory) in partic- schematically in Figure 4. However, it is important to note
ular produce substantial case-control differences that prob- that cognition-mediating processes will only amplify or
ably distinguish more than 70% of patients and controls in diminish ESs if these processes exist unequally in patient
a joint distribution. The memory findings presented in and control groups or interact with the disease in some
Figure 3 were produced by the Wechsler Memory Scale way. After all, the purpose of matching and control group
and its revisions (e.g., Wechsler, 1987) and by the Califor- designs is to eliminate or at least limit extraneous influ-
nia Verbal Learning Test (Delis, Kramer, Kaplan, & Ober, ences on group differences. Still, many potential cognition-
1987) and the Rey Auditory Verbal Learning Test (Spreen mediating factors, from medication to the influence of a
& Strauss, 1998, pp. 326 –340). The selective attention chronic illness, cannot be equalized between patient and
version of dichotic listening (Egeth, 1992), whereby re- control groups and either exist selectively in patient popu-
search participants shadow one message and ignore an- lations or represent interacting variables.
other, is in the same range of effect magnitudes. Pathophysiology
In contrast to these large cognitive performance dif-
ferences between patients and healthy people, structural One cognition mediator that may occur preferentially in
MRI studies of the left temporal lobe and subregions like schizophrenia patients and not in healthy people is illness-
the hippocampus yield very modest but stable evidence. related brain disturbance or pathophysiology. Cognitive
These ESs suggest that tissue volumes are below the nor- performance depends on the integrity of brain systems that
mal range in one quarter to one third of the patient popu- mediate information processing. When this integrity is

April 2005 ● American Psychologist 233

Figure 2
Meta-Analytic Findings in Left Frontal Lobe System Domains

Note. This summary shows grand mean effect sizes and their 95% confidence intervals synthesized from studies of phonemic word fluency (Controlled Oral Word
Association Test [COWAT]; Benton & Hamsher, 1983; Heinrichs, 2001), the category score from the Wisconsin Card Sorting Test (WCST; Heaton et al., 1993;
Heinrichs, 2001), Continuous Performance Test (CPT) scores indexing response accuracy and discrimination (d⬘; Barch et al., 2001; Heinrichs, 2001), positron
emission tomography (PET) and xenon imaging in active and resting conditions, and structural magnetic resonance (MRI) measures of left frontal lobe brain volumes
(Davidson & Heinrichs, 2003).

compromised through disease, trauma, or faulty develop-
ment, then performance problems ensue. Yet cerebral in-
tegrity is multidimensional, and cognition typically de-
pends on distributed neural mechanisms rather than on one
circumscribed region. For example, formation and recall of
new memories seems to involve several structures includ-
ing the hippocampus, dorsomedial thalamus, and basal
forebrain, with possibly a special role for cholinergic neu-
rotransmission within this system (Baddeley et al., 2000).
Similarly, analogical reasoning is fractionated across the
brain (Wharton et al., 2000). However, some abilities are
more focally represented. Thus, a small region of the infe-
rior temporal lobe may play a crucial role in category-
specific naming (Pouratian, Bookheimer, Rubino, Martin,
& Toga, 2003). Overall, the cerebral representation of
cognitive abilities is understood to be complex, multifocal,
and dynamic (Mar, 2004; Sporns, Chialvo, Kaiser, &
Hilgetag, 2004).
Many researchers and clinicians believe that schizo-
phrenia compromises normal function in fronto-temporal
brain systems, giving rise to the cognitive impairments
seen in most patients. Yet demonstrating and describing the
nature of this cerebral compromise remains a challenge
(Harrison, 1999; Harrison & Weinberger, 2005). There are
few signs of obvious lesions, although postmortem brain
tissue may reveal cell disorganization and other possible
echoes of arrested neurodevelopment (Selemon, 2001). For
the most part, findings on brain dysfunction in schizophre-
nia derive from neuroimaging studies like those summa-
rized in Figures 1–3. Hence the picture of cerebral com-
promise that emerges is one of reduced tissue volumes in
key structures, altered or absent patterns of regional blood
flow and metabolism, and increased or decreased neuro-
transmitter densities. Meta-analysis reveals that these find-
ings probably occur in minorities of schizophrenia patients.
