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Is perseveration uniquely characteristic of schizophrenia?
Schizophrenia Research 118 (2010) 128–133
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Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Is perseveration uniquely characteristic of schizophrenia? Rachel N. Waford a,⁎, Richard Lewine b a b
University of Louisville, 1st Street and Cardinal Boulevard, Life Sciences Building, Rm 317B, Louisville, KY 40204, USA University of Louisville, 1st Street and Cardinal Boulevard, Life Sciences Building, Rm 343, Louisville, KY 40204, USA
a r t i c l e
i n f o
Article history: Received 16 July 2009 Received in revised form 21 January 2010 Accepted 29 January 2010 Available online 3 March 2010 Keywords: Schizophrenia WCST Perseveration Executive function
a b s t r a c t Evidence for the existence of categorically distinct disorders such as schizophrenia, bipolar disorder, and major depression is mixed: neuropsychological impairments may be similar in schizophrenia and bipolar disorder; schizophrenia and major depression show similar neuropsychological and frontal lobe disturbances; and overlap in biochemical anomalies among the disorders has also been reported. Interestingly, there are very few studies that directly compare all diagnoses. The present study compares cognitive perseveration in these three diagnostic groups using the Wisconsin Card Sorting Task (WCST) to examine performance across patients with schizophrenia (n = 143), bipolar disorder (n = 25) and major depression (n = 21). Individuals used in this sample were 18–45 years old at time of testing to eliminate confounds of aging. Sex ratios within each diagnostic group are comparable to those of the national population. Univariate analyses examining diagnostic group and percent perseverative error revealed no significant differences in WCST performance across the diagnostic groups. Examination of clinical variables in the sample of individuals with schizophrenia revealed that perseveration is related to negative symptoms and depressive symptoms in young adults. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Individuals with schizophrenia experience a host of different symptoms that can impact daily functioning. Cognitive impairments are particularly important because such deficits are trait-like, core features of the disorder and may show more robust relationships with functional outcome than negative or positive symptoms alone (Tuulio-Henriksson, 2004; Elvevag and Goldberg, 2000; Addington and Addington, 1999). Cognitive impairments are often pervasive and present before the onset of any other symptoms (TuulioHenriksson, 2004), and are associated with social problem solving, skill acquisition, and community outcome (Koren et al., 2006; Tuulio-Henriksson, 2004).
⁎ Corresponding author. Tel.: +1 270 303 6973, +1 502 852 3955 (office); fax: +1 502 852 8904. E-mail addresses: [email protected] (R.N. Waford), [email protected] (R. Lewine). 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.01.031
Cognitive flexibility describes the ability to organize and restructure knowledge based on an evaluation of situational demands. Perseveration, a measure of cognitive flexibility impairment and an element of executive function, characterizes behaviors that are unintentionally repeated in the presence of feedback indicating the response is incorrect or inappropriate, despite situations in which novel responses are required. Perseveration is a consistently replicated deficit in schizophrenia and therefore warrants continued examination in an attempt to understand the characteristics of this deficit in schizophrenia and other psychiatric disorders. The Wisconsin Card Sorting Task (WCST; Heaton et al., 1993) has been widely used to assess executive function in a variety of psychiatric (especially schizophrenia) and neurologic samples via measures of set-shifting ability, conceptual reasoning, response inhibition, and goal-directed searching and planning. In particular, WCST Percent Perseverative Error (PPE) is consistently greater in schizophrenia patients than in individuals with schizoaffective disorder (Szoke et al., 2008), individuals with psychosis (Reed et al., 2002), and healthy controls (see
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Appendix A) (Morice, 1990; Perry and Braff, 1998; Rossi et al., 2000; Saoud et al., 2000; Keri et al., 2001; Liu et al., 2003; Szoke et al., 2008). Moreover, Liu et al. (2003) and Saoud et al. (2000) provided evidence for perseveration as a biomarker of schizophrenia: unaffected siblings of those with the disorder committed significantly more perseveration errors on the WCST than healthy controls, (unaffected siblings of individuals with schizophrenia=22.8, healthy controls=14.8; unaffected siblings of individuals with schizophrenia = 42.24, healthy controls=28.16, respectively). It is not clear, however, how unique perseveration is among psychiatric disorders. Evidence for the existence of categorically distinct disorders such as schizophrenia, bipolar disorder, and major depression is mixed: neuropsychological (Schretlen et al., 2007; Dickerson et al., 2004), and cognitive and social (Dickerson et al., 2001) impairments may be similar in schizophrenia and bipolar disorder; schizophrenia and major depression show similar neuropsychological and frontal lobe disturbances (Franke et al., 1993); overlap in biochemical anomalies among the disorders has been reported (Cotter et al., 2005; Torrey et al., 2005); and insight appears to exist on a continuum across the three disorders (Yen et al., 2008). Interestingly, there are very few studies that directly compare all diagnoses, particularly with regard to measures of neuropsychological functioning. At best, the literature supports a continuum of schizophrenia, schizoaffective, and affective disorders (Szoke et al., 2008), but few studies directly compare schizophrenia, bipolar disorder, and major depression on measures of executive function (Brown et al., 2008; Rempfer et al., 2006; Mojtabai et al., 2000). A form of perseveration, rumination, does occur in affective disorders, specifically major depression and is described