REVIEW
THE NATURE AND SIGNIFICANCE OF COGNITIVE IMPAIRMENT
IN SCHIZOPHRENIA
—
I
David J. Schretlen, PhD, ABPP*
ABSTRACT
Defining features of schizophrenia include
abnormal perceptions (hallucinations) or
thoughts (delusions), disordered thinking, disorganized or catatonic behavior, and “negative”
symptoms, such as emotional blunting, decreased
initiative, and impoverished speech. In addition,
there is growing evidence that cognitive deficits
precede, accompany, and outlast the more dramatic positive symptoms of schizophrenia and its
treatment. Functions that appear to be most
affected include verbal learning, memory, psychomotor speed, and vigilance. This article offers
a review of the prevalence of cognitive impairment in schizophrenia, in addition to the nature
and severity of the deficits and their functional significance. Recent studies have found that 75% to
85% of patients experience at least some degree
of cognitive impairment. Moreover, even those
who appear cognitively intact actually show mildly depressed functioning on sensitive measures of
information processing. Cognitive impairment has
been shown to negatively affect daily functioning,
work outcomes, level of required residential care,
and treatment adherence. Also included in the
article is a discussion of the development process
for a standardized cognitive battery designed to
serve as an outcome measure for clinical trials of
cognition-enhancing drugs and cognitive rehabilitation programs.
(Adv Stud Med. 2007;7(3):72-78)
*Associate Professor, Department of Psychiatry and
Behavioral Sciences, Johns Hopkins University School of
Medicine, Baltimore, Maryland.
Address correspondence to: David J. Schretlen, PhD,
ABPP, Associate Professor, Department of Psychiatry and
Behavioral Sciences, Johns Hopkins University School of
Medicine, The Johns Hopkins Hospital, 600 North Wolfe
Street, Meyer 218, Baltimore, MD 21287-7218.
E-mail: [email protected].
72
ncreasingly recognized as a heterogeneous disorder with more than one etiology, schizophrenia burdens its patients with signs and
symptoms in multiple domains. Defining features include abnormal perceptions (hallucinations) or thoughts (delusions), formal thought
disorder (illogical speech), grossly disorganized or catatonic behavior, and “negative” symptoms, such as
emotional blunting, decreased initiative, and impoverished speech. Patients experience varied admixtures of
these abnormalities. One might be plagued by the
whispered comments of unseen critics. Another
believes that he is burdened with God-like power to
control world events. Some patients are convinced that
external forces or even an implanted device controls
their thoughts and behavior. Many patients spend
most of their time alone, doing little more than sitting
or watching television. They speak with a monotone
voice and make oddly idiosyncratic remarks when
engaged in conversation. In addition, virtually all
affected individuals show impaired functioning in the
areas of work, social interaction, or self-care.
PREVALENCE OF COGNITIVE IMPAIRMENT
SCHIZOPHRENIA
IN
The standard diagnostic nomenclature for schizophrenia includes an extensive list of symptoms.
Conspicuously absent from the diagnostic criteria is
any reference to cognitive impairment.1 However, several lines of evidence suggest that neuropsychological
compromise is a core feature of schizophrenia.
Children who later develop the illness have been
observed to display intellectual deficits long before the
emergence of psychotic symptoms.2 Moreover, unaffected relatives of patients with schizophrenia exhibit
qualitatively similar cognitive deficits, with severity
corresponding to the degree of genetic susceptibility.3
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Cognitive deficits do not result from hallucinations,
delusions, apathy, or other primary disease symptoms;
they also do not result from medications used to treat
schizophrenia.4 Cognitive impairment also has been
found to remain relatively stable over time, with the
nature and severity of neuropsychological deficits seen
in drug-naïve, first-episode patients resembling those
of chronic patients.5 In short, there is growing evidence that cognitive deficits precede, accompany, and
outlast the more dramatic positive symptoms of schizophrenia and its treatment.
The recognition of cognitive impairment as a core
feature of the illness raises the question of whether it is
present in all cases. Although observed rates are lower,
the exact proportion of individuals with schizophrenia
who suffer from cognitive deficits remains unclear.
Some early studies suggested that fewer than 50% of
persons with schizophrenia may be afflicted.
