Australian and New Zealand Journal of Psychiatry http://anp.sagepub.com/
Comparing neurocognition in severe chronic schizophrenia and frontotemporal dementia Hui-Minn Chan, Rene Stolwyk, Wendy Kelso, Joanna Neath, Mark Walterfang, Ramon Mocellin, Alexia Pavlis and Dennis Velakoulis Aust N Z J Psychiatry 2014 48: 828 originally published online 7 April 2014 DOI: 10.1177/0004867414529477 The online version of this article can be found at: http://anp.sagepub.com/content/48/9/828
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0010.1177/0004867414529477Australian & New Zealand Journal of PsychiatryChan et al. research-article2014
Research
Comparing neurocognition in severe chronic schizophrenia and frontotemporal dementia
Australian & New Zealand Journal of Psychiatry 2014, Vol. 48(9) 828–837 DOI: 10.1177/0004867414529477 © The Royal Australian and New Zealand College of Psychiatrists 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav anp.sagepub.com
Hui-Minn Chan1,2, Rene Stolwyk1, Wendy Kelso2, Joanna Neath2, Mark Walterfang2, Ramon Mocellin2, Alexia Pavlis2 and Dennis Velakoulis2
Abstract Objective: Previous research has suggested cognitive similarities between schizophrenia and frontotemporal dementia. In the current study, we compared neurocognition in a group of hospitalised patients with chronic schizophrenia, who may have a more severe form of schizophrenia resembling Emil Kraepelin’s dementia praecox, with patients with frontotemporal dementia. We hypothesised minimal group differences in cognitive performance, and a large overlap in between-group score distributions in each cognitive domain. Methods: Retrospective neuropsychological data for 26 patients with severe chronic schizophrenia and 34 patients with frontotemporal dementia (behavioural variant) was collated. Neuropsychological measures were categorised into 16 cognitive domains. Raw scores were converted into standardised z-scores for each measure, which were then averaged across measures within each domain. In addition to difference analysis, equivalence testing was utilised, whereby overlap percentages were computed to reflect the amount of score distribution overlap in each domain between groups. Results: A statistically significant difference was observed only in the executive function sub-domain of Switching. Smallto-moderate and moderate effect sizes were noted in four other domains. Equivalence testing showed more than 85% of overlap in score distribution in most domains. Conclusions: Our findings suggest that some patients with severe chronic schizophrenia have cognitive deficits similar in degree and pattern to patients with frontotemporal dementia. The few differences observed between both groups of patients are important for differential diagnostic purposes. One limitation is the retrospective nature of the study. Suggestions for future research include longitudinal follow-up studies of these two patient populations and studies of aspects beyond neurocognition. An implication of our findings is that the ‘dementia of schizophrenia’ concept may be applicable to patients with severe chronic schizophrenia. Keywords Neuropsychology, neurocognition, chronic schizophrenia, frontotemporal dementia, dementia praecox, behavioural variant frontotemporal lobar degeneration, poor-outcome schizophrenia, Kraepelinian schizophrenia
Introduction The concept of schizophrenia emerged in 1896 as dementia praecox, when Kraepelin combined three forms of ‘insanity’ with ages of onset in adolescence to early adulthood and a progressive course leading to dementia in most cases (Kraepelin, 1987; McKenna, 2007). Kraepelin speculated that dementia praecox involves a ‘tangible morbid process occurring in the brain’ (Kraepelin, 1987, p. 23). He considered dementia praecox to be a disorder of volition, or executive dysfunction (Zec, 1995), with the seat of pathology lying in the frontal and temporal lobes (Kraepelin, 1971/1919).
The concept of a ‘dementia of schizophrenia’ has been more recently considered (de Oliveira-Souza et al., 2007; de Vries et al., 2001; Gregory et al., 1998; Mitelman and Buchsbaum, 2007). This concept is especially pertinent in 1School
of Psychological Sciences, Monash University, Clayton, Australia Unit, Royal Melbourne Hospital, Melbourne, Australia
2Neuropsychiatry
Corresponding author: Hui-Minn Chan, School of Psychological Sciences, Building 17, Wellington Road, Monash University, Clayton, VIC 3800, Australia Email: [email protected]
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Chan et al. those patients with schizophrenia who require long-term or recurrent hospitalisation, or are highly dependent on carers for basic needs if living in the community. Arguably, these patients have the most severe and chronic form of the disorder, with a clinical course that may closely resemble that of Kraepelin’s dementia praecox and which has thus been referred to as ‘Kraepelinian schizophrenia’ (Keefe et al., 1987). More recently, Mitelman and Buchsbaum (2007) described this subtype of poor-outcome schizophrenia as an as yet undefined dementia, with a biphasic progressive deterioration of ‘frontotemporal schizophrenia-like clinical and morphological features’ early in the course of disease and then ‘insidious posteriorisation of cortical grey matter deficits’ leading to the quick decline of neurocognitive functions seen later in life (p. 354). The nature of this putative dementia does not appear to conform to the cognitive, clinical and neurobiological profiles of dementias such as Alzheimer’s disease or multi-infarct dementia, but may instead be more similar to the pre-senile frontotemporal dementia (FTD) which is more slowly progressing and involves frontal and temporal dysfunction as in schizophrenia (de Vries et al., 2001). Clinical observations lend support to the concept of a ‘dementia of schizophrenia’. These chronically unwell, poorly functioning patients with schizophrenia are often referred to specialist services for severe cognitive and functional impairments, representing a continuous deterioration from pre-morbid or peri-onset levels considered atypical of the ‘static encephalopathy’ of chronic schizophrenia (Goldberg et al., 1993). The clinical question is frequently whether there is an underlying dementia or if an additional diagnosis of dementia is necessary. Bedside assessments of cognitive functioning such as the Neuropsychiatric Unit Cognitive Assessment Tool (NUCOG) (Walterfang et al., 2006) typically reveal the extent of the impairment in these patients with severe chronic schizophrenia. Due to the nature of their illness, these patients are usually unable to tolerate more extensive neuropsychological investigations and as a consequence are often excluded from research studies. The behavioural variant of frontotemporal lobar degeneration, or FTD, is a leading cause of pre-senile dementia (Ratnavalli et al., 2002). Similarly to schizophrenia, FTD involves the frontal and temporal lobes, with corresponding executive dysfunction (Neary et al., 1998). FTD is also characterised by early neuropsychiatric changes, including disturbances of behaviour and personality, loss of empathy and insight, emotional blunting, and apathy (McKhann et al., 2001; Neary et al., 1998). Some FTD patients, especially younger ones, may present initially with psychosis and be misdiagnosed with a psychiatric disorder such as schizophrenia (Velakoulis et al., 2009a). Beyond overlaps in clinical features, we have previously reported FTD-like pathological abnormalities in a small subset of patients who presented with schizophrenia aged 50 years or older
(Velakoulis et al., 2009b). Two very recent reviews of the overlaps between schizophrenia and FTD did not report any conclusive phenotypic or genotypic relationship, although it was proposed that the same causal mechanisms may be involved early in schizophrenia and late in FTD (Cooper and Ovsiew, 2013; Harciarek et al., 2013). Consistent with the locus of brain atrophy, patients with schizophrenia and FTD typically demonstrate executive dysfunction and selective memory deficits (Binetti et al., 2000; Fioravanti et al., 2005; Heinrichs and Zakzanis, 1998; Hodges and Patterson, 2007; McKenna, 2007). Few studies have directly compared the neuropsychological profiles of schizophrenia and FTD, and only two studies have utilised a comprehensive assessment battery. The first study (Zakzanis et al., 2001) compared patients with lateonset schizophrenia (LOS) and FTD on 38 individual test variables and found more overlap than distinction in group profiles. Nonetheless, patients with FTD were significantly more impaired in letter fluency and Category Fluency, with some evidence of reduced set-shifting/switching ability. The second study (Ziauddeen et al., 2011) compared executive functioning in FTD patients and chronic schizophrenia patients with predominantly negative symptoms. The FTD group exhibited significantly reduced Category Fluency and Inhibition, whereas group differences were not significant in letter fluency, cognitive estimation, letter–number sequencing, rule attainment, and a naturalistic multi-tasking test. A third study (Weickert et al., 2013) found probabilistic association learning, thought to involve fronto-striatal circuits, to be similarly impaired in patients with schizophrenia/schizoaffective disorder and patients with FTD. Finally, a Dutch study (Sanders et al., 2012) comparing FTD patients and elderly schizophrenia patients (> 60 years of age) reported significantly poorer general cognition [as measured by the Mini-Mental State Examination (Folstein et al., 1975)] and executive functioning [as assessed by the Frontal Assessment Battery (Dubois and Litvan, 2000)] in FTD patients. Some of these findings, however, may be specific to patients with LOS, those with primarily negative symptoms, and elderly schizophrenia patients. In summary, modern researchers have identified some patients with particularly severe and chronic schizophrenia who conform to the progressively declining course of Kraepelin’s dementia praecox. Our clinical observations support the existence of these poor-outcome patients in whom a differential diagnosis of dementia is often raised. Interesting parallels have been drawn between schizophrenia and FTD, but there is a lack of comparative research in the Kraepelinian schizophrenia subtype with FTD. One reason could be that this subgroup is exceptionally ‘untestable’ in comparison to the broader chronic schizophrenia group. Given the heterogeneity of schizophrenia, focusing on a particular subtype would yield clearer findings. Further, it is conceivable that the Kraepelinian subtype Australian & New Zealand Journal of Psychiatry, 48(9)
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830 would share more overlaps with FTD compared to other schizophrenia subtypes, based on its resemblance to Kraepelin’s dementia praecox. Our state-wide, tertiary neuropsychiatric service specialises in the diagnostic assessment and treatment of the two clinical populations in question (i.e. severe chronic schizophrenia and FTD), and therefore we were presented with the rare opportunity to address this gap in the schizophrenia research literature. In this study, based on neuropsychological data collected clinically over a decade, we aimed to directly compare performance across various neuropsychological domains in patients with severe chronic schizophrenia and FTD. From findings of previous studies and our clinical observations, we hypothesised that the two groups would not differ significantly across most domains. We speculated that the FTD group would show significantly poorer performance in some aspects of executive functioning. In addition, we sought to identify whether group means were equivalent. We hypothesised that equivalence testing would demonstrate substantial overlap between groups in distribution of test scores in most cognitive domains.