as focusing perseveratively about one's own thoughts and problems (NolenHoeksema et al., 2008). In fact, rumination was identified as the “form most strongly and consistently related to depressive symptoms” (Nolen-Hoeksema et al., 2008, p. 400). Originally developed to “assess abstract reasoning ability and the ability to shift cognitive strategies in response to changing environmental contingencies,” (Heaton et al., 1993, p. 1) the WCST is a valuable tool to assess cognitive inflexibility, specifically perseveration, as it is an impairment directly related to poor community outcome and poor social and occupational functioning in individuals with schizophrenia (Addington and Addington, 1999; Green, 1996; Lysaker et al., 2005). Examining perseveration across these three diagnostic groups will provide additional evidence that addresses whether perseveration is a characteristic unique to schizophrenia or is common to other psychiatric disorders as well. It was hypothesized that WCST PPE, at clinically impaired levels, would be significantly greater and occur more often in schizophrenia than in individuals with bipolar disorder and major depression. In addition, we expected strong associations between perseveration and core clinical symptoms of schizophrenia. 2. Methods 2.1. Participants The data for the present study were taken from a larger database consisting of 664 patients recruited or referred to participate in an investigation of sex differences in neuro-
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psychological functioning (see Lewine et al., 1996 for full recruitment procedure; Thurston-Snoha and Lewine, 2007). The present study examined perseveration in individuals with schizophrenia (N = 143), bipolar disorder, (N = 25) and major depression (N = 21). Only individuals with complete neuropsychological data and clinical data (for the schizophrenia group only) were retained for this study. Furthermore, individuals N45 years of age were excluded to control for aging effects. Finally, only individuals with complete WCST and clinical data (for schizophrenia patients only) were retained, yielding a final full sample size of 189 patients. 2.2. Procedure Participation included a 13-hour neuropsychological battery completed over the course of several sessions, an MRI, and a battery of clinical measures (for schizophrenia patients only). For the schizophrenia patients only, the range of sample sizes for the clinical measures was 82–143. Missing data occurred largely due to fatigue and missed appointments. 2.3. Measures 2.3.1. Clinical assessment The Schedule for Affective Disorders and SchizophreniaLifetime Version (SADS-L; Spitzer and Endicott, 1975) was administered to determine psychiatric diagnoses. SADS-L scores and a weekly consensus diagnostic meeting were used to determine final diagnoses. Patients in the schizophrenia study completed a large battery of clinical assessments including the Andreasen's Scale for Assessment for Negative Symptoms (SANS; Andreasen, 1983), Andreasen's Scale for Assessment for Positive Symptoms (SAPS; Andreasen, 1984), Hamilton Depression Rating Scale (HDRS; Hamilton, 1960), Beck Depression Inventory (BDI; Beck et al., 1961), and Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962). 2.3.2. Neuropsychological assessment For a complete list of neuropsychological assessments administered in the larger study, see Lewine et al., 1996. The focus of the current study is performance on the WCST, the measure chosen to evaluate perseveration. The data were collected using the card version of the assessment. Because our interest is in perseveration, we chose to focus on PPE because of its direct measure of the phenomenon, its frequent use in the field as a measure of perseveration, and its frequent use and replication in schizophrenia research. 2.4. Analyses The first set of analyses examined perseveration across the three diagnostic groups. A one-way ANOVA was conducted for PPE for the three groups (independent variable) to examine a cross-diagnosis comparison of perseveration. Participants within each diagnostic group were then classified as either clinically impaired or not impaired using the clinical metric identified by Heaton et al. (1993, p. 31). Individuals with PPE Standard Scores ranging from ≤54 to 84 were classified as impaired while those with Standard Scores ranging from 85 to ≥107 were classified as not impaired. The
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relationship between age at time of test and impairment yielded an r = 0.008, p = 0.954, confirming our use of a restricted age range to eliminate possible age confounds. Chisquare analyses were completed to examine the distribution of impairment across the three diagnostic groups. The second set of analyses examining perseveration and clinical symptoms in schizophrenia involved several 2 × 2 univariate ANOVAs examining impairment (impaired, not impaired) and age at first hospitalization (≤21 years of age, ≥ 22 years of age), sex (male, female), and education (≤12 years of school, ≥ 13 years of school) with measures of positive symptoms, negative symptoms, depression, anhedonia, and psychosis. Traditionally, a MANOVA would have been used for this data but because of missing data, univariate ANOVAs were run to fully explore each variable. Sex, age at first hospitalization, and education were included in the ANOVAs to examine mediating effects of schizophrenia dysfunction previously cited in the literature (Hochman and Lewine, 2004; Lewine, 2004; Lewine et al., 1997; Liu et al., 2003; McEvoy et al., 2006). 3. Results
Table 1 Means and standard deviations for sociodemographics for each diagnostic group.
Age Age at first hospitalization* Duration of illness Years Of education** GAF Sex* Male Female Total Race White Black Oriental Hispanic Missing Total
Schizophrenia
Bipolar disorder
Major depression
31.64 years (6.71) 21.48 (5.70)
34.44 years (6.71) 26.57 (7.39)
33.86 years (6.97) 26.85 (7.49)
9.98 years (6.55) 12.87 years (2.02) 47.12 (12.62)
7.48 years (6.58) 14.11 years (2.40)
6.80 years (9.69) 14.43 years (3.14)
110 33 143
13 12 25
3 18 21
111 31 0 0 1 142
22 0 0 0 3 22
17 4 0 0 0 21
* pb0.001; ** pb0.01.