Still, many applications of neuroimaging show that re-
gional anatomy and physiology vary with cognitive perfor-
mance in the illness, and this finding supports the idea that
a disturbed brain may contribute to the severity of cognitive
deficits.
For example, recent fronto-temporal neuroimaging
findings correlate with word generation (Watanabe & Kato,
2004), verbal memory (Harrison, 2004; Weiss et al., 2004),
and abstraction (Yacubian et al., 2002) performance in

234 April 2005 ● American Psychologist

Figure 3
Meta-Analytic Findings in Left Temporal Lobe System Domains

Note. The summary includes grand mean effect sizes and their 95% confidence intervals synthesized from measures of words or paragraphs recalled over trials
(verbal memory; Heinrichs & Zakzanis, 1998), auditory selective attention or shadowing performance (dichotic listening) studies (Heinrichs, 2001), volumetric
structural magnetic resonance imaging (MRI) studies of the hippocampal subregion and entire left temporal lobe as well as positron emission tomography (PET) and
xenon imaging during task active and resting conditions (Davidson & Heinrichs, 2003).

schizophrenia patients. In addition, special high-resolution
techniques are beginning to articulate the abnormal cir-
cuitry that may underpin at least some cases of the illness.
Hence, Nestor et al. (2004) used diffusion tensor imaging,
which provides data on brain fiber tract integrity, to study
cerebral correlates of cognitive performance. The coher-
ence and directionality of the fronto-temporal tract ac-
counted for more than half the variance in patients’ Wech-
sler Memory Scale—Third Edition (Wechsler, 1997) verbal
recall scores. Such findings not only support the idea that
impaired cognitive performance in schizophrenia reflects
an impaired brain, they provide potential clues about the
underlying pathophysiology.
Against this support it must be admitted that cognitive
impairments do not always correlate with neurobiological
data in a predictable or consistent way. For example, hip-
pocampal volumes associate with executive function in-
stead of with verbal memory performance in some studies
(Szeszko et al., 2002; Torres, Flashman, O’Leary, Swayze,
& Andreasen, 1997). Indeed, a recent review concluded
that memory deficit–regional brain correlations are ex-
tremely inconsistent in schizophrenia patients (Weiss &
Heckers, 2001). Accordingly, it is likely, but not proven,
that an underlying brain disturbance enhances the sensitiv-
ity of cognitive performance to schizophrenia. A convinc-
ing and reproducible demonstration with details on the
nature of this disturbance is still missing. Hence, increas-
ingly, research on pathophysiology is being linked to neu-
rogenetic paradigms in an effort to clarify both the origins
and the location of the putative schizophrenic brain distur-
bance.
Genetic Influences
One of the most important constraints on cognitive ability
in health or illness is genetic in nature. General cognitive
ability is under strong genetic influence, and this general
factor contributes to many different tasks (Plomin & Spi-
nath, 2002). Therefore, inheritance plays a role in every
patient’s—and every healthy person’s— cognitive strengths
and weaknesses. In principle, the use of healthy research
participants should randomize the contribution of these
cognition genes across patient and control groups. Unless,
of course, one or more genes involved in cognition are also
involved in causing schizophrenia. In that case, the gene
may contribute selectively to impairment in the patient
group.

April 2005 ● American Psychologist 235


Figure 4
Multiple Influences on Cognitive Performance in
Schizophrenia
Genetic relatedness is one of the few factors consis-
tently shown to elevate a person’s risk for developing
schizophrenia (Gottesman, 2001). For example, having one
parent with the illness alters the risk from a population base
rate of 1% to a risk of about 13%. In the special case of
identical twins and fully shared genetic endowment, the
risk to one twin if the other develops schizophrenia ap-
proaches 50%. Adoption studies have shown that it is
primarily biology and not family environment that predicts
these elevations (Ingraham & Kety, 2000). Yet the search
for specific genes, regulatory mechanisms, and gene prod-
ucts involved in schizophrenia is an ongoing enterprise that
has yielded no definitive answers.