However, more recent studies have found that 75%
to 85% of patients experience at least some degree of
cognitive impairment.6 Those patients who show no
signs of neuropsychological dysfunction also raise the
question of whether it is possible to have schizophrenia without cognitive impairment.7 Although it is
logically impossible to answer this question definitively, many patients who appear cognitively intact
actually show mildly depressed functioning on selected, highly sensitive measures of information processing. For example, Kremen et al found that the 23%
of patients with schizophrenia who produced “normal” neurocognitive profiles also showed higher estimated premorbid IQs than healthy control subjects.8
Furthermore, when each cognitively “normal”
patient was matched in overall cognitive functioning
with a healthy control subject, the patients performed significantly worse than control subjects on
tests of executive functioning and psychomotor
speed, yet they performed better than control subjects on tests of general verbal ability. When patients
in another study were matched individually to within 3 IQ points with healthy adults, patients with
above average to superior intelligence (IQs ≥110
points) still performed significantly worse than
healthy adults on tests of immediate memory.9 These
results suggest that most patients with schizophrenia,
including those who appear cognitively intact or
show above average intelligence, have at least mild
selective deficits, relative to their own premorbid
level of functioning.
Johns Hopkins Advanced Studies in Medicine
n
NATURE AND SEVERITY OF THE DEFICITS
Any group of individuals with schizophrenia will
perform worse than demographically similar healthy
adults on virtually any reliable and valid measure of
neurocognitive functioning. The very consistency of
this observation complicates identification of a neuropsychological “signature” of schizophrenia. Whether
investigators examined a very discrete aspect of information processing or broad cognitive domains, hundreds of studies have shown that schizophrenia confers
cognitive impairment, with some deficits being less
prominent than others. In fact, accumulating literature
suggests a neurodevelopmental basis for this illness,
because affected children manifest intellectual deficits
years prior to developing psychotic symptoms and
adults with schizophrenia even show impairment on
tests designed to assess “premorbid” ability. Keefe et al
found that patients in the Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) study scored well
below expectations on a word reading test used to estimate premorbid ability.10 In another study, 91 adults
with schizophrenia performed worse than their firstdegree relatives, patients with affective psychoses, their
relatives, and healthy control subjects on another word
reading task (the National Adult Reading Test or
NART) designed to assess premorbid IQ.11
Attempts to identify a neuropsychological profile
of schizophrenia must begin with the recognition that
this disease affects virtually all cognitive domains. In
examining the literature, studies that assess a broad
spectrum of abilities can shed light on differential
impairment across domains, whereas meta-analyses
(quantitatively combined findings from narrower
studies) can offer insight into particular types of cognitive deficits. The latter analysis involves computing the magnitude of difference between 2 groups
(ie, healthy adults vs patients with schizophrenia) on
a common dependent variable (ie, IQ) that is reported by several different investigators. Between-group
differences in IQ are expressed in terms of the variance shown by each group (usually the pooled SD),
which also is used to estimate the size of the effect.
These effect size estimates can then be averaged
across studies to quantify the magnitude of the
group difference on each cognitive measure reported
in the existing literature.
The most widely cited meta-analysis of cognitive
functioning in schizophrenia was conducted by
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Effect size, Cohen’s d
Heinrichs and Zakzanis, which computed 509 effect
Despite limitations that are inherent to various
sizes for the comparisons that were reported in 204
approaches used to identify schizophrenia-associated
studies based on 7420 patients and 5865 healthy concognitive domains, converging evidence suggests that
trol subjects.12 As one would assume, the studies that
verbal learning, memory, psychomotor speed, and vigprovided data for their meta-analysis used a multitude
ilance are among the affected functions. Visual learnof different cognitive tests. The authors assigned effect
ing/memory, problem solving, verbal fluency, and
sizes to 1 of 22 variables, which were based on a single
executive functioning also are impaired, but perhaps
test or combined measures from different instruments.
