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Neurocognitive functioning and quality of life in patients with and without deficit syndrome of schizophrenia
Author’s Accepted Manuscript Neurocognitive Functioning and Quality of Life in Patients with and without Deficit Syndrome of Schizophrenia Min Yi Sum, Kai Hong Tay, Somnath Sengupta, Kang Sim www.elsevier.com/locate/psychres
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S0165-1781(17)31133-2 https://doi.org/10.1016/j.psychres.2018.02.025 PSY11199
To appear in: Psychiatry Research Received date: 21 June 2017 Revised date: 2 February 2018 Accepted date: 12 February 2018 Cite this article as: Min Yi Sum, Kai Hong Tay, Somnath Sengupta and Kang Sim, Neurocognitive Functioning and Quality of Life in Patients with and without Deficit Syndrome of Schizophrenia, Psychiatry Research, https://doi.org/10.1016/j.psychres.2018.02.025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Neurocognitive Functioning and Quality of Life in Patients with and without Deficit Syndrome of Schizophrenia Min Yi Sum^a Kai Hong Tay^b Somnath Senguptab Kang Sim*a,b ^These authors contributed equally to this work a
Research Division, Institute of Mental Health, 10 Buangkok View, Buangkok Green Medical
Park, 539747, Singapore b
Department of General Psychiatry, Institute of Mental Health, 10 Buangkok View, Buangkok
Green Medical Park, 539747, Singapore
Running title: Neurocognitive deficits and QOL in Deficit Schizophrenia Word counts and Tables/Figure: 186 words for abstract and 2862 words for word text, 4 Tables and 1 Figure *Corresponding Author: Associate Professor Kang Sim Department of General Psychiatry, Institute of Mental Health/Woodbridge Hospital 10, Buangkok View, Singapore 539747 Telephone: 65-63892000 Fax: 65-63855900 E-mail: [email protected]
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Abstract Deficit syndrome of schizophrenia is a subtype of schizophrenia characterized by primary and enduring negative symptoms. This study examined the differences in neurocognitive functioning and quality of life (QOL) between deficit and non-deficit patients, and specific predictors of both clinical measures. Overall, 344 subjects (175 patients with non-deficit schizophrenia (NDSZ), 58 patients with deficit schizophrenia (DSZ) and 111 healthy controls) were evaluated on severity of psychopathology, QOL and a smaller subset of 198 subjects (104 NDSZ, 27 DSZ, 67 healthy controls) underwent neurocognitive assessments. Multivariate analyses were used to determine differences in outcomes between subject groups and predictors of clinical measures. Both DSZ and NDSZ had significantly worse QOL compared with healthy controls. DSZ had more extensive cognitive deficits compared with healthy controls and performed worse on semantic fluency task compared to NDSZ. Multiple linear regression analysis found that DSZ, shorter duration of illness were associated with poorer QOL whereas fewer years of education, lower premorbid intelligence were associated with poorer overall neurocognitive functioning. The poorer QOL, greater extent of neurocognitive deficits especially semantic fluency associated with DSZ behoves the need for greater attention during clinical evaluation and treatment planning of this subgroup of individuals with schizophrenia. .
Keywords: Deficit schizophrenia, Quality of life, Neurocognitive functioning
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1. Introduction The deficit syndrome of schizophrenia (DSZ) refers to the presence of enduring and primary negative symptoms observed in patients with schizophrenia over at least 12 months, during which these negative symptoms have to be present even during periods of clinical stability and are not related to presence of positive, depressive symptoms, drug effects, or psychosocial deprivation (Carpenter et al., 1988; Kirkpatrick et al., 1989). Besides differences in symptomatology, patients with DSZ have been observed to differ from the patients with nondeficit schizophrenia (NDSZ) regarding associated clinical features including neurological soft signs, more severe neurocognitive impairments, and worse level of psychosocial functioning. (Bora et al., 2017; Buchanan et al., 1994; Bryson et al., 2001; Tek et al., 2001; Galderisi et al., 2002; Gourevitch et al., 2004; Voineskos et al., 2013 Peralta et al., 2014). The strengths of the deficit syndrome are in better subtyping of the heterogeneous schizophrenia syndrome related to negative symptoms, incorporation of clinical assessments, longitudinal observations, and parcellation from more transient negative symptoms which may be amenable to optimization of available treatments (Carpenter et al., 1988; Bucci and Galderisi 2017). The limitations may be related to overlap with other potential clinical confounders such as substance abuse, environmental deprivation which may not always be clear cut and general paucity of satisfactory treatments after establishment of subtype (Bucci and Galderisi 2017; Kirkpatrick et al., 2000). There are overall sparse data on the quality of life (QOL) in patients with DSZ compared with NDSZ (Delamillieure et al., 2005; Gourevitch et al., 2004; Tek et al., 2001). Gourevitch et al. (2004) examined a sample of 47 patients with schizophrenia using the Quality of Life Interview (QLI) visual analogue scale to assess subjective QOL in addition to objective QOL assessed using the Heinrich’s Quality of Life Scale (QLS), and reported that patients with DSZ had poorer QOL compared to NDSZ on both the scales. In the only longitudinal study of QOL in DSZ, Tek 3
et al. (2001) used the Heinrich’s Quality of Life Scale and found that the DSZ group had poorer overall QOL than those with NDSZ at baseline and during the 5 year follow up even after controlling for demographic differences. In contrast, Delamillieure et al. (2005), examined their study sample of 142 subjects with SZ (30 DSZ, 112 NDSZ) using the Lehman Quality of Life interview (Lehman, 1988) but did not find any difference in subjective QOL between DSZ and NDSZ patients. In comparison, there were more studies which have examined cognitive functioning in DSZ patients, with some studies observing impairments in global cognitive functioning (Cohen et al., 2007), and others reporting cognitive impairments in specific domains such as executive functioning, working memory, verbal fluency, and visual spatial memory (Buchanan et al., 1994; 1997; Bryson et al., 2001; Brazo et al., 2002; Wang et al., 2008) or both (Bora et al., 2017; Réthelyi et al., 2012). Cascella and colleagues (2008) found that DSZ performed worse on all cognitive domains compared to NDSZ but Tiryaki and colleagues (2003) did not detect differences in cognitive functioning between the two patient groups. Due to the paucity of studies examining QOL together with neurocognitive functioning in DSZ, we aimed to examine subjective QOL and neurocognitive impairments within schizophrenia patients with and without deficit syndrome, as well as whether DSZ affect both clinical outcomes in patients with schizophrenia. Based on existing evidence and clinical impressions, we hypothesized that DSZ would have poorer self-rated QOL and more impaired neurocognitive functioning and predict both outcomes.
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2. Methods 2.1 Study Sample Three hundred and forty four subjects (111 healthy controls, 175 NDSZ and 58 DSZ) participated in this study, all of whom were assessed on QOL using the World Health Organization Quality of Life – Brief Form. Out of these, a subset of 198 participants (67 healthy controls, 104 NDSZ, and 27 DSZ) were assessed on their neurcognitive functioning and premorbid intelligence. Patients were recruited from the Institute of Mental Health, Singapore, and confirmation of diagnosis was made by team psychiatrists (S.S., K.S.), via information from patients’ clinical history, existing medical records, and administration of the Structured Clinical Interview for DSM-IV Axis I disorders – Patient Version (SCID-P; First et al., 2002a). All patients were maintained on a stable dose of psychotropic medication for at least 2 weeks prior to the recruitment and did not have their medications withdrawn for the purpose of the study. Healthy controls recruited from the community were free of any history of psychiatric disorders, ascertained by the Structured Interview for DSM-IV Axis I disorders – Non-patient Version (SCID-NP; First et al., 2002b). None of the participants had a history of significant and/or unstable/untreated medical illnesses such as seizure disorder, head trauma, or cerebrovascular accidents. All participants provided signed, written informed consent prior to any study procedures and the study was approved by the institutional review boards of the hospital and the National Healthcare Group.
