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Stability and Course of Neuropsychological Deficits in Schizophrenia
Robert K. Heaton, PhD;
Julie Akiko Gladsjo, PhD;
Barton W. Palmer, PhD;
Julia Kuck, PhD;
Thomas D. Marcotte, PhD;
Dilip V. Jeste, MD
Arch Gen Psychiatry. 2001;58:24-32.
ABSTRACT
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Background Neuropsychological deficits in schizophrenia appear to predate clinical
symptoms of the disease and become more pronounced at illness onset, but controversy
exists about whether and when further neuropsychological progression may occur.
Objective To identify and characterize any subset of patients who evidenced progressive
neuropsychological impairment, we compared the longitudinal stability of neuropsychological
functioning in schizophrenic outpatients and normal comparison subjects.
Methods One hundred forty-two schizophrenic outpatients and 206 normal comparison
subjects were given annually scheduled comprehensive neuropsychological evaluations
during an average of 3 years (range, 6 months to 10 years). Clinically and
demographically defined subgroups were compared, and test-retest norms were
used to identify individual patients who showed unusual worsening over time.
Results The schizophrenic group was neuropsychologically more impaired than
the normal comparison subjects but showed comparable test-retest reliability
and comparable neuropsychological stability over both short (mean, 1.6 years)
and long (mean, 5 years) follow-up periods. No significant differences in
neuropsychological change were found between schizophrenic subgroups defined
by current age, age at onset of illness, baseline level of neuropsychological
impairment, improvement or worsening of clinical symptoms, and occurrence
of incident tardive dyskinesia. Norms for change also failed to show neuropsychological
progression in individuals with schizophrenia.
Conclusions Neuropsychological impairment in ambulatory persons with schizophrenia
appears to remain stable, regardless of baseline characteristics and changes
in clinical state. Our results may not be generalizable to the minority of
institutionalized poor-outcome patients.
INTRODUCTION
THERE IS a high prevalence of neuropsychological impairment in persons
with schizophrenia, ranging from mild deficits to frank dementia.1, 2, 3, 4, 5
Consistent with a neurodevelopmental view, some such deficits appear to predate
clinical symptoms and exacerbate with typical illness onset during late adolescence
or early adulthood.6, 7, 8
There remains considerable controversy about whether there is further
progression of neuropsychological deficits after the onset of the illness.9 With a few notable exceptions,10, 11, 12
cross-sectional studies generally have not found evidence of increased neuropsychological
deficits in association with duration of illness or (relative to age-matched
controls) in older than in younger patients with schizophrenia.2, 13, 14, 15, 16, 17
Definitive answers to questions regarding possible progression of neuropsychological
deficits in schizophrenia must come from longitudinal studies. The available
studies, however, provide conflicting results and have a variety of methodologic
limitations (eg, small or nonrepresentative samples, no controls, brief follow-ups,
and/or limited neuropsychological testing).2, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36
Both neurodevelopmental and neurodegenerative views of neuropsychological
deficits in schizophrenia seemingly remain viable.10
While progression of deficit after illness onset clearly is not universal,
or even typical of the disorder, a subset of persons with schizophrenia may
evidence cognitive deterioration over time. The size and nature of that subgroup
are unclear, but the existing studies suggest that potentially relevant issues
include subject age, duration of illness, level of initial neuropsychological
impairment, improvement or deterioration in clinical status, and emergence
of neuroleptic-induced dyskinesia.2, 29, 30, 31
The current study addressed these issues by longitudinally observing
sizable samples of ambulatory schizophrenic patients and normal comparison
subjects (NCs) with a comprehensive battery of neuropsychological tests. These
groups were compared with respect to test-retest correlations and neuropsychological
stability over shorter vs longer follow-up periods. Also compared were schizophrenic
subgroups defined on the basis of demographic and clinical variables, as well
as initial level of neuropsychological functioning. Finally, data from NCs
were used to define normal test-retest variability; these definitions were
then applied to the results of the schizophrenic subjects, in an attempt to
identify and characterize any subgroup of individuals who demonstrated unusual
decreases in neuropsychological functioning over time.