not disproportionately. Functions that are probably
The 22 variables were then grouped into 8 cognitive
least affected by schizophrenia include attention span,
domains: memory, motor skills, attention, general intelperceptual discrimination, and basic linguistic abililigence, spatial ability, executive functioning, language,
ties, such as naming and receptive vocabulary.4,12,15,16
Some investigators have argued that schizophrenia
and tactile-transfer. Although their assignment of indiis characterized by a unique pattern of cognitive
vidual measures to 22 variables and the grouping of
deficits.17 However, recent studies suggest that the cogvariables into cognitive domains could be questioned,
nitive deficits shown by patients with bipolar disorder
the task was daunting and the resulting effect sizes make
are, albeit milder, qualitatively similar to those seen in
intuitive sense in most respects. The effect sizes ranged
schizophrenia. In one analysis, 9 cognitive measures
from 0.5 to 1.4 (mean of 0.9), indicating that patients
(each assigned to 1 of 6 cognitive domains) were
performed nearly 1 SD below healthy control subjects
administered to 106 outpatients with schizophrenia,
across all measures of cognitive function. However, a
66 outpatients with bipolar disorder, and 316 reasoncounterintuitive finding was that one of the largest
ably healthy control subjects.18 Test scores were adjusteffects was for Wechsler Adult Intelligence Scale13
ed for age, sex, race, and years of education, and
Revised (WAIS-R) Performance IQ scores, whereas
one of the smallest effects emerged for a WAIS-R subestimated premorbid IQ, and effect sizes for differtest (Block Design) that is used to compute
ences between healthy control subjects and each
Performance IQ. In any case, the effect size for Full
patient group were computed (Figure).18 Both patient
groups performed significantly worse than healthy
Scale IQ scores was 1.1, suggesting that patients with
schizophrenia scored slightly more than 16 IQ
points below that of healthy control subjects.
The statistical method of factor analysis is
another way of defining cognitive domains. This
Figure. Cognitive Profiles of Patients with SZ and BD
method can elucidate a few “latent” abilities that
account for most of the observed variation in per0
formance on many different tests. However, one
BD
SZ
-0.2
limiting factor is the dependence of the latent fac-2..4
tor structure on specific measures included in the
-0.6
analysis. Different factor solutions can come from
-0.8
2 patient samples administered the same test, as
-1
well as from a single sample, depending on which
-1.2
measures are included in the analysis. Also, the
-1.4
possibility that schizophrenia alters the underly-1.6
ing organization of cognitive domains cannot be
-1.8
Psychomotor
Attention
Fluency
Visual
Executive
Verbal
excluded.14 For example, a factor analysis of test
speed
memory
function
memory
scores included in the CATIE study baseline
Cognitive domain
assessment revealed that a single factor best
Mean effect sizes for 6 cognitive domains based on demographically adjusted T-scores produced by patients with SZ and BD, compared to healthy adults. Repeated measures analysis
described the data, even though the measures
of variance planned contrasts confirmed that each patient group differed significantly from
were selected with the goal of representing 5 coghealthy controls on every cognitive domain (P <.01). Bonferroni-corrected post hoc comparisons showed the SZ and BD groups differed significantly (P <.05) on all domains except
nitive domains.10 Such findings complicate conattention.
ceptualization of cognitive domains based on
BD = bipolar disorder; SZ = schizophrenia.
factor analysis.
Reprinted with permission from Schretlen et al. Biol Psychiatry. 2006;[Epub ahead of print].
18
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control subjects in every domain, and patients with
schizophrenia performed significantly worse than
those with bipolar disorder in all but 1 domain (attention). But despite clear differences in the severity of cognitive deficits between patients with schizophrenia and
those with bipolar disorder, the cognitive profiles produced by these groups were qualitatively similar. These
observations suggest that any treatment that improves
cognition in schizophrenia may have broader application.
FUNCTIONAL SIGNIFICANCE OF COGNITIVE IMPAIRMENT
Cognitive functioning has attracted increasing attention because it appears to play a central role in many
aspects of functional outcome in schizophrenia.4,19 For
example, Velligan et al found that measures of global
cognitive functioning accounted for more than 40% of
the variance in activities of daily living in 2 separate
patient samples.20 Most importantly, after researchers
accounted for cognitive function, they found that severity of psychosis and negative symptoms did not improve
the prediction of everyday functioning in either sample.
Cognitive impairment has also been found to correlate
with the required level of residential care. Patients with
more severe deficits are more likely to require long-term
hospitalization or nursing home placement.21 Difficulties
in performing specific everyday tasks, such as planning
activities and paying bills, also have been shown to correlate with the severity of cognitive deficits.