2.2 Clinical, QOL and Cognitive Assessments
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Information on patients’ clinical history including age of first onset, duration of illness (DOI) and duration of untreated psychosis (DUP) were obtained via patients’ self-report, history from carers if available and confirmed with relevant case records. Age of onset refers to the age when patients first experienced psychotic symptoms, DOI refers to the time period between first onset of illness and the time at which patients were enrolled in the study, and DUP refers to the time period from onset of psychotic symptoms to initiation of treatment. The Positive and Negative Symptoms Scale (PANSS; Kay et al., 1987) was used to assess the severity of clinical symptoms and it is a 30-item rating scale used to evaluate the severity of positive, negative (7-items each), and general psychopathology (16-items) symptoms on a 7point scale. Scores from individual items were added within each domain to obtain an overall rating score, with higher scores suggesting more severe psychopathology. Patients were classified as DSZ or NDSZ using the Proxy for the Deficit Syndrome criteria (PDS) based on PANSS (Kirkpatrick et al., 1993). The PDS is a proxy case identification method that has good specificity, sensitivity, and accuracy for identification of deficit patients (Kirkpatrick et al., 1993). It has been shown to be a valid tool for the categorization of patients with schizophrenia into deficit and non-deficit groups (Goetz et al., 2007). The PDS is defined as the sum of the scores (from the PANSS) of the anxiety, guilt feelings, depressive mood, and hostility items subtracted from the blunted affect item score. PDS index score = PANSS items blunted affect (N1) – [anxiety (G2) + guilt feelings (G3) + depression (G6) + hostility (P7)]. As with previous studies using the PDS (Kirkpatrick et al., 1993; Voineskos et al., 2013), an index cut-off point of -2 was used to classify deficit versus non-deficit patients. To ensure the stability of the diagnosis, the negative symptoms have to be present for at least a year (Fenton and McGlashan, 1994).
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Quality of life was assessed using the World Health Organization Quality of Life – Brief Form (WHOQOL-BREF, The WHOQOL Group, 1998). The WHOQOL-BREF is a 26-item, 5point self-rated questionnaire. It assesses subjective QOL in four domains, namely Physical Health (7-items), Psychological Health (6-items), Social Relationships (3 items), Environment (8-items) and the 2 remaining items assess perception of overall QOL and overall health satisfaction. After reversed-scoring for some items, items within each domain were added up to obtain domain scores. Higher scores indicate better subjective QOL. Total QOL was calculated by summing up ratings on all 26-items from WHOQOL-BREF, taking into account the items where scorings needed to be reversed. Participants were assessed on neurocognitive functioning using the Brief Assessment of Cognition in Schizophrenia (BACS; Keefe et al., 2004). It comprises of a brief battery of tests that takes approximately 30 minutes to complete and consists of six subtests, namely, List Learning, Digit Sequencing Task, Token Motor task, Semantic and Letter Fluency, Symbol Coding, and Tower of London, which assess verbal memory, working memory, motor speed, verbal fluency, attention, and executive functioning respectively. Pre-morbid intelligence was estimated using the Wide Range Achievement Test (WRAT) Reading Test, 3rd edition (Wilkinson, 1993).
2.3 Statistical Analysis Socio-demographic and clinical characteristics of all three groups were compared using one way analysis of variance analyses (ANOVA), chi-square test, and independent samples t-test, as appropriate. Univariate ANCOVA controlling for marital and employment status was used to compare differences in QOL, while a univariate ANCOVA controlling for years of education, and premorbid IQ assessed using the WRAT Reading Test was used to compare the differences 7
in cognitive functioning between all three groups. Further analyses, using general linear model, were conducted to test for differences in QOL and neurocognitive functioning between the two patient groups, additionally controlling for duration of illness, GAF scores and CPZ (chlorpromazine) equivalents for QOL and neurocognitive functioning. Correlations between the PDS index scores and QOL and BACS scores were also conducted. Multiple linear regression analysis was used to examine predictors of total QOL and overall neurocognitive functioning. Specifically, for total QOL as outcome, schizophrenia subtype, age, gender, years of education, employment status, marital status, illness duration, and CPZ equivalent were entered into the regression model as predictors. For overall neurocognitive functioning as outcome, schizophrenia subtype, age, gender, years of education, premorbid intelligence, illness duration and CPZ equivalent were entered into the regression model as predictors. All analyses were conducted using the SPSS version 23.0 (IBM Corp, Armonk, New York). To take into account the different QOL and neurocognitive domains, the corrected statistical significance was set a priori at an alpha of 0.01 (two tailed) for QOL and 0.005 (two tailed) for neurocognitive functioning. Statistical significance for all other analyses required two tailed p<0.05.
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3.
Results All three groups of participants did not differ significantly in terms of age and gender (see
Table 1). Patients tended to have fewer years of education and were more likely to be single and unemployed compared with healthy controls. The patient groups did not differ significantly on clinical variables (age of first onset, DOI and DUP), as well as their daily antipsychotic dose in daily CPZ mg equivalents. The same pattern of baseline findings was found in the subset with 199 participants who completed neurocognitive assessments. Comparison of WRAT III scores using a one way ANOVA found a significant difference between all three groups (p<0.05), however, post-hoc analysis using Bonferroni adjustment revealed that the difference only lies between healthy controls and the deficit syndrome group (p<0.05), and there was no significant difference in estimated premorbid IQ between the two patient groups. For QOL (see Figure 1 and Table 2), comparisons across all three subject groups (N=344) using ANCOVA, controlling for marital and employment status, found significant difference in most QOL domains and total QOL, with healthy controls having the highest ratings. Both DSZ and NDSZ scored lower in QOL compared with healthy controls (Figure 1). Of note, further analysis controlling for marital status, employment status, antipsychotic dose (CPZ equivalents), and duration of illness did not find differences in QOL ratings between deficit and non-deficit syndrome schizophrenia patients on all four QOL domains, suggesting comparable impact on QOL for both DSZ and NDSZ. Regarding neurocognitive functioning (see Table 3), comparisons across the three subject groups using ANCOVA and controlling for years of education and estimated premorbid IQ found significant differences between the three groups on all domains except motor speed, letter fluency and executive functioning. Compared with healthy controls, DSZ performed poorer in 9
more extensive neurocognitive domains compared with NDSZ (Table 3). Further analyses controlling for years of education, estimated premorbid IQ, age, gender, duration of illness, antipsychotic dose, and level of psychosocial functioning (GAF scores) found that DSZ scored worse than NDSZ in semantic fluency (p<0.005). Correlating PDS index score as a continuous variable with the clinical outcomes, there was no significant correlation between PDS index score and total QOL and subdomain scores. Negative correlation was found between PDS index score and verbal memory total (p=0.011), digit sequencing (p=0.011), semantic verbal fluency (p=0.004), symbol coding (p=0.049), and BACS composite z score (p=0.029). Multiple linear regression analysis on the clinical sample found that DSZ and shorter illness duration predicted lower total QOL and fewer years of education and lower estimated premorbid IQ predicted poorer overall cognitive functioning using total BACS scores (see Table 4).