SUBJECTS AND METHODS
SUBJECTS
Subjects included 142 outpatients with schizophrenia and 206 NCs, who
had completed at least 2 comprehensive neuropsychological evaluations. Each
patient and NC was a participant in 1 of 3 university-based clinical research
centers, and most have contributed baseline neuropsychological data to previously
published reports.37, 38, 39, 40
Diagnostic procedures for subjects in both groups included the Structured
Clinical Interview for the DSM-III-R or DSM-IV.41, 42 Subjects were
also screened by a physician using a physical examination and a structured
medical history questionnaire; those with current or past medical conditions
likely to affect central nervous system functioning (such as significant head
injuries, seizure disorder, or acute medical conditions), as well as those
meeting DSM-III-R43
or DSM-IV44 criteria
for current alcohol or substance abuse or dependence, were excluded. All subjects
provided written informed consent before participation in the research.
NEUROPSYCHOLOGICAL EXAMINATIONS
The patients and NCs were assessed with an annually scheduled comprehensive
neuropsychological test battery (in actuality, the mean test-retest interval
between the first 2 of these evaluations was 16.6 months [SD, 8.6 months;
range, 6-81 months]). Eighty-nine schizophrenic patients and 119 NCs completed
at least 1 additional neuropsychological follow-up evaluation. The total number
of evaluations ranged from 2 to 10 (mean, 3.38; SD, 1.57; median, 3.00). The
interval between the first and last neuropsychological evaluations ranged
from 6 to 125 months and was not significantly different for the schizophrenic
patients vs NCs (mean and SD, 37.0 and 22.3 months vs 37.1 and 25.7 months,
respectively; t346 = 0.05, P = .96).
Except where otherwise indicated, each of the neuropsychological measures
was part of the expanded Halstead-Reitan battery, and details of administration
and scoring were as described by Reitan and Wolfson45
and Heaton and colleagues.46, 47
The individual measures were grouped into 7 ability areas based on the neuropsychological
constructs that they are putatively designed to measure. The verbal ability
area included the Aphasia Screening Test, Boston Naming Test, and the Controlled
Oral Word Association Test.48, 49
Scores on the latter test were unavailable for a few subjects, so the Thurstone
(written) Word Fluency task was substituted for 2 subjects at the baseline
evaluation and 5 subjects at the first follow-up. The psychomotor ability
area included the block design, object assembly, and digit symbol subtests
from the Wechsler Adult Intelligence Scale–Revised (WAIS-R)50 and the Trail Making Test Part A (total time), Tactual
Performance Test (total time), and Digit Vigilance Test (time). The abstraction
and cognitive flexibility ability area included the Category Test (errors),
Trail Making Test Part B (total time), and Wisconsin Card Sorting Test51 (perseverative responses). The attention ability area
included the digit span and arithmetic subtests from the WAIS-R,50
the Rhythm Test, Speech Sounds Perception Test, and Digit Vigilance (errors).
The learning and delayed recall ability areas included those scores from the Figure 1 and Story Memory Tests, and the California
Verbal Learning Test.52 The motor skills ability
area included the right- and left-hand scores on Finger Tapping, Grooved Pegboard,
and Hand Dynamometer.
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Changes in overall neuropsychological performance by diagnostic group
and duration of follow-up. Short follow-up indicates less than 36 months;
long follow-up, 36 months or longer; NC, normal comparison group; and SC,
schizophrenic patient group. In the short–follow-up groups, sample sizes
were 121 for NC and 75 for SC; in the long–follow-up groups, they were
85 for NC and 67 for SC. Vertical lines depict SEMs.