Methods Participants This research was conducted in the Neuropsychiatry Unit (NPU) of the Royal Melbourne Hospital, Melbourne, a highly specialised tertiary/quaternary referral unit for the assessment and treatment of patients with neuropsychiatric conditions. The diagnostic process on the NPU involves an inpatient assessment. During the assessment patients have medical, neuropsychiatric, neurological, neuropsychological, neuroimaging (MRI, SPECT, CT) and occupational therapy functional assessments as deemed necessary in each individual case. A prerequisite of referral to the unit is access to all past psychiatric files, allowing detailed file review and longitudinal diagnostic clarification. In addition, information is sought from treating doctors, families and carers. Following multidisciplinary assessment, diagnoses are made based on clinical diagnostic criteria for schizophrenia/ schizoaffective disorder (DSM-IV-TR; American Psychiatric Association, 2000) and FTD (Neary et al., 1998). From a database of patients seen since 1998, we identified 41 patients with chronic schizophrenia/schizoaffective disorder (defined as an illness duration of greater than 5 years), and 35 patients with FTD (i.e. behavioural variant) for whom neuropsychological data was available. These patients had undertaken neuropsychological testing as part of a comprehensive clinical diagnostic assessment. Patients were excluded if they had a significant substance abuse history and/or a comorbid condition (e.g. neurological and psychiatric disorder, acquired brain injury, intellectual disability) that substantially contributed to their clinical presentation, as documented in their medical discharge
ANZJP Articles summary. Fifteen schizophrenia patients were excluded: four had a significant substance abuse history (two had chronically abused alcohol, one was diagnosed with alcohol-related brain injury, and another had a long history of polysubstance use), nine had a severe comorbid neurological condition (vascular dementia, aceruloplasminaemia, Parkinson’s disease, multiple sclerosis, epilepsy), one had sustained significant head injury, and another had mild intellectual disability. One FTD patient who subsequently developed choreiform movements was excluded. The final database consisted of data from 26 schizophrenia patients (including five patients with schizoaffective disorder) and 34 FTD patients. An overview of the participant selection protocol is presented in Figure 1. All patients with schizophrenia and 16 (47%) FTD patients were on atypical antipsychotics. The percentages of patients on antipsychotic medication were (schizophrenia/FTD): olanzapine 23.1/20.6, quetiapine 11.5/14.7, fluphenazine 7.7/0, aripiprazole 7.7/2.9, risperidone 30.8/8.8, clozapine 19.2/2.9, zuclopenthixol 11.5/0. Information was unavailable for three patients with schizophrenia and one FTD patient. Demographic data (age, gender) and clinical data [duration of illness, NUCOG (Walterfang et al., 2006) scores] were collated.
Procedure Each patient seen on the NPU is administered neuropsychological tests tailored to address their particular diagnostic question, by fully qualified and experienced clinical neuropsychologists. Patients were not administered the same tests due to varying levels of ‘testability’ and compliance but the clinical assessment ensured that the major cognitive domains would be assessed, either with the ‘gold standard’ test or a similar test designed for lower-functioning patients [for example, to measure aspects of the domain of memory, in place of the Rey Auditory Verbal Learning Test (Rey, 1964), a shorter word list such as the Hopkins Verbal Learning Test (Brandt and Benedict, 2001) could be administered to patients who were more unwell]. Given the above methodological considerations, we compared patients on cognitive domains rather than individual tests. For each patient, each test was allocated to a cognitive domain by consulting test descriptions by the original developers and key neuropsychological texts (Lezak et al., 2012; Strauss et al., 2006). This yielded 16 cognitive domains (including six executive function sub-domains) from 19 measures with 40 test variables (Table 1, supplementary material). The number of patients from each group who had undertaken each measure was largely comparable (Table 2, supplementary material). Individual test scores were transformed into z-scores for comparison across different scales and test versions (Strauss et al., 2006). Due to the differences in range of z-scores derived from different normative data (i.e. z-scores computed
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Figure 1. An overview of the selection of study participants from the Neuropsychiatry Unit (NPU) clinical database between 1998 and 2011. NPU clinical database (1998-2011) Inclusion criteria: -Chronic schizophrenia/ schizoaffective disorder -FTD (behavioural) -Neuropsychological data available Total fulfiling criteria: 41 SCZ 35 FTD Exclusion criteria (SCZ/FTD): -Substance abuse (4/0) -Co-morbid neurological condition (9/1) -Significant head injury (1/0) -Intellectual disability (1/0) Final sample: 26 SCZ patients 34 FTD patients
Table 1. Demographic and clinical data of schizophrenia (SCZ) and FTD patients [mean (SD)] and associated p-values. SCZ (N = 26)
FTD (N = 34)
p
Age (years) (range)
48.08 (13.72) (23–68)
52.21 (9.46) (37–71)
0.20
Gender (M:F)
15:11
19:15
0.52
DOI (months)a
259.91 (140.23) (N = 23)
36.33 (22.64) (N = 33)
< 0.001
Educations (years)
11.17 (3.28) (N = 24)
11.44 (2.53) (N = 32)
0.73
NUCOG
68.54 (12.13) (N =13)
67.52 (19.30) (N = 23)
0.87
aLevene’s
test for equality of variances was significant.
from scaled scores, but not those calculated from means and standard deviations, are bound by an interval of −3 to 3), any z-scores lower than −3 and above 3 were truncated. An average z-score was then derived for each cognitive domain.
independent samples t-tests for continuous variables and chi-square/Fisher’s tests for categorical variables.