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4. Discussion There were several main findings in this study. First, DSZ and NDSZ were found to have poorer QOL in all domains as well as total QOL compared with healthy controls. Amongst the patients, both DSZ and NDSZ had comparable poorer QOL ratings on all domains. Second, compared to healthy controls, DSZ had more extensive neurocognitive deficits than NDSZ. Compared with NDSZ, DSZ was found to perform significantly worse on the semantic fluency task. Finally, we found that DSZ and shorter illness duration were associated with lower overall QOL and fewer years of education and lower premorbid intelligence were associated with poorer neurocognitive functioning. Whilst the entire patient group scored lower on the four QOL domains (physical, psychological, social relationships, and environment), as well as total QOL compared to healthy controls, both patient groups (DSZ and NDSZ) were found to be similarly affected in their subjective QOL. This finding was consistent with that of an earlier study (Delamillieure et al. 2005), in which no difference was observed in subjective QOL between patients with deficit syndrome and those without. The difference in the pattern of QOL findings in our study compared to a previous study (Tek et al., 2001) which found lower QOL in DSZ versus NDSZ could be related to the nature of rating tool which highlights discrepancies between subjective and objective measures of perceived health status both of which are still valid from varying perspectives of patient and treating clinician (Hayhurst et al., 2014). In an earlier study, Gourevitch et al. (2004) examined the relationship between deficit symptoms and QOL, found that while DSZ had poorer QOL compared with NDSZ, the difference depended on the QOL rating measures used. Specific QOL items in the Quality of Life Scale (QLS) (Heinrichs et al., 1984) known as more “psychopathological” items such as related to intrapsychic functions were 11
the most discriminating between the 2 groups. Conversely, “behavioral” items, which are more independent of symptoms, show less difference between DSZ and NDSZ. Furthermore, selfrated QOL was not rated differently between the 2 patient groups. We observed negative correlations between PDS index score and cognitive domains including verbal memory, digit sequencing, symbol coding and semantic fluency. Compared with healthy controls, DSZ had greater extent of neurocognitive deficits than NDSZ which is consistent with findings of other studies (Bora et al., 2017; Réthelyi et al., 2012). Réthelyi et al. (2012) found that DSZ was a function of global and domain specific
neurocognitive deficits including
attention, working memory, verbal memory, cognitive flexibility and ideation fluency, and that DSZ suffered from more severe neurocognitive impairments compared with NDSZ. In a recent meta-analysis by Bora et al. (2017) reported that whilst DSZ and NDSZ were associated with neurocognitive deficits in multiple domains, DSZ were found with more severe neurocognitive deficits than NDSZ. In addition, DSZ performed significantly poorer on semantic fluency compared with NDSZ. Of note, Cascella et al. (2008) found that DSZ performed worse than NDSZ in several cognitive domains examined (attention, psychomotor speed, executive function, verbal fluency, visual memory, and verbal memory), with only verbal fluency reaching statistical significance. Henry and Crawford (2005) found in their meta-analytic review of 84 studies that schizophrenia patients, in comparison with healthy controls, showed greater impairment in semantic fluency compared to phonetic fluency, and suggested that schizophrenia is a condition associated with compromise in reserve in the semantic domain. In a study by Sumiyoshi and colleagues (2005), an association between alogia and semantic memory disorganization (assessed using category fluency task) was also observed. Our finding of more severe semantic fluency impairment in DSZ may underlie the poverty of speech observed in DSZ, and which reflects a breakdown in the semantic organisation. 12
DSZ was found to predict poorer QOL, this is consistent with previous findings, in which patients with more severe psychopathology including negative symptoms had poorer QOL (Brissos et al., 2008). Shorter duration of illness was also found to predict poorer QOL, which was in contrast to the findings of Hsiao et al. (2011), who found that patients with longer duration of illness had lower perceived QOL, although they did not find illness duration to be a predictor of QOL in their multivariate regression analysis. Consistent with our findings, Larsen and Gerlach (1996) found that patients with chronic schizophrenia reported better QOL, suggesting that patients with longer illness duration may have learned to accept and cope with their illness over time, hence scoring higher in their self-rated QOL. In terms of neurocognitive functioning, we found that fewer years of education, as well as lower estimated premorbid IQ predicted worse overall neurocognitive functioning. Previous studies of the inter-relationship between education, cognitive performance albeit involving older non-patient population found that better neurocognitive functioning or slower cognitive decline was associated with more years of education (Le Carret et al., 2003; Portin et al., 1995; Evans et al., 1993), which supports our current finding. What are the clinical implications? First, the poor QOL associated with DSZ behoves greater attention and monitoring by the multidisciplinary team during clinical assessment and treatment planning for this subgroup of patients with SZ. Second, whilst semantic fluency performance is thought to be stable in schizophrenia, it is also associated with recovery from the illness thus making it a possible target for cognitive remediation (Kopelowicz et al., 2005; Szoke et al., 2009). There is preliminary evidence that cognitive remediation may improve verbal fluency, verbal learning and processing speed in schizophrenia and future studies are warranted to evaluate domain specific neurocognitive changes over time following treatment modalities such as cognitive remediation therapy (Sartory et al., 2005). This study had several limitations. As this 13
was a cross-sectional study, a longitudinal study in DSZ to observe the changes in QOL and neurocognitive functioning with treatment is warranted. Second, the inclusion of both subjective and objective measures of QOL and additional neurocognitive testing would allow better elucidation of the inter-related nature of these measures within our subjects. Third, the neurocognitive findings in a smaller subject subset who completed the relevant assessments need to be replicated in other populations. In conclusion, our findings of DSZ being associated with poor QOL, more extensive neurocognitive impairments especially more severe semantic fluency highlight the need for further research to elucidate the malleability of associated clinical factors to earlier intervention and the effectiveness of different pharmacological and psychosocial approaches in the treatment of DSZ and associated neurocognitive findings.
Acknowledgements The authors would like to thank all participants, their families and the clinical staff for their support of this study. Funding This study was supported by the National Healthcare Group, Singapore [SIG/05004]; and the ASTAR [RP C-009/2006] research grants awarded to K.S. Role of funding source The identified funding sources had no role in the study design; collection, analysis and interpretation of the data; writing of report; and the decision to submit the paper for publication.
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Disclosure of interest The authors declare that they have no competing interest.
