Annotated Bibliography, Introduction, and Summary Paragraph: Seeking the Truth

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Full-Length Research Report

Cognitive Performance in Patients

with Chronic Schizophrenia Across

the Lifespan Christina Josefa Herold1, Lena Anna Schmid1, Marc Montgomery Lässer1,

Ulrich Seidl2, and Johannes Schröder1,3

1 Section of Geriatric Psychiatry, Department of General Psychiatry, University of Heidelberg, Heidelberg, Germany 2 Center for Mental Health, Klinikum Stuttgart, Stuttgart, Germany 3 Institute of Gerontology, University of Heidelberg, Heidelberg, Germany

DOI 10.1024/1662-9647/a000164

Abstract: Chronic schizophrenia involves neuropsychological deficits that primarily strike executive functions and episodic memory. Our study

investigated these deficits throughout the lifespan in patients with chronic schizophrenia and in healthy controls. Important neuropsycholog-

ical functions were tested in 94 patients and 66 healthy controls, who were assigned to three age groups. Compared with the healthy controls,

patients performed significantly poorer on all tests applied. Significant age effects occurred on all tests except the digit span forward, with

older subjects scoring well below the younger ones. With respect to cognitive flexibility, age effects were more pronounced in the patients.

These findings underline the importance of cognitive deficits in chronic schizophrenia and indicate that diminished cognitive flexibility shows

age-associated differences.

Keywords: schizophrenia, cognition, aging, executive functions, memory

Cognitive impairment is a hallmark of schizophrenia. The pattern

of deficits and their relationship to psychosocial functioning have

been illustrated in a large number of neuropsychological studies

over the past few decades (Dickinson & Gold, 2008; Green,

1996; Schröder, Tittel, Stockert, & Karr, 1996). It is generally

assumed that cognitive function is often already below average in

premorbid periods (Reichenberg et al., 2006; Woodberry, Giu-

liano, & Seidman, 2008) and decreases with manifestation of the

disease (Bilder et al., 2000; Mesholam-Gately, Giuliano, Goff,

Faraone, & Seidman, 2009). The respective deficits continue in

patients with chronic schizophrenia, including those in whom

symptoms have partially remitted (Barbarotto, Castignoli, Pasetti,

& Laiacona, 2001; Heinrichs & Zakzanis, 1998).

Cognitive and functional losses occur with normal aging in

the entire population. The frontal-lobe hypothesis (West, 1996)

posits that the frontal lobe is particularly susceptible to age-re-

lated deterioration in healthy adults. This assumption is sup-

ported by neuroimaging data that demonstrate both structural

and functional changes in the frontal lobe with aging (Hazlett

et al., 1998; Raz et al., 1997; Salat et al., 2004). In addition,

neuropsychological studies describe a worsening of frontal ex-

ecutive functions with aging in healthy adults (Salthouse, At-

kinson, & Berish, 2003; Sorel & Pennequin, 2008).

The question of the extent to which this decline of frontal

functions with age also applies to patients with chronic schizo-

phrenia remains unresolved. While some studies indicate that

certain cognitive domains such as information processing and

executive functioning might bear a greater risk of worsening

with age (Bowie, Reichenberg, McClure, Leung, & Harvey,

2008; Fucetola et al., 2000; Irani et al., 2012; Loewenstein,

Czaja, Bowie, & Harvey, 2012), others did not find any differ-

ential aging effects (Heaton et al., 2001; Hijman, Hulshoff Pol,

Sitskoorn, & Kahn, 2003; Mockler, Riordan, & Sharma,

1997). These divergent findings may reflect methodological dif-

ferences between the studies, which are detailed in the Discus-

sion section below. Recently, Kirkpatrick et al. (2008) estab-

lished the hypothesis that schizophrenia is a syndrome of ac-

celerated aging – as already conceptualized by the term

“dementia praecox” (Kraepelin, 1913) – since cognitive deficits

in chronic schizophrenia primarily strike those domains that

are typically affected in the physiological aging process. This

hypothesis also conforms to the frontal cortex changes fre-

quently described in patients with schizophrenia in neuroimag-

ing studies (Bachmann et al., 2004; Buchsbaum et al., 1982;

DeLisi, Szulc, Bertisch, Majcher, & Brown, 2006; Schröder,

Buchsbaum et al., 1996). Despite the renewed interest in cog-

nition in old age schizophrenia, considerable controversy still

lingers over this topic.