3.1. Diagnostic comparisons Descriptive analyses were conducted for diagnostic group and sex, race, age at first hospitalization, age at time of assessment, years of education, and illness duration. Subsequent univariate analyses revealed differences across diagnoses with regard to sex, F(2186) = 21.224, p b 0.001, age at first hospitalization, F(2181) = 11.96, p b 0.001, and years of education F(2179) = 6.315, p b 0. 01. ANCOVA analyses were then conducted for the three significant variables, covarying each one with diagnosis for PPE. The ANCOVAs were not significant for diagnosis and years of education, F(2178) = 0.844, p = 0.432, sex F(2185) = 1724, p = 0.181 or age at first hospitalization F(2180) = 1.155, p = 0.317. See Table 1 for means and standard deviations. Univariate ANOVAs were conducted to examine the effects of the diagnostic group on PPE. The effect of the diagnostic group on PPE approached a conventional level of statistical significance, F(2186) = 2.796, p = 0.064. The mean PPE for schizophrenia, bipolar, and depression were 21.60%, 16.03%, and 15.81%, respectively. Additional univariate analyses for the mean PPE conducted for the impaired individuals only in each group revealed no significant group differences, F(2,75) = 0.035, p = 0.966, with a mean PPE of 33.22% for schizophrenia, 33.54% for bipolar, and 34.82% for major depression. Though no mean differences emerged for the impaired individuals with regard to PPE, the distribution of impairment across diagnoses was significantly different, x2(2, N = 189) = 6.125, p b 0.05. 46.2% of individuals with schizophrenia were impaired, followed by 28% of bipolar patients, and 23.8% of individuals with major depression.
≥22 years of age), sex (male, female), and education (≤12 years of school, ≥13 years of school) were conducted for measures of positive symptoms, negative symptoms, anhedonia, depression, and psychosis. The factors were chosen due to earlier relationships with diagnostic group, support in the literature noted above, and age of first hospitalization, particularly, as an index of illness severity. With one exception, see below, the only significant result was a main effect of impairment. There were no other main or interaction effects with sex, age at first hospitalization, and education. See Table 2 for means and standard deviations for each 2 × 2 ANOVA. For each 2 (impairment) × 2 (sex), 2 (education), and 2 (age at first hospitalization) ANOVA, there were significant effects of impairment on PPE for SANS total score: F(1, 104) = 6.383, p b 0.05, F(1, 104) = 6.631, p b 0.05, and F(1, 103) = 9.704, p b 0.01, respectively. Subsequent post hoc testing was significant, t(110) = 2.868, p b 0.01, revealing that impaired individuals had higher SANS total scores than non-impaired individuals (mean = 10.27 and mean = 7.78, respectively). Finally, there was a significant interaction between impairment and age at first hospitalization for HDRS total score, F(1, 72) = 4.991, p b 0.05. Subsequent univariate post hoc analyses with a Bonferroni correction revealed that impaired individuals ≤21at first hospitalization (mean = 12.06) had significantly higher HDRS scores than non-impaired individuals ≤21 years old at first hospitalization, F(1, 72) = 8.687, p b 0.01. Means for non-impaired and ≤21, impaired and ≥22, and non-impaired and ≥22 were 5.88, 7.40, and 8.21, respectively. There was no main effect of impairment for HDRS.
3.2. Clinical comparisons for schizophrenia sample
4. Discussion
In an effort to further examine the role of perseveration in schizophrenia, 2×2 ANOVAs examining impairment (impaired, not impaired) and age at first hospitalization (≤21 years of age,
Although perseveration has been historically associated with schizophrenia, few studies have compared perseveration in schizophrenia with other psychiatric disorders, in particular
R.N. Waford, R. Lewine / Schizophrenia Research 118 (2010) 128–133 Table 2 Means and standard deviations for sociodemographics for each diagnostic group. Assessment Impairment and sex SAPS Impaired, male Not impaired, male Impaired, female Not impaired, female SANS* Impaired, male Not impaired, male Impaired, female Not impaired, female HDRS Impaired, male Not impaired, male Impaired, female Not impaired, female BDI Impaired, male Not impaired, male Impaired, female Not impaired, female BPRS Impaired, male Not impaired, male Impaired, female Not impaired, female Anhedonia-social Impaired, male Not impaired, male Impaired, female Not impaired, female Anhedonia-physical Impaired, male Not impaired, male Impaired, female Not impaired, female
Mean
Standard deviation
6.53 4.74 5.30 6.14
4.55 3.65 2.83 4.38
10.36 7.79 10.64 7.87
5.16 3.95 5.35 4.60
8.91 6.82 11.08 7.22
6.19 7.31 8.55 4.44
14.94 11.22 11.44 11.70
11.52 9.76 12.02 10.75
40.35 35.70 32.82 30.50
15.55 12.92 11.32 9.47
17.43 13.97 10.89 14.82
13.04 8.03 5.78 8.88
11.62 10.82 10.78 10.91
4.76 5.85 6.18 6.36
Impairment and age at first hospitalization SAPS Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 SANS ** Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 HDRS Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 BDI Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 BPRS Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 Anhedonia-social Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22
7.27 4.71 5.21 5.54
4.65 3.49 3.16 4.27
10.50 8.37 10.67 7.21
5.64 4.18 4.37 3.97
12.06* 5.87 7.40 8.21
8.11 4.67 4.41 8.71
15.70 11.54 13.26 11.09
12.44 9.92 10.60 10.01
39.16 34.82 35.50 35.35
15.48 10.57 10.64 14.61
17.84 15.83 14.11 12.38
16.11 7.60 6.19 8.54
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Table 2 (continued) Assessment Anhedonia-physical Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22
Mean
Standard deviation
10.33 11.87 12.21 9.71
5.30 4.92 4.79 6.77
6.32 5.46 6.17 4.82
4.09 3.83 4.57 3.90
11.40 8.32 8.95 7.42
4.97 3.63 5.19 4.42
7.94 5.73 11.41 8.14
6.52 4.75 7.34 8.33
13.77 10.85 14.61 11.7
11.96 9.83 11.40 10.05
35.43 36.44 39.36 33.89
13.80 10.06 15.05 14.62
17.00 13.80 14.38 14.50
14.77 8.40 6.49 8.11
11.68 10.35 11.06 11.25
4.90 5.50 5.40 6.31
Impairment and education SAPS Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years SANS* Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years HDRS Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years BDI Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years BPRS Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years Anhedonia-social Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years Anhedonia-physical Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years * pb0.001; ** pb0.01.