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We also had data from baseline and at least 1 retest evaluation with
an even more comprehensive neuropsychological evaluation on a subsample of
patients and NCs, permitting calculation of the WAIS-R Verbal, Performance,
and Full-Scale IQs50 for 81 patients and 86
NCs, and the Halstead-Reitan battery Average Impairment Rating53
for 74 patients and 82 NCs.
Neuropsychological test raw scores were converted to standardized scaled
scores (mean and SD, 10 and 3, respectively, in normal subjects) and age-,
education-, and sex-corrected T-scores (mean and SD, 50 and 10, respectively,
in normal subjects), by means of previously published normative data.46, 47, 48, 51, 54
We then calculated the mean scaled scores and T-scores within each ability
area, and a composite global scaled score and T-score.
PSYCHIATRIC AND MOTOR SYMPTOM RATINGS
Longitudinal ratings of psychiatric symptoms were also obtained for
a subset (n = 116) of the schizophrenic patients, as well as a smaller subset
of NCs (n = 86 to 88). Psychiatric symptom rating scales included the Brief
Psychiatric Rating Scale55 and the Scales for
the Assessment of Positive and Negative Symptoms (SAPS and SANS, respectively).56 Tardive dyskinesia was assessed with the Abnormal
Involuntary Movement Scale.57
STATISTICAL METHODS AND ANALYSES
The test-retest reliability of neuropsychological measures and symptom
rating scales was assessed in terms of McGraw and Wong's58
intraclass correlation coefficients for degree of consistency between measurements
at the baseline and 1-year follow-up evaluations. The magnitudes of the intraclass
correlation coefficients for the neuropsychological and symptom rating scale
scores of patients and NCs were compared by means of Fisher r-to-z transformations for intraclass correlation
coefficients.58 The neuropsychological scaled
scores, rather than T-scores, were used for these analyses, since the latter
would underestimate the stability of neuropsychological performance by removing
variance related to the stable traits of education and sex.
To examine the effects of length of follow-up on neuropsychological
stability, patients and NCs were divided into diagnosis–by–length
of follow-up groups, wherein "short" follow-up was defined as less than 36
months and "long" follow-up was defined as 36 months or longer. This yielded
121 NCs and 75 schizophrenic patients with short follow-up (mean, 19.5 months;
SD, 6.8 months) and 85 NCs and 67 schizophrenic patients with long follow-up
(mean, 59.7 months; SD, 19.6 months).
In addition to the primary subject groupings described above, we were
interested in examining the possible influence of substantial differences
in current age, age at onset of illness, duration of illness, and symptom
changes on the stability of neuropsychological performance among the schizophrenic
patients. Hence, we conducted a series of analyses in which we dichotomized
the schizophrenic patients in terms of these characteristics. The definition
of the symptom change groups and the resulting samples are described later.
The other groupings included 22 elderly patients (age at study entry,  65
years; mean, 69.2 years; SD, 3.3 years) vs 120 younger patients (age at study
entry, <65 years; mean, 43.7 years; SD, 13.7 years); 24 patients with late-onset
schizophrenia (aged 45 years at onset of prodromal symptoms; mean, 55.0
years; SD, 5.6 years) vs 118 with earlier onset (onset at age <45 years;
mean, 22.7 years; SD, 7.3 years); and 30 patients with a duration of illness
less than 5 years (mean, 2.0 years; SD, 1.4 years) vs 105 subjects with a
duration of illness of 5 years or more (mean, 23.6 years; SD, 12.5 years).
We also dichotomized patients in terms of sex and initial level of neuropsychological
functioning (low [global neuropsychological T-score,  39] vs high [global
neuropsychological T-score, >45]) and anticholinergic use (receiving vs not
receiving anticholinergic medication).