Statistical analysis
We explored group differences using independent samples t-tests to compare mean z-scores in the 16 cognitive domains. An alpha level of 0.01 was adopted to correct for multiple comparisons. Effect sizes (Cohen’s d) were
Statistical analysis was performed with IBM SPSS Statistics (v18.0). Demographic and clinical data were analysed with
Difference analysis
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Table 2. Summary of results from analyses of difference [mean (SD), p-value, d] and equivalence (OL%) between chronic schizophrenia (SCZ) and frontotemporal dementia (FTD) across 16 cognitive domains. Domain
Group
N
Mean
SD
p
d
OL%a
Speed
SCZ FTD
20 28
−1.84 −1.70
0.92 0.97
0.62
0.15
89
Attentional Capacity
SCZ FTD
26 29
−0.36 −0.36
0.85 1.12
0.98
0.01
99
Working Memory
SCZ FTD
25 29
−0.62 −0.78
0.92 0.98
0.53
0.17
85
Immediate Memoryb
SCZ FTD
24 31
−1.70 −1.70
0.68 1.06
1.00
0.00
100
Delayed Memory
SCZ FTD
22 31
−1.29 −1.15
0.78 0.95
0.56
0.17
85
Percentage Retention
SCZ FTD
20 29
−0.89 −0.90
0.76 1.11
0.97
0.01
99
Recognition Memory
SCZ FTD
19 28
−0.94 −1.12
1.51 1.18
0.65
0.13
92
Visuo-construction
SCZ FTD
12 22
−1.03 −1.16
1.38 1.46
0.80
0.09
92
Executive function Verbal Reasoning
SCZ FTD
22 33
−0.75 −1.37
1.29 1.14
0.07
0.51
67
Non-verbal Reasoning
SCZ FTD
21 29
−0.89 −0.79
0.97 1.17
0.76
0.09
92
Letter Fluency
SCZ FTD
18 24
−1.39 −1.82
0.97 1.11
0.20
0.42
73
Category Fluency
SCZ FTD
17 18
−1.94 −1.82
1.19 1.29
0.77
0.10
92
Switching
SCZ FTD
18 20
−2.00 −1.02
0.91 1.11
0.006
0.96
45
Inhibition
SCZ FTD
8 12
−0.63 −1.19
1.47 1.67
0.45
0.36
73
Verbal Intelligence
SCZ FTD
22 29
−0.67 −0.88
0.84 1.29
0.50
0.20
85
Naming
SCZ FTD
6 16
−1.08 −1.70
1.70 1.39
0.39
0.40
73
aRounded
to the nearest whole number. test for equality of variances was significant. Note: OL% = overlap percentage (amount of overlap between group score distributions). bLevene’s
computed. Based on Cohen’s (1988) recommendation, we considered d = 0.20 as small, 0.50 as medium, and 0.80 as large. Given the differences in medication status between the two groups (all patients with schizophrenia were medicated, compared to only half the patients with FTD), we additionally conducted an analysis of covariance (ANCOVA).
Equivalence analysis A non-significant finding on difference analysis does not mean that two groups are equivalent. Thus, in addition, we utilised equivalence testing adopted from the biopharmaceutical field (Cribbie and Arpin-Cribbie, 2009; Rogers et al., 1993). Firstly, we derived overlap percentages (OL%)
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Figure 2. Mean z-scores for each cognitive domain in the chronic schizophrenia and FTD groups. The two lines emphasise the cognitive profiles in each group. 0.00
Sp Attn WM IM DM PR RM VC VR NVR LF
CF Sw Inh
VI
N
Domain z-score
-0.50 -1.00 -1.50 -2.00 SCZ FTD
-2.50
SCZ
Cognitive Domain
FTD
SCZ: schizophrenia; Sp: Speed; Attn: Attentional Capacity; WM: Working Memory; IM: Immediate Memory; DM: Delayed Memory; PR: Percentage Retention; RM: Recognition Memory; VC: Visuo-construction; VR: Verbal Reasoning; NVR: Non-verbal Reasoning; LF: Letter Fluency; CF: Category Fluency; Sw: Switching; Inh: Inhibition; VI: Verbal Intelligence; N: Naming.
by subtracting the corresponding Cohen’s U1 non-overlap for each effect size estimate (Cohen, 1988, Table 2.2.1, p. 22) from 100. OL% reflects the degree of overlap between groups in average z-score distribution in each cognitive domain (Zakzanis, 1998, 2001). The larger the OL%, the more overlap in score distribution, and hence the more similar the two groups are. Formal interpretation criteria are not available, but we propose a cut-off of 85%, which corresponds to a small effect size of 0.20 (Cohen, 1988), whereby only OL% of 85% or above would be considered meaningful. Further, we constructed a visual summary of the overlap of means and 95% confidence intervals (CIs) of the means between groups. This approach was derived from equivalence testing using inferential CIs (Tryon, 2001).
Results Demographic and clinical data are shown in Table 1. Age, gender proportion, years of education, and estimates of bedside cognitive functioning (NUCOG scores) did not differ significantly between groups. As expected, patients with schizophrenia had a significantly longer duration of illness.
Difference analysis (Table 2 and Figure 2) Significant group difference was seen only in the executive function sub-domain of Switching, with the schizophrenia group performing more poorly. No other significant group differences were observed. ANCOVA with medication status (on or off antipsychotics) as covariate revealed that
medication status was significantly associated to the Working Memory domain only (p = 0.01). Statistically controlling for the effects of medication did not change the findings from the t-tests. In particular, group differences in Switching remained highly significant (p = 0.009 cf. p = 0.006). The largest effect size was seen in Switching. Verbal Reasoning was associated with a medium effect size. Small-to-medium effect sizes were seen in Inhibition, Letter Fluency, and Naming. Effect sizes in the remaining 11 domains were all 0.20 or smaller. The smallest effect sizes were for the Attentional Capacity, Immediate Memory, and Percentage Retention domains (Table 2). The cognitive profile of each group showed similar ‘troughs’ and ‘peaks’ across the domains (Figure 2). Both groups were least impaired in Attentional Capacity, and most impaired in Speed of Processing, Immediate Memory, and Category Fluency.
Equivalence analysis (Table 2 and Figure 3) In 11 out of 16 domains, the OL% were 85% or larger [range = 45–100, mean (SD) = 83.81 (14.52)]. The largest amount of overlap (99–100%) was seen in Immediate Memory, Attentional Capacity, and Percentage Retention domains. Consistent with results from the difference analysis, the smallest overlap (45%) was in Switching. Verbal Reasoning, Letter Fluency, Inhibition, and Naming domains had OL% around 70%. Figure 3 shows individual group means and the 95% lower and upper CIs of the means in each domain. Consistent with the high OL%, there was a significant Australian & New Zealand Journal of Psychiatry, 48(9)
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Figure 3. Schizophrenia group means (left, denoted by blue •) and FTD group means (right, denoted by red •), as well as corresponding 95% lower and upper CIs of the means, for each cognitive domain. 1.00 0.50
Domain z-score
0.00 -0.50 -1.00 -1.50 -2.00 -2.50 -3.00 -3.50 Cognive Domain Sp: Speed; Attn: Attentional Capacity; WM: Working Memory; IM: Immediate Memory; DM: Delayed Memory; PR: Percentage Retention; RM: Recognition Memory; VC: Visuo-construction; VR: Verbal Reasoning; NVR: Non-verbal Reasoning; LF: Letter Fluency; CF: Category Fluency; Sw: Switching; Inh: Inhibition; VI: Verbal Intelligence; N: Naming; OL%: overlap percentages (amount of overlap between group score distributions).
amount of overlap in the CIs for 13 out of 16 domains (the CIs for Inhibition and Naming reflected large variability in within-group performances, most likely due to the small N). There was a smaller amount of overlap in the CIs for Verbal Reasoning and Letter Fluency, and no overlap at all in the CIs for Switching.
