Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue2.2000:

Age and Neuropsychologic Function in Schizophrenia:
A Decline in Executive Abilities beyond That Observed
in Healthy Volunteers
Robert Fucetola, Larry J. Seidman, William S. Kremen, Stephen V. Faraone,
Jill M. Goldstein, and Ming T. Tsuang
Background: Kraepelin originally conceptualized schizophrenia as a degenerative brain disorder. It remains
unclear whether the illness is characterized by a static
encephalopathy or a deterioration of brain function, or
periods of each condition. Assessments of cognitive function, as measured by neuropsychologic assessment, can
provide additional insight into this question. Few studies
of patients with schizophrenia have investigated the effect
of aging on executive functions, in an extensive neuropsychologic battery across a wide age range, compared to
healthy volunteers.
Methods: We examined the interaction of aging and
neuropsychologic function in schizophrenia through a
cross-sectional study in patients (n 5 87) and healthy
control subjects (n 5 94). Subjects were divided into three
age groups (20 –35, 36 – 49, and 50 –75), and performance
on an extensive neuropsychologic battery was evaluated.
Results: Compared to control subjects, patients with
schizophrenia demonstrated similar age-related declines

across most neuropsychologic functions, with the exception of abstraction ability, in which significant evidence of
a more accelerated decline was observed.
Conclusions: These results are consistent with previous
reports indicating similar age effects on most aspects of
cognition in patients with schizophrenia and healthy
adults, but they support the hypothesis that a degenerative
process may result in a more accelerated decline of some
executive functions in older age in schizophrenia. Biol
Psychiatry 2000;48:137–146 © 2000 Society of Biological Psychiatry

From Washington University School of Medicine, Department of Neurology, St.
Louis, Missouri (RF); the Harvard Medical School Department of Psychiatry at
Massachusetts Mental Health Center, Boston (LJS, SVF, JMG, MTT), Harvard
Medical School Department of Psychiatry at Brockton/West Roxbury VA
Medical Center, Brockton (LJS, SVF, JMG, MTT), Harvard Institute of
Psychiatric Epidemiology and Genetics, Boston (LJS, SVF, JMG, MTT), and
Harvard School of Public Health, Department of Epidemiology, Boston (MTT),
Massachusetts; and University of California, Davis School of Medicine,
Department of Psychiatry, Sacramento and University of California, Davis–
Napa Psychiatric Research Center, Napa (WSK).

Address reprint requests to Larry J. Seidman, Ph.D., Harvard Medical School,
Massachusetts Mental Health Center, 74 Fenwood Road, Boston MA 02115.
Received August 9, 1999; revised January 12, 2000; accepted January 13, 2000.

© 2000 Society of Biological Psychiatry

Key Words: Schizophrenia, neuropsychology, executive
functions, age, deterioration

Introduction

A

central question in schizophrenia is whether the
disorder is developmental, degenerative, or both.
From the earliest descriptions of schizophrenia by Kraepelin (1919), the disorder has generally been considered a
deteriorating illness; however, there is limited research
confirming the long-held contention that deterioration
occurs beyond that found in the first few years of illness
(i.e., “dementia praecox”). Moreover, much recent evidence supports the hypothesis (e.g., Murray and Lewis

1987; Seidman 1990; Weinberger 1987) that patients with
schizophrenia have primary neurodevelopmental etiologies, usually involving obstetric complications, genetic
factors, or both. The presence of neurodevelopmental
abnormality, however, does not negate the possibility of
subsequent deterioration.
In this study we evaluate whether neuropsychologic
deficits, prominent early in the disorder (Hoff et al 1992;
Saykin et al 1994), decline further during the illness.
Neuropsychologic impairments associated with schizophrenia involve a broad range of functions and appear to
be present in most schizophrenic patients (Kremen et al
1999; Levin et al 1989; Palmer et al 1997; Randolph et al
1993; Seidman et al 1992). Impairments in sustained and
selective attention, executive functions (i.e., abstract reasoning, planning, and cognitive flexibility), working memory, motor and psychomotor functions, declarative memory, and olfaction have been documented in schizophrenia.
In reviews of the literature, Heaton and Drexler (1988),
Seidman (1983), and Goldberg and Seidman (1991) noted
little evidence indicating decline in neuropsychologic
functioning over time; however, Seidman (1983), based on
the few studies then available, summarized the evidence
suggesting that if there was a deterioration, the brain
system involved was the frontal-executive network. Other

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PII S0006-3223(00)00240-7

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investigators have suggested that olfaction and executive
function, both of which are associated with frontal networks, may deteriorate more rapidly with age in schizophrenia (Moberg et al 1997; Sullivan et al 1994). Complicating this view of the relationship of aging and
schizophrenia is the possibility that age at disease onset or
illness duration may have independent and/or interactive
effects on neuropsychologic status.
The neurodegenerative hypothesis has been tested using
neuropsychologic, neuroimaging, and electrophysiological
techniques. Although this paper will focus on evidence
from neuropsychology, it is notable that some longitudinal
reports have indicated that frontal lobe volume reductions
occur early in the course of the illness and may progress
over time (Gur et al 1998). In addition, progressive

ventricular enlargement has been documented among
subsets of chronic patients (e.g., DeLisi et al 1997), though
not consistently. Neuropsychologic studies indicate that
there may be at least a subset of patients who demonstrate
premature brain degeneration and accelerated cognitive
decline (Buchsbaum and Hazlett 1997); however, evidence suggests that a substantial portion of patients do not
decline beyond an initial deterioration of cognitive function that apparently occurs during the first 5 years of
illness (Bilder et al 1992; Heaton and Drexler 1988).
Several longitudinal studies have observed no overall
decline in global cognitive functioning over 8 month to
5-year periods (Harvey et al 1990, 1995; Sweeney et al
1991; Waddington et al 1990). In a recent review of 15
longitudinal studies of neuropsychologic function in
schizophrenia, Rund (1998) concluded that cognitive deficits are relatively stable over the course of the illness;
however, the conclusions reached are limited by the
variable ages, phases of illness, and length of follow-up
periods used in these studies. In contrast to most longitudinal reports, Harvey et al (1999) recently demonstrated
that a significant subset of chronically institutionalized,
older patients with schizophrenia exhibited detectable
declines in cognitive and functional status over a longer