Repeated-measures analysis of variance (ANOVA) was used to examine effects
of diagnosis (schizophrenic patients vs NCs) and length of follow-up (as noted
above, short vs long) on changes in neuropsychological performance. These
analyses were conducted on T-scores (to correct for changes attributable to
the effects of normal aging during long-term follow-up) for the entire neuropsychological
battery (global neuropsychological T-score) as well as for each of the specific
neuropsychological ability areas. We also used repeated-measures ANOVA to
examine the various pairs of schizophrenic subgroups on changes in global
neuropsychological performance and the 7 ability domains.
To assess the relationship between clinical change and neuropsychological
functioning, patients were categorized into 3 groups based on change in clinical
symptom scores from baseline to follow-up. Patients whose clinical symptom
score (either SAPS or SANS total score) fell in the lower 25% of the distribution
were considered to have a "low" level of symptoms, those in the middle 50%
were labeled "middle," and those in the upper 25% of the distribution were
categorized as "high." To meet criteria for a clinically significant change
in symptoms, a subject had to move at least 1 category from baseline to follow-up,
and by at least 3 points. Separate analyses were conducted for the SAPS- and
SANS-defined change groups.
We also examined significant decreases in global neuropsychological
T-scores of individual subjects, by means of the reliable change index method
with adjustments for practice effect.59, 60
This approach involves constructing prediction intervals around each subject's
expected follow-up score. The predicted follow-up score is the subject's baseline
score, adjusted for practice effects among cognitively stable individuals
(as determined from the mean change observed among the NCs). The boundary
values of the prediction interval around the predicted follow-up score are
determined by the normal variability of baseline to follow-up changes (SE
of the difference) determined from the NC group. Specifically, 90% prediction
intervals were built around these predicted follow-up scores by multiplying
the SD of the difference among NCs by 1.64. Subjects whose observed follow-up
scores were below the lower limits of the 90% prediction interval (ie, the
bottom 5% of normal controls) were considered to have shown significant declines
in neuropsychological functioning. These procedures were conducted twice:
once to evaluate changes from baseline to first retest among all patients
and NCs, and then again in terms of changes from the first to last neuropsychological
assessment among subjects with long follow-ups.
Two-tailed tests were used for all analyses. To help avoid type I errors
associated with multiple comparisons, significance was defined as P<.01.
RESULTS
BASELINE CHARACTERISTICS
As shown in Table 1, there
were small but statistically significant group differences in age, education,
and test-retest interval. There were no significant differences in sex or
ethnicity. As expected, the patients had substantially greater global neuropsychological
impairment and more severe clinical symptoms than the NCs.
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Table 1. Baseline Characteristics of Normal Comparison Subjects and
Patients With Schizophrenia*
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There were some differences between subjects with and without WAIS-R
IQ scores and Average Impairment Rating scores, which primarily reflected
different demographic recruiting emphases and slight differences in neuropsychological
protocols among the 3 research centers from which the present sample was drawn.
Schizophrenic patients who had WAIS-R IQ scores were different from those
without only in age (mean, 41.4 years [SD, 16.6 years] vs 55.9 years [SD,
9.5 years], respectively; t131.65 = 6.55; P<.001). Relative to NCs without WAIS-R IQ scores, those
with WAIS-R IQ scores were younger (mean age, 45.4 years [SD, 16.8 years]
vs 56.2 years [SD, 21.1 years], respectively; t201.65 = 4.09; P<.001); completed slightly
more education (mean education, 14.8 years [SD, 2.4 years] vs 13.7 years [SD,
2.9 years], respectively; t200.73 = 3.12; P = .002); had higher baseline neuropsychological performance
(mean global neuropsychological T-score, 50.8 [SD, 4.0] vs 48.6 [SD, 4.9],
respectively; t204 = 3.46, P = .001); and were more likely to be male (76.7% vs 55.0%;  21,N = 206 = 10.29; P = .002) and
white (94.2% vs 72.5%; 21,N = 206 = 15.66; P<.001). There were no significant differences between
the 2 subgroups of NCs in the interval between the baseline to first-retest
neuropsychological evaluation. More important, the same patterns of neuropsychological
test-retest change were present for schizophrenic patients and NCs with vs
without the Halstead-Reitan battery Average Impairment Rating score.