major depression and bipolar disorder (Liu et al., 2003; Reed et al., 2002; Keri et al., 2001; Perry and Braff, 1998; Cuesta et al., 1995). This comparison is critical as it speaks directly to the issue of specificity of perseveration in schizophrenia. Rempfer et al. (2006) is one of the few to compare these three groups, with a study addressing learning potential and proficiency on the WCST. When using WCST performance and learning proficiency to classify individuals as “high achievers,” “learners,” and “nonretainers,” Rempfer et al. (2006) found no significant association between learner status and diagnostic group. Moreover, diagnostic group was not significantly related to any additional measures of cognitive functioning. While our results confirm previous research taking rates of clinical levels of perseveration into account, they also reveal that perseveration is not unique to schizophrenia. Individuals with bipolar disorder and major depression are, when perseverative, as perseverative as individuals with schizophrenia. These findings are consistent with Rempfer et al.'s (2006) finding indicating little difference in measures of cognitive functioning between individuals with schizophrenia, bipolar
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disorder, and major depression. In short, while perseveration appears to be more prevalent in schizophrenia, when it does occur in bipolar disorder and major depression, virtually no difference in severity occurs between the groups. These findings are quite compelling when considering the paucity of research directly comparing executive function among these diagnostic groups. Additionally, our results are consistent with those studies of schizophrenia that report a link between impairment and clinical symptoms. Previous research has indicated that negative symptoms prevalent in schizophrenia are significantly related to measures of executive function (Faerden et al., 2009; O'Leary et al., 2000; Cuesta et al., 1995; Frith et al., 1991), and severity of cognitive impairment (Tuulio-Henriksson, 2004). The current findings upheld previous conclusions, in that ratings of negative symptoms were significantly, positively related to cognitive impairment as measured by perseveration and age at first hospitalization, sex, and years of education. Depressive symptoms are also prevalent in individuals with schizophrenia and associated with higher levels of dysfunction. The present study indicated that impairment and age at first hospitalization were significantly related to self-reported levels of depression and posits that age may be a moderator of the relationship between impairment and depressive symptoms. Specifically, impaired individuals ≤21 years old at their first hospitalization reported higher depression scores at the time of test. This is consistent with the idea that later onset of symptoms of schizophrenia is associated with better course and prognosis and therefore younger individuals may be more likely to experience greater depression related to the onset of their symptoms. This finding also supports research suggesting that subjective mood impacts performance, therefore individuals with schizophrenia may be experiencing more depressive symptoms related to their illness, thereby impacting WCST performance (Halari et al., 2006). The present study is not without its limitations. The sample size within the schizophrenia group was considerably larger than the sample sizes for the affective groups. Because of the nature of the study, there is a larger sample of individuals with schizophrenia, relative to all the diagnostic groups (see Lewine et al., 1996 for full recruitment procedures). However, the proportion of impairment within each diagnostic group revealed robust findings, with a greater proportion of individuals with schizophrenia being impaired relative to the rest of their diagnostic group. The large difference in sample size may account for some of our results. Replication and further study is necessary to determine if these results will hold. Another limitation is the lack of complete clinical data for individuals with bipolar disorder and major depression. Due to study constraints, clinical data were only collected for individuals in the schizophrenia study. In addition, there is a selection bias in this study that contributes to what may be a more severe group of depressed and bipolar patients. Individuals in the database were recruited or referred due to the possibility of a schizophrenia diagnoses. Therefore, these individuals were experiencing some level of psychosis that brought them in touch with the study in one form or another. Moreover, examination of the schizophrenia scale
from the MMPI revealed no difference in level of psychosis between individuals with schizophrenia (81.02), bipolar disorder (76.71) and major depression (75.79), F(2164) = 1.122, p = 0.328. Again, replication and further study are warranted. The present study supports growing recognition of the importance of broad, dimensional dysfunctions that cut across traditional psychiatric diagnoses (Westen et al., 2002). It appears that perseveration is not specific to any disorder and may be more of a generic impairment that is not diagnostically useful. As Simonsen et al. (2009) suggested, both categories of function and the same brain areas, mechanisms, and pathways can be impaired across multiple disorders. Therefore, studying perseveration as a dimensional impairment may provide more information by allowing for the examination of questions such as why one should become perseverative with a range of psychiatric disorders. Is it an issue of limited cognitive resources, mental stiffness or a reduced range of behaviors? Approaching diagnosis and impairment dimensionally forces one to think outside the box and develop hypotheses that cut across diagnoses, especially as diagnostic assessment moves toward a continuum of impairment. Role of funding source The original study was funded by an NIMH MERIT Award, but the current analyses were not funded. Contributors Rachel Waford, as first author, conceptualized the hypothesis, conducted the data analysis, and prepared the manuscript. Richard Lewine supervised the data collection, coding and management, supervised data analysis, and oversaw all manuscript revisions. Conflict of interest There are no conflicts of interest for either author. Acknowledgments The collection of the original data was supported by an NIMH MERIT Award, (RL).