The current study examines the association between age and

cognitive performance in chronic schizophrenia. We concen-

trate specifically on patients and psychiatrically healthy controls

ranging in age from young adulthood to old age.

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We hypothesized that patients with chronic schizophrenia

of all ages show substantial cognitive deficits. In addition, we

expected these deficits to worsen with age. This effect should

primarily involve executive functions, while episodic memory

deficits should remain more stable.

Methods

Subjects and Procedures

Cognitive performance was assessed in healthy subjects and

patients with chronic schizophrenia in the age range 18 to 82

years. The patients and healthy controls were each subdivided

into three age groups (“young” ≤ 34 years, “middle” 35–49 years, and “older” ≥ 50 years).

94 patients with chronic or subchronic schizophrenia ac-

cording to DSM-IV (American Psychiatric Association, 2000)

were recruited from three psychiatric long-term units (n = 40)

and a mental state hospital (n = 54). All patients were in a stable

condition and had received antipsychotic therapy; dosage was

evaluated in mg chlorpromazine (CPZ) equivalents (Woods,

2003). The diagnosis was established by experienced psychia-

trists. Inclusion criteria for patients were (1) a diagnosis of

schizophrenia according to DSM-IV (American Psychiatric As-

sociation, 2000), (2) German as the primary language, and (3)

a minimum of 8 years school education. Patients with late onset

schizophrenia with a manifestation of the disease after age 45

were not included as this condition may have involved a differ-

ent etiology (Howard, Rabins, Seeman, & Jeste, 2000; Schmid,

Lässer, & Schröder, 2011). Further exclusion criteria included

a history of any neurological condition affecting the central ner-

vous system, head injury, or substance abuse.

Healthy controls (n = 66) were recruited among the hospital

staff and through advertisements in a newspaper. The Mini In-

ternational Neuropsychiatric Interview (interrater and retest-

reliability Cohen’s κ > 0.75, Sheehan et al., 1998) and the Beck Depression Inventory II (Cronbach’s α = 0.89, retest-reliability r = 0.78, Hautzinger, Keller, & Kühner, 2006) were performed

to screen controls for current psychopathology. They were care-

fully matched to patients with respect to age and sex (main

effect “diagnosis,” p > .30).

Informed consent was obtained from all participants after

the study had been fully explained. The study was approved by

the local ethics committee.

Measures

Symptoms were assessed using the Brief Psychiatric Rating

Scale (BPRS, 18 items, maximum score = 108, interrater-reli-

ability r = 0.8; Ligon & Thyer, 2000; Mass, Burmeister, &

Krausz, 1997; Overall & Gorham, 1962), the Scale for the As-

sessment of Positive Symptoms (SAPS) and the Scale for the

Assessment of Negative Symptoms (SANS) (34 and 25 items

respectively, maximum global score = 20 and 25 respectively,

interrater-reliability r = 0.63 and r = 0.52 for SAPS and SANS

respectively, Cronbach’s α SAPS = 0.77–0.91 and SANS = 0.83–0.92; Andreasen & Olsen, 1982; Norman, Malla, Cor-

tese, & Diaz, 1996).

Important neuropsychological domains typically involved in

chronic schizophrenia were assessed by using a comprehensive

test battery. Therefore, verbal learning and memory, short-term

and working memory, processing speed, and cognitive flexibil-

ity were taken into account; the Mini-Mental State Examination

(MMSE, maximum score = 30, retest-reliability r = 0.80, Cron-

bach’s α = 0.91) was used as a screening instrument for cogni- tive ability (Folstein, Folstein, & McHugh, 1975; Marioni, Chat-

field, Brayne, & Matthews, 2011). All subjects completed the

logical memory subtests of the Wechsler Memory Scale (Här-

ting et al., 2000) to assess verbal learning and memory (logical

memory I and logical memory II, maximum score each = 50,

retest-reliability r = 0.79, interrater-reliability r = 0.99), and the

digit span forward and backward subtests, assessing short-term

and working memory (each maximum score = 12, retest-reli-

ability r = 0.83). As an index of processing speed and cognitive

flexibility, we used the scores of the Trail Making Test (TMT A

– max. 180 s, TMT B – max. 240 s, retest-reliability r = 0.74

and r = 0.43 for TMT A and B, respectively (Conway Greig,

Nicholls, Wexler, & Bell, 2004; Reitan, 1992)).