Discussion The current study aimed to compare neurocognition in patients with chronic schizophrenia with patients with FTD by utilising a variety of statistical indices. Our hypotheses were mostly confirmed – both groups did not differ significantly in their performance across 15 out of 16 cognitive domains, and had overlap percentages (OL%) 85% or above in 11 domains. The groups demonstrated the largest discrepancy in executive function sub-domains; however, the only significant difference was in Switching (OL% was also smallest at 45%) although contrary to our expectations, the chronic schizophrenia patients performed worse. Our findings highlight the degree of cognitive similarity between patients with chronic schizophrenia and patients with FTD, and contribute to the small body of research that has investigated overlapping features between the two disorders. Our study is unique in that we have managed to cognitively assess a subgroup of patients with schizophrenia who would not normally have been the focus of research studies. Our results are consistent with Zakzanis et al.’s (2001) non-significant findings on 34 out of 38 test variables. Similarly to Zakzanis et al., we found our groups differed most substantially in aspects of executive functioning. In addition to the significant group difference in Switching, a
trend to significance corresponding to a medium effect size and only 67% overlap was seen in Verbal Reasoning. Group differences in Letter Fluency and Inhibition were associated with small-to-medium effect sizes and around 70% overlap. The group differences in these executive function subdomains were in the predicted direction, i.e. the FTD group scored lower, consistent with both Zakzanis et al. (2001) and Ziauddeen et al. (2011). These findings are also in line with lower FAB scores (i.e. poorer overall executive functioning) in the FTD group in the Sanders et al. (2012) study. There were, however, differences between these past studies and the current study. We observed significantly poorer switching ability in our chronic schizophrenia group, whereas Zakzanis et al. (2001) found significantly poorer performance in their FTD group on only one out of two measures of mental flexibility. Zakzanis et al. (2001) reported significantly reduced letter fluency and Category Fluency in FTD patients, but Ziauddeen et al. (2010) found a significant difference only in Category Fluency. In our study, neither fluency domain was significantly different between groups, although letter fluency was associated with a small-tomedium effect size. Ziauddeen et al. (2010) observed significantly reduced Inhibition in FTD patients, whereas we found a non-significant difference with small-to-medium effect size. Similarly to our findings, tests of verbal reasoning were not significantly different between groups in the Zakzanis et al. (2001) study. Finally, in the current study, Naming was associated with a small-to-medium effect size, with FTD patients scoring lower. Neither of the previous studies explored confrontation naming. In comparing findings across studies, account needs to be taken of differences in patient characteristics [i.e. late-onset
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Chan et al. schizophrenia in Zakzanis et al. (2001) and negative syndrome schizophrenia in Ziauddeen et al. (2010), compared to severe chronic schizophrenia in our study]. The average duration of illness in the Zakzanis et al. (2001) schizophrenia group was shorter compared to ours (13 vs. 21 years). The FTD groups were older in both previous studies (62 and 63 vs. 52 years) and may have been more impaired. Other issues to consider are methodological differences in statistical techniques and the cognitive tasks utilised. The current observation of substantial between-group similarities is probably due to our emphasis on a subgroup of patients who had been referred to a specialist neuropsychiatric service with a cognitive and/or functional decline. As a consequence, we reduced the impact of disease heterogeneity on our results. This subtype of schizophrenia may most closely resemble Kraepelin’s dementia praecox, Keefe et al.’s (1987) Kraepelinian schizophrenia, and Mitelman and Buchsbaum’s (2007) poor-outcome schizophrenia. Findings of severe cognitive impairments in our schizophrenia group, which paralleled those seen in FTD, lend support to the ‘dementia of schizophrenia’ concept, particularly in a severely unwell subgroup. It is notable that the patients in this subgroup ranged in age from 23 to 68 years and did not represent an elderly population. The age range here is very similar to that in de Vries et al.’s (2001) study investigating an additional diagnosis of dementia in chronically hospitalised and age-disoriented schizophrenia patients. The current results, in conjunction with de Vries et al.’s findings, suggest that the ‘dementia of schizophrenia’ is independent of age and may follow a distinct trajectory to currently known neurodegenerative processes. Furthermore, our findings are comparable with de Vries et al.’s observation of dementia-like cognitive impairments in their institutionalised chronic schizophrenia population. A plausible explanation, proposed by Mitelman and Buchsbaum (2007), is that there exists a subtype of chronic schizophrenia with a very slowly progressive dementia which remains undefined. The neuropsychological similarities and differences identified here between the chronic schizophrenia and FTD groups are important on several levels. Firstly, after matching the groups on general level of cognitive functioning, we found that both chronic schizophrenia and FTD patients demonstrated some of the most severe deficits (> 1.5 SD below the norm) in the same cognitive domains, namely Speed of Processing, Immediate Memory, and Category Fluency. Basic Attentional Capacity was relatively preserved in both groups (< 0.5 SD below the population norm). Secondly, we observed significantly reduced mental switching ability in chronic schizophrenia rather than FTD patients. This probably reflects the extent of cognitive deficits in this group of schizophrenia patients. When our results are considered in the context of previous findings, the lack of a consistent pattern of executive function differences suggests that executive function measures may not
distinguish between chronic schizophrenia and FTD. Executive function is a broad cognitive domain that can be fractionated into discrete sub-domains reflecting different sets of abilities, and there is a need for further research into these different aspects with larger populations of patients. Thirdly, dysfunction in the dorsolateral prefrontal–subcortical circuit has been proposed to underlie deficits in fluency, set-shifting, Inhibition and abstraction ability (Cummings, 1995, as cited in Duke and Kaszniak, 2000). Previous studies have identified similar fronto-striatal impairments in schizophrenia and frontal lobe disorders (e.g. Pantelis et al., 1997; Weickert et al., 2013). The current findings of significantly poorer set-shifting ability in chronic schizophrenia and numerically lower scores in FTD in several aspects of executive functioning (i.e. Verbal Reasoning, Letter Fluency and Inhibition) support the involvement of fronto-subcortical circuits (particularly the dorsolateral prefrontal–subcortical loop) in the neuropathology of chronic schizophrenia and FTD. The poorer performance in confrontation naming in the FTD group suggests that temporal dysfunction may be more prominent in FTD compared to chronic schizophrenia. The current findings need to be interpreted in light of several methodological limitations. Firstly, this was a retrospective study based on neuropsychological data collected for clinical purposes and not all patients had undertaken the same tests. We addressed this issue by categorising tests into cognitive domains. The number of patients from each group who had undertaken each test was mostly comparable and each domain had an equal representation of different tests in both groups. Secondly, our patient numbers may appear relatively small given that we collated data over a 15-year period. The small numbers reflect the difficulty of assessing these two groups of patients, whereby a flexible clinical approach to neuropsychological assessment is warranted. The current study is one of the few studies to have amassed a substantial amount of neuropsychological data in an oft-excluded ‘real world’ chronic schizophrenia subgroup compared to patients with FTD. We are not aware of any other studies that have been able to assess these two patient population groups within the one centre. Thirdly, our findings may not be applicable to the broader group of patients with chronic schizophrenia, given that patients referred to our clinical service are highly selected. Patients are referred due to clinical concerns of cognitive or functional decline in the setting of a background diagnosis of schizophrenia. This limitation in generalisability can conversely be viewed as the major strength of our study. The referral process itself may have identified a group of patients with chronic schizophrenia whom clinicians thought were atypical enough in their presentation to refer to a specialised neuropsychiatric service. Further, we did not include a third patient group with a different underlying neuropathological process (i.e. involving areas other than the frontal and temporal brain regions) as a comparison Australian & New Zealand Journal of Psychiatry, 48(9)
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836 group. Demonstration of a different neurocognitive profile in this comparison group to the chronic schizophrenia and FTD groups would strengthen our argument that similar frontotemporal dysfunction underlies chronic schizophrenia and FTD. Finally, all patients in the schizophrenia group were medicated compared to only half of the patients in the FTD group. We have attempted to statistically control for the group differences in medication status, although future studies may consider using chlorpromazine equivalent dosage as a stronger covariate. In summary, we have characterised the neuropsychological profiles of a group of patients with ‘real world’ chronic schizophrenia and FTD, across a number of cognitive domains, using various statistical indices. We have identified substantial similarities between the groups in a number of cognitive domains. We observed differences in aspects of executive functioning and confrontation naming, which may be important for the purposes of differential diagnosis. Our findings are important in that they strongly suggest that some patients with severe chronic schizophrenia have cognitive deficits similar in degree and pattern to patients with frontotemporal dementia. The study does not address the question of whether the chronic schizophrenia group exhibits progressive changes. Future directions include comparison of the two patient groups on aspects beyond neuropsychology [e.g. social cognition (a notable study is that by Kosmidis et al. (2008), which indirectly compared theory of mind in patients with schizophrenia and patients with FTD), neuroimaging, neuropathology], a longitudinal follow-up study of patients with severe chronic schizophrenia and FTD, and including a third patient comparison group with a different neuropathological process. This research was approved by the Melbourne Health Human Research Ethics Committee (HREC Project Number 2008.663). Acknowledgements The authors would like to acknowledge Dr Aidan Sudbury (Monash University) and Professor Geoff Cumming (La Trobe University) for their statistical advice.