Appendix A Mean % perseverative errors for schizophrenia groups and healthy controls.
Morice (1990) Perry and Braff (1998) Rossi et al. (2000) Saoud et al. (2000) Keri et al. (2001) Liu et al. (2003) Szoke et al. (2008)
Schizophrenia
Healthy controls
34.7 43.6 17.54 48.6 22.0 25.8 26.8
15.5 13.5 8.81 28.16 10.0 14.8 9.7
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Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Is perseveration uniquely characteristic of schizophrenia? Rachel N. Waford a,⁎, Richard Lewine b a b
University of Louisville, 1st Street and Cardinal Boulevard, Life Sciences Building, Rm 317B, Louisville, KY 40204, USA University of Louisville, 1st Street and Cardinal Boulevard, Life Sciences Building, Rm 343, Louisville, KY 40204, USA
a r t i c l e
i n f o
Article history: Received 16 July 2009 Received in revised form 21 January 2010 Accepted 29 January 2010 Available online 3 March 2010 Keywords: Schizophrenia WCST Perseveration Executive function
a b s t r a c t Evidence for the existence of categorically distinct disorders such as schizophrenia, bipolar disorder, and major depression is mixed: neuropsychological impairments may be similar in schizophrenia and bipolar disorder; schizophrenia and major depression show similar neuropsychological and frontal lobe disturbances; and overlap in biochemical anomalies among the disorders has also been reported. Interestingly, there are very few studies that directly compare all diagnoses. The present study compares cognitive perseveration in these three diagnostic groups using the Wisconsin Card Sorting Task (WCST) to examine performance across patients with schizophrenia (n = 143), bipolar disorder (n = 25) and major depression (n = 21). Individuals used in this sample were 18–45 years old at time of testing to eliminate confounds of aging. Sex ratios within each diagnostic group are comparable to those of the national population. Univariate analyses examining diagnostic group and percent perseverative error revealed no significant differences in WCST performance across the diagnostic groups. Examination of clinical variables in the sample of individuals with schizophrenia revealed that perseveration is related to negative symptoms and depressive symptoms in young adults. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Individuals with schizophrenia experience a host of different symptoms that can impact daily functioning. Cognitive impairments are particularly important because such deficits are trait-like, core features of the disorder and may show more robust relationships with functional outcome than negative or positive symptoms alone (Tuulio-Henriksson, 2004; Elvevag and Goldberg, 2000; Addington and Addington, 1999). Cognitive impairments are often pervasive and present before the onset of any other symptoms (TuulioHenriksson, 2004), and are associated with social problem solving, skill acquisition, and community outcome (Koren et al., 2006; Tuulio-Henriksson, 2004).
⁎ Corresponding author. Tel.: +1 270 303 6973, +1 502 852 3955 (office); fax: +1 502 852 8904. E-mail addresses: [email protected] (R.N. Waford), [email protected] (R. Lewine). 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.01.031
Cognitive flexibility describes the ability to organize and restructure knowledge based on an evaluation of situational demands. Perseveration, a measure of cognitive flexibility impairment and an element of executive function, characterizes behaviors that are unintentionally repeated in the presence of feedback indicating the response is incorrect or inappropriate, despite situations in which novel responses are required. Perseveration is a consistently replicated deficit in schizophrenia and therefore warrants continued examination in an attempt to understand the characteristics of this deficit in schizophrenia and other psychiatric disorders. The Wisconsin Card Sorting Task (WCST; Heaton et al., 1993) has been widely used to assess executive function in a variety of psychiatric (especially schizophrenia) and neurologic samples via measures of set-shifting ability, conceptual reasoning, response inhibition, and goal-directed searching and planning. In particular, WCST Percent Perseverative Error (PPE) is consistently greater in schizophrenia patients than in individuals with schizoaffective disorder (Szoke et al., 2008), individuals with psychosis (Reed et al., 2002), and healthy controls (see
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Appendix A) (Morice, 1990; Perry and Braff, 1998; Rossi et al., 2000; Saoud et al., 2000; Keri et al., 2001; Liu et al., 2003; Szoke et al., 2008). Moreover, Liu et al. (2003) and Saoud et al. (2000) provided evidence for perseveration as a biomarker of schizophrenia: unaffected siblings of those with the disorder committed significantly more perseveration errors on the WCST than healthy controls, (unaffected siblings of individuals with schizophrenia=22.8, healthy controls=14.8; unaffected siblings of individuals with schizophrenia = 42.24, healthy controls=28.16, respectively). It is not clear, however, how unique perseveration is among psychiatric disorders. Evidence for the existence of categorically distinct disorders such as schizophrenia, bipolar disorder, and major depression is mixed: neuropsychological (Schretlen et al., 2007; Dickerson et al., 2004), and cognitive and social (Dickerson et al., 2001) impairments may be similar in schizophrenia and bipolar disorder; schizophrenia and major depression show similar neuropsychological and frontal lobe disturbances (Franke et al., 1993); overlap in biochemical anomalies among the disorders has been reported (Cotter et al., 2005; Torrey et al., 2005); and insight appears to exist on a continuum across the three disorders (Yen et al., 2008). Interestingly, there are very few studies that directly compare all diagnoses, particularly with regard to measures of neuropsychological functioning. At best, the literature supports a continuum of schizophrenia, schizoaffective, and affective disorders (Szoke et al., 2008), but few studies directly compare schizophrenia, bipolar disorder, and major depression on measures of executive function (Brown et al., 2008; Rempfer et al., 2006; Mojtabai et al., 2000). A form of perseveration, rumination, does