Schizophrenia is one of the most common causes of
work disability. Although estimates of the proportion of
patients with schizophrenia who do not work vary, a
recent large-scale US survey found that 22.5% of
patients are employed, with 12% having full-time status.22 In the CATIE study, only 15% of patients were
working (7% full-time and 8% part-time) at baseline.
Several studies reveal that cognitive test performance correlates with or predicts work outcomes, such as employment status, work duration, and earned income.23,24
Although it is also important to consider the well-documented impact of other symptoms (ie, positive and negative) on work outcomes, cognitive impairment appears
to disrupt work ability independently from other symptoms and in proportion to the degree of deficit.
In addition to limiting the ability to live independently, manage activities of daily living, and work
competitively, cognitive deficits in schizophrenia are
associated with poor treatment adherence, medical
comorbidities, and increased treatment costs. Patients
Johns Hopkins Advanced Studies in Medicine
n
may lose medications, forget to take doses or refill prescriptions, fail to establish routines for medication use,
and misunderstand dosing directions.25 Comorbidities
are likely to further complicate treatment compliance,
because patients who poorly adhere to schizophrenia
medication are expected to have similar issues with
treatment for other conditions. Deficits in attention
and memory may also impede the ability of some
patients to make healthy lifestyle choices, such as not
smoking.26 In a recent prospective study of 85 patients
with schizophrenia, poor cognitive test performance at
baseline predicted increased costs for medical, psychiatric, and community care, even after symptom severity and social withdrawal were taken into account.27
Increasing evidence also indicates that cognitive difficulties contribute to decreased quality of life (QOL) in
patients with schizophrenia.4 Several studies have
shown that patients with more severe cognitive deficits
are less accurate in rating their social functioning than
patients with less severe deficits.28
Contradictory findings have been reported for all
the aforementioned research. Some studies failed to
find significant associations between cognitive functioning and other aspects of illness outcome or morbidity, whereas others found that, compared with
cognitive functioning, symptom severity, or social support account for more variance in work, QOL, and
other outcomes. Still, there is a reasonable and growing consensus that cognitive impairment is not only a
core feature of schizophrenia, it is also an aspect of the
illness with broad implications.
Unfortunately, despite the critical role of cognitive impairment in schizophrenia, antipsychotic
drugs have, at best, modest impact on cognition.17
Even patients receiving adequate antipsychotic treatment continue to experience significant cognitive
and functional impairment. These considerations
led the National Institute of Mental Health (NIMH)
to establish an initiative called Measurement and
Treatment Research to Improve Cognition in
Schizophrenia (MATRICS). In 2004, MATRICS
investigators, officials from the NIMH and the US
Food and Drug Administration, and experts from
academia and the pharmaceutical industry held a
meeting to develop guidelines for clinical trials of
cognition-enhancing drugs for schizophrenia. Initial
priorities included identifying specific cognitive
deficits that characterize schizophrenia and developing instruments to measure them.
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STANDARDIZED TESTING OF COGNITIVE FUNCTIONING
Numerous reliable cognitive tests have been validated for the assessment of schizophrenia. Some assessments, such as the Wechsler scales of intelligence, are
lengthy and include several subtests. Others, like the
Trail Making Test,29 are less time consuming and sensitive, but involve nonspecific tasks that require many cognitive processes for successful performance. Still other
tests assess discrete cognitive functions, like reaction
time. Most tests are administered individually using pencil and paper or other stimuli, but a few are administered
using computer or audio cassette. In practice, neuropsychologists usually administer a battery of tests to assess
functioning across multiple cognitive domains.
From one perspective, the availability of varied
instruments is useful because it allows for the elucidation of which cognitive functions are more or less
compromised by schizophrenia. If every study used the
same tests, it would be impossible to disentangle the
impairment of underlying cognitive abilities from the
method variance associated with each test. Test limitations would also hinder the discovery of new cognitive
abnormalities and their relationship with other disease
markers. Conversely, the diversity of instruments complicates a comparison of findings across studies. One
compromise is to identify a brief set of tests that assess
a core group of cognitive domains and augment these
with others tests as needed. In order to develop such a
test battery, a MATRICS committee consulted experts
in the field and identified criteria for test selection.