Statistical Analyses

The effects of diagnosis and age were examined using multivar-

iate analyses of variance (MANOVA) with diagnosis (patients,

controls) and age group (young, middle, older) as the between-

group factors, and the different demographical/clinical charac-

teristics and the cognitive parameters as the dependent vari-

ables, while controlling for years of education in the latter.

These analyses were followed by Bonferroni posthoc tests. An

α level of 0.05 (two-tailed) was used for all statistical tests. Analyses were conducted by means of the Predictive Analy-

sis Soft Ware (PASW/SPSS 18.0).

Results

Sample Characteristics

In a first step, demographic and clinical characteristics of the

three age groups were tested for significant group differences

(Table 1). Patient and control groups showed only minor, non-

significant differences with regard to age and sex (main effect

36 C. J. Herold et al.: Cognitive Performance in Schizophrenia

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C. J. Herold et al.: Cognitive Performance in Schizophrenia 37

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“diagnosis,” p > .30), while the healthy subjects had received a

significantly longer school education than the patients (mean

of years of education M = 12.47 (SD = 2.78) vs. M = 13.58 (SD

= 2.30), F(1, 154) = 6.755, p = .010, η2 = 0.042). Further analysis of the patient group revealed that the three

age groups did not differ in dosage of antipsychotic medication

(CPZ equivalents), negative and positive symptoms, with a

trend-level significant effect for SAPS global score, indicating

more distinctive positive symptoms in the young patient group,

F(2, 91) = 2.870, p = .062. With respect to BPRS sum score a

significant effect for “age,” F(2, 91) = 5.238, p = .007, shows

additionally evidence for a more severe psychopathology in

younger patient groups. Posthoc tests revealed significant dif-

ferences between the older patients and both patient groups of

middle (p = .015) and young (p = .032) age.

As expected, significant differences were noticeable with re-

gard to illness duration, F(2, 91) = 64.016, p < .001, the patient

groups differed each with p < .001, and age at onset of the

illness, F(2, 91) = 5.631, p = .005. Posthoc tests showed a sig-

nificant difference between young and old patients (p = .004),

whereas other comparisons failed to reach significance (p >

.09).

There was a significant age cohort effect for dwelling status,

χ² = 9.542, p = .008, with middle and older patients being more

often hospitalized in comparison to young patients at the time

point of study.

Age Effects on Cognitive Performance

In a second step it was shown that, compared with the healthy

controls, patients performed lower on all tests applied (Figure

1). Test performance tended to be lower in the oldest than the

young and middle-aged groups. With respect to TMT B, this

effect was more pronounced in the patient groups in whom a

sharper decline of performance with age became evident (Fig-

ure 2).

These findings were confirmed by a MANOVA (Table 2)

which yielded a significant main effect for “diagnosis,”

F(7, 147) = 19.227, p < .001, η2 = 0.478. Further comparisons revealed significant differences between patients and healthy

controls for all neuropsychological tests applied, thus indicat-

ing a pronounced performance deficit of the patients (0.04 > p

= .000).

The main effect for “age” reached significance level too,

F(14, 296) = 4.280, p < .001, η2 = 0.168, with older subjects being more impaired (0.03 > p = .000), except for digit span

forward (p = .145).

Figure 1. Neuropsychological profiles of patients (black lines) and healthy controls (gray lines). Raw test scores of all cognitive parameters were

transformed to z-scores, based on the norm values of the specific test.

38 C. J. Herold et al.: Cognitive Performance in Schizophrenia

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Posthoc tests revealed that MMSE performance was signifi-

cantly lower for old than for young subjects (p = .007), while

the difference between groups of old and middle-aged subjects

failed to reach significance (p = .062). In case of logical memory

I, the old subjects had significant impairments in contrast to

the young subjects (p = .044); in the case of logical memory II,

the old subjects showed marked deficits in comparison to both

younger groups (p < .02). Working memory performance, as

indicated by digit span backward, was significantly reduced in

the old subject group in contrast to the young group (p = .003).