30-month study period in old age.
The majority of cross-sectional studies of age-related
neuropsychologic change also find little evidence of decline (Chen et al 1996; Goldberg et al 1993; Hyde et al
1994; Kremen 1990; Mockler et al 1997), though not all
concur (Bilder et al 1992; Davidson et al 1995). Davidson
et al (1995) found a slight decline with increasing age on
mental status examination scores in a sample of very ill
schizophrenia patients (ages 25–95) with low mental
status scores overall, compared to control subjects (mean
Mini-Mental Status score was 9.6); however, age-related
differences in patients with schizophrenia may disappear
when the effects of normal aging are accounted for
(Heaton et al 1994). Chen et al (1996) studied a large

R. Fucetola et al

group of patients aged 16 to 65 and found similar
age-related effects on neuropsychologic performance in
comparison to healthy control subjects when looking at
patients with varying disease durations. Mockler et al

(1997) found no evidence of deterioration in intelligence
or memory functioning with age in schizophrenic patients
(at least to age 69). Finally, Hyde et al (1994) studied five
cohorts of patients using neuropsychologic measures of
naming, verbal learning and fluency, as well as a global
dementia rating scale and a mental status examination, and
found no evidence of decline across age groups. As with
the Mockler et al (1997) report mentioned above, however, a control group was not included. In sum, most, but
not all, of the cross-sectional reports are consistent with
the longitudinal studies indicating that little if any deterioration occurs with advanced age in most patient with
schizophrenia, beyond that which would be expected with
normal aging. It is important to note, however, that most
reports indicating no decline with old age in schizophrenia
studied relatively young elderly patients (younger than age
70).
Several methodological issues have limited the interpretation of previous studies of neuropsychologic decline in
schizophrenia. Longitudinal studies suffer from short follow-up periods, variable follow-up intervals, and a limited
range of instruments. Cross-sectional studies in particular
have been limited by the absence of appropriate agematched control groups. Moreover, few studies have
considered the possible confound of age of onset. Finally,

the selection of neurocognitive functions measured may
have an influence on the identification of an age-related
effect in schizophrenia. There is some evidence that a
younger age of onset and longer disease duration are
associated with greater impairment in executive functioning (i.e., abstraction/cognitive flexibility) (Albus et al
1996; Sullivan et al 1994). For example, Sweeney et al
(1992) compared young first-episode and young patients
with multiple episodes on neuropsychologic measures and
found greater impairment in patients with multiple episodes on tests of frontal lobe function and verbal memory,
suggesting the possibility of progressive decline in these
functions with more frequent episodes. Kremen et al
(1999) suggested that age of onset is related to neuropsychologic function based on the observation that schizophrenia patients with relatively normal neuropsychologic
profiles had a later onset of illness than those with
abnormal profiles. Some recent work, however, suggests
that age at disease onset and duration of illness may be
unrelated to neuropsychologic functioning (Chen et al
1996; Heaton et al 1994), indicating that more research is
needed to answer this question.
The present study addressed these questions through a
cross-sectional examination of age-related changes in

Age and Neuropsychologic Function

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139

Table 1. Demographic Characteristics of Patients with Schizophrenia and Control Subjects by Age Group (Mean and SD)
Schizophrenia

Age (years)
Education (years)
Estimated IQ
Parental SES
WRAT-R Reading

Women
Ethnicity
Caucasian

Control

Young
(n 5 23)

Middle
(n 5 38)

Older
(n 5 26)

Young
(n 5 39)

Middle
(n 5 27)

Older
(n 5 28)

30.0 (3.6)
11.9 (2.3)
97.9 (16.4)
3.1 (1.1)
95.3 (19.3)

41.1 (4.2)
12.3 (2.0)
96.5 (13.1)
3.4 (1.1)
100.5 (16.1)

58.3 (5.6)
11.8 (2.8)
94.2 (14.9)
3.5 (1.1)
101.6 (15.4)

28.5 (4.4)
13.7 (2.2)
102.8 (12.8)
3.0 (1.2)
97.4 (12.1)

41.3 (3.8)
14.1 (2.2)
108.0 (12.9)
3.4 (0.8)
106.8 (10.0)

62.5 (7.2)
12.6 (2.9)
110.9 (15.8)
3.6 (1.1)
103.3 (16.2)

n

%

n

%

n

%

n

%

n

%

n

%

5

22

10

26

4

15

24

62

15

56

12

43

20

87

30

79

22

85

36

95

25

93

21

78

2

Significant group differences were found for gender [Pearson x (5) 5 23.22, p ,.001]. Within each diagnostic group, participants were not significantly different on
education and IQ. All six groups were not significantly different on parental socioeconomic status (SES), ethnicity, and WRAT-R Reading score. WRAT-R, Wide Range
Achievement Test—Revised.

neuropsychologic functioning among a large sample of
patients with schizophrenia and healthy control subjects.
An extensive battery of neuropsychologic tests was utilized to permit the assessment of a wide range of neurocognitive functions, including assessment of executive
functions. We hypothesized that similar age-related reductions in cognitive performance would be detected in
patients and control subjects based on earlier crosssectional work, but that if age-related declines were
present, they would be detected on measures of executive
function. We also examined the impact of age of onset on
the relationship between age and neuropsychologic
function.