Funding This work was supported by the Monash University Doctoral Research budget and the Melbourne Neuropsychiatry Centre Research Higher Degree Award.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Chan et al. Mitelman SA and Buchsbaum MS (2007) Very poor outcome schizophrenia: clinical and neuroimaging aspects. International Review of Psychiatry 19: 345–357. Neary D, Snowden JS, Gustafson L, et al. (1998) Frontotemporal lobar degeneration A consensus on clinical diagnostic criteria. Neurology 51: 1546–1554. Pantelis C, Barnes T, Nelson HE, et al. (1997) Frontal-striatal cognitive deficits in patients with chronic schizophrenia. Brain 120: 1823–1843. Ratnavalli E, Brayne C, Dawson K, et al. (2002) The prevalence of frontotemporal dementia. Neurology 58: 1615–1621. Rey A (1964) L’examen Clinique en Psychologie. Paris: Presses Universitaires de France. Rogers JL, Howard KI and Vessey JT (1993) Using significance tests to evaluate equivalence between two experimental groups. Psychological Bulletin 113: 553–565. Sanders F, Smeets-Janssen M, Meesters P, et al. (2012) Frontotemporal dementia and schizophrenia in later life: A comparison of executive and general cognitive functioning. Tijdschrift voor psychiatrie 54: 409–417. Strauss EH, Sherman EM and Spreen O (2006) A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. Oxford: Oxford University Press. Tryon WW (2001) Evaluating statistical difference, equivalence, and indeterminacy using inferential confidence intervals: An integrated alternative method of conducting null hypothesis statistical tests. Psychological Methods 6: 371–386. Velakoulis D, Walterfang M, Mocellin R, et al. (2009a) Frontotemporal dementia presenting as schizophrenia-like psychosis in young
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Comparing neurocognition in severe chronic schizophrenia and frontotemporal dementia Hui-Minn Chan, Rene Stolwyk, Wendy Kelso, Joanna Neath, Mark Walterfang, Ramon Mocellin, Alexia Pavlis and Dennis Velakoulis Aust N Z J Psychiatry 2014 48: 828 originally published online 7 April 2014 DOI: 10.1177/0004867414529477 The online version of this article can be found at: http://anp.sagepub.com/content/48/9/828
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0010.1177/0004867414529477Australian & New Zealand Journal of PsychiatryChan et al. research-article2014
Research
Comparing neurocognition in severe chronic schizophrenia and frontotemporal dementia
Australian & New Zealand Journal of Psychiatry 2014, Vol. 48(9) 828–837 DOI: 10.1177/0004867414529477 © The Royal Australian and New Zealand College of Psychiatrists 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav anp.sagepub.com
Hui-Minn Chan1,2, Rene Stolwyk1, Wendy Kelso2, Joanna Neath2, Mark Walterfang2, Ramon Mocellin2, Alexia Pavlis2 and Dennis Velakoulis2
Abstract Objective: Previous research has suggested cognitive similarities between schizophrenia and frontotemporal dementia. In the current study, we compared neurocognition in a group of hospitalised patients with chronic schizophrenia, who may have a more severe form of schizophrenia resembling Emil Kraepelin’s dementia praecox, with patients with frontotemporal dementia. We hypothesised minimal group differences in cognitive performance, and a large overlap in between-group score distributions in each cognitive domain. Methods: Retrospective neuropsychological data for 26 patients with severe chronic schizophrenia and 34 patients with frontotemporal dementia (behavioural variant) was collated. Neuropsychological measures were categorised into 16 cognitive domains. Raw scores were converted into standardised z-scores for each measure, which were then averaged across measures within each domain. In addition to difference analysis, equivalence testing was utilised, whereby overlap percentages were computed to reflect the amount of score distribution overlap in each domain between groups. Results: A statistically significant difference was observed only in the executive function sub-domain of Switching. Smallto-moderate and moderate effect sizes were noted in four other domains. Equivalence testing showed more than 85% of overlap in score distribution in most domains. Conclusions: Our findings suggest that some patients with severe chronic schizophrenia have cognitive deficits similar in degree and pattern to patients with frontotemporal dementia. The few differences observed between both groups of patients are important for differential diagnostic purposes. One limitation is the retrospective nature of the study. Suggestions for future research include longitudinal follow-up studies of these two patient populations and studies of aspects beyond neurocognition. An implication of our findings is that the ‘dementia of schizophrenia’ concept may be applicable to patients with severe chronic schizophrenia. Keywords Neuropsychology, neurocognition, chronic schizophrenia, frontotemporal dementia, dementia praecox, behavioural variant frontotemporal lobar degeneration, poor-outcome schizophrenia, Kraepelinian schizophrenia
Introduction The concept of schizophrenia emerged in 1896 as dementia praecox, when Kraepelin combined three forms of ‘insanity’ with ages of onset in adolescence to early adulthood and a progressive course leading to dementia in most cases (Kraepelin, 1987; McKenna, 2007). Kraepelin speculated that dementia praecox involves a ‘tangible morbid process occurring in the brain’ (Kraepelin, 1987, p. 23). He considered dementia praecox to be a disorder of volition, or executive dysfunction (Zec, 1995), with the seat of pathology lying in the frontal and temporal lobes (Kraepelin, 1971/1919).
The concept of a ‘dementia of schizophrenia’ has been more recently considered (de Oliveira-Souza et al., 2007; de Vries et al., 2001; Gregory et al., 1998; Mitelman and Buchsbaum, 2007). This concept is especially pertinent in 1School
of Psychological Sciences, Monash University, Clayton, Australia Unit, Royal Melbourne Hospital, Melbourne, Australia
2Neuropsychiatry
Corresponding author: Hui-Minn Chan, School of Psychological Sciences, Building 17, Wellington Road, Monash University, Clayton, VIC 3800, Australia Email: [email protected]
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Chan et al. those patients with schizophrenia who require long-term or recurrent hospitalisation, or are highly dependent on carers for basic needs if living in the community. Arguably, these patients have the most severe and chronic form of the disorder, with a clinical course that may closely resemble that of Kraepelin’s dementia praecox and which has thus been referred to as ‘Kraepelinian schizophrenia’ (Keefe et al., 1987). More recently, Mitelman and Buchsbaum (2007) described this subtype of poor-outcome schizophrenia as an as yet undefined dementia, with a biphasic progressive deterioration of ‘frontotemporal schizophrenia-like clinical and morphological features’ early in the course of disease and then ‘insidious posteriorisation of cortical grey matter deficits’ leading to the quick decline of neurocognitive functions seen later in life (p. 354). The nature of this putative dementia does not appear to conform to the cognitive, clinical and neurobiological profiles of dementias such as Alzheimer’s disease or multi-infarct dementia, but may instead be more similar to the pre-senile frontotemporal dementia (FTD) which is more slowly progressing and involves frontal and temporal dysfunction as in schizophrenia (de Vries et al., 2001). Clinical observations lend support to the concept of a ‘dementia of schizophrenia’. These chronically unwell, poorly functioning patients with schizophrenia are often referred to specialist services for severe cognitive and functional impairments, representing a continuous deterioration from pre-morbid or peri-onset levels considered atypical of the ‘static encephalopathy’ of chronic schizophrenia (Goldberg et al., 1993). The clinical question is frequently whether there is an underlying dementia or if an additional diagnosis of dementia is necessary. Bedside assessments of cognitive functioning such as the Neuropsychiatric Unit Cognitive Assessment Tool (NUCOG) (Walterfang et al., 2006) typically reveal the extent of the impairment in these patients with severe chronic schizophrenia. Due to the nature of their illness, these patients are usually unable to tolerate more extensive neuropsychological investigations and as a consequence are often excluded from research studies. The behavioural variant of frontotemporal lobar degeneration, or FTD, is a leading cause of pre-senile dementia (Ratnavalli et al., 2002). Similarly to schizophrenia, FTD involves the frontal and temporal lobes, with corresponding executive dysfunction (Neary et al., 1998). FTD is also characterised by early neuropsychiatric changes, including disturbances of behaviour and personality, loss of empathy and insight, emotional blunting, and apathy (McKhann et al., 2001; Neary et al., 1998). Some FTD patients, especially younger ones, may present initially with psychosis and be misdiagnosed with a psychiatric disorder such as schizophrenia (Velakoulis et al., 2009a). Beyond overlaps in clinical features, we have previously reported FTD-like pathological abnormalities in a small subset of patients who presented with schizophrenia aged 50 years or older