One concern about participant attrition in a longitudinal study is that
nonrandom factors may influence who remains in the study, resulting in nonrepresentative
(biased) samples. We used Mann-Whitney tests to compare the baseline characteristics
of subjects who completed at least 1 follow-up evaluation with patients who
dropped out after completing the baseline assessment. Demographic characteristics
(except for age), baseline clinical symptoms and cognitive performance (including
IQ), and global neuropsychological functioning did not differ between the
groups. Patients who dropped out were, however, older than those with follow-up
visits (mean ages, 57 and 48 years, respectively; Mann-Whitney P<.001).
TEST-RETEST RELIABILITY
The test-retest reliability coefficients (intraclass correlation coefficients)
of neuropsychological and psychiatric rating scale scores for NCs and patients
were highly significant within each group (Table 2). With the exception of Performance IQ (where the test-retest
reliability was higher in the schizophrenic group), the magnitudes of the
test-retest correlations for the patients were not significantly different
from those observed among the NCs.
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Table 2. Test-Retest Reliability of Neuropsychological and Psychiatric
Symptom Rating Scale Scores for Normal Comparison Subjects vs Patients With
Schizophrenia*
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MAGNITUDE OF PRACTICE EFFECTS: BASELINE TO FIRST AND LAST REPEATED
ASSESSMENT
There were no significant differences between schizophrenic patients
and NCs with respect to practice effects (T-score at first follow-up visit
minus T-score at baseline visit) for the WAIS-R IQs, neuropsychological summary
scores, or neuropsychological ability area scores (Table 3).
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Table 3. Change in Neuropsychological T-Scores (First Retest Minus
Baseline T-Score) for Normal Comparison Subjects vs Patients With Schizophrenia*
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Figure 1 depicts the changes
in global neuropsychological T-scores from baseline to last follow-up, for
subgroups with short vs long follow-up periods. Regardless of length of follow-up,
the test-retest changes for schizophrenic patients and NCs were essentially
parallel lines. Repeated-measures ANOVAs confirmed this finding, not only
for the global neuropsychological score but also for all neuropsychological
ability areas. There were highly significant group effects (P<.001), and sometimes significant time effects (reflecting modest
improvement because of practice), but no significant diagnostic group x
time interactions.
ADDITIONAL SCHIZOPHRENIC SUBGROUP COMPARISONS
To further examine the change in cognitive functioning over time, we
compared longitudinal global neuropsychological performance changes in subgroups
of schizophrenic subjects defined on the bases of demographic and clinical
variables (as listed and defined above). These ANOVAs disclosed no significant
group effects. As shown in Table 4,
with 1 exception there also were no significant group x time interactions,
indicating that the characteristics defining the various groups were not related
to changes in neuropsychological performance over time. The 1 significant
interaction reflected the fact that the schizophrenic subgroup with short
duration of illness (mean, 2 years at baseline) had a slightly larger neuropsychological
improvement than the subgroup with long duration (mean, 24 years at baseline).
The smaller "improvement" (practice effect) shown by the long-duration group
was the same as that of the NCs (both means, 1.3 T-score points).
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Table 4. Repeated-Measures Analyses of Variance of Schizophrenia Subgroups
on Global Neuropsychological Functioning
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Using the SAPS to categorize clinical change status resulted in 11 patients
being classified as worse, 27 as better, and 78 as stable. With the use of
repeated-measures ANOVAs, no significant group x time interactions were
found for the neuropsychological global score or for scores on any of the
7 ability areas (Table 4). Categorization
of schizophrenic patients on the basis of SANS scores yielded 19 subjects
identified as significantly worse, 80 subjects as stable, and 17 subjects
as better. The results of repeated-measures ANOVAs for the neuropsychological
global score were similar to those with the SAPS change groups, ie, no significant
group x time interactions.