Methods and Materials
Subjects
All participants (87 patients with schizophrenia, 94 healthy
control subjects) gave informed consent and were paid for their
participation in this study. Patients were recruited from three
Boston-area public hospitals specializing in the treatment of
chronic mental illness. Inclusion criteria for patients were a
diagnosis of schizophrenia according to the DSM-III-R (American Psychiatric Association 1987), age between 18 and 75,
English as the primary language, and a minimum of 8 years of
formal education. Exclusion criteria included neurologic disease
or damage, current substance abuse (within the past 6 months),
history of head injury with loss of consciousness greater than 5
minutes or with documented neurocognitive sequelae, mental
retardation, and medical illnesses associated with significant
cognitive dysfunction.
The mean number of hospitalizations was 7.8 (SD 5 5.2), with
a mean lifetime length of hospitalization of 72.6 (SD 5 72.0)
months. The mean age at first hospitalization was 24.0 (SD 5
6.4) years. At the time of testing, 66% of the patients were
outpatients (n 5 57) and 34% were inpatients (n 5 30). Patients
were generally tested while on antipsychotic medications (mean

dosage in chlorpromazine equivalents 5 634.8; SD 5 589.4),
and while clinically stable (see Table 1 for demographics).
Fifty-one of the patients with schizophrenia (59%) were taking
anticholinergic medication. SANS and SAPS (Scales for the
Assessment of Negative and Positive Symptoms; Andreasen and
Olsen 1982) global scores were grouped into the three factors
typically found when these scores have been factor-analyzed:
Negative Symptoms, Positive Symptoms (“Reality Distortion”),
and Disorganization factors (Toomey et al 1997). Schizophrenia
patients for whom clinical data was available (n 5 56) had a
mean Negative Symptom score of 1.81 6 1.0, a Reality Distortion score of 2.07 6 1.5, and a Disorganization score of 1.38 6
1.0.
Healthy control subjects (n 5 94) were recruited through
advertisements placed in the community and from among the
nonprofessional hospital staffs. With the exception of presence of
current psychopathology or family history of psychosis, selection
criteria were the same as for patients. In place of a diagnostic
interview, a short form of the Minnesota Multiphasic Personality
Inventory (MMPI-168; Vincent et al 1984) was used to screen
control subjects for current psychopathology. Further details
about ascertainment of control subjects are provided in previous
reports (Faraone et al 1995; Kremen et al 1996).
Control subjects were similar to patients in age, ethnicity,
single word reading ability (Wide Range Achievement TestRevised), and parental socioeconomic status. As can be seen in
Table 1, control subjects had more years of education and higher
IQ estimates (based on age-scaled Vocabulary and Block Design
scores; Brooker and Cyr 1986) than patients, as expected;
however, the performance of the control subjects on estimated IQ
and reading ability were solidly in the average range. Moreover,
the six groups were matched on reading ability, which we and
others have argued is an appropriate way to match schizophrenia
patients and control subjects (cf., Kremen et al 1996). The patient
group overall was composed of significantly more men and
fewer women than the control group. Subjects were divided into
three age groups: “young” (age 20 –35: 23 schizophrenics, 39
control subjects); “middle” (age 36 – 49: 38 schizophrenics, 27

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Table 2. Neuropsychologic Battery of Tests Grouped by
Function
Abstraction
Wisconsin Card Sorting Test (WCST); number of categories and
perseverative responses
Visual-Verbal Test (VVT); total misses
Verbal memory
Logical Memory I and II and Percent Retention (“Savings”) Score
(WMS-R)
Verbal skills
WAIS-R Vocabulary, WRAT-R Reading and Spelling scores
Visual skills
WAIS-R Block Design, Benton Judgment of Line Orientation Test,
Hooper Visual Organization Test; total score
Executive motor skills
Luria Graphic Sequences (alternating open square/triangle)
Manual Position Sequencing Task (palm-fist-side); total number of
qualitative errors
Perceptual motor skills
Trail Making Test (A & B) and WAIS-R Digit Symbol
Sustained attention
Dichotic Listening Test and Auditory Continuous Performance Test
Mental control
WAIS-R Digit Span and WRAT-R Arithmetic
WMS-R, Wechsler Memory Scale—Revised; WAIS-R, Wechsler Adult Intelligence Scale—Revised; WRAT-R, Wide Range Achievement Test—Revised.

control subjects); and “older” (age 50 –75: 26 schizophrenics, 28
control subjects). The six cohorts of patients and control subjects
(three age cohorts per group) were not significantly different on
reading ability and parental socioeconomic status (all Fs , 2.0).
Differences between patient groups were found on age at first
hospitalization, with the oldest cohort (mean 5 27.5; SD 5 6.5
years) showing an older age at first hospitalization compared to
the young group [mean 5 21.3; SD 5 4.4years; t(46) 5 1.61,
p , .0001]. Middle patients did not differ significantly from
either group in age at first hospitalization (mean 5 23.4; SD 5
6.4 years). Because of the possibility that age of first hospitalization (a possible indicator of disease severity) could account
for any age-related changes detected, we analyzed the data with
and without adjustment for age at first hospitalization.

dichotic listening measure was the total digits apprehended
(regardless of which ear the subject identified s/he heard the
digits) in both ears over 48 trials (cf. Seidman et al 1993) rather
than the 24 trials used to study relatives of schizophrenic patients
(Faraone et al 1995). Each trial consisted of strings of three digits
presented simultaneously to each ear (Kimura 1967) at an equal
intensity (80 dB). Percent retention of verbal memory passages
was delayed recall divided by immediate recall 3 100 (described
in Seidman et al 1998). The Wisconsin Card Sort (WCST) was
the original 128 card, noncomputerized version used in all of our
studies (Heaton 1981; Koren et al 1998).

Data Analysis
First, raw test scores on each test in Table 5 were transformed to
Z scores (mean 5 0; SD 5 1). Standardization of these individual
raw scores (to a mean of zero and a standard deviation of 1) was
completed using the control mean and the pooled standard
deviation within all groups (i.e., root mean square error). Second,
composite function scores were created by averaging Z scores
within each theoretical domain.
Pearson product-moment correlations were used first to examine the association between age and each of the eight function
scores in each group (schizophrenia patients and control subjects). We used Fisher’s r-to-Z transformation to test for between-group differences for each set of correlations. To determine whether age at first hospitalization influenced age-related
changes in neuropsychologic performance, partial correlations
between age and the eight function scores were also calculated
(controlling for age at first hospitalization). The groups were
each subdivided into three roughly equal size subgroups, in part,
because performance patterns in some subgroups could be
obscured by using simple correlations. Multivariate analysis of
covariance (MANCOVA) was then used with diagnosis (patients, control subjects) and age group (young, middle-aged,
older) as the between-group factors, and the eight neuropsychologic composite function scores as the dependent variables.
Gender was included as a covariate because of the significant
difference in the gender distribution between patients and control
subjects. This was followed by within-group contrasts on each
function.

