Annotated Bibliography, Introduction, and Summary Paragraph: Seeking the Truth
C. J. Herold et al.: Co gnitive Performance in Schizophren iaGeroPsych (20 17), 30 (1), 35 –44© 20 17 Hogrefe Full-Length Research Report Cognitive Performance in Patients with Chronic Schizophrenia Across the Lifespan Christina Josefa Herold 1, Lena Anna Schmid 1, Marc Montgomery Lässer 1, Ulrich Seidl 2, and Johannes Schröder 1,3 1Section of Geriatric Psychiatry, Department of General Psychiatry, University of Heidelberg, Heidelberg, Germany2Center for Mental Health, Klinikum Stuttgart, Stuttgart, Germany3Institute 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 thatcertain 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.
© 2017 HogrefeGeroPsych (2017), 30 (1), 35–44 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’sκ> 0.75, Sheehan et al., 1998) and the Beck Depression Inventory II (Cronbach’sα= 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- abilityr= 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-reliabilityr= 0.63 andr= 0.52 for SAPS and SANS respectively, Cronbach’sαSAPS = 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-reliabilityr= 0.80, Cron- bach’sα= 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-reliabilityr= 0.79, interrater-reliabilityr= 0.99), and the digit span forward and backward subtests, assessing short-term and working memory (each maximum score = 12, retest-reli- abilityr= 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-reliabilityr= 0.74 andr= 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 αlevel 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 36C. J. Herold et al.: Cognitive Performance in Schizophrenia GeroPsych (2017), 30 (1), 35–44© 2017 Hogrefe C. J. Herold et al.: Cognitive Performance in Schizophrenia37 © 2017 HogrefeGeroPsych (2017), 30 (1), 35–44 “diagnosis,”p> .30), while the healthy subjects had received a significantly longer school education than the patients (mean of years of educationM= 12.47 (SD= 2.78) vs.M= 13.58 (SD = 2.30),F(1, 154) = 6.755,p=.010,η 2= 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 withp< .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 moreoften 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,η 2= 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,η 2= 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 toz-scores, based on the norm values of the specific test.
38C. J. Herold et al.: Cognitive Performance in Schizophrenia GeroPsych (2017), 30 (1), 35–44© 2017 Hogrefe 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 Schizophrenia39 © 2017 HogrefeGeroPsych (2017), 30 (1), 35–44 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, wherez-scores nearly reached the mark ofz= –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 ofM= 30.0 (SD= 3.6),M=41.1(SD= 4.2) andM= 58.3 (SD= 5.6) years in the patient groups andM= 28.5 (SD= 4.4),M=41.3(SD= 3.8) andM= 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, withz-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’sdisease (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).
40C. J. Herold et al.: Cognitive Performance in Schizophrenia GeroPsych (2017), 30 (1), 35–44© 2017 Hogrefe 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 reducedcognitive 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 Schizophrenia41 © 2017 HogrefeGeroPsych (2017), 30 (1), 35–44 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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