We also compared patients with initial high vs low global neuropsychological
performance (global neuropsychological T-score 45 vs 39, respectively),
and those with vs without tardive dyskinesia as defined by the Schooler and
Kane criteria63 and those used by Waddington.64 Again, the groups did not differ significantly with
respect to the change in the global neuropsychological score or the 7 neuropsychological
ability domain scores (Table 4).
SUBJECTS WITH UNUSUAL DECREASES IN GLOBAL NEUROPSYCHOLOGICAL T-SCORES
The modified Reliable Change Index method, described above, was used
to identify and compare the percentages of individual NCs and schizophrenic
patients who evidenced unusual neuropsychological worsening from baseline
to first retest. With the use of the 90% prediction interval, 10 NCs were
so identified (about 5% of the total sample); the latter proportion did not
differ significantly from the 5.6% of patients with schizophrenia who evidenced
unusual worsening (21,N = 348 = 0.10; P = .75).
The above procedures were also used to evaluate baseline to final follow-up
scores of the 85 individual NCs and 67 patients with schizophrenia with follow-up
intervals of 36 months or longer (mean, 59.7 months; SD, 68 months). Again,
the proportion of patients below the 90% prediction interval was not significantly
different from that of the NCs (7.5% vs 4.7%, respectively; 21,N = 152 = 0.51; P = .48).
COMMENT
To our knowledge, this is the first longitudinal study to compare comprehensive
neuropsychological test results of large samples of NCs and patients with
schizophrenia during a multiyear follow-up period. After comparing the two
groups with respect to test-retest reliabilities, we attempted to determine
whether the schizophrenic patients, or even a subset of that group, evidenced
progressive neuropsychological decline.
Consistent with previous reports,22, 65
presence of psychosis did not appear to affect the reliability of neuropsychological
test performance. Across the entire neuropsychological battery, reliability
estimates were quite high, and were at least as high for the schizophrenic
group as for the NCs. This was true even though clinical symptoms were relatively
variable over time (Table 2), and
even though the test-retest intervals were longer than those in most previous
reliability studies with NCs.50, 66
These stability results support the view that neuropsychological deficits
in schizophrenia are stable traitlike dimensions of the disorder, rather than
reflecting state-related features.
Acceptable test-retest reliability does not rule out the possibility
that neuropsychological deficits may be progressive in at least some patients
with schizophrenia. Our results, however, provided no evidence of a deteriorating
neuropsychological course in the total schizophrenic group, or in subgroups
defined on the basis of age, sex, early vs late or recent vs remote onset
of illness, baseline level of neuropsychological impairment, or length of
follow-up. In each analysis, the schizophrenic groups showed slight improvements
that were comparable with those evidenced by the NCs, and these likely represented
practice effects. Even rather extreme clinical changes did not appear to influence
the subjects' neuropsychological performance.
Longitudinal research in institutional settings has shown evidence of
neuropsychological decline in some low-functioning, chronically hospitalized
patients with schizophrenia.29, 30, 31
Even in those studies, however, such worsening was observed only in small
subsets of the groups being followed up. In the absence of longitudinal data
from a neurologically stable comparison group, it is unclear whether these
observed neuropsychological changes represent true neuropsychological decline,
as in a neurodegenerative disorder, or whether they represent the tail of
the distribution of test-retest fluctuations in neurologically stable (albeit
very low-functioning) persons. It might be argued that the types of change
observed in these patients (eg, change in the rated level of dementia) are
too gross to be considered "normal fluctuation" and are pathognomonic of a
progressive disorder. During approximately a 4-year follow-up interval, however,
Ivnik and colleagues67 found remarkable test-retest
differences in neuropsychological performances of some elderly subjects who
did not have any neuromedical disorder likely to affect cognition, eg, on
neuropsychological factor scores with IQ-type scaling, test-retest differences
of 20 or more points were not unusual. Therefore, the outer range of possible
fluctuation in performance of neurologically stable persons cannot be assumed
and should be established by means of an appropriate comparison group.