Procedure
Trained research assistants interviewed patients with the Schedule for Affective Disorders and Schizophrenia (SADS; Spitzer
and Endicott 1978), with the Scales for the Assessment of
Negative and Positive Symptoms (Andreasen and Olsen 1982),
reviewed all medical records, and conferred with treating physicians. At least two psychologists and/or psychiatrists reviewed
all available information to determine consensus lifetime DSMIII-R diagnoses.
Trained examiners administered an extensive neuropsychologic test battery that involved about 6 – 8 hours of testing. The
test battery is presented in Table 2 with tests grouped by function
and is described in detail elsewhere (cf., Faraone et al 1995;
Lezak 1995). Grouping of neuropsychologic tests into function
scores was also based on previous factor-analytic studies (Kremen et al 1992; Mirsky et al 1991). It should be noted that the

Results
Correlations of Age with Neuropsychologic
Function Scores
Zero-order Pearson correlations of age with each of the
eight function scores for each group are shown in Table 3.
Among patients with schizophrenia, increasing age was
associated with significantly decreased performance on
Abstraction, Visual Skills, and Perceptual Motor Skills
functions. Among control subjects, increasing age was
also associated with decreased performance on the Abstraction, Visual Skills, and Perceptual Motor Skills functions, as well as on the Memory, Executive Motor, and
Sustained Attention functions. No group differences were

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Table 3. Pearson Correlations of Age and Neuropsychologic
Function Scores by Group
Function
Abstraction
Verbal memory
Verbal skills
Visual skills
Executive motor skills
Perceptual motor skills
Mental control
Sustained attention

Schizophrenia

Control

20.31b
20.13
0.08
20.32b
20.01
20.39b
20.05
20.01

20.32b
20.47b
0.05
20.30b
20.24a
20.53b
20.08
20.29a

ns
c

ns
ns
ns
ns
ns
ns

a

p , .05.
p , .005.
A significant difference was found between groups on correlations of Verbal
Memory and age (t 5 22.51, p , .05).
b

141

ling for age at first hospitalization among the schizophrenics to see if the zero-order correlations discussed above
remained significant. Results indicated that the negative
correlations between age and Abstraction, Visual Skills,
and Perceptual Motor Skills remained significant (and
were stronger) when the effects of age at first hospitalization were controlled (r 5 2.47, r 5 2.38, and r 5 2.50,
respectively). There were no significant associations between the three symptom dimensions (derived from the
SANS and SAPS), age, and the eight neuropsychologic
functions in the patients with schizophrenia (all rs , .21,
all ps . .20).

c

observed in correlations between age and function scores
with the exception of the Verbal Memory function in
which control subjects exhibited a significantly stronger
association.
Indicators of disease severity may obscure interpretation of age-related declines, because differences along
such variables may reflect cohort effects (i.e., an older age
at first hospitalization may reflect a less severe illness
and/or limited access to psychiatric resources; Kremen
1990). Indeed, age was positively correlated with age at
first hospitalization in our sample of schizophrenics (r 5
.43, p , .0001), indicating that our oldest patients (ages
50 –75) were older at their first hospitalization compared
to middle and younger patients. Furthermore, significant
correlations were found between age at first hospitalization and the Verbal Skills, Executive Motor Skills, Mental
Control, and Sustained Attention function scores in the
patients (all ps , .02). We calculated partial correlations
between age and each of the eight function scores control-

Multivariate Analysis of Age Effects on
Neuropsychologic Function Scores
Figure 1 plots the neuropsychologic profiles of the patients
with schizophrenia (graph on the left) and control subjects
(graph on the right) according to age group (young,
middle, and older). Schizophrenic patients scored lower
than control subjects across all neuropsychologic functions except the Verbal Function [F(1,161) 5 21.63, p ,
.0001]. This main effect can be seen in Figure 1 (the
profiles for all patient groups lie below the mean of zero).
A significant multivariate age group 3 diagnosis interaction was also detected [F(2,161) 5 1.86, p 5 .02];
however, the only significant univariate age group 3
diagnosis interaction was on Abstraction [F(2,161) 5
3.29, p 5 .040; see Figure 1], in which the oldest patients
had significantly worse deficits in functioning. This twoway interaction remained significant when neuroleptic
dose was controlled statistically (p 5 .042), and when
patients on anticholinergic medications were excluded
from the analysis (p 5 .037). The magnitude of difference

Figure 1. Neuropsychologic profiles of patients with schizophrenia (left) and healthy control (right) subjects (mean Z scores of the
eight functions). Left graph is data from patients with schizophrenia. Right graph is data from normal control subjects.

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Table 4. Performance on Abstraction Function by Age Group
(Mean Z score 1 SD): WCST and VVT Variables

Group
Schizophrenia
Young (n 5 23)
Middle (n 5 38)
Older (n 5 26)
Control
Young (n 5 39)
Middle (n 5 27)
Older (n 5 28)

WCSTCategories
(Mean 6 SD)

WCST-PR
(Mean 6 SD)

VVT
(Mean 6 SD)

20.70 6 1.29a
21.33 6 1.17
21.84 6 0.86

20.64 6 1.32a
21.15 6 1.32a
21.93 6 1.45

21.33 6 1.41
21.25 6 1.08
21.79 6 1.33

0.17 6 0.57b
0.03 6 0.61
20.26 6 0.96

0.10 6 0.24b
0.00 6 0.38
20.13 6 0.50

0.04 6 0.61
0.12 6 0.53
0.18 6 0.68

VVT (Visual-Verbal Test) scores are Total Miss Score (Feldman and Drasgow
1981). WCST-PR is number of perseverative responses on the Wisconsin Card
Sorting Test task. Z scores have a mean of 0 and a standard deviation of 1.0. All
three variables are scored in the same direction (minus is worse performance).
a
Significant differences were found between young and older patients with
schizophrenia on WCST categories [t(36) 5 3.49, p 5 .001] and perseverations
[t(45) 5 23.17, p 5 .003], but not VVT score. Middle-aged patients differed from
older patients on WCST perseverations only [t(48) 5 22.15, p 5 .037].
b
Significant differences were found between younger and older controls on
WCST categories [t(41) 5 2.13, p 5 .039] and perseverations [t(37) 5 22.26, p 5
.030], but not VVT score.

between the youngest and the oldest age groups was
approximately 1.0 SD in patients, versus 0.4 SD in control
subjects. This was accounted for by lower performance on
the WCST rather than by conceptual impairment on the
Visual Verbal Test (VVT; Feldman and Drasgow 1981)
(see Table 4 and discussion below). Although visual

inspection of the profile levels in Figure 1 suggests strong
age-related declines in Perceptual Motor Skills (particularly in the oldest schizophrenics), statistical differences in
the magnitude of age-related decline were not found
between patients and control subjects. For descriptive
purposes only, mean scores (including age-scaled scores
for Wechsler Adult Intelligence Scale—Revised and Wide
Range Achievement Test—Revised scores) on all neuropsychologic measures, for each age sub-group, are presented in Table 5.