The latter included test-retest reliability, appropriateness as a repeated measure, relationship to functional
outcomes, potential sensitivity to medications, and
tolerability and practicality.30 In identifying “separable
cognitive factors,” the committee reviewed 13 factor
analytic studies of patients with schizophrenia versus
healthy control subjects and found 6 replicated cognitive factors to adequately represent the major cognitive
deficits seen in schizophrenia and later added a seventh
factor (social cognition).31 The final set of factors represents an abstraction of previous reports in the sense
that no single study actually found these 6 factors.
Following a series of additional steps and β testing, the
NIMH-MATRICS Consensus Cognitive Battery
(MCCB) was finalized and published by Matrics
Assessment Inc. The 7 factors and tests used to assess
them are shown in the Table.32
Table. MATRICS Consensus Cognitive Battery
Domain
Test
Speed of processing
Brief Assessment of Cognition in Schizophrenia:
Symbol-Coding
Category Fluency: Animal Naming
Trail Making Test: Part A
Continuous Performance Test-Identical Pairs
Attention-vigilance
Working memory
Verbal learning
Visual learning
Reasoning & problem
solving
Social cognition
Description
Timed test in which respondent uses a key to write digits that correspond to symbols
Oral test of speeded animal naming in 1 min
Timed test of scanning and sequencing numbered circles
Computer-administered test of ability to press buttons when
matching numbers are presented consecutively
Wechsler Memory Scale-3rd Edition: Spatial Span Test of ability to tap sequence of irregularly spaced cubes in same
(or reverse) sequence as examiner
Letter-Number Span
Oral test of ability to re-order strings of letters and numbers
Hopkins Verbal Learning Test-Revised
Test of ability to remember as many words as possible after each
of 3 oral presentations of 12-word list
Brief Visuospatial Memory Test-Revised
Test of ability to remember as many figures as possible after each
of 3 presentations of 6 geometric figures
Neuropsychological Assessment Battery Mazes
Seven timed pencil-and-paper mazes of increasing difficulty that
measure look-ahead planning
Mayer-Salovey-Caruso Emotional Intelligence Test: Pencil-and-paper multiple-choice test that assesses how people
Managing Emotions
manage their emotions
MATRICS = Measurement and Treatment Research to Improve Cognition in Schizophrenia.
Reprinted with permission from MATRICS—Measurement and Treatment Research to Improve Cognition in Schizophrenia. MATRICS Psychometric Validation Study.
Available at: http://www.matricsinc.org/MCCB.htm#1.32 Copyright 2006 Matrics Assessment Inc. All Rights Reserved.
76
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The MCCB was designed to serve as an outcome
measure for clinical trials of cognition-enhancing
drugs and cognitive rehabilitation programs. Two tests
(Hopkins Verbal Learning Test-Revised and Brief
Visuospatial Memory Test-Revised) have 6 alternate
forms and 1 test (Neuropsychological Assessment
Battery Mazes) has 2 forms. This structure provides the
MCCB with some suitability for repeated assessments.
Several tests in the battery are published separately with
their own normative samples. Performances on all of the
tests can be expressed in a uniform metric (T-scores),
and they are adjusted for age and sex. The MCCB measures were co-normed on a sample of healthy adults
aged 20 to 59 years and, for validation purposes, a β version was administered to 176 adult outpatients with
schizophrenia and then re-administered 4 weeks later.
Results of these studies have not yet been published in
peer-reviewed journals. The MATRICS initiative will
ensure adoption of the MCCB in clinical trials.
However, many other reliable and valid tests of cognitive abilities warrant consideration, not only for clinical assessment, but for use in neuropsychological
investigations and in clinical trials as well.
CONCLUSIONS
Cognitive impairment is increasingly recognized as
a critical aspect of schizophrenia, with a direct impact
on functional outcomes. Studies continue to uncover
varying degrees of impairment throughout the entire
course of the illness, including the prodrome period.
Even patients who appear cognitively intact usually
have subtle deficits on close examination. In order to
optimize available therapeutic modalities and, more
importantly, to develop viable cognition-enhancing
treatments, it is important to standardize assessment of
cognitive function and focus on schizophrenia-associated cognitive factors.
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