Figure 2. TMT A (above) and TMT B (below) performance as a function

of age for patients (black lines) and healthy subjects (gray lines).

C. J. Herold et al.: Cognitive Performance in Schizophrenia 39

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Information processing speed, assessed via TMT A, was also

significantly impaired in the older subjects compared to both

younger groups (p < .001). With respect to cognitive flexibility,

as assessed using TMT B, significant differences between each

age group and the other groups were evident (.05 > p = .000).

The interaction “diagnosis × age” showed a significant effect

for TMT B, F(2, 153) = 4.869, p = .009, with trend-level signif-

icance for TMT A, F(2, 153) = 2.716, p = .069. A trend-level

significant “diagnosis × age” interaction with respect to MMSE

also appeared, additionally indicating a cognitive deterioration

in older patients, F(2, 153) = 2.774, p = .066.

Discussion

The present study revealed three major findings regarding cog-

nitive impairment of patients with chronic schizophrenia: (1)

a confirmation of broad deficits in a variety of important neu-

ropsychological domains which (2) apply to all life periods from

young adulthood to early age; and (3) evidence that cognitive

flexibility is particularly affected in the older patients.

The poorer test performance of patients with chronic schiz-

ophrenia in comparison to healthy subjects covers a wide range

of cognitive domains. This was particularly evident with regard

to verbal learning and memory, where z-scores nearly reached

the mark of z = –1.5 for all age groups. Information processing

speed and cognitive flexibility were impaired to a comparable

extent with a considerable stronger dip in the older patients.

In contrast, short-term memory remained rather spared with

performance still ranging in low average levels.

These results corroborate findings from previous studies on

cognitive deficits in young and middle-aged patients with chron-

ic schizophrenia (Heinrichs & Zakzanis, 1998; Irani et al.,

2012) and extend them for an older group. One of the studies

investigating cognition in schizophrenia over a wide age range

was conducted by Fucetola et al. (2000), who examined 87

patients and 94 healthy controls assigned to three groups with

an average age of M = 30.0 (SD = 3.6), M = 41.1 (SD = 4.2)

and M = 58.3 (SD = 5.6) years in the patient groups and M =

28.5 (SD = 4.4), M = 41.3 (SD = 3.8) and M = 62.5 (SD = 7.2)

years in the control groups, respectively. Cognitive deficits in

the patient group involved verbal memory, perceptual motor

skills, and abstraction, with z-scores below –1 throughout the

three age groups. As in the present study, performance in mem-

ory and learning, information processing, and cognitive flexi-

bility was well within the range of that typically obtained in

older patients with a diagnosis of mild cognitive impairment

(Sattler, 2012).

At this point it should be emphasized that even the marked

deficits typically observed in older patients with chronic schiz-

ophrenia are not directly comparable to the impairments char-

acteristic of neurodegenerative illnesses such as Alzheimer’s

disease (AD), since declarative memory remains relatively

spared and does not further deteriorate with progression of the

disease. As in the present study, a consistent pattern of neuro-

psychological deficits was already described by McBride et al.

(2002) and Ting et al. (2009). The MMSE scores of our patient

group were – though reduced and at trend-level deteriorating

with increasing age – not comparable to that of patients with

AD (Barth, Schönknecht, Pantel, & Schröder, 2005; Dos San-

tos et al., 2011). These findings parallel results from a review

of neuropathological studies, which concluded that AD pathol-

ogy does not occur more frequently among patients with schiz-

ophrenia than in the general population (Niizato, Genda, Na-

kamura, Iritani, & Ikeda, 2001).

While a wealth of studies investigated cognitive performance

in schizophrenia in general, only few authors focused on the

potential interaction effects between age and illness with regard

to cognitive functioning. The present study demonstrated that

older patients showed a significantly poorer performance in

cognitive flexibility compared to their younger counterparts.

Along with this, a trend toward significant interaction of diag-

nosis with age was found for information processing. In con-

trast, none of the other cognitive domains examined showed

such a differential effect of aging in the patient group compared

to the healthy controls. In the study cited above, Fucetola et al.