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*
**
*
**
*
**
**
*
** **
Figure 1. Comparison of Quality of Life Scores across All Groups Abbreviations: NDSZ, Non-Deficit Schizophrenia; DSZ, Deficit Schizophrenia *p<0.005, **p<0.001
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Figure 1. Comparison of Quality of Life Scores across All Groups Abbreviations: NDSZ, Non-Deficit Schizophrenia; DSZ, Deficit Schizophrenia *p<0.005, **p<0.001
Table 1. Clinical and demographic features of entire sample (N=344) Controlsa (n = 111)
Non-deficit SZa
Deficit SZa
Between-group differences
(n = 58)
Test statistic
p
(n = 175) 32.17 (9.382)
32.58 (9.350)
34.24 (9.253)
F = 0.979
0.377
Male
68 (61.3)
111 (63.4)
37 (63.8)
2 = 0.167
0.920
Female
43 (38.7)
64 (36.6)
21 (36.2)
14.23 (2.004)
11.54 (2.550)
11.17 (2.341)
F = 53.359
<0.001
Age at onset of illness
-
26.03 (7.828)
26.22 (6.911)
t = -0.170
0.865
Duration of untreated psychosis (years)
-
1.50 (2.272)
1.65 (2.314)
t = -0.445
0.657
Illness duration (years)
-
6.57 (7.511)
8.02 (8.317)
t = -1.239
0.217
Antipsychotic dose in daily CPZ mg equivalents
-
210.23 (179.705)
244.40 (201.096)
t = -1.218
0.225
2 = 144.278
<0.001
Age
Sex (%)
Years of education
Employment status (%)
6 (5.4)
114 (65.1)
44 (75.9)
Unemploy
22
ed Employed
102 (91.9)
46 (26.3)
9 (15.5)
3 (2.7)
15 (8.6)
5 (8.6)
Others Marital status (%) Single
69 (62.2)
148 (84.6)
52 (89.7)
Married
41 (36.9)
20 (11.4)
4 (6.9)
1 (0.9)
7 (4.0)
2 (3.4)
10.800 (3.695)
11.207 (4.158)
8.091 (2.110)
12.897 (4.167)
20.726 (4.001)
20.810 (3.701)
39.617 (7.925)
44.914 (9.329)
49.67 (17.923)
46.88 (14.495)
52.49 (19.112)
49.64 (16.438)
51.40 (17.725)
47.02 (15.413)
Divorced/
2 = 36.551
<0.001
t = -0.704
0.482
t = -8.433
<0.001
t = -0.142
0.887
t = -4.215
<0.001
t = 1.196
0.234
t = 1.019
0.309
t = 1.681
0.094
Widowed PANSS
-
Positive Negative General psychopathology Total
GAF Total Symptoms Disability
-
Abbreviations: CPZ, Chlorpromazine; PANSS, Positive and Negative Syndrome Scale; GAF, Global Assessment of Functioning a
All values are mean (SD) unless otherwise stated
23
Table 2. Comparison of Quality of Life scores across the three subject groups Healthy controls (n=111)
ANCOVAa
ANCOV Ab NDSZ vs. DSZ F p
NDSZ (n=175)
DSZ (n=58)
15.60 (1.59)
13.89 (2.70)
13.12 (2.35)
12. <0.0 40 01*
18. 299
<0.0 01*
25. 002
<0.0 01*
2.9 69
0.0 86
Domain 2 Psychological
14.92 (1.70)
13.22 (3.21)
12.51 (2.59)
7.1 <0.0 2 1*
10. 300
<0.0 05*
12. 583
<0.0 05*
0.1 94
0.6 60
Domain 3 Social Relationships
15.23 (2.20)
13.10 (3.31)
12.16 (3.38)
9.4 <0.0 8 01*
14. 459
<0.0 01*
10. 175
<0.0 05*
0.1 44
0.7 05
Domain 4 Environment
15.13 (1.70)
13.51 (2.79)
12.67 (2.92)
9.3 <0.0 0 01*
11. 822
<0.0 05*
18. 599
<0.0 01*
1.1 38
0.2 87
QOL 1 Overall perception of QOL
3.92 (0.59)
3.43 (0.99)
3.26 (1.02)
4.1 0.01 0 7
7.8 08
<0.0 1*
2.8 32
0.09 4
0.3 44
0.5 58
QOL 2 Overall health satisfaction
3.81 (0.67)
3.46 (1.03)
3.31 (1.22)
3.2 0.03 7 9
5.4 18
0.02 1
3.9 27
0.0 90
0.7 65
99.05 (9.12)
88.20 (16.53)
82.72 (15.67)
12. <0.0 19 01*
16. 719
<0.0 01*
22. 883
0.04 9 < 0.00 1*
0.9 88
0.3 21
Domain 1 Physical Health
Total QOL
All Groups F p
HC vs. NDSZ F p
HC vs. DSZ F p
Abbreviations: NDSZ, Non-Deficit Schizophrenia; DSZ, Deficit Schizophrenia a ANCOVA model controlled for marital status and occupational status b ANCOVA model controlled for marital status, occupational status, CPZ equivalent, and duration of illness
Table 3. Comparison of neurocognitive functioning across the three subject groups
Verbal Memory
Healthy controls (n=67)
NonDeficit (n=104)
Deficit (n=27)
47.35 (9.312)
38.15 (11.182)
31.74 (11.568)
ANCOVAa All Groups F p 14. <0. 40 001 7 *
HC vs. NDSZ F p 16. <0. 61 001 9 *
HC vs. DSZ F p 23. <0.0 04 01* 6
ANCOV Ab NDSZ vs. DSZ F p 4. 0.02 86 9 8 24
Digit Sequencing Tokens Correct Semantic Fluency Letter Fluency Verbal Fluency Total Symbol Coding Tower of London
21.07 (3.461)
18.73 (4.518)
16.33 (4.481)
7.5 91
76.25 (13.493)
69.00 (58.376)
60.52 (12.439)
1.2 24
<0. 005 * 0.29 6
24.90 (6.071)
19.66 (5.772)
15.78 (5.853)
27.90 (8.070)
23.57 (8.576)
22.33 (8.718)
16. 40 6 2.1 73
<0. 001 * 0.11 7
52.79 (12.095)
43.23 (12.151)
38.11 (11.762)
8.8 62
63.84 (10.456)
48.78 (12.015)
44.30 (11.472)
17.66 (2.422)
16.28 (4.008)
16.46 (4.052)
34. 41 2 0.6 55
4.6 64
0.03 2
0.6 68
0.41 5
13. 85 7
<0. 001 *
19. 50 8 17. 79 4 25. 79 9
3.0 28
0.08 4
2.9 72
<0. 001 9.3 * 08 <0. 55. 001 51 * 7 0.52 1.7 0 90
<0. 003 * <0. 001 *
14. 29 6 47. 92 3
0.18 3
0.3 28
<0.0 01* <0.0 01* <0.0 01* 0.08 8 <0.0 01* < 0.00 1* 0.56 8
2. 80 1 0. 29 6 8. 91 9 0. 01 3 2. 26 7 1. 52 6 0. 33 0
0.09 7 0.58 8 <0. 005 * 0.91 1 0.13 5 0.21 9 0.56 7
15. <0. 56. < 1. 0.16 13. <0. 02 001 38 0.00 95 4 91 001 8 * 1 1* 8 5 * BACS -0.02 (0.982) -1.64 -2.33 32. <0. 44. <0. 57. <0.0 3. 0.08 Composite z (1.297) (1.174) 34 001 01 001 40 01* 08 2 score 5 7 * 2 * 3 Abbreviations: NDSZ, Non-Deficit Schizophrenia; DSZ, Deficit Schizophrenia a ANCOVA model controlled for years of education, estimated premorbid IQ, age, and gender b ANCOVA model controlled for years of education, estimated premorbid IQ, age, gender, duration of illness, CPZ equivalent, and GAF (total, symptoms, disability) BACS total
278.79 (30.969)
233.17 (67.740)
206.85 (38.361)
Table 4. Linear regression analyses showing significant factors associated with total Quality of Life scores and Neurocognitive Functioning in patients Explanatory variables Standardised B coefficient t p-value Total Quality of Life Schizophrenia subtype*
-0.175
-2.53
0.012
Age
0.104
1.19
0.236
Gender
-0.055
-0.80
0.426
Years of education
0.028
0.41
0.684
Employment status
0.040
0.51
0.609 25
Marital status
0.079
1.13
0.259
Illness duration*
0.419
2.98
0.003
CPZ equivalent
-0.039
-0.58
0.584
Schizophrenia subtype
-0.152
-1.70
0.093
Age
-0.016
-0.18
0.861
Gender
0.163
1.82
0.071
Years of education*
0.291
3.07
0.003
Premorbid intelligence
0.250
2.64
0.010
Illness duration
-0.145
-1.63
0.107
CPZ equivalent
-0.123
-1.37
0.174
Neurocognitive Functioning
(WRAT III)*
Abbreviations: CPZ, chlorpromazine; WRAT III, Wide Range Achievement Test 3rd Ed Reading Subtest * p < .05
Highlights
Differences in outcomes were examined between deficit (DSZ) and non-deficit schizophrenia Both DSZ and NDSZ had significantly worse QOL compared with healthy controls Deficit group performed worse on semantic fluency compared to non-deficit patients The poorer QOL, greater extent of neurocognitive deficits associated with DSZ behoves the need for greater clinical attention
26
PII: DOI: Reference:
S0165-1781(17)31133-2 https://doi.org/10.1016/j.psychres.2018.02.025 PSY11199
To appear in: Psychiatry Research Received date: 21 June 2017 Revised date: 2 February 2018 Accepted date: 12 February 2018 Cite this article as: Min Yi Sum, Kai Hong Tay, Somnath Sengupta and Kang Sim, Neurocognitive Functioning and Quality of Life in Patients with and without Deficit Syndrome of Schizophrenia, Psychiatry Research, https://doi.org/10.1016/j.psychres.2018.02.025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Neurocognitive Functioning and Quality of Life in Patients with and without Deficit Syndrome of Schizophrenia Min Yi Sum^a Kai Hong Tay^b Somnath Senguptab Kang Sim*a,b ^These authors contributed equally to this work a
Research Division, Institute of Mental Health, 10 Buangkok View, Buangkok Green Medical
Park, 539747, Singapore b