Discussion
In this cross-sectional investigation of the effects of aging
on neuropsychologic function in patients with schizophrenia, similar patterns of age effects on neuropsychologic
functions were observed in patients and healthy control
subjects, with the exception of significantly greater agerelated declines in abstraction functions among the patients, observed when the patients and control subjects
were subdivided into three age groups (“young,” “middle,” “older”). The decline in abstraction is consistent with
some previous cross-sectional and longitudinal studies
using electrophysiological and neuropsychologic measures (O’Donnell et al 1995; Sullivan et al 1994).
Correlational analyses revealed similarly significant
age-related declines on most functions in patients and in

Table 5. Mean Scores on Neuropsychologic Measures by Age Group
Patients with schizophrenia (n 5 87)

Variable
WMS-R Logical Memory I, % recalled
WMS-R Logical Memory II, % recalled
WMS-R Logical Memory, % retained
WCST categories
WCST perseverative responses
VVT, total miss score
Luria Manual Sequencing
Luria Graphic Sequence errors
Trail Making A seconds
Trail Making B seconds
Hooper Visual Organization
Benton Line Orientation
WAIS-R Vocabulary, Age SS
WAIS-R Digit Symbol, Age SS
WAIS-R Digit Span, Age SS
WAIS-R Block Design, Age SS
Auditory CPT errors
WRAT-R Reading SS
WRAT-R Spelling SS
WRAT-R Arithmetic SS

Control subjects (n 5 94)

Young

Middle

Older

Young

Middle

Older

Mean (SD)

Mean (SD)

Mean (SD)

Mean (SD)

Mean (SD)

Mean (SD)

36 (19)
28 (19)
75 (27)
3.9 (2.6)
28.7 (39.2)
28.4 (15.3)
21.1 (6.5)
1.3 (1.2)
41.7 (19.9)
136.1 (106.6)
25.2 (4.1)
22.4 (5.6)
10.0 (4.2)
6.1 (1.8)
8.6 (2.3)
9.3 (2.7)
6.9 (7.4)
95.3 (19.3)
91.8 (21.2)
82.0 (14.6)

43 (19)
33 (17)
73 (19)
2.7 (2.3)
43.7 (39.0)
27.5 (11.7)
14.9 (9.3)
1.4 (.94)
45.7 (13.7)
125.4 (66.3)
23.5 (4.2)
23.8 (4.6)
10.2 (3.0)
6.8 (1.9)
9.6 (2.5)
8.5 (2.5)
5.6 (5.6)
100.5 (16.1)
99.8 (17.3)
88.8 (16.2)

33 (19)
25 (17)
69 (31)
1.6 (1.7)
66.7 (43.0)
33.3 (14.4)
16.5 (8.6)
1.3 (.97)
73.0 (47.9)
184.8 (109.8)
18.5 (6.1)
21.8 (6.9)
9.4 (2.8)
7.2 (1.9)
8.9 (2.6)
8.6 (3.3)
4.9 (4.3)
101.6 (15.5)
105.0 (17.3)
90.6 (13.7)

64 (8)
58 (10)
91 (10)
5.7 (1.2)
6.8 (7.2)
13.4 (6.6)
23.7 (4.2)
0.68 (.59)
25.4 (8.9)
57.4 (25.2)
26.7 (1.7)
24.2 (4.8)
10.4 (2.7)
11.0 (2.4)
10.2 (2.5)
10.6 (2.5)
1.1 (1.4)
97.4 (12.1)
98.7 (12.5)
92.0 (12.3)

62 (11)
52 (14)
83 (12)
5.4 (1.2)
9.7 (11.4)
12.5 (5.8)
24.1 (2.7)
0.77 (.85)
26.2 (7.6)
66.9 (23.7)
27.5 (1.9)
24.6 (3.9)
12.1 (2.7)
11.3 (2.8)
11.9 (2.1)
10.8 (2.4)
1.0 (1.1)
106.8 (10.0)
102.5 (13.8)
102.3 (15.1)

49 (12)
41 (13)
82 (18)
4.8 (1.9)
13.6 (14.8)
15.8 (7.3)
23.7 (4.3)
1.2 (.85)
35.0 (17.1)
88.3 (43.0)
24.4 (3.6)
24.8 (4.2)
12.8 (4.3)
11.6 (2.5)
11.6 (2.4)
11.0 (2.4)
1.0 (1.5)
103.3 (6.2)
99.7 (18.5)
97.9 (18.5)

WAIS-R and WRAT-R scores in this table are age-scaled scores presented for descriptive purposes only (raw scores were used for statistical analyses).
WMS-R, Wechsler Memory Scale—Revised; WCST, Wisconsin Card Sorting Test; VVT, Visual Verbal Test; CPT, Continuous Performance Test; WAIS-R, Wechsler
Adult Intelligence Scale—Revised; WRAT-R; Wide Range Achievement Test—Revised.