(2000) found similar age-related performance differences be-

tween patients and controls across various domains, while a

significant interaction was restricted to abstract thinking as as-

sessed on the Wisconsin Card Sorting Test. In a recent study,

Irani et al. (2012) tested two groups of 624 patients with schiz-

ophrenia and healthy controls on a computerized version of

the Continuous Performance Test and on a Letter-N-Back Test

and came to similar conclusions. Compared with the healthy

controls, the patients showed significantly lower values regard-

less of age in most indices of cognitive performance. However,

the older group under investigation showed a reduced speed

but not accuracy in the N-back task compared to the younger

patients. This indicates that the executive component of work-

ing memory performance was predominantly affected. Loewen-

stein et al. (2012) analyzed age-associated cognitive differences

in a sample of 226 patients with chronic schizophrenia and 834

healthy controls, which were compiled from different data-

bases. All participants were older than 40 years; the clinical

course of the disorder was not further specified. The study

yielded greater age effects for patients than for controls on mea-

sures of information processing i.e., the TMT A, the Stroop and

the Digit Symbol Test, which also assess at least to a certain

extent cognitive flexibility.

The results of our study indicate that patients with chronic

schizophrenia show a slope of cognitive decline with advancing

age similar to controls in all cognitive domains except for cog-

nitive flexibility as a typical executive function. Although this

effect was rather small, it clearly refers to progressive cerebral

changes in normal aging, which particularly strike the frontal

lobes (DeCarli et al., 2005; Raz et al., 1997; Salat et al., 2004).

40 C. J. Herold et al.: Cognitive Performance in Schizophrenia

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Longitudinally, the extent of progressive brain tissue decrease

in patients with schizophrenia is found to be twice that of

healthy subjects and particularly affects frontal areas (Hulshoff

Pol & Kahn, 2008; Olabi et al., 2011). Similar significant re-

ductions in superior frontal gyrus and orbitofrontal regions

were observed in a small male sample of young patients with

schizophrenia and older healthy subjects in comparison to a

young healthy control group (Convit et al., 2001). Moreover,

gray matter decreases in frontal cortex were greater in chronic

than in first-episode schizophrenia (Chan, Di, McAlonan, &

Gong, 2011; Ellison-Wright, Glahn, Laird, Thelen, & Bullmore,

2008).

Except for cognitive flexibility, our pattern of findings with

rather stable deficits across different groups is consistent with

the results of previous studies. Mockler et al. (1997) confirmed

widespread cognitive deficits, but did not report any significant

age effects on cognitive functioning in 62 patients with chronic

schizophrenia between 18 and 69 years of age. However, the

majority of patients were below 50 years, and just 6 patients

formed the oldest group (60 to 69 years). Moreover, executive

functions were not specifically addressed. Similarly, Hijman et

al. (2003) who compared performance on four subtests of the

Wechsler Adult Intelligence Test between 112 patients with

chronic schizophrenia and 70 healthy controls (age range: 16

to 56 years) did not describe a significant interaction effect of

age with group, while patients performed worse on all subtests.

The oldest group (46 to 56 years) comprised 17 patients; the

majority of patients were below 46 years of age. Performance

on the subtest picture arrangement, which shares aspects of

executive functioning, decreased with age, a process which ap-

peared to be slightly more pronounced in the patient group.

Bowie and colleagues (2008) also reported deficits in a number

of important neuropsychological domains including psychomo-

tor speed and cognitive flexibility. Performance levels compare

to the “middle-aged” and “older” patient subgroups investigat-

ed in the present study. However, Bowie et al. (2008) recruited

a group of old patients (50–85 years), but did not include

younger patients with chronic schizophrenia. In light of the re-

duced life expectancy of patients with chronic schizophrenia

(Laursen, 2011), the subgroup of old patients (70–85 years)

may represent a number of survivors who either had a more

favorable course of the disorder or were less vulnerable to its

consequences during the aging process. The study showed ev-

idence for age-associated cognitive decline on the more com-

plex components of an information-processing test, which Bow-

ie et al. (2008) alternatively referred to “the course of illness

and the processing demands of the cognitive measure of inter-

est.” However, their results mirror our findings because they

did not only show a significant age-associated decline in the

TMT A, but also a similar although nonsignificant trend toward

for the TMT B in the patients.