One possibility is that genes influencing key brain
regions like the frontal lobes are those that also confer a
susceptibility to schizophrenia. The COMT (catechol-O-
methyltransferase) Val(158)Met polymorphism and adja-
cent genes that mediate brain development are possible
candidates in this regard (Bilder et al., 2002; Sanders et al.,
2004). In addition, genes involved in cognition, but not in
the etiology of schizophrenia, may interact with the com-
plex biology of the illness. For example, the NOTCH4 gene
is believed to influence frontal brain tissue volume and
cognition. Recent evidence implies that the NOTCH4 does
not associate with susceptibility to the illness but does
mediate cognition differently in patients and healthy people
(Wassink, Nopoulos, Pietila, Crowe, & Andreasen, 2003).
Accordingly, it is probable that complex interactions be-
tween disease susceptibility and cognition-related genes as
well as their direct effects enhance the sensitivity of cog-
nitive performance to schizophrenia.
236
Task Content and Structure
Cognitive performance also reflects the tasks and proce-
dures used to measure it. Moreover, it is apparent that
cognitive tasks vary in their discriminating power when
administered to schizophrenia patients and healthy people.
For example, the timed phonemic fluency or COWAT
(Benton & Hamsher, 1989) included in Figure 2 yields a
mean ES of 1.09 (Heinrichs, 2001; see also Bokat &
Goldberg, 2003). In contrast, the well-known Block Design
subtest of the Wechsler Adult Intelligence Scale—Revised
(Wechsler, 1981) yields an ES of only 0.46. The respec-
tive—and nonoverlapping—95% confidence intervals for
these means (COWAT: 0.92–1.26; Block Design: 0.24 –
0.68) suggest that the word fluency effect is significantly
larger than the Block Design effect. If the clinical samples
used to generate these effects are similar, then it is tempting
to conclude that schizophrenia involves a more severe
impairment in rapid word generation than in spatial rea-
soning. Hence, all other things being equal, tests of these
two abilities will differ in their sensitivity to the illness.
However, many things are not equal, and this compli-
cates the interpretation of task performance and inferences
about test sensitivity. Most popular tasks in schizophrenia
research are standardized clinical tests measuring more
than one aspect of cognition at a time. The phonemic
fluency task mentioned above is a case in point. The
COWAT elicits words beginning with specified letters over
three 1-min trials, with the total number produced repre-
senting the main performance index. Yet the test taker is
also instructed to observe a rule that responses cannot be
proper nouns or variations of a previous response. Accord-
ingly, the test can be viewed as an index of language
function because it involves word retrieval. But it also taps
executive ability and working memory because of the re-
quirement to maintain and apply a response rule while
searching and selecting candidate words. Finally, the pho-
nemic word fluency test measures processing speed be-
cause of the time limit imposed. Is one or all of these
abilities especially sensitive to schizophrenia?
In the clinical practice of neuropsychological assess-
ment, psychologists usually use batteries of tests varying in
performance requirements to aid interpretation of an indi-
vidual patient’s cognitive status (see Lezak, Howiesen, &
Loring, 2004). Hence, impaired word fluency in the pres-
ence of normal performance on other language-related and
working memory tasks may mean that processing speed is
the most compromised function. Researchers in cognitive
neuroscience parse the mind with experimental paradigms
and focus on more refined operations like lexical phono-
logical retrieval instead of standard word generation (see
Martin, 2003). Yet controversies dog basic science as well
as practice with respect to the nature, composition, and
measurement of key cognitive constructs (Logan, 2004;
Tulving, 2002). The general consensus in schizophrenia
research is that multiple aspects of cognition are impaired,
including attention, working memory, encoding acquisi-
tion, and executive ability (Blanchard & Neale, 1994;
Heinrichs, 1993). These impairments are captured power-
April 2005 ● American Psychologist
fully but rather coarsely by commonly used tests of cog-
nitive ability, and more detailed articulation is required.