occur in affective disorders, specifically major depression and is described as focusing perseveratively about one's own thoughts and problems (NolenHoeksema et al., 2008). In fact, rumination was identified as the “form most strongly and consistently related to depressive symptoms” (Nolen-Hoeksema et al., 2008, p. 400). Originally developed to “assess abstract reasoning ability and the ability to shift cognitive strategies in response to changing environmental contingencies,” (Heaton et al., 1993, p. 1) the WCST is a valuable tool to assess cognitive inflexibility, specifically perseveration, as it is an impairment directly related to poor community outcome and poor social and occupational functioning in individuals with schizophrenia (Addington and Addington, 1999; Green, 1996; Lysaker et al., 2005). Examining perseveration across these three diagnostic groups will provide additional evidence that addresses whether perseveration is a characteristic unique to schizophrenia or is common to other psychiatric disorders as well. It was hypothesized that WCST PPE, at clinically impaired levels, would be significantly greater and occur more often in schizophrenia than in individuals with bipolar disorder and major depression. In addition, we expected strong associations between perseveration and core clinical symptoms of schizophrenia. 2. Methods 2.1. Participants The data for the present study were taken from a larger database consisting of 664 patients recruited or referred to participate in an investigation of sex differences in neuro-
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psychological functioning (see Lewine et al., 1996 for full recruitment procedure; Thurston-Snoha and Lewine, 2007). The present study examined perseveration in individuals with schizophrenia (N = 143), bipolar disorder, (N = 25) and major depression (N = 21). Only individuals with complete neuropsychological data and clinical data (for the schizophrenia group only) were retained for this study. Furthermore, individuals N45 years of age were excluded to control for aging effects. Finally, only individuals with complete WCST and clinical data (for schizophrenia patients only) were retained, yielding a final full sample size of 189 patients. 2.2. Procedure Participation included a 13-hour neuropsychological battery completed over the course of several sessions, an MRI, and a battery of clinical measures (for schizophrenia patients only). For the schizophrenia patients only, the range of sample sizes for the clinical measures was 82–143. Missing data occurred largely due to fatigue and missed appointments. 2.3. Measures 2.3.1. Clinical assessment The Schedule for Affective Disorders and SchizophreniaLifetime Version (SADS-L; Spitzer and Endicott, 1975) was administered to determine psychiatric diagnoses. SADS-L scores and a weekly consensus diagnostic meeting were used to determine final diagnoses. Patients in the schizophrenia study completed a large battery of clinical assessments including the Andreasen's Scale for Assessment for Negative Symptoms (SANS; Andreasen, 1983), Andreasen's Scale for Assessment for Positive Symptoms (SAPS; Andreasen, 1984), Hamilton Depression Rating Scale (HDRS; Hamilton, 1960), Beck Depression Inventory (BDI; Beck et al., 1961), and Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962). 2.3.2. Neuropsychological assessment For a complete list of neuropsychological assessments administered in the larger study, see Lewine et al., 1996. The focus of the current study is performance on the WCST, the measure chosen to evaluate perseveration. The data were collected using the card version of the assessment. Because our interest is in perseveration, we chose to focus on PPE because of its direct measure of the phenomenon, its frequent use in the field as a measure of perseveration, and its frequent use and replication in schizophrenia research. 2.4. Analyses The first set of analyses examined perseveration across the three diagnostic groups. A one-way ANOVA was conducted for PPE for the three groups (independent variable) to examine a cross-diagnosis comparison of perseveration. Participants within each diagnostic group were then classified as either clinically impaired or not impaired using the clinical metric identified by Heaton et al. (1993, p. 31). Individuals with PPE Standard Scores ranging from ≤54 to 84 were classified as impaired while those with Standard Scores ranging from 85 to ≥107 were classified as not impaired. The
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relationship between age at time of test and impairment yielded an r = 0.008, p = 0.954, confirming our use of a restricted age range to eliminate possible age confounds. Chisquare analyses were completed to examine the distribution of impairment across the three diagnostic groups. The second set of analyses examining perseveration and clinical symptoms in schizophrenia involved several 2 × 2 univariate ANOVAs examining impairment (impaired, not impaired) and age at first hospitalization (≤21 years of age, ≥ 22 years of age), sex (male, female), and education (≤12 years of school, ≥ 13 years of school) with measures of positive symptoms, negative symptoms, depression, anhedonia, and psychosis. Traditionally, a MANOVA would have been used for this data but because of missing data, univariate ANOVAs were run to fully explore each variable. Sex, age at first hospitalization, and education were included in the ANOVAs to examine mediating effects of schizophrenia dysfunction previously cited in the literature (Hochman and Lewine, 2004; Lewine, 2004; Lewine et al., 1997; Liu et al., 2003; McEvoy et al., 2006). 3. Results
Table 1 Means and standard deviations for sociodemographics for each diagnostic group.
Age Age at first hospitalization* Duration of illness Years Of education** GAF Sex* Male Female Total Race White Black Oriental Hispanic Missing Total
Schizophrenia
Bipolar disorder
Major depression
31.64 years (6.71) 21.48 (5.70)
34.44 years (6.71) 26.57 (7.39)
33.86 years (6.97) 26.85 (7.49)
9.98 years (6.55) 12.87 years (2.02) 47.12 (12.62)
7.48 years (6.58) 14.11 years (2.40)
6.80 years (9.69) 14.43 years (3.14)
110 33 143
13 12 25
3 18 21
111 31 0 0 1 142
22 0 0 0 3 22
17 4 0 0 0 21
* pb0.001; ** pb0.01.