In the present study, executive functions were only ad-

dressed by using the TMT, while other tests such as the Wis-

consin Card Sorting Test were not applied. Because of reduced

cognitive capacity of especially the older patients, we restricted

our cognitive assessment to a few tests.

While groups were carefully matched for age and sex, in the

patients years of education were significantly reduced, which

may be expected in a group of patients with a chronic course

of the disease, of whom 20–60% were hospitalized. For this

reason years of education were controlled for in the MANOVA.

Negative symptoms differed nonsignificantly between the pa-

tient groups, while positive symptoms (trend-level only) and

BPRS total score were lower in older than younger patients.

These differences correspond to the amelioration of acute

schizophrenic symptoms with increasing age (Schmid et al.,

2011), already described by Bleuler (1949). That the older pa-

tients are nonetheless severely affected is indicated by their

dwelling status, illustrating that older patients are more often

institutionalized.

Given that age and duration of illness coincide because of

onset of the disease in early adulthood and the exclusion of

patients with late onset schizophrenia, the three age groups

differed significantly with respect to illness duration. The mar-

ginal, albeit significant group difference of age at illness onset,

determined on basis of the patients’ history and case notes, may

well be explained by the fact that the youngest group per defi-

nitionem does not comprise patients with a later onset, which

is also reflected by the respective standard deviations.

Data concerning the predominant treatment of the patients

in the past were unfortunately not available. At the time of as-

sessment the majority of the patients were receiving atypical

antipsychotics only or typical and atypical antipsychotic medi-

cation in combination. Potential medication effects cannot be

entirely excluded as patients were examined cross-sectionally,

although the three patient groups showed only marginally, non-

significant differences with respect to CPZ equivalents. Simi-

larly, significant medication effects were not identified in the

large meta-analysis by Irani and colleagues (2011). In contrast,

other studies indicate a beneficial impact of atypical (Guilera,

Pino, Gómez-Benito, & Rojo, 2009; Thornton, Van Snellen-

berg, Sepehry, & Honer, 2006; Woodward, Purdon, Meltzer,

& Zald, 2005) and typical (Davidson et al., 2009; Mishara &

Goldberg, 2004; Schröder, Tittel et al., 1996) antipsychotic

medication on cognition in schizophrenia. Especially the latter

findings are important given that particularly the older patients

of our sample might have received mainly classical antipsychot-

ics in the past.

Additional factors other than age are likely to affect cognitive

flexibility: The large meta-analysis cited above (Irani et al.,

2011) revealed a significant role for both demographic (age,

sex, education, race) and clinical factors (living status, age of

onset, duration of illness, clinical symptoms). From a clinical

standpoint, co-morbid somatic conditions and other life-style

factors should also be added in longitudinal studies, as physical

illnesses like the metabolic syndrome, which increases in inci-

dence with rising age and is associated with cognitive deterio-

ration (Schröder & Pantel, 2011), are more common in patients

C. J. Herold et al.: Cognitive Performance in Schizophrenia 41

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with schizophrenia (Oud & Meyboom-de Jong, 2009; Sebas-

tian & Beer, 2007).

The results of the present cross-sectional study underline the

importance of cognitive deficits in chronic schizophrenia and

indicate that diminished cognitive flexibility undergoes age-as-

sociated differences, which can be assigned to frontal lobe

changes. This pattern of cognitive deficits facilitates the differ-

entiation from neurodegenerative diseases such as mild cogni-

tive impairment and AD and underlines the need for appropri-

ate training programs for elderly patients with chronic schizo-

phrenia.

Declaration of Conflicts of Interest

The authors declare that no conflicts of interest exist.

Acknowledgments

The study was supported by the Dietmar Hopp Foundation,

Germany.

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Manuscript received: 17.07.2015

Manuscript accepted after revision: 17.12.2015

Dipl.-Psych. Dr. Christina Herold

Section of Geriatric Psychiatry

University of Heidelberg

Voßstr. 4

69115 Heidelberg

Germany

[email protected]

44 C. J. Herold et al.: Cognitive Performance in Schizophrenia

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