Apart from the putative function or process tapped by
a given task, there is the level of complexity, difficulty, and
therefore mental effort it requires. Hence, it is possible to
design and administer easy or demanding cognitive tasks,
and this difficulty dimension can augment or reduce group
differences (Chapman & Chapman, 1989). For example,
impaired word production in schizophrenia may reflect
faulty search strategies or faulty selection from competing
alternatives— or both. But then consider the difficulty of
corresponding tasks and conditions. Marvel, Schwartz, and
Isaacs (2004) found that patients showed only search def-
icits when search and selection conditions were equalized
for level of difficulty. It is possible that many cognitive
tasks are sensitive to schizophrenia simply because they are
effort demanding rather than because they require mental
operations selectively impaired in the illness.
These considerations are complemented by the likeli-
hood that the processing requirements of a cognitive test
interact dynamically with preserved and impaired brain
systems to influence discriminating power and ES. Thus, if
defects in specific cerebral systems underlie schizophrenia,
then tasks mediated by those systems will be impaired.
However, compensatory brain regions may take over and
normalize performance if part of a neural system is ren-
dered inoperative by disease. It seems, for example, that
some aspects of memory lend themselves to compensation
and others do not. Memory-impaired schizophrenia pa-
tients with deficient hippocampal activation benefit nor-
mally from encoding manipulations designed to enhance
recall (Weiss et al., 2003). Put another way, verbal learning
and recall tests are highly sensitive to the illness (Aleman,
Hijman, de Haan, & Kahn, 1999), but encoding manipula-
tion tests are not. This differential sensitivity may occur
because patients increase prefrontal activation in the ab-
sence of hippocampal activation. It seems that greater
prefrontal activity compensates for lack of hippocampal
recruitment during a memory task. It follows, therefore,
that the sensitivity of a cognitive task depends on its overall
difficulty level, on whether operations required by the task
are compromised in schizophrenia, and on whether these
operations lend themselves to compensation through re-
cruitment of preserved brain systems.
Stress, Distress, and Treatment
Prolonged stress and distress may act negatively on cogni-
tive performance and contribute to the magnitude of group
differences. Indeed, any stressful medical or psychiatric
condition can have a debilitating influence, and evidence is
mounting that stress biology mediates both cognitive and
neuroimaging findings (Erickson, Drevets, & Schulkin,
2003; Hull, 2002). Hence, it is perhaps not surprising that
motor vehicle accident survivors with whiplash but no
brain injury demonstrate impairments on cognitive tasks
(Kessels, Aleman, Verhagen, & van Luijtelaar, 2000). Sim-
ilarly, patients with posttraumatic stress disorder are im-
paired relative to healthy people on attention and immedi-
ate memory tasks (Horner & Hamner, 2002). In contrast,
April 2005 ● American Psychologist
conditions not associated with stress and distress, like
antisocial personality disorder, show normal cognitive
function (Crowell, Kieffer, Kugeares, & Vanderploeg,
2003).
It is known that a substantial proportion of schizo-
phrenia patients experience stress, anxiety, and a related
decline in life quality (Ponizovsky, Grinshpoon, Sasson, &
Levav, 2004; Steer, Kumar, Pinninti, & Beck, 2003; Weth-
erell et al., 2003). Moreover, stress hormone levels predict
patients’ cognitive performance (Halari et al., 2004). How-
ever, it is less clear whether chronic stress and distress are
by-products of schizophrenia or precede and contribute to
illness onset in the first place. For example, there is evi-
dence of abnormal stress hormone biology in adolescents at
risk for psychosis (Walker, Walder, & Reynolds, 2001).
Yet cognitive impairment is relatively mild during the
prodrome period prior to the first psychotic episode
(Hawkins et al., 2004). At the same time, there is little to
suggest that most patients undergo a progressive cognitive
deterioration over the course of illness (Albus et al., 2002;
Friedman, Harvey, Kemether, Byne, & Davis, 1999). On
balance, it is reasonable to argue that the persisting stress
and distress experienced by many schizophrenia patients
have a performance-reducing effect on cognition. How-
ever, ambiguity remains with respect to the origin, nature,
and consistency of this reduction.