Department of General Psychiatry, Institute of Mental Health, 10 Buangkok View, Buangkok
Green Medical Park, 539747, Singapore
Running title: Neurocognitive deficits and QOL in Deficit Schizophrenia Word counts and Tables/Figure: 186 words for abstract and 2862 words for word text, 4 Tables and 1 Figure *Corresponding Author: Associate Professor Kang Sim Department of General Psychiatry, Institute of Mental Health/Woodbridge Hospital 10, Buangkok View, Singapore 539747 Telephone: 65-63892000 Fax: 65-63855900 E-mail: [email protected]
1
Abstract Deficit syndrome of schizophrenia is a subtype of schizophrenia characterized by primary and enduring negative symptoms. This study examined the differences in neurocognitive functioning and quality of life (QOL) between deficit and non-deficit patients, and specific predictors of both clinical measures. Overall, 344 subjects (175 patients with non-deficit schizophrenia (NDSZ), 58 patients with deficit schizophrenia (DSZ) and 111 healthy controls) were evaluated on severity of psychopathology, QOL and a smaller subset of 198 subjects (104 NDSZ, 27 DSZ, 67 healthy controls) underwent neurocognitive assessments. Multivariate analyses were used to determine differences in outcomes between subject groups and predictors of clinical measures. Both DSZ and NDSZ had significantly worse QOL compared with healthy controls. DSZ had more extensive cognitive deficits compared with healthy controls and performed worse on semantic fluency task compared to NDSZ. Multiple linear regression analysis found that DSZ, shorter duration of illness were associated with poorer QOL whereas fewer years of education, lower premorbid intelligence were associated with poorer overall neurocognitive functioning. The poorer QOL, greater extent of neurocognitive deficits especially semantic fluency associated with DSZ behoves the need for greater attention during clinical evaluation and treatment planning of this subgroup of individuals with schizophrenia. .
Keywords: Deficit schizophrenia, Quality of life, Neurocognitive functioning
2
1. Introduction The deficit syndrome of schizophrenia (DSZ) refers to the presence of enduring and primary negative symptoms observed in patients with schizophrenia over at least 12 months, during which these negative symptoms have to be present even during periods of clinical stability and are not related to presence of positive, depressive symptoms, drug effects, or psychosocial deprivation (Carpenter et al., 1988; Kirkpatrick et al., 1989). Besides differences in symptomatology, patients with DSZ have been observed to differ from the patients with nondeficit schizophrenia (NDSZ) regarding associated clinical features including neurological soft signs, more severe neurocognitive impairments, and worse level of psychosocial functioning. (Bora et al., 2017; Buchanan et al., 1994; Bryson et al., 2001; Tek et al., 2001; Galderisi et al., 2002; Gourevitch et al., 2004; Voineskos et al., 2013 Peralta et al., 2014). The strengths of the deficit syndrome are in better subtyping of the heterogeneous schizophrenia syndrome related to negative symptoms, incorporation of clinical assessments, longitudinal observations, and parcellation from more transient negative symptoms which may be amenable to optimization of available treatments (Carpenter et al., 1988; Bucci and Galderisi 2017). The limitations may be related to overlap with other potential clinical confounders such as substance abuse, environmental deprivation which may not always be clear cut and general paucity of satisfactory treatments after establishment of subtype (Bucci and Galderisi 2017; Kirkpatrick et al., 2000). There are overall sparse data on the quality of life (QOL) in patients with DSZ compared with NDSZ (Delamillieure et al., 2005; Gourevitch et al., 2004; Tek et al., 2001). Gourevitch et al. (2004) examined a sample of 47 patients with schizophrenia using the Quality of Life Interview (QLI) visual analogue scale to assess subjective QOL in addition to objective QOL assessed using the Heinrich’s Quality of Life Scale (QLS), and reported that patients with DSZ had poorer QOL compared to NDSZ on both the scales. In the only longitudinal study of QOL in DSZ, Tek 3
et al. (2001) used the Heinrich’s Quality of Life Scale and found that the DSZ group had poorer overall QOL than those with NDSZ at baseline and during the 5 year follow up even after controlling for demographic differences. In contrast, Delamillieure et al. (2005), examined their study sample of 142 subjects with SZ (30 DSZ, 112 NDSZ) using the Lehman Quality of Life interview (Lehman, 1988) but did not find any difference in subjective QOL between DSZ and NDSZ patients. In comparison, there were more studies which have examined cognitive functioning in DSZ patients, with some studies observing impairments in global cognitive functioning (Cohen et al., 2007), and others reporting cognitive impairments in specific domains such as executive functioning, working memory, verbal fluency, and visual spatial memory (Buchanan et al., 1994; 1997; Bryson et al., 2001; Brazo et al., 2002; Wang et al., 2008) or both (Bora et al., 2017; Réthelyi et al., 2012). Cascella and colleagues (2008) found that DSZ performed worse on all cognitive domains compared to NDSZ but Tiryaki and colleagues (2003) did not detect differences in cognitive functioning between the two patient groups. Due to the paucity of studies examining QOL together with neurocognitive functioning in DSZ, we aimed to examine subjective QOL and neurocognitive impairments within schizophrenia patients with and without deficit syndrome, as well as whether DSZ affect both clinical outcomes in patients with schizophrenia. Based on existing evidence and clinical impressions, we hypothesized that DSZ would have poorer self-rated QOL and more impaired neurocognitive functioning and predict both outcomes.
4
2. Methods 2.1 Study Sample Three hundred and forty four subjects (111 healthy controls, 175 NDSZ and 58 DSZ) participated in this study, all of whom were assessed on QOL using the World Health Organization Quality of Life – Brief Form. Out of these, a subset of 198 participants (67 healthy controls, 104 NDSZ, and 27 DSZ) were assessed on their neurcognitive functioning and premorbid intelligence. Patients were recruited from the Institute of Mental Health, Singapore, and confirmation of diagnosis was made by team psychiatrists (S.S., K.S.), via information from patients’ clinical history, existing medical records, and administration of the Structured Clinical Interview for DSM-IV Axis I disorders – Patient Version (SCID-P; First et al., 2002a). All patients were maintained on a stable dose of psychotropic medication for at least 2 weeks prior to the recruitment and did not have their medications withdrawn for the purpose of the study. Healthy controls recruited from the community were free of any history of psychiatric disorders, ascertained by the Structured Interview for DSM-IV Axis I disorders – Non-patient Version (SCID-NP; First et al., 2002b). None of the participants had a history of significant and/or unstable/untreated medical illnesses such as seizure disorder, head trauma, or cerebrovascular accidents. All participants provided signed, written informed consent prior to any study procedures and the study was approved by the institutional review boards of the hospital and the National Healthcare Group.