3.1. Diagnostic comparisons Descriptive analyses were conducted for diagnostic group and sex, race, age at first hospitalization, age at time of assessment, years of education, and illness duration. Subsequent univariate analyses revealed differences across diagnoses with regard to sex, F(2186) = 21.224, p b 0.001, age at first hospitalization, F(2181) = 11.96, p b 0.001, and years of education F(2179) = 6.315, p b 0. 01. ANCOVA analyses were then conducted for the three significant variables, covarying each one with diagnosis for PPE. The ANCOVAs were not significant for diagnosis and years of education, F(2178) = 0.844, p = 0.432, sex F(2185) = 1724, p = 0.181 or age at first hospitalization F(2180) = 1.155, p = 0.317. See Table 1 for means and standard deviations. Univariate ANOVAs were conducted to examine the effects of the diagnostic group on PPE. The effect of the diagnostic group on PPE approached a conventional level of statistical significance, F(2186) = 2.796, p = 0.064. The mean PPE for schizophrenia, bipolar, and depression were 21.60%, 16.03%, and 15.81%, respectively. Additional univariate analyses for the mean PPE conducted for the impaired individuals only in each group revealed no significant group differences, F(2,75) = 0.035, p = 0.966, with a mean PPE of 33.22% for schizophrenia, 33.54% for bipolar, and 34.82% for major depression. Though no mean differences emerged for the impaired individuals with regard to PPE, the distribution of impairment across diagnoses was significantly different, x2(2, N = 189) = 6.125, p b 0.05. 46.2% of individuals with schizophrenia were impaired, followed by 28% of bipolar patients, and 23.8% of individuals with major depression.
≥22 years of age), sex (male, female), and education (≤12 years of school, ≥13 years of school) were conducted for measures of positive symptoms, negative symptoms, anhedonia, depression, and psychosis. The factors were chosen due to earlier relationships with diagnostic group, support in the literature noted above, and age of first hospitalization, particularly, as an index of illness severity. With one exception, see below, the only significant result was a main effect of impairment. There were no other main or interaction effects with sex, age at first hospitalization, and education. See Table 2 for means and standard deviations for each 2 × 2 ANOVA. For each 2 (impairment) × 2 (sex), 2 (education), and 2 (age at first hospitalization) ANOVA, there were significant effects of impairment on PPE for SANS total score: F(1, 104) = 6.383, p b 0.05, F(1, 104) = 6.631, p b 0.05, and F(1, 103) = 9.704, p b 0.01, respectively. Subsequent post hoc testing was significant, t(110) = 2.868, p b 0.01, revealing that impaired individuals had higher SANS total scores than non-impaired individuals (mean = 10.27 and mean = 7.78, respectively). Finally, there was a significant interaction between impairment and age at first hospitalization for HDRS total score, F(1, 72) = 4.991, p b 0.05. Subsequent univariate post hoc analyses with a Bonferroni correction revealed that impaired individuals ≤21at first hospitalization (mean = 12.06) had significantly higher HDRS scores than non-impaired individuals ≤21 years old at first hospitalization, F(1, 72) = 8.687, p b 0.01. Means for non-impaired and ≤21, impaired and ≥22, and non-impaired and ≥22 were 5.88, 7.40, and 8.21, respectively. There was no main effect of impairment for HDRS.
3.2. Clinical comparisons for schizophrenia sample
4. Discussion
In an effort to further examine the role of perseveration in schizophrenia, 2×2 ANOVAs examining impairment (impaired, not impaired) and age at first hospitalization (≤21 years of age,
Although perseveration has been historically associated with schizophrenia, few studies have compared perseveration in schizophrenia with other psychiatric disorders, in particular
R.N. Waford, R. Lewine / Schizophrenia Research 118 (2010) 128–133 Table 2 Means and standard deviations for sociodemographics for each diagnostic group. Assessment Impairment and sex SAPS Impaired, male Not impaired, male Impaired, female Not impaired, female SANS* Impaired, male Not impaired, male Impaired, female Not impaired, female HDRS Impaired, male Not impaired, male Impaired, female Not impaired, female BDI Impaired, male Not impaired, male Impaired, female Not impaired, female BPRS Impaired, male Not impaired, male Impaired, female Not impaired, female Anhedonia-social Impaired, male Not impaired, male Impaired, female Not impaired, female Anhedonia-physical Impaired, male Not impaired, male Impaired, female Not impaired, female
Mean
Standard deviation
6.53 4.74 5.30 6.14
4.55 3.65 2.83 4.38
10.36 7.79 10.64 7.87
5.16 3.95 5.35 4.60
8.91 6.82 11.08 7.22
6.19 7.31 8.55 4.44
14.94 11.22 11.44 11.70
11.52 9.76 12.02 10.75
40.35 35.70 32.82 30.50
15.55 12.92 11.32 9.47
17.43 13.97 10.89 14.82
13.04 8.03 5.78 8.88
11.62 10.82 10.78 10.91
4.76 5.85 6.18 6.36
Impairment and age at first hospitalization SAPS Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 SANS ** Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 HDRS Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 BDI Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 BPRS Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22 Anhedonia-social Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22
7.27 4.71 5.21 5.54
4.65 3.49 3.16 4.27
10.50 8.37 10.67 7.21
5.64 4.18 4.37 3.97
12.06* 5.87 7.40 8.21
8.11 4.67 4.41 8.71
15.70 11.54 13.26 11.09
12.44 9.92 10.60 10.01
39.16 34.82 35.50 35.35
15.48 10.57 10.64 14.61
17.84 15.83 14.11 12.38
16.11 7.60 6.19 8.54
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Table 2 (continued) Assessment Anhedonia-physical Impaired, ≤21 Not impaired, ≤21 Impaired, ≥22 Not impaired, ≥22
Mean
Standard deviation
10.33 11.87 12.21 9.71
5.30 4.92 4.79 6.77
6.32 5.46 6.17 4.82
4.09 3.83 4.57 3.90
11.40 8.32 8.95 7.42
4.97 3.63 5.19 4.42
7.94 5.73 11.41 8.14
6.52 4.75 7.34 8.33
13.77 10.85 14.61 11.7
11.96 9.83 11.40 10.05
35.43 36.44 39.36 33.89
13.80 10.06 15.05 14.62
17.00 13.80 14.38 14.50
14.77 8.40 6.49 8.11
11.68 10.35 11.06 11.25
4.90 5.50 5.40 6.31
Impairment and education SAPS Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years SANS* Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years HDRS Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years BDI Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years BPRS Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years Anhedonia-social Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years Anhedonia-physical Impaired, ≤12 years Not impaired, ≤12 years Impaired, ≥13 years Not impaired, ≥13 years * pb0.001; ** pb0.01.