In contrast, the potential influence of antipsychotic
medication on cognitive performance can only occur fol-
lowing exposure to mental health care services and a pro-
visional diagnosis. It has been known for 3 decades that
psychotic symptoms diminish to the extent that drugs block
receptors for dopamine and other neurotransmitters (See-
man & Lee, 1975). Furthermore, there is evidence that the
brain responds to this blockade by growing more receptors
(Cooper, Bloom, & Roth, 1996, pp. 313–330). In a way,
drug treatment alters the working brains of people with
schizophrenia. The question is whether this alteration me-
diates the cognitive impairments that are so prevalent in the
illness.
Unfortunately, finding a definitive answer to the ques-
tion of drug-induced impairment in schizophrenia is no
easy matter. In pursuing the issue, it is especially important
to evaluate medication-naive patients never exposed to
antipsychotic medication, not just those who are medica-
tion free at the time of testing. Therefore, it is noteworthy
that Barch, Carter, MacDonald, Braver, and Cohen (2003)
reported results with a version of the Continuous Perfor-
mance Test in medication-naive schizophrenia patients.
These patients were impaired on the Continuous Perfor-
mance Test, and impairment persisted beyond the acute
illness phase and after medication was introduced. Indeed,
ESs derived from the data (average ES ⫽ 1.14) approxi-
mate those obtained with medicated and more chronic
schizophrenia patients (average ES ⫽ 1.04; Heinrichs &
Zakzanis, 1998). In addition, Hill, Schuepbach, Herbener,
Keshavan, and Sweeney (2004) recently reported impair-
ment across many cognitive domains prior to initial anti-
psychotic drug treatment. Finally, cognitive deficit has
been documented in high-risk and prepsychotic popula-
237
tions well before medication exposure takes place (Erlen-
meyer-Kimling et al., 2000).
Another perspective on the medication– cognition in-
terface holds that newer or atypical antipsychotic drugs
actually exercise a positive influence on cognition (Sharma,
2002; Weickert et al., 2003). Even the older, typical neu-
roleptics like chlorpromazine and haloperidol are being
reevaluated in light of evidence that they provide patients
with mild cognitive benefits (Mishara & Goldberg, 2004).
However, given the presence of countervailing findings,
especially with respect to the older drugs, it is unlikely that
this controversial issue can be resolved easily (Bilder,
1997). It may also be that supplementary medication, in-
cluding anticholinergic agents prescribed to alleviate side
effects, contributes to specific cognitive impairments like
memory deficit.
Education, Gender, and Culture
An important influence on cognitive performance that may
operate differentially in schizophrenia and healthy compar-
ison participants is educational background and experience.
It is known that educational achievement predicts perfor-
mance on most cognitive tests (Stratta, Prosperini, Dane-
luzzo, Bustini, & Rossi, 2001). However, the nature and
direction of the relationship is complex. Cognitive ability
levels, partly determined by genes, may set an upper limit
on educational achievement. But deficient educational ex-
perience can also set limits on test performance, especially
in terms of abilities like verbal and academic skills that are
enhanced by formal schooling.
Case-control differences should not be influenced by a
variable like education if achievements are similar in pa-
tient and control groups. Yet achievements are not similar
because education is affected negatively by symptomatic
schizophrenia and by its prodrome and childhood anteced-
ents (Fuller et al., 2002; Van Oel, Sitskoorn, Cremer, &
Kahn, 2002). Most patients do not complete postsecondary
studies and many do not even complete high school. This
premature end to education makes it hard to create com-
parable groups and can lead to underestimates of expected
intellectual ability in the patients (Meehl, 1970). Partial
solutions to the problem include matching patients and
control participants on parental education. When this in-
formation is hard to obtain, reading recognition scores
provide another way of estimating academic potential in
patient and comparison groups (Kremen et al., 1996).