2.2 Clinical, QOL and Cognitive Assessments
5
Information on patients’ clinical history including age of first onset, duration of illness (DOI) and duration of untreated psychosis (DUP) were obtained via patients’ self-report, history from carers if available and confirmed with relevant case records. Age of onset refers to the age when patients first experienced psychotic symptoms, DOI refers to the time period between first onset of illness and the time at which patients were enrolled in the study, and DUP refers to the time period from onset of psychotic symptoms to initiation of treatment. The Positive and Negative Symptoms Scale (PANSS; Kay et al., 1987) was used to assess the severity of clinical symptoms and it is a 30-item rating scale used to evaluate the severity of positive, negative (7-items each), and general psychopathology (16-items) symptoms on a 7point scale. Scores from individual items were added within each domain to obtain an overall rating score, with higher scores suggesting more severe psychopathology. Patients were classified as DSZ or NDSZ using the Proxy for the Deficit Syndrome criteria (PDS) based on PANSS (Kirkpatrick et al., 1993). The PDS is a proxy case identification method that has good specificity, sensitivity, and accuracy for identification of deficit patients (Kirkpatrick et al., 1993). It has been shown to be a valid tool for the categorization of patients with schizophrenia into deficit and non-deficit groups (Goetz et al., 2007). The PDS is defined as the sum of the scores (from the PANSS) of the anxiety, guilt feelings, depressive mood, and hostility items subtracted from the blunted affect item score. PDS index score = PANSS items blunted affect (N1) – [anxiety (G2) + guilt feelings (G3) + depression (G6) + hostility (P7)]. As with previous studies using the PDS (Kirkpatrick et al., 1993; Voineskos et al., 2013), an index cut-off point of -2 was used to classify deficit versus non-deficit patients. To ensure the stability of the diagnosis, the negative symptoms have to be present for at least a year (Fenton and McGlashan, 1994).
6
Quality of life was assessed using the World Health Organization Quality of Life – Brief Form (WHOQOL-BREF, The WHOQOL Group, 1998). The WHOQOL-BREF is a 26-item, 5point self-rated questionnaire. It assesses subjective QOL in four domains, namely Physical Health (7-items), Psychological Health (6-items), Social Relationships (3 items), Environment (8-items) and the 2 remaining items assess perception of overall QOL and overall health satisfaction. After reversed-scoring for some items, items within each domain were added up to obtain domain scores. Higher scores indicate better subjective QOL. Total QOL was calculated by summing up ratings on all 26-items from WHOQOL-BREF, taking into account the items where scorings needed to be reversed. Participants were assessed on neurocognitive functioning using the Brief Assessment of Cognition in Schizophrenia (BACS; Keefe et al., 2004). It comprises of a brief battery of tests that takes approximately 30 minutes to complete and consists of six subtests, namely, List Learning, Digit Sequencing Task, Token Motor task, Semantic and Letter Fluency, Symbol Coding, and Tower of London, which assess verbal memory, working memory, motor speed, verbal fluency, attention, and executive functioning respectively. Pre-morbid intelligence was estimated using the Wide Range Achievement Test (WRAT) Reading Test, 3rd edition (Wilkinson, 1993).
2.3 Statistical Analysis Socio-demographic and clinical characteristics of all three groups were compared using one way analysis of variance analyses (ANOVA), chi-square test, and independent samples t-test, as appropriate. Univariate ANCOVA controlling for marital and employment status was used to compare differences in QOL, while a univariate ANCOVA controlling for years of education, and premorbid IQ assessed using the WRAT Reading Test was used to compare the differences 7
in cognitive functioning between all three groups. Further analyses, using general linear model, were conducted to test for differences in QOL and neurocognitive functioning between the two patient groups, additionally controlling for duration of illness, GAF scores and CPZ (chlorpromazine) equivalents for QOL and neurocognitive functioning. Correlations between the PDS index scores and QOL and BACS scores were also conducted. Multiple linear regression analysis was used to examine predictors of total QOL and overall neurocognitive functioning. Specifically, for total QOL as outcome, schizophrenia subtype, age, gender, years of education, employment status, marital status, illness duration, and CPZ equivalent were entered into the regression model as predictors. For overall neurocognitive functioning as outcome, schizophrenia subtype, age, gender, years of education, premorbid intelligence, illness duration and CPZ equivalent were entered into the regression model as predictors. All analyses were conducted using the SPSS version 23.0 (IBM Corp, Armonk, New York). To take into account the different QOL and neurocognitive domains, the corrected statistical significance was set a priori at an alpha of 0.01 (two tailed) for QOL and 0.005 (two tailed) for neurocognitive functioning. Statistical significance for all other analyses required two tailed p<0.05.
8
3.
Results All three groups of participants did not differ significantly in terms of age and gender (see
Table 1). Patients tended to have fewer years of education and were more likely to be single and unemployed compared with healthy controls. The patient groups did not differ significantly on clinical variables (age of first onset, DOI and DUP), as well as their daily antipsychotic dose in daily CPZ mg equivalents. The same pattern of baseline findings was found in the subset with 199 participants who completed neurocognitive assessments. Comparison of WRAT III scores using a one way ANOVA found a significant difference between all three groups (p<0.05), however, post-hoc analysis using Bonferroni adjustment revealed that the difference only lies between healthy controls and the deficit syndrome group (p<0.05), and there was no significant difference in estimated premorbid IQ between the two patient groups. For QOL (see Figure 1 and Table 2), comparisons across all three subject groups (N=344) using ANCOVA, controlling for marital and employment status, found significant difference in most QOL domains and total QOL, with healthy controls having the highest ratings. Both DSZ and NDSZ scored lower in QOL compared with healthy controls (Figure 1). Of note, further analysis controlling for marital status, employment status, antipsychotic dose (CPZ equivalents), and duration of illness did not find differences in QOL ratings between deficit and non-deficit syndrome schizophrenia patients on all four QOL domains, suggesting comparable impact on QOL for both DSZ and NDSZ. Regarding neurocognitive functioning (see Table 3), comparisons across the three subject groups using ANCOVA and controlling for years of education and estimated premorbid IQ found significant differences between the three groups on all domains except motor speed, letter fluency and executive functioning. Compared with healthy controls, DSZ performed poorer in 9
more extensive neurocognitive domains compared with NDSZ (Table 3). Further analyses controlling for years of education, estimated premorbid IQ, age, gender, duration of illness, antipsychotic dose, and level of psychosocial functioning (GAF scores) found that DSZ scored worse than NDSZ in semantic fluency (p<0.005). Correlating PDS index score as a continuous variable with the clinical outcomes, there was no significant correlation between PDS index score and total QOL and subdomain scores. Negative correlation was found between PDS index score and verbal memory total (p=0.011), digit sequencing (p=0.011), semantic verbal fluency (p=0.004), symbol coding (p=0.049), and BACS composite z score (p=0.029). Multiple linear regression analysis on the clinical sample found that DSZ and shorter illness duration predicted lower total QOL and fewer years of education and lower estimated premorbid IQ predicted poorer overall cognitive functioning using total BACS scores (see Table 4).