(Velakoulis et al., 2009b). Two very recent reviews of the overlaps between schizophrenia and FTD did not report any conclusive phenotypic or genotypic relationship, although it was proposed that the same causal mechanisms may be involved early in schizophrenia and late in FTD (Cooper and Ovsiew, 2013; Harciarek et al., 2013). Consistent with the locus of brain atrophy, patients with schizophrenia and FTD typically demonstrate executive dysfunction and selective memory deficits (Binetti et al., 2000; Fioravanti et al., 2005; Heinrichs and Zakzanis, 1998; Hodges and Patterson, 2007; McKenna, 2007). Few studies have directly compared the neuropsychological profiles of schizophrenia and FTD, and only two studies have utilised a comprehensive assessment battery. The first study (Zakzanis et al., 2001) compared patients with lateonset schizophrenia (LOS) and FTD on 38 individual test variables and found more overlap than distinction in group profiles. Nonetheless, patients with FTD were significantly more impaired in letter fluency and Category Fluency, with some evidence of reduced set-shifting/switching ability. The second study (Ziauddeen et al., 2011) compared executive functioning in FTD patients and chronic schizophrenia patients with predominantly negative symptoms. The FTD group exhibited significantly reduced Category Fluency and Inhibition, whereas group differences were not significant in letter fluency, cognitive estimation, letter–number sequencing, rule attainment, and a naturalistic multi-tasking test. A third study (Weickert et al., 2013) found probabilistic association learning, thought to involve fronto-striatal circuits, to be similarly impaired in patients with schizophrenia/schizoaffective disorder and patients with FTD. Finally, a Dutch study (Sanders et al., 2012) comparing FTD patients and elderly schizophrenia patients (> 60 years of age) reported significantly poorer general cognition [as measured by the Mini-Mental State Examination (Folstein et al., 1975)] and executive functioning [as assessed by the Frontal Assessment Battery (Dubois and Litvan, 2000)] in FTD patients. Some of these findings, however, may be specific to patients with LOS, those with primarily negative symptoms, and elderly schizophrenia patients. In summary, modern researchers have identified some patients with particularly severe and chronic schizophrenia who conform to the progressively declining course of Kraepelin’s dementia praecox. Our clinical observations support the existence of these poor-outcome patients in whom a differential diagnosis of dementia is often raised. Interesting parallels have been drawn between schizophrenia and FTD, but there is a lack of comparative research in the Kraepelinian schizophrenia subtype with FTD. One reason could be that this subgroup is exceptionally ‘untestable’ in comparison to the broader chronic schizophrenia group. Given the heterogeneity of schizophrenia, focusing on a particular subtype would yield clearer findings. Further, it is conceivable that the Kraepelinian subtype Australian & New Zealand Journal of Psychiatry, 48(9)
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830 would share more overlaps with FTD compared to other schizophrenia subtypes, based on its resemblance to Kraepelin’s dementia praecox. Our state-wide, tertiary neuropsychiatric service specialises in the diagnostic assessment and treatment of the two clinical populations in question (i.e. severe chronic schizophrenia and FTD), and therefore we were presented with the rare opportunity to address this gap in the schizophrenia research literature. In this study, based on neuropsychological data collected clinically over a decade, we aimed to directly compare performance across various neuropsychological domains in patients with severe chronic schizophrenia and FTD. From findings of previous studies and our clinical observations, we hypothesised that the two groups would not differ significantly across most domains. We speculated that the FTD group would show significantly poorer performance in some aspects of executive functioning. In addition, we sought to identify whether group means were equivalent. We hypothesised that equivalence testing would demonstrate substantial overlap between groups in distribution of test scores in most cognitive domains.
Methods Participants This research was conducted in the Neuropsychiatry Unit (NPU) of the Royal Melbourne Hospital, Melbourne, a highly specialised tertiary/quaternary referral unit for the assessment and treatment of patients with neuropsychiatric conditions. The diagnostic process on the NPU involves an inpatient assessment. During the assessment patients have medical, neuropsychiatric, neurological, neuropsychological, neuroimaging (MRI, SPECT, CT) and occupational therapy functional assessments as deemed necessary in each individual case. A prerequisite of referral to the unit is access to all past psychiatric files, allowing detailed file review and longitudinal diagnostic clarification. In addition, information is sought from treating doctors, families and carers. Following multidisciplinary assessment, diagnoses are made based on clinical diagnostic criteria for schizophrenia/ schizoaffective disorder (DSM-IV-TR; American Psychiatric Association, 2000) and FTD (Neary et al., 1998). From a database of patients seen since 1998, we identified 41 patients with chronic schizophrenia/schizoaffective disorder (defined as an illness duration of greater than 5 years), and 35 patients with FTD (i.e. behavioural variant) for whom neuropsychological data was available. These patients had undertaken neuropsychological testing as part of a comprehensive clinical diagnostic assessment. Patients were excluded if they had a significant substance abuse history and/or a comorbid condition (e.g. neurological and psychiatric disorder, acquired brain injury, intellectual disability) that substantially contributed to their clinical presentation, as documented in their medical discharge
ANZJP Articles summary. Fifteen schizophrenia patients were excluded: four had a significant substance abuse history (two had chronically abused alcohol, one was diagnosed with alcohol-related brain injury, and another had a long history of polysubstance use), nine had a severe comorbid neurological condition (vascular dementia, aceruloplasminaemia, Parkinson’s disease, multiple sclerosis, epilepsy), one had sustained significant head injury, and another had mild intellectual disability. One FTD patient who subsequently developed choreiform movements was excluded. The final database consisted of data from 26 schizophrenia patients (including five patients with schizoaffective disorder) and 34 FTD patients. An overview of the participant selection protocol is presented in Figure 1. All patients with schizophrenia and 16 (47%) FTD patients were on atypical antipsychotics. The percentages of patients on antipsychotic medication were (schizophrenia/FTD): olanzapine 23.1/20.6, quetiapine 11.5/14.7, fluphenazine 7.7/0, aripiprazole 7.7/2.9, risperidone 30.8/8.8, clozapine 19.2/2.9, zuclopenthixol 11.5/0. Information was unavailable for three patients with schizophrenia and one FTD patient. Demographic data (age, gender) and clinical data [duration of illness, NUCOG (Walterfang et al., 2006) scores] were collated.
Procedure Each patient seen on the NPU is administered neuropsychological tests tailored to address their particular diagnostic question, by fully qualified and experienced clinical neuropsychologists. Patients were not administered the same tests due to varying levels of ‘testability’ and compliance but the clinical assessment ensured that the major cognitive domains would be assessed, either with the ‘gold standard’ test or a similar test designed for lower-functioning patients [for example, to measure aspects of the domain of memory, in place of the Rey Auditory Verbal Learning Test (Rey, 1964), a shorter word list such as the Hopkins Verbal Learning Test (Brandt and Benedict, 2001) could be administered to patients who were more unwell]. Given the above methodological considerations, we compared patients on cognitive domains rather than individual tests. For each patient, each test was allocated to a cognitive domain by consulting test descriptions by the original developers and key neuropsychological texts (Lezak et al., 2012; Strauss et al., 2006). This yielded 16 cognitive domains (including six executive function sub-domains) from 19 measures with 40 test variables (Table 1, supplementary material). The number of patients from each group who had undertaken each measure was largely comparable (Table 2, supplementary material). Individual test scores were transformed into z-scores for comparison across different scales and test versions (Strauss et al., 2006). Due to the differences in range of z-scores derived from different normative data (i.e. z-scores computed
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Chan et al.
Figure 1. An overview of the selection of study participants from the Neuropsychiatry Unit (NPU) clinical database between 1998 and 2011. NPU clinical database (1998-2011) Inclusion criteria: -Chronic schizophrenia/ schizoaffective disorder -FTD (behavioural) -Neuropsychological data available Total fulfiling criteria: 41 SCZ 35 FTD Exclusion criteria (SCZ/FTD): -Substance abuse (4/0) -Co-morbid neurological condition (9/1) -Significant head injury (1/0) -Intellectual disability (1/0) Final sample: 26 SCZ patients 34 FTD patients
Table 1. Demographic and clinical data of schizophrenia (SCZ) and FTD patients [mean (SD)] and associated p-values. SCZ (N = 26)
FTD (N = 34)
p
Age (years) (range)
48.08 (13.72) (23–68)
52.21 (9.46) (37–71)
0.20
Gender (M:F)
15:11
19:15
0.52
DOI (months)a
259.91 (140.23) (N = 23)
36.33 (22.64) (N = 33)
< 0.001
Educations (years)
11.17 (3.28) (N = 24)
11.44 (2.53) (N = 32)
0.73
NUCOG
68.54 (12.13) (N =13)
67.52 (19.30) (N = 23)
0.87
aLevene’s
test for equality of variances was significant.
from scaled scores, but not those calculated from means and standard deviations, are bound by an interval of −3 to 3), any z-scores lower than −3 and above 3 were truncated. An average z-score was then derived for each cognitive domain.
independent samples t-tests for continuous variables and chi-square/Fisher’s tests for categorical variables.