The mean global neuropsychological score for our patient group was 1.62
SDs below that of NCs (Table 1),
consistent with the range of effect sizes in a recent meta-analytic review
of studies comparing controls and schizophrenic patients.5
Although severely demented patients were not represented in our sample, our
"low-functioning" subgroup (n = 45; Table
4) was very significantly impaired (ie, more than 3 SDs below NCs
on the global neuropsychological T-score).
Limitations of this study include absence of chronically institutionalized
patients, and therefore its results may not be generalizable to that minority
of patients (but most contemporary schizophrenic patients are not institutionalized).68, 69, 70 Also, there was limited
representation of elderly subjects, and subjects who evidenced substantial
clinical change or incident tardive dyskinesias during follow-up (Table 4). Although relatively few of our
patients were tested initially very early in the course of their illness,
2 recent studies of first-break schizophrenia showed no significant cognitive
decline during the first several years of illness.35, 36
Morover, despite the limited power associated with some of the subgroup analyses
in the current study, the data summarized in Table 4 show that these various subject characteristics were associated
with clinically trivial effect sizes for changes in cognitive performance.
Considered together, the results of available longitudinal studies strongly
suggest that the large majority of people with schizophrenia do not experience
progressive neuropsychological decline after the initial onset of their illness.
We found no evidence of such decline, even in our ambulatory patients with
long follow-up, who were observed for an average of 5 years. It remains possible
that a subset of patients with very poor outcome (not represented in our study)
do experience progressive neuropsychological decline. Future research with
this population should attempt to document such decline by ruling out nonsignificant
fluctuations in performance as evidence of progressive impairment. This might
be done by using neuropsychological norms for change developed with a similarly
impaired but neurologically stable comparison group, and determining whether
any unusual neuropsychological worsening in the schizophrenic patients remains
stable or progresses further during a subsequent follow-up period. If future
research should conclusively establish progressive neuropsychological decline
in a subset of schizophrenic patients, questions arise as to why only a minority
are so affected. Is this another example of the heterogeneous manifestations
of a common disease,71, 72, 73, 74
or are other factors involved, such as treatment history75
or comorbid neuromedical conditions (eg, age-related neurodegenerative changes,
possibly in combination with schizophrenia-related low "cognitive reserve")?76 There is a need for larger, collaborative studies
using the same methods with patients in different treatment settings.
AUTHOR INFORMATION
Accepted for publication July 20, 2000.
This study was supported in part by grants MH43695, MH45131, MH49671,
MH19934, MH01452, and MH45294 from the National Institute of Mental Health,
Bethesda, Md; State of California (Sacramento) Department of Mental Health
grant DMH 89-7000; and the Department of Veterans Affairs, Washington, DC.
Preliminary versions of this work were presented in part at the Mt Sinai
Conference on the Role of Cognitive Dysfunction in Schizophrenia, New York,
NY, April 6, 1996; the annual meeting of the International Neuropsychological
Society, Chicago, Ill, February 16, 1996; and the annual meeting of the American
Association of Geriatric Psychiatry, San Diego, Calif, March 10, 1998.
We thank Lou Ann McAdams, PhD, for her comments on an earlier draft
of this article.
From the Department of Psychiatry, University of California, San Diego
(Drs Heaton, Gladsjo, Palmer, Kuck, Marcotte, and Jeste, and the Veterans
Affairs San Diego Healthcare System, San Diego, Calif (Dr Jeste).
Reprints: Robert K. Heaton, PhD, Department of Psychiatry, University
of California, San Diego, 140 Arbor Dr, San Diego, CA 92103 (e-mail: rheaton{at}ucsd.edu).
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