Age and Neuropsychologic Function

control subjects, with the exception of the Verbal Memory
function, in which control subjects demonstrated a stronger association with age than patients. The significant
correlations between age and the Executive Motor, Verbal
Memory, and Sustained Attention functions found in
control subjects were not observed for patients perhaps
because deficits in these areas occurred early in the disease
process (i.e., earlier onset of cognitive deficit), though this
hypothesis is speculative and needs empirical support. The
significant association between age and the Abstraction
function was not attenuated when the effects of age at first
hospitalization (a possible confound and indicator of
disease severity) was controlled. Differences between the
groups could not be attributed to any gender differences as
this was controlled in the analyses.
Multivariate analyses confirmed that although patients
with schizophrenia performed at lower levels than control
subjects on all functions (except the Verbal function), the
magnitude of age-related declines on most functions was
similar in both groups. This was consistent with most other
studies demonstrating that neuropsychologic functions do
not decline significantly in most patients after the early
years of the illness, but are vulnerable to the same effects
of normal aging as those of healthy adults (Goldberg et al
1993; Harvey et al 1995; Hyde et al 1994; Rund 1998;
Seidman 1983; Weinberger 1987). Recently, Goldstein et
al (1998) reported similar correlations between age and a
global index of cognitive functioning among mildly impaired patients with schizophrenia, patients with progressive dementias and control subjects; however, consistent
with our results, a more severely impaired subset of
schizophrenia patients showed no significant associations
between age and the impairment index, indicating early
and substantial cognitive loss in some patients which may
be nonprogressive.
Consistent with speculations by Seidman (1983), we
found evidence of significantly greater decline in executive functions (in the Abstraction function) among the
patients with schizophrenia, when the groups were subdivided into three roughly equal size age groups. The greater
decline in Abstraction in patients with schizophrenia than
in control subjects, in the MANCOVA as compared to the
correlational analyses, reflects functioning in different age
defined subgroups of patients obscured by simple correlations within the entire group. The magnitude of the
difference between diagnostic groups was approximately
0.6 SD. Furthermore, this finding could not be accounted
for by antipsychotic medication dose (in chlorpromazine
equivalents), anticholinergic medication, or the later age at
first hospitalization of our oldest group of patients. Clinical symptoms as measured by the SANS and SAPS were
not significantly correlated with age or any of the eight
neuropsychologic function scores, indicating that positive

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2000;48:137–146

143

and negative symptomatology could not account for the
age-related decline found in our sample.
It is notable that later age at first hospitalization in the
older group would tend to reduce the difference. Sullivan
et al (1994) reported a relationship between age at first
hospitalization and executive functioning in schizophrenic
patients which could account for “selective” age-related
declines in these functions. In our sample, however, age at
first hospitalization was not correlated with the Abstraction function in patients, and the difference in rate of
decline in Abstraction between schizophrenic patients and
control subjects remained significant after controlling for
age at first hospitalization. As seen in Table 4, the
age-related decline observed in patients on VVT performance was substantially smaller than on the WCST, and
significant differences were not found on the VVT between age groups among patients or control subjects. In
contrast, age-group differences were detected on both
WCST variables among patients and control subjects
(Table 4). Thus, the accelerated decline detected in the
Abstraction function among patients appeared to be accounted for largely by performance on the WCST.
Interestingly, in a study of the nonpsychotic relatives of
patients with schizophrenia (Faraone et al 1995), performance on the WCST significantly discriminated relatives
and control subjects, but the VVT did not. The VVT
requires verbal generation of concepts, set-shifting and
generation of a second concept, whereas the WCST does
not require verbalization of responses. The WCST requires
more shifting of set, utilization of feedback and reinforcement, and probably a greater contribution from working
memory (Goldman-Rakic 1991). Patients with schizophrenia have shown a significant inverse relationship between
WCST performance and dorsolateral prefrontal blood
flow, indicating that the WCST may be particularly
sensitive to both schizophrenia (Koren et al 1998) and
integrity of prefrontal cortex in schizophrenia (Weinberger
et al 1986). It is unclear whether frontal networks degenerate at a more accelerated pace than other brain systems
in schizophrenia, although this possibility has been raised
by some neuroimaging and neurophysiological studies
(Gur et al 1998; O’Donnell et al 1995; Siegel et al 1994).
There is some evidence that prefrontal cortical volumes
age more rapidly than other regions in healthy humans
(Raz et al 1997). If prefrontal regions are more vulnerable
to age in healthy persons, they may be even more
vulnerable in patients with schizophrenia, providing some
structural basis for cognitive decline. This possible association may also be mediated by severity of lifetime
functional outcome, as those studies that have demonstrated cognitive decline in older age patients with schizophrenia (Davidson et al 1995) have tended to study very
poor outcome patients who may have the most damaged

144

R. Fucetola et al

BIOL PSYCHIATRY
2000;48:137–146

brains. This interpretation is speculative and awaits direct
empirical test.
Strengths of the present study include use of a large
group of patients and well-matched control subjects, a
comprehensive neuropsychologic battery of tests, including measures of executive functions, and a wide age range
of subjects; however, there are several limitations to the
study, which merit consideration. First, cross-sectional
studies are sensitive to cohort effects that may confound
differential effects of age on performance. We found a
relationship between age of onset and age in our sample,
but controlling for this variable did not diminish agerelated declines. Longitudinal studies over longer time
periods that utilize comprehensive neuropsychologic batteries would provide definitive data. Second, we did not
study the “very” old patients with schizophrenia (older
than 75 years of age), and thus it is not clear whether
similar effects of aging would be observed in an older
group. Third, our patients were recruited from hospitals
that specialize in the treatment of chronically psychotic
people. Thus, results may not generalize to other subgroups of patients (although about 65% were outpatients).
Moreover, our older patient group was not necessarily a
more severely impaired subgroup, because their single
word oral reading scores (a premorbid matching variable)
were actually higher than that of the older control subjects.
Thus, despite average premorbid intellectual ability, these
patients showed the largest relative decline with age on
some executive functions. Finally, although gender was
used as a covariate in all analyses, the results may not
generalize to female patients with schizophrenia, given the
relatively small representation of women in the current
sample. Future studies should include larger samples of
female patients to address any interaction between cognitive functioning, age and gender (Goldstein et al 1998).
In summary, similar age-related declines on most neuropsychologic functions were observed in patients with
schizophrenia and control subjects, indicating that most
patients do not show a progressive, widespread “dementing” course later in the illness. We did find evidence,
however, of larger patient-control differences in some
higher-order executive functions among the older subjects,
as reflected in Wisconsin Card Sorting deficits, which may
reflect deterioration of frontal system networks in older
patients with schizophrenia. The possibility that there is
another phase of deterioration in old age in patients with
schizophrenia, long after the decline observed in the first
few years of illness, is a hypothesis worthy of further
study.