10
4. Discussion There were several main findings in this study. First, DSZ and NDSZ were found to have poorer QOL in all domains as well as total QOL compared with healthy controls. Amongst the patients, both DSZ and NDSZ had comparable poorer QOL ratings on all domains. Second, compared to healthy controls, DSZ had more extensive neurocognitive deficits than NDSZ. Compared with NDSZ, DSZ was found to perform significantly worse on the semantic fluency task. Finally, we found that DSZ and shorter illness duration were associated with lower overall QOL and fewer years of education and lower premorbid intelligence were associated with poorer neurocognitive functioning. Whilst the entire patient group scored lower on the four QOL domains (physical, psychological, social relationships, and environment), as well as total QOL compared to healthy controls, both patient groups (DSZ and NDSZ) were found to be similarly affected in their subjective QOL. This finding was consistent with that of an earlier study (Delamillieure et al. 2005), in which no difference was observed in subjective QOL between patients with deficit syndrome and those without. The difference in the pattern of QOL findings in our study compared to a previous study (Tek et al., 2001) which found lower QOL in DSZ versus NDSZ could be related to the nature of rating tool which highlights discrepancies between subjective and objective measures of perceived health status both of which are still valid from varying perspectives of patient and treating clinician (Hayhurst et al., 2014). In an earlier study, Gourevitch et al. (2004) examined the relationship between deficit symptoms and QOL, found that while DSZ had poorer QOL compared with NDSZ, the difference depended on the QOL rating measures used. Specific QOL items in the Quality of Life Scale (QLS) (Heinrichs et al., 1984) known as more “psychopathological” items such as related to intrapsychic functions were 11
the most discriminating between the 2 groups. Conversely, “behavioral” items, which are more independent of symptoms, show less difference between DSZ and NDSZ. Furthermore, selfrated QOL was not rated differently between the 2 patient groups. We observed negative correlations between PDS index score and cognitive domains including verbal memory, digit sequencing, symbol coding and semantic fluency. Compared with healthy controls, DSZ had greater extent of neurocognitive deficits than NDSZ which is consistent with findings of other studies (Bora et al., 2017; Réthelyi et al., 2012). Réthelyi et al. (2012) found that DSZ was a function of global and domain specific
neurocognitive deficits including
attention, working memory, verbal memory, cognitive flexibility and ideation fluency, and that DSZ suffered from more severe neurocognitive impairments compared with NDSZ. In a recent meta-analysis by Bora et al. (2017) reported that whilst DSZ and NDSZ were associated with neurocognitive deficits in multiple domains, DSZ were found with more severe neurocognitive deficits than NDSZ. In addition, DSZ performed significantly poorer on semantic fluency compared with NDSZ. Of note, Cascella et al. (2008) found that DSZ performed worse than NDSZ in several cognitive domains examined (attention, psychomotor speed, executive function, verbal fluency, visual memory, and verbal memory), with only verbal fluency reaching statistical significance. Henry and Crawford (2005) found in their meta-analytic review of 84 studies that schizophrenia patients, in comparison with healthy controls, showed greater impairment in semantic fluency compared to phonetic fluency, and suggested that schizophrenia is a condition associated with compromise in reserve in the semantic domain. In a study by Sumiyoshi and colleagues (2005), an association between alogia and semantic memory disorganization (assessed using category fluency task) was also observed. Our finding of more severe semantic fluency impairment in DSZ may underlie the poverty of speech observed in DSZ, and which reflects a breakdown in the semantic organisation. 12
DSZ was found to predict poorer QOL, this is consistent with previous findings, in which patients with more severe psychopathology including negative symptoms had poorer QOL (Brissos et al., 2008). Shorter duration of illness was also found to predict poorer QOL, which was in contrast to the findings of Hsiao et al. (2011), who found that patients with longer duration of illness had lower perceived QOL, although they did not find illness duration to be a predictor of QOL in their multivariate regression analysis. Consistent with our findings, Larsen and Gerlach (1996) found that patients with chronic schizophrenia reported better QOL, suggesting that patients with longer illness duration may have learned to accept and cope with their illness over time, hence scoring higher in their self-rated QOL. In terms of neurocognitive functioning, we found that fewer years of education, as well as lower estimated premorbid IQ predicted worse overall neurocognitive functioning. Previous studies of the inter-relationship between education, cognitive performance albeit involving older non-patient population found that better neurocognitive functioning or slower cognitive decline was associated with more years of education (Le Carret et al., 2003; Portin et al., 1995; Evans et al., 1993), which supports our current finding. What are the clinical implications? First, the poor QOL associated with DSZ behoves greater attention and monitoring by the multidisciplinary team during clinical assessment and treatment planning for this subgroup of patients with SZ. Second, whilst semantic fluency performance is thought to be stable in schizophrenia, it is also associated with recovery from the illness thus making it a possible target for cognitive remediation (Kopelowicz et al., 2005; Szoke et al., 2009). There is preliminary evidence that cognitive remediation may improve verbal fluency, verbal learning and processing speed in schizophrenia and future studies are warranted to evaluate domain specific neurocognitive changes over time following treatment modalities such as cognitive remediation therapy (Sartory et al., 2005). This study had several limitations. As this 13
was a cross-sectional study, a longitudinal study in DSZ to observe the changes in QOL and neurocognitive functioning with treatment is warranted. Second, the inclusion of both subjective and objective measures of QOL and additional neurocognitive testing would allow better elucidation of the inter-related nature of these measures within our subjects. Third, the neurocognitive findings in a smaller subject subset who completed the relevant assessments need to be replicated in other populations. In conclusion, our findings of DSZ being associated with poor QOL, more extensive neurocognitive impairments especially more severe semantic fluency highlight the need for further research to elucidate the malleability of associated clinical factors to earlier intervention and the effectiveness of different pharmacological and psychosocial approaches in the treatment of DSZ and associated neurocognitive findings.
Acknowledgements The authors would like to thank all participants, their families and the clinical staff for their support of this study. Funding This study was supported by the National Healthcare Group, Singapore [SIG/05004]; and the ASTAR [RP C-009/2006] research grants awarded to K.S. Role of funding source The identified funding sources had no role in the study design; collection, analysis and interpretation of the data; writing of report; and the decision to submit the paper for publication.
14
Disclosure of interest The authors declare that they have no competing interest.
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The WHOQOL Group., 1998. Development of the World Health Organization WHOQOL-BREF quality of life assessment. Psychol. Med. 28, 551-558. Wilkinson, G., 1993. The Wide Range Achievement Test 3-administration manual, third ed. Jastack Associated Inc, Wilmington, Delaware.