Statistical analysis
We explored group differences using independent samples t-tests to compare mean z-scores in the 16 cognitive domains. An alpha level of 0.01 was adopted to correct for multiple comparisons. Effect sizes (Cohen’s d) were
Statistical analysis was performed with IBM SPSS Statistics (v18.0). Demographic and clinical data were analysed with
Difference analysis
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ANZJP Articles
Table 2. Summary of results from analyses of difference [mean (SD), p-value, d] and equivalence (OL%) between chronic schizophrenia (SCZ) and frontotemporal dementia (FTD) across 16 cognitive domains. Domain
Group
N
Mean
SD
p
d
OL%a
Speed
SCZ FTD
20 28
−1.84 −1.70
0.92 0.97
0.62
0.15
89
Attentional Capacity
SCZ FTD
26 29
−0.36 −0.36
0.85 1.12
0.98
0.01
99
Working Memory
SCZ FTD
25 29
−0.62 −0.78
0.92 0.98
0.53
0.17
85
Immediate Memoryb
SCZ FTD
24 31
−1.70 −1.70
0.68 1.06
1.00
0.00
100
Delayed Memory
SCZ FTD
22 31
−1.29 −1.15
0.78 0.95
0.56
0.17
85
Percentage Retention
SCZ FTD
20 29
−0.89 −0.90
0.76 1.11
0.97
0.01
99
Recognition Memory
SCZ FTD
19 28
−0.94 −1.12
1.51 1.18
0.65
0.13
92
Visuo-construction
SCZ FTD
12 22
−1.03 −1.16
1.38 1.46
0.80
0.09
92
Executive function Verbal Reasoning
SCZ FTD
22 33
−0.75 −1.37
1.29 1.14
0.07
0.51
67
Non-verbal Reasoning
SCZ FTD
21 29
−0.89 −0.79
0.97 1.17
0.76
0.09
92
Letter Fluency
SCZ FTD
18 24
−1.39 −1.82
0.97 1.11
0.20
0.42
73
Category Fluency
SCZ FTD
17 18
−1.94 −1.82
1.19 1.29
0.77
0.10
92
Switching
SCZ FTD
18 20
−2.00 −1.02
0.91 1.11
0.006
0.96
45
Inhibition
SCZ FTD
8 12
−0.63 −1.19
1.47 1.67
0.45
0.36
73
Verbal Intelligence
SCZ FTD
22 29
−0.67 −0.88
0.84 1.29
0.50
0.20
85
Naming
SCZ FTD
6 16
−1.08 −1.70
1.70 1.39
0.39
0.40
73
aRounded
to the nearest whole number. test for equality of variances was significant. Note: OL% = overlap percentage (amount of overlap between group score distributions). bLevene’s
computed. Based on Cohen’s (1988) recommendation, we considered d = 0.20 as small, 0.50 as medium, and 0.80 as large. Given the differences in medication status between the two groups (all patients with schizophrenia were medicated, compared to only half the patients with FTD), we additionally conducted an analysis of covariance (ANCOVA).
Equivalence analysis A non-significant finding on difference analysis does not mean that two groups are equivalent. Thus, in addition, we utilised equivalence testing adopted from the biopharmaceutical field (Cribbie and Arpin-Cribbie, 2009; Rogers et al., 1993). Firstly, we derived overlap percentages (OL%)
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Figure 2. Mean z-scores for each cognitive domain in the chronic schizophrenia and FTD groups. The two lines emphasise the cognitive profiles in each group. 0.00
Sp Attn WM IM DM PR RM VC VR NVR LF
CF Sw Inh
VI
N
Domain z-score
-0.50 -1.00 -1.50 -2.00 SCZ FTD
-2.50
SCZ
Cognitive Domain
FTD
SCZ: schizophrenia; Sp: Speed; Attn: Attentional Capacity; WM: Working Memory; IM: Immediate Memory; DM: Delayed Memory; PR: Percentage Retention; RM: Recognition Memory; VC: Visuo-construction; VR: Verbal Reasoning; NVR: Non-verbal Reasoning; LF: Letter Fluency; CF: Category Fluency; Sw: Switching; Inh: Inhibition; VI: Verbal Intelligence; N: Naming.
by subtracting the corresponding Cohen’s U1 non-overlap for each effect size estimate (Cohen, 1988, Table 2.2.1, p. 22) from 100. OL% reflects the degree of overlap between groups in average z-score distribution in each cognitive domain (Zakzanis, 1998, 2001). The larger the OL%, the more overlap in score distribution, and hence the more similar the two groups are. Formal interpretation criteria are not available, but we propose a cut-off of 85%, which corresponds to a small effect size of 0.20 (Cohen, 1988), whereby only OL% of 85% or above would be considered meaningful. Further, we constructed a visual summary of the overlap of means and 95% confidence intervals (CIs) of the means between groups. This approach was derived from equivalence testing using inferential CIs (Tryon, 2001).
Results Demographic and clinical data are shown in Table 1. Age, gender proportion, years of education, and estimates of bedside cognitive functioning (NUCOG scores) did not differ significantly between groups. As expected, patients with schizophrenia had a significantly longer duration of illness.
Difference analysis (Table 2 and Figure 2) Significant group difference was seen only in the executive function sub-domain of Switching, with the schizophrenia group performing more poorly. No other significant group differences were observed. ANCOVA with medication status (on or off antipsychotics) as covariate revealed that
medication status was significantly associated to the Working Memory domain only (p = 0.01). Statistically controlling for the effects of medication did not change the findings from the t-tests. In particular, group differences in Switching remained highly significant (p = 0.009 cf. p = 0.006). The largest effect size was seen in Switching. Verbal Reasoning was associated with a medium effect size. Small-to-medium effect sizes were seen in Inhibition, Letter Fluency, and Naming. Effect sizes in the remaining 11 domains were all 0.20 or smaller. The smallest effect sizes were for the Attentional Capacity, Immediate Memory, and Percentage Retention domains (Table 2). The cognitive profile of each group showed similar ‘troughs’ and ‘peaks’ across the domains (Figure 2). Both groups were least impaired in Attentional Capacity, and most impaired in Speed of Processing, Immediate Memory, and Category Fluency.
Equivalence analysis (Table 2 and Figure 3) In 11 out of 16 domains, the OL% were 85% or larger [range = 45–100, mean (SD) = 83.81 (14.52)]. The largest amount of overlap (99–100%) was seen in Immediate Memory, Attentional Capacity, and Percentage Retention domains. Consistent with results from the difference analysis, the smallest overlap (45%) was in Switching. Verbal Reasoning, Letter Fluency, Inhibition, and Naming domains had OL% around 70%. Figure 3 shows individual group means and the 95% lower and upper CIs of the means in each domain. Consistent with the high OL%, there was a significant Australian & New Zealand Journal of Psychiatry, 48(9)
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Figure 3. Schizophrenia group means (left, denoted by blue •) and FTD group means (right, denoted by red •), as well as corresponding 95% lower and upper CIs of the means, for each cognitive domain. 1.00 0.50
Domain z-score
0.00 -0.50 -1.00 -1.50 -2.00 -2.50 -3.00 -3.50 Cognive Domain Sp: Speed; Attn: Attentional Capacity; WM: Working Memory; IM: Immediate Memory; DM: Delayed Memory; PR: Percentage Retention; RM: Recognition Memory; VC: Visuo-construction; VR: Verbal Reasoning; NVR: Non-verbal Reasoning; LF: Letter Fluency; CF: Category Fluency; Sw: Switching; Inh: Inhibition; VI: Verbal Intelligence; N: Naming; OL%: overlap percentages (amount of overlap between group score distributions).
amount of overlap in the CIs for 13 out of 16 domains (the CIs for Inhibition and Naming reflected large variability in within-group performances, most likely due to the small N). There was a smaller amount of overlap in the CIs for Verbal Reasoning and Letter Fluency, and no overlap at all in the CIs for Switching.