major depression and bipolar disorder (Liu et al., 2003; Reed et al., 2002; Keri et al., 2001; Perry and Braff, 1998; Cuesta et al., 1995). This comparison is critical as it speaks directly to the issue of specificity of perseveration in schizophrenia. Rempfer et al. (2006) is one of the few to compare these three groups, with a study addressing learning potential and proficiency on the WCST. When using WCST performance and learning proficiency to classify individuals as “high achievers,” “learners,” and “nonretainers,” Rempfer et al. (2006) found no significant association between learner status and diagnostic group. Moreover, diagnostic group was not significantly related to any additional measures of cognitive functioning. While our results confirm previous research taking rates of clinical levels of perseveration into account, they also reveal that perseveration is not unique to schizophrenia. Individuals with bipolar disorder and major depression are, when perseverative, as perseverative as individuals with schizophrenia. These findings are consistent with Rempfer et al.'s (2006) finding indicating little difference in measures of cognitive functioning between individuals with schizophrenia, bipolar
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disorder, and major depression. In short, while perseveration appears to be more prevalent in schizophrenia, when it does occur in bipolar disorder and major depression, virtually no difference in severity occurs between the groups. These findings are quite compelling when considering the paucity of research directly comparing executive function among these diagnostic groups. Additionally, our results are consistent with those studies of schizophrenia that report a link between impairment and clinical symptoms. Previous research has indicated that negative symptoms prevalent in schizophrenia are significantly related to measures of executive function (Faerden et al., 2009; O'Leary et al., 2000; Cuesta et al., 1995; Frith et al., 1991), and severity of cognitive impairment (Tuulio-Henriksson, 2004). The current findings upheld previous conclusions, in that ratings of negative symptoms were significantly, positively related to cognitive impairment as measured by perseveration and age at first hospitalization, sex, and years of education. Depressive symptoms are also prevalent in individuals with schizophrenia and associated with higher levels of dysfunction. The present study indicated that impairment and age at first hospitalization were significantly related to self-reported levels of depression and posits that age may be a moderator of the relationship between impairment and depressive symptoms. Specifically, impaired individuals ≤21 years old at their first hospitalization reported higher depression scores at the time of test. This is consistent with the idea that later onset of symptoms of schizophrenia is associated with better course and prognosis and therefore younger individuals may be more likely to experience greater depression related to the onset of their symptoms. This finding also supports research suggesting that subjective mood impacts performance, therefore individuals with schizophrenia may be experiencing more depressive symptoms related to their illness, thereby impacting WCST performance (Halari et al., 2006). The present study is not without its limitations. The sample size within the schizophrenia group was considerably larger than the sample sizes for the affective groups. Because of the nature of the study, there is a larger sample of individuals with schizophrenia, relative to all the diagnostic groups (see Lewine et al., 1996 for full recruitment procedures). However, the proportion of impairment within each diagnostic group revealed robust findings, with a greater proportion of individuals with schizophrenia being impaired relative to the rest of their diagnostic group. The large difference in sample size may account for some of our results. Replication and further study is necessary to determine if these results will hold. Another limitation is the lack of complete clinical data for individuals with bipolar disorder and major depression. Due to study constraints, clinical data were only collected for individuals in the schizophrenia study. In addition, there is a selection bias in this study that contributes to what may be a more severe group of depressed and bipolar patients. Individuals in the database were recruited or referred due to the possibility of a schizophrenia diagnoses. Therefore, these individuals were experiencing some level of psychosis that brought them in touch with the study in one form or another. Moreover, examination of the schizophrenia scale
from the MMPI revealed no difference in level of psychosis between individuals with schizophrenia (81.02), bipolar disorder (76.71) and major depression (75.79), F(2164) = 1.122, p = 0.328. Again, replication and further study are warranted. The present study supports growing recognition of the importance of broad, dimensional dysfunctions that cut across traditional psychiatric diagnoses (Westen et al., 2002). It appears that perseveration is not specific to any disorder and may be more of a generic impairment that is not diagnostically useful. As Simonsen et al. (2009) suggested, both categories of function and