A further possible factor in cognitive performance is
gender. Although population base rates for schizophrenia
are approximately equal in men and women, patient re-
search samples are often 80% male (Heinrichs & Zakzanis,
1998). Patient and control groups are typically matched on
gender composition so that the same high proportion occurs
in each group. The problem is that schizophrenia and
cognitive impairment may be more severe in men than in
women. Therefore, predominately male patient samples
will be more impaired than patient samples with equal
gender proportions. Thus, a clinical versus control group
comparison with, say, 80% men in both groups will yield a
larger cognitive ES than a comparison with 50% men in
238
each group. Trends across studies in support of this pre-
diction were detected by moderator analysis (Heinrichs &
Zakzanis, 1998) and confirmed in a recent study of verbal
memory (Sota & Heinrichs, 2003). Male patients deviated
more than female patients from gender-based healthy pop-
ulation norms. Thus, gender may amplify cognitive impair-
ment unless study samples accurately reflect the gender
proportions of the schizophrenia patient population.
Finally, it is possible that socioeconomic and cultural
attributes operate differentially in patient and control sam-
ples despite efforts to control them through design or
matching strategies. Schizophrenia has a higher incidence
in disadvantaged immigrants than in the general population
(Eaton & Harrison, 2000). Moreover, ethnic background
predicts cognitive performance, especially in relation to
language-based tests, even in native English-speaking pop-
ulations (Gladsjo et al., 1999). Hence, schizophrenia sam-
ples with strong representation of disadvantaged sociocul-
tural and language groups will also be at a cognitive
disadvantage. Once again, sampling and matching strate-
gies designed to equate such attributes between patient and
control groups are no guarantee that extraneous influences
have been eliminated. Cognitive ESs will increase if the
cognitive disadvantage normally conferred by some socio-
economic and cultural factors is compounded by greater
disease severity in the disadvantaged group. Therefore, as
is the case with gender, care must be taken to ensure that
socioeconomic and cultural profiles of clinical samples
accurately reflect the broad patient population. Healthy
control participants can then be recruited to match these
profiles.
Conclusions: Capturing the Causes of
Schizophrenia With Cognitive
Measures
Cognitive differences between schizophrenia patients and
healthy people have emerged systematically as the most
powerful findings across hundreds of studies and 2 decades
of neuroscience-based research. On average, cognitive
measures yield ESs that are twice as large as those obtained
with measures of regional brain volume (structural MRI),
blood flow, metabolism, and receptor occupancy (PET/
xenon). In addition, the stability and reproducibility of
cognitive evidence compares favorably with these neuro-
imaging measures. The reason for such large and robust
case-control differences must inhere in variables that co-
exist with schizophrenia and other prolonged illnesses,
occur disproportionately in patient samples, or interact with
the disease process. These variables may include stress and
distress, pathophysiology and its interactions with task
structure, and a variety of genetic and background influ-
ences that nest within patient samples. In concert, such
variables have a performance-reducing influence on cogni-
tion, giving rise to the large differences found between
schizophrenia patients and healthy people.
Yet the challenge of understanding why cognitive
brain function is so sensitive to schizophrenia has a corol-
lary. The glass of evidence is half empty as well as half full.
April 2005 ● American Psychologist
Although cognitive ESs are large, they are not large enough
to be markers for any condition defined by the DSM–IV
schizophrenia category. The largest cognitive and psycho-
physiological findings, obtained for verbal recall deficit
(ES ⫽ 1.41) and the P502 evoked potential (ES ⫽ 1.55),
imply that about 70% of patients are distinguishable from
healthy comparison participants (Heinrichs, 2001). Aver-
aging across cognitive literatures, somewhat more than half
of the patient population is likely to show any given im-
pairment. But why are cognitive effects not even larger,
large enough to capture virtually all of the patient popula-
tion? Such markers might involve findings in the range of
ES ⫽ 3.00, whereby over 90% of cases in a joint distribu-
tion are separated. What limits the sensitivity of cognitive
performance to schizophrenia, and why is a substantial
minority of patients apparently unimpaired on any given
measure?