Discussion The current study aimed to compare neurocognition in patients with chronic schizophrenia with patients with FTD by utilising a variety of statistical indices. Our hypotheses were mostly confirmed – both groups did not differ significantly in their performance across 15 out of 16 cognitive domains, and had overlap percentages (OL%) 85% or above in 11 domains. The groups demonstrated the largest discrepancy in executive function sub-domains; however, the only significant difference was in Switching (OL% was also smallest at 45%) although contrary to our expectations, the chronic schizophrenia patients performed worse. Our findings highlight the degree of cognitive similarity between patients with chronic schizophrenia and patients with FTD, and contribute to the small body of research that has investigated overlapping features between the two disorders. Our study is unique in that we have managed to cognitively assess a subgroup of patients with schizophrenia who would not normally have been the focus of research studies. Our results are consistent with Zakzanis et al.’s (2001) non-significant findings on 34 out of 38 test variables. Similarly to Zakzanis et al., we found our groups differed most substantially in aspects of executive functioning. In addition to the significant group difference in Switching, a
trend to significance corresponding to a medium effect size and only 67% overlap was seen in Verbal Reasoning. Group differences in Letter Fluency and Inhibition were associated with small-to-medium effect sizes and around 70% overlap. The group differences in these executive function subdomains were in the predicted direction, i.e. the FTD group scored lower, consistent with both Zakzanis et al. (2001) and Ziauddeen et al. (2011). These findings are also in line with lower FAB scores (i.e. poorer overall executive functioning) in the FTD group in the Sanders et al. (2012) study. There were, however, differences between these past studies and the current study. We observed significantly poorer switching ability in our chronic schizophrenia group, whereas Zakzanis et al. (2001) found significantly poorer performance in their FTD group on only one out of two measures of mental flexibility. Zakzanis et al. (2001) reported significantly reduced letter fluency and Category Fluency in FTD patients, but Ziauddeen et al. (2010) found a significant difference only in Category Fluency. In our study, neither fluency domain was significantly different between groups, although letter fluency was associated with a small-tomedium effect size. Ziauddeen et al. (2010) observed significantly reduced Inhibition in FTD patients, whereas we found a non-significant difference with small-to-medium effect size. Similarly to our findings, tests of verbal reasoning were not significantly different between groups in the Zakzanis et al. (2001) study. Finally, in the current study, Naming was associated with a small-to-medium effect size, with FTD patients scoring lower. Neither of the previous studies explored confrontation naming. In comparing findings across studies, account needs to be taken of differences in patient characteristics [i.e. late-onset
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Chan et al. schizophrenia in Zakzanis et al. (2001) and negative syndrome schizophrenia in Ziauddeen et al. (2010), compared to severe chronic schizophrenia in our study]. The average duration of illness in the Zakzanis et al. (2001) schizophrenia group was shorter compared to ours (13 vs. 21 years). The FTD groups were older in both previous studies (62 and 63 vs. 52 years) and may have been more impaired. Other issues to consider are methodological differences in statistical techniques and the cognitive tasks utilised. The current observation of substantial between-group similarities is probably due to our emphasis on a subgroup of patients who had been referred to a specialist neuropsychiatric service with a cognitive and/or functional decline. As a consequence, we reduced the impact of disease heterogeneity on our results. This subtype of schizophrenia may most closely resemble Kraepelin’s dementia praecox, Keefe et al.’s (1987) Kraepelinian schizophrenia, and Mitelman and Buchsbaum’s (2007) poor-outcome schizophrenia. Findings of severe cognitive impairments in our schizophrenia group, which paralleled those seen in FTD, lend support to the ‘dementia of schizophrenia’ concept, particularly in a severely unwell subgroup. It is notable that the patients in this subgroup ranged in age from 23 to 68 years and did not represent an elderly population. The age range here is very similar to that in de Vries et al.’s (2001) study investigating an additional diagnosis of dementia in chronically hospitalised and age-disoriented schizophrenia patients. The current results, in conjunction with de Vries et al.’s findings, suggest that the ‘dementia of schizophrenia’ is independent of age and may follow a distinct trajectory to currently known neurodegenerative processes. Furthermore, our findings are comparable with de Vries et al.’s observation of dementia-like cognitive impairments in their institutionalised chronic schizophrenia population. A plausible explanation, proposed by Mitelman and Buchsbaum (2007), is that there exists a subtype of chronic schizophrenia with a very slowly progressive dementia which remains undefined. The neuropsychological similarities and differences identified here between the chronic schizophrenia and FTD groups are important on several levels. Firstly, after matching the groups on general level of cognitive functioning, we found that both chronic schizophrenia and FTD patients demonstrated some of the most severe deficits (> 1.5 SD below the norm) in the same cognitive domains, namely Speed of Processing, Immediate Memory, and Category Fluency. Basic Attentional Capacity was relatively preserved in both groups (< 0.5 SD below the population norm). Secondly, we observed significantly reduced mental switching ability in chronic schizophrenia rather than FTD patients. This probably reflects the extent of cognitive deficits in this group of schizophrenia patients. When our results are considered in the context of previous findings, the lack of a consistent pattern of executive function differences suggests that executive function measures may not
distinguish between chronic schizophrenia and FTD. Executive function is a broad cognitive domain that can be fractionated into discrete sub-domains reflecting different sets of abilities, and there is a need for further research into these different aspects with larger populations of patients. Thirdly, dysfunction in the dorsolateral prefrontal–subcortical circuit has been proposed to underlie deficits in fluency, set-shifting, Inhibition and abstraction ability (Cummings, 1995, as cited in Duke and Kaszniak, 2000). Previous studies have identified similar fronto-striatal impairments in schizophrenia and frontal lobe disorders (e.g. Pantelis et al., 1997; Weickert et al., 2013). The current findings of significantly poorer set-shifting ability in chronic schizophrenia and numerically lower scores in FTD in several aspects of executive functioning (i.e. Verbal Reasoning, Letter Fluency and Inhibition) support the involvement of fronto-subcortical circuits (particularly the dorsolateral prefrontal–subcortical loop) in the neuropathology of chronic schizophrenia and FTD. The poorer performance in confrontation naming in the FTD group suggests that temporal dysfunction may be more prominent in FTD compared to chronic schizophrenia. The current findings need to be interpreted in light of several methodological limitations. Firstly, this was a retrospective study based on neuropsychological data collected for clinical purposes and not all patients had undertaken the same tests. We addressed this issue by categorising tests into cognitive domains. The number of patients from each group who had undertaken each test was mostly comparable and each domain had an equal representation of different tests in both groups. Secondly, our patient numbers may appear relatively small given that we collated data over a 15-year period. The small numbers reflect the difficulty of assessing these two groups of patients, whereby a flexible clinical approach to neuropsychological assessment is warranted. The current study is one of the few studies to have amassed a substantial amount of neuropsychological data in an oft-excluded ‘real world’ chronic schizophrenia subgroup compared to patients with FTD. We are not aware of any other studies that have been able to assess these two patient population groups within the one centre. Thirdly, our findings may not be applicable to the broader group of patients with chronic schizophrenia, given that patients referred to our clinical service are highly selected. Patients are referred due to clinical concerns of cognitive or functional decline in the setting of a background diagnosis of schizophrenia. This limitation in generalisability can conversely be viewed as the major strength of our study. The referral process itself may have identified a group of patients with chronic schizophrenia whom clinicians thought were atypical enough in their presentation to refer to a specialised neuropsychiatric service. Further, we did not include a third patient group with a different underlying neuropathological process (i.e. involving areas other than the frontal and temporal brain regions) as a comparison Australian & New Zealand Journal of Psychiatry, 48(9)
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836 group. Demonstration of a different neurocognitive profile in this comparison group to the chronic schizophrenia and FTD groups would strengthen our argument that similar frontotemporal dysfunction underlies chronic schizophrenia and FTD. Finally, all patients in the schizophrenia group were medicated compared to only half of the patients in the FTD group. We have attempted to statistically control for the group differences in medication status, although future studies may consider using chlorpromazine equivalent dosage as a stronger covariate. In summary, we have characterised the neuropsychological profiles of a group of patients with ‘real world’ chronic schizophrenia and FTD, across a number of cognitive domains, using various statistical indices. We have identified substantial similarities between the groups in a number of cognitive domains. We observed differences in aspects of executive functioning and confrontation naming, which may be important for the purposes of differential diagnosis. Our findings are important in that they strongly suggest that some patients with severe chronic schizophrenia have cognitive deficits similar in degree and pattern to patients with frontotemporal dementia. The study does not address the question of whether the chronic schizophrenia group exhibits progressive changes. Future directions include comparison of the two patient groups on aspects beyond neuropsychology [e.g. social cognition (a notable study is that by Kosmidis et al. (2008), which indirectly compared theory of mind in patients with schizophrenia and patients with FTD), neuroimaging, neuropathology], a longitudinal follow-up study of patients with severe chronic schizophrenia and FTD, and including a third patient comparison group with a different neuropathological process. This research was approved by the Melbourne Health Human Research Ethics Committee (HREC Project Number 2008.663). Acknowledgements The authors would like to acknowledge Dr Aidan Sudbury (Monash University) and Professor Geoff Cumming (La Trobe University) for their statistical advice.
Funding This work was supported by the Monash University Doctoral Research budget and the Melbourne Neuropsychiatry Centre Research Higher Degree Award.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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