Preparation of this article was supported in part by an award from the
NARSAD Foundation to Dr. Robert Fucetola, National Institute of
Mental Health Grants No. MH 43518 and No. MH 46318 to Dr. Ming T.

Tsuang, Stanley and NARSAD Foundation Awards to Dr. Larry J.
Seidman, and National Institute of Mental Health Grant No. SDA K21
MH 00976 to Dr. Jill M. Goldstein.
The authors thank the following people for their contributions to this
project: Gwen Barnes, Mimi Braude, Deborah Catt, Joanne Donatelli,
Tova Ferro, Lisa Gabel, David Goldfinger, Robin Green, Dr. Keith
Hawkins, Lynda Jacobs, Denise Leville, Dr. Michael Lyons, Catherine
Monaco, Dr. Theresa Pai, Dr. John Pepple, Anne Shore, Dr. Rosemary
Toomey, Jason Tourville, Rob Trachtenberg, and Judith Wides.
This work was presented, in part, as a paper at the annual meeting of
the International Neuropsychological Society, February 10 –13, 1999,
Boston.

References
Albus M, Hubmann W, Ehrenberg C, Forcht U, Mohr F,
Sobizack N, et al (1996): Neuropsychological impairment in
first-episode and chronic schizophrenic patients. Eur Arch
Psychiatr Clin Neurosci 246:249 –255.
American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington,
DC: American Psychiatric Press.
Andreasen NC, Olsen S (1982): Negative v. positive schizophrenia. Definition and validation. Arch Gen Psychiatry 39:789 –
794.
Bilder RM, Lipschutz-Broch L, Reiter G, Geisler SH, Mayerhoff
DL, Lieberman JA (1992): Intellectual deficits in firstepisode schizophrenia: Evidence for a progressive deterioration. Schizophr Bull 18:437– 448.
Brooker BH, Cyr JJ (1986): Tables for clinicians to use to
convert WAIS-R short forms. J Clin Psychol 42:983–986.
Buchsbaum MS, Hazlett EA (1997): Functional brain imaging
and aging in schizophrenia. Schizophr Res 27:129 –141.
Chen EYH, Lam LCW, Chen RYL, Nguyen DGH, Chan CKY
(1996): Prefrontal neuropsychological impairment and illness
duration in schizophrenia: A study of 204 patients in Hong
Kong. Acta Psychiatr Scand 93:144 –150.
Davidson M, Harvey PD, Parrella M, White L, Knobler HY,
Losonczy MF, et al (1995): Severity of symptoms in chronically institutionalized geriatric schizophrenic patients. Am J
Psychiatry 152:197–207.
DeLisi LE, Sakuma M, Tew W, Kushner M, Hoff AL, Grimson
R (1997): Schizophrenia as a chronic active brain process: A
study of progressive brain structural change subsequent to the
onset of schizophrenia. Psychiatry Res 74:129 –140.
Faraone SV, Seidman LJ, Kremen WS, Pepple JR, Lyons MJ,
Tsuang MT (1995): Neuropsychological functioning among
the nonpsychotic relatives of schizophrenic patients: A diagnostic efficiency analysis. J Abnorm Psychol 104:286 –304.
Feldman MJ, Drasgow J (1981): The Visual-Verbal Test. Los
Angeles: Western Psychological Services.
Goldberg E, Seidman LJ (1991): Higher cortical functions in
normals and in schizophrenia: A selective review. In: Steinhauer S, Gruzelier J, Zubin J, editors. Handbook of Schizophrenia, Vol. 5: Neuropsychology, Psychophysiology and
Information Processing. New York: Elsevier, 553–597.
Goldberg TE, Hyde TM, Kleinman JE, Weinberger DR (1993):
Course of schizophrenia: Neuropsychological evidence for a
static encephalopathy. Schizophr Bull 19:797– 804.

Age and Neuropsychologic Function

Goldman-Rakic, PS (1991): Prefrontal cortical dysfunction in
schizophrenia: The relevance of working memory. In: Carroll
BJ, Barret JE, editors. Psychopathology and the Brain. New
York: Raven, 1–23.
Goldstein G, Allen DN, van Kammen DP (1998): Individual
differences in cognitive decline in schizophrenia. Am J
Psychiatry 155:1117–1118.
Goldstein JM, Seidman LJ, Goodman JM, Koren D, Lee H,
Weintraub S, et al (1998): Are there sex differences in
neuropsychological functions among schizophrenia patients?
Results from a case control study. Am J Psychiatry 155:
1358 –1364.
Gur RE, Cowell P, Turetsky BI, Gallacher F, Cannon T, Bilker
W, et al (1998): A follow-up magnetic resonance imaging
study of schizophrenia: Relationship of neuroanatomical
changes to clinical and neurobehavioral measures. Arch Gen
Psychiatry 55:145–152.
Harvey PD, Docherty NM, Serper MR, Rasmussen M (1990):
Cognitive deficits and thought disorder: II. An eight month
follow-up study. Schizophr Bull 16:147–156.
Harvey PD, Silverman JM, Mohs RC, Parrella M, White L,
Powchik P, et al (1999): Cognitive decline in late-life
schizophrenia: A longitudinal study of geriatric chronically
hospitalized patients. Biol Psychiatry 45:32– 40.
Harvey PD, White L, Parrella M, Putnam KM, Kincaid MM,
Powchik P, et al (1995): The longitudinal stability of cognitive impairment in schizophrenia: Mini-Mental State scores at
one- and two-year follow-ups in geriatric inpatients. Br J
Psychiatry 166:630 – 633.
Heaton R, Paulsen JS, McAdams LA, Kuck J, Zisook S, Braff D,
et al (1994): Neuropsychological deficits in schizophrenics:
Relationship to age, chronicity and dementia. Arch Gen
Psychiatry 51:469 – 476.
Heaton RK (1981): The Wisconsin Card Sorting Test Manual.
Odessa, FL: Psychological Assessment Resources.
Heaton RK, Drexler M (1988): Clinical neuropsychological
findings in schizophrenia and aging. In: Miller NE, Cohen
GD, editors. The Psychiatric Clinics of North America:
Psychosis and Depression in the Elderly. Philadelphia: Saunders, 15–32.
Hoff AL, Riordan H, O’Donnell D, Stritzke P, Neale C, Boccio
A, et al (1992): Anomalous lateral sulcus asymmetry and
cognitive function in first-episode schizophrenia. Schizophr
Bull 18: 257–270.
Hyde TM, Nawroz S, Goldberg TE, Bigelow LB, Strong D,
Ostrem JL, et al (1994): Is there cognitive decline in schizophrenia: a cross-sectional study. Br J Psychiatry 164:494 –
500.
Kimura D (1967): Functional asymmetry of the brain in dichotic
listening. Cortex 3:163–178.
Koren D, Seidman LJ, Harrison RH, Lyons MJ, Kremen WS,
Caplan BB, et al (1998): Factor structure of the Wisconsin
Card Sorting Test: Dimensions of deficit in schizophrenia.
Neuropsychology 12:289 –302.
Kraepelin E (1919): Dementia Praecox and Paraphrenia. Edinburgh, UK: E & S Livingstone.
Kremen WS (1990): Age and neuropsychological functioning in
DSM-III-R schizophrenia (Doctoral dissertation, Boston University). Dissertation Abstr Int 51: 991B. (University Microfilms No. ADG90 –17583, 9000)