One way of understanding the evidence is through the
concepts of endophenotype and disease variant. Endophe-
notypes are defined as biobehavioral abnormalities that are
linked to the genetic and neurobiological causes of mental
illness (Gottesman & Gould, 2003). They are intermediate
between the phenomenal world of symptoms and the mi-
croscopic realm of biology. More objective and measurable
than delusions or apathy, they represent illness-promoting
vulnerabilities. Endophenotypes are rooted in genes and
brain systems but may express themselves in response to
the environment and experience. Specific endophenotypes
probably occur at fairly high frequency in the broad schizo-
phrenia patient population. However, there is no reason to
assume that all patients with the DSM–IV diagnosis share
any single endophenotype (Kendell & Jablensky, 2003).
Indeed, schizophrenia patients are no more likely than
people with epilepsy, movement disorders, or dementia to
have one inclusive biobehavioral defect.
It is likely that large cognitive ESs reflect the presence
of endophenotypes embedded in the artificial and exces-
sively broad schizophrenia category (Heinrichs, 2004).
Discovery and articulation of specifically cognitive endo-
phenotypes would spur research closer to the causes of the
illness by organizing patients into more homogenous
groups. In the future, schizophrenia may resolve into etio-
logically distinct disorders in the way that dementia has
resolved into Alzheimer’s and cerebrovascular conditions.
From this perspective, it is the complex composition and
heterogeneous nature of schizophrenia that has set the
upper limit on average ESs and on the diagnostic sensitivity
of cognitive findings.
Yet it is unlikely that any given deficit in cognitive
performance automatically qualifies as a cognitive endo-
phenotype. First, although dozens of clinical and experi-
mental tests and paradigms are in common use, the number
of separable cognitive performance dimensions is much
smaller (Nuechterlein et al., 2004). Second, cognitive sub-
types or putative endophenotypes are often derived from
cross-sectional data and may not represent true neurobe-
havioral traits that persist over time (Heinrichs, Ruttan,
Zakzanis, & Case, 1997). Finally, a cognitive trait must do
more than show high prevalence and convincing stability in
April 2005 ● American Psychologist
schizophrenia patients. It must also show evidence of her-
itability and segregation with the illness in families
(Gottesman & Gould, 2003). Taken together, these consid-
erations suggest that many hurdles must be passed on the
road from cognitive performance to cognitive endopheno-
type (Keri & Janka, 2004).
Nonetheless, recent empirical studies in cognitive sub-
typing and genetic epidemiology are promising and lend
support to the existence of cognitive endophenotypes and
variants within the schizophrenia population (Seaton,
Goldstein, & Allen, 2001). There is suggestive evidence
that global cognitive impairment defines a subgroup pos-
sibly linked to susceptibility genes on chromosome 6 (Hall-
mayer et al., 2003). Impaired verbal memory may also
indicate a genetic liability to schizophrenia (Toulopoulou,
Morris, Rabe-Hesketh, & Murray, 2003) and define a sub-
group of patients with poor medication response (Joober et
al., 2002) and severe functional disabilities (McDermid
Vaz & Heinrichs, 2002). It is perhaps ironic that cognitive
performance, less obvious and striking than the symptoms
used to define the illness and less technically impressive
than brain imaging, may in the end be the signpost that
leads to the source of madness.
Hence, it is important to acknowledge the lessons of
meta-analysis. Neurobiological measures, especially neu-
roimaging techniques, have underestimated differences be-
tween schizophrenia patients and healthy people relative to
cognitive measures. Make the brain do cognitive work and
measure performance in behavioral terms to maximize
differences between patients and healthy people. It must be
that the brain’s cognitive operating principles lie close to
the causes of schizophrenia and its variants. The task of
research is to identify those operating principles and trans-
late them into terms that can be measured and modified
through treatment.
2
The P50 brain wave abnormality comprises a voltage shift in
response to a brief auditory event like a click. Measured with an electro-
encephalograph, the shift is positive and peaks about 50 ms after the
stimulus event. Healthy people typically show a reduced P50 in response
to a repeated click because the brain habituates to the stimulus. However,
many schizophrenia patients demonstrate an abnormally robust P50, sug-
gesting failure of the brain’s ability to habituate or gate a sensory event
(Siegel, Waldo, Mizner, Adler, & Freedman, 1984).
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