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*
**
*
**
*
**
**
*
** **
Figure 1. Comparison of Quality of Life Scores across All Groups Abbreviations: NDSZ, Non-Deficit Schizophrenia; DSZ, Deficit Schizophrenia *p<0.005, **p<0.001
21
Figure 1. Comparison of Quality of Life Scores across All Groups Abbreviations: NDSZ, Non-Deficit Schizophrenia; DSZ, Deficit Schizophrenia *p<0.005, **p<0.001
Table 1. Clinical and demographic features of entire sample (N=344) Controlsa (n = 111)
Non-deficit SZa
Deficit SZa
Between-group differences
(n = 58)
Test statistic
p
(n = 175) 32.17 (9.382)
32.58 (9.350)
34.24 (9.253)
F = 0.979
0.377
Male
68 (61.3)
111 (63.4)
37 (63.8)
2 = 0.167
0.920
Female
43 (38.7)
64 (36.6)
21 (36.2)
14.23 (2.004)
11.54 (2.550)
11.17 (2.341)
F = 53.359
<0.001
Age at onset of illness
-
26.03 (7.828)
26.22 (6.911)
t = -0.170
0.865
Duration of untreated psychosis (years)
-
1.50 (2.272)
1.65 (2.314)
t = -0.445
0.657
Illness duration (years)
-
6.57 (7.511)
8.02 (8.317)
t = -1.239
0.217
Antipsychotic dose in daily CPZ mg equivalents
-
210.23 (179.705)
244.40 (201.096)
t = -1.218
0.225
2 = 144.278
<0.001
Age
Sex (%)
Years of education
Employment status (%)
6 (5.4)
114 (65.1)
44 (75.9)
Unemploy
22
ed Employed
102 (91.9)
46 (26.3)
9 (15.5)
3 (2.7)
15 (8.6)
5 (8.6)
Others Marital status (%) Single
69 (62.2)
148 (84.6)
52 (89.7)
Married
41 (36.9)
20 (11.4)
4 (6.9)
1 (0.9)
7 (4.0)
2 (3.4)
10.800 (3.695)
11.207 (4.158)
8.091 (2.110)
12.897 (4.167)
20.726 (4.001)
20.810 (3.701)
39.617 (7.925)
44.914 (9.329)
49.67 (17.923)
46.88 (14.495)
52.49 (19.112)
49.64 (16.438)
51.40 (17.725)
47.02 (15.413)
Divorced/
2 = 36.551
<0.001
t = -0.704
0.482
t = -8.433
<0.001
t = -0.142
0.887
t = -4.215
<0.001
t = 1.196
0.234
t = 1.019
0.309
t = 1.681
0.094
Widowed PANSS
-
Positive Negative General psychopathology Total
GAF Total Symptoms Disability
-
Abbreviations: CPZ, Chlorpromazine; PANSS, Positive and Negative Syndrome Scale; GAF, Global Assessment of Functioning a
All values are mean (SD) unless otherwise stated
23
Table 2. Comparison of Quality of Life scores across the three subject groups Healthy controls (n=111)
ANCOVAa
ANCOV Ab NDSZ vs. DSZ F p
NDSZ (n=175)
DSZ (n=58)
15.60 (1.59)
13.89 (2.70)
13.12 (2.35)
12. <0.0 40 01*
18. 299
<0.0 01*
25. 002
<0.0 01*
2.9 69
0.0 86
Domain 2 Psychological
14.92 (1.70)
13.22 (3.21)
12.51 (2.59)
7.1 <0.0 2 1*
10. 300
<0.0 05*
12. 583
<0.0 05*
0.1 94
0.6 60
Domain 3 Social Relationships
15.23 (2.20)
13.10 (3.31)
12.16 (3.38)
9.4 <0.0 8 01*
14. 459
<0.0 01*
10. 175
<0.0 05*
0.1 44
0.7 05
Domain 4 Environment
15.13 (1.70)
13.51 (2.79)
12.67 (2.92)
9.3 <0.0 0 01*
11. 822
<0.0 05*
18. 599
<0.0 01*
1.1 38
0.2 87
QOL 1 Overall perception of QOL
3.92 (0.59)
3.43 (0.99)
3.26 (1.02)
4.1 0.01 0 7
7.8 08
<0.0 1*
2.8 32
0.09 4
0.3 44
0.5 58
QOL 2 Overall health satisfaction
3.81 (0.67)
3.46 (1.03)
3.31 (1.22)
3.2 0.03 7 9
5.4 18
0.02 1
3.9 27
0.0 90
0.7 65
99.05 (9.12)
88.20 (16.53)
82.72 (15.67)
12. <0.0 19 01*
16. 719
<0.0 01*
22. 883
0.04 9 < 0.00 1*
0.9 88
0.3 21
Domain 1 Physical Health
Total QOL
All Groups F p
HC vs. NDSZ F p
HC vs. DSZ F p
Abbreviations: NDSZ, Non-Deficit Schizophrenia; DSZ, Deficit Schizophrenia a ANCOVA model controlled for marital status and occupational status b ANCOVA model controlled for marital status, occupational status, CPZ equivalent, and duration of illness
Table 3. Comparison of neurocognitive functioning across the three subject groups
Verbal Memory
Healthy controls (n=67)
NonDeficit (n=104)
Deficit (n=27)
47.35 (9.312)
38.15 (11.182)
31.74 (11.568)
ANCOVAa All Groups F p 14. <0. 40 001 7 *
HC vs. NDSZ F p 16. <0. 61 001 9 *
HC vs. DSZ F p 23. <0.0 04 01* 6
ANCOV Ab NDSZ vs. DSZ F p 4. 0.02 86 9 8 24
Digit Sequencing Tokens Correct Semantic Fluency Letter Fluency Verbal Fluency Total Symbol Coding Tower of London
21.07 (3.461)
18.73 (4.518)
16.33 (4.481)
7.5 91
76.25 (13.493)
69.00 (58.376)
60.52 (12.439)
1.2 24
<0. 005 * 0.29 6
24.90 (6.071)
19.66 (5.772)
15.78 (5.853)
27.90 (8.070)
23.57 (8.576)
22.33 (8.718)
16. 40 6 2.1 73
<0. 001 * 0.11 7
52.79 (12.095)
43.23 (12.151)
38.11 (11.762)
8.8 62
63.84 (10.456)
48.78 (12.015)
44.30 (11.472)
17.66 (2.422)
16.28 (4.008)
16.46 (4.052)
34. 41 2 0.6 55
4.6 64
0.03 2
0.6 68
0.41 5
13. 85 7
<0. 001 *
19. 50 8 17. 79 4 25. 79 9
3.0 28
0.08 4
2.9 72
<0. 001 9.3 * 08 <0. 55. 001 51 * 7 0.52 1.7 0 90
<0. 003 * <0. 001 *
14. 29 6 47. 92 3
0.18 3
0.3 28
<0.0 01* <0.0 01* <0.0 01* 0.08 8 <0.0 01* < 0.00 1* 0.56 8
2. 80 1 0. 29 6 8. 91 9 0. 01 3 2. 26 7 1. 52 6 0. 33 0
0.09 7 0.58 8 <0. 005 * 0.91 1 0.13 5 0.21 9 0.56 7
15. <0. 56. < 1. 0.16 13. <0. 02 001 38 0.00 95 4 91 001 8 * 1 1* 8 5 * BACS -0.02 (0.982) -1.64 -2.33 32. <0. 44. <0. 57. <0.0 3. 0.08 Composite z (1.297) (1.174) 34 001 01 001 40 01* 08 2 score 5 7 * 2 * 3 Abbreviations: NDSZ, Non-Deficit Schizophrenia; DSZ, Deficit Schizophrenia a ANCOVA model controlled for years of education, estimated premorbid IQ, age, and gender b ANCOVA model controlled for years of education, estimated premorbid IQ, age, gender, duration of illness, CPZ equivalent, and GAF (total, symptoms, disability) BACS total
278.79 (30.969)
233.17 (67.740)
206.85 (38.361)
Table 4. Linear regression analyses showing significant factors associated with total Quality of Life scores and Neurocognitive Functioning in patients Explanatory variables Standardised B coefficient t p-value Total Quality of Life Schizophrenia subtype*
-0.175
-2.53
0.012
Age
0.104
1.19
0.236
Gender
-0.055
-0.80
0.426
Years of education
0.028
0.41
0.684
Employment status
0.040
0.51
0.609 25
Marital status
0.079
1.13
0.259
Illness duration*
0.419
2.98
0.003
CPZ equivalent
-0.039
-0.58
0.584
Schizophrenia subtype
-0.152
-1.70
0.093
Age
-0.016
-0.18
0.861
Gender
0.163
1.82
0.071
Years of education*
0.291
3.07
0.003
Premorbid intelligence
0.250
2.64
0.010
Illness duration
-0.145
-1.63
0.107
CPZ equivalent
-0.123
-1.37
0.174
Neurocognitive Functioning
(WRAT III)*
Abbreviations: CPZ, chlorpromazine; WRAT III, Wide Range Achievement Test 3rd Ed Reading Subtest * p < .05
Highlights
Differences in outcomes were examined between deficit (DSZ) and non-deficit schizophrenia Both DSZ and NDSZ had significantly worse QOL compared with healthy controls Deficit group performed worse on semantic fluency compared to non-deficit patients The poorer QOL, greater extent of neurocognitive deficits associated with DSZ behoves the need for greater clinical attention
26