BIOL PSYCHIATRY
2000;48:137–146

145

Kremen WS, Seidman LJ, Faraone SV, Pepple JR, Lyons MJ,
Tsuang MT (1996): The “3 Rs” and neuropsychological
function in schizophrenia: An empirical test of the matching
fallacy. Neuropsychology 10:22–31.
Kremen WS, Seidman LJ, Faraone SV, Pepple JR, Tsuang MT
(1992): Attention/information-processing factors in psychotic
disorders: Replication and extension of recent neuropsychological findings. J Nerv Ment Dis 180:89 –93.
Kremen WR, Seidman LJ, Faraone SV, Toomey R, Tsuang MT
(1999): The question of neuropsychologically normal schizophrenia. Schizophr Res 36:140 –141.
Levin S, Yurgelun-Todd D, Craft S (1989): Contributions of
clinical neuropsychology to the study of schizophrenia. J
Abnorm Psychol 98:341–356.
Lezak MD (1995): Neuropsychological Assessment, 3rd ed. New
York: Oxford University Press.
Mirsky AF, Anthony BJ, Duncan CC, Ahearn MB, Kellam SG
(1991): Analysis of the elements of attention: A neuropsychological approach. Neuropsychol Rev 2:109 –145.
Moberg PJ, Doty RL, Turetsky BI, Arnold SE, Mahr RN, Gur
RC, et al (1997): Olfactory identification deficits in schizophrenia: Correlation with duration of illness. Am J Psychiatry
154:1016 –1018.
Mockler D, Riordan J, Sharma T (1997): Memory and intellectual deficits do not decline with age in schizophrenia. Schizophr Res 26:1–7.
Murray RM, Lewis SW (1987): Is schizophrenia a neurodevelopmental disorder? BMJ 295:681– 682.
O’Donnell BF, Faux SF, McCarley RW, Kimble MO, Salisbury
DF, Nestor PG, et al (1995): Increased rate of P300 latency
prolongation with age in schizophrenia. Electrophysiological
evidence for a neurodegenerative process. Arch Gen Psychiatry 52:544 –549.
Palmer BW, Heaton RK, Paulsen JS, Kuck J, Braff D, Harris MJ,
et al (1997): Is it possible to be schizophrenic yet neuropsychologically normal? Neuropsychology 11:437– 446.
Randolph C, Goldberg TE, Weinberger DR (1993): The neuropsychology of schizophrenia. In: Heilman KM, Valenstein E,
editors. Clinical Neuropsychology. New York: Oxford University Press, 499 –522.
Raz N, Gunning FM, Head D, Dupuis JH, McQuain J, Briggs
SD, et al (1997): Selective aging of the human cerebral cortex
observed in vivo: Differential vulnerability of the prefrontal
gray matter. Cereb Cortex 7:268 –282.
Rund BR (1998): A review of longitudinal studies of cognitive
functions in schizophrenia patients. Schizophr Bull 24:425–
435.
Saykin AJ, Shtasel DL, Gur RE, Kester DB, Mozley LH,
Stafiniak P, et al (1994): Neuropsychological deficits in
neuroleptic naive patients with first-episode schizophrenia.
Arch Gen Psychiatry 51:124 –131.
Seidman LJ (1983): Schizophrenia and brain dysfunction: An
integration of recent neurodiagnostic findings. Psychol Bull
94:195–238.
Seidman LJ (1990): The neuropsychology of schizophrenia: A
neurodevelopmental and case study approach. J Neuropsychiatry 2:301–312.
Seidman LJ, Cassens G, Kremen WS, Pepple JR (1992): The
neuropsychology of schizophrenia. In: White RF, editor.

146

BIOL PSYCHIATRY
2000;48:137–146

Clinical Syndromes in Adult Neuropsychology: The Practictioner’s Handbook. New York: Elsevier, 381– 449.
Seidman LJ, Pepple JR, Faraone SV, Kremen WS, Green AI,
Brown WA, et al (1993): Neuropsychological performance in
chronic schizophrenia in response to neuroleptic dose reduction. Biol Psychiatry 33:575–584.
Seidman LJ, Stone WS, Jones R, Harrison RH, Mirsky AF
(1998): Comparative effects of schizophrenia and temporal
lobe epilepsy on memory. J Int Neuropsychol Soc 4:342–352.
Siegel BV, Reynolds C, Lohr JB, Nuechterlein KH, Bracha HS,
Potkin SG, et al (1994): Changes in regional cerebral metabolic rate with age in schizophrenics and normal adults. Dev
Brain Dysfunct 7:132–146.
Spitzer RL, Endicott J (1978): Schedule for Affective Disorders
and Schizophrenia, 3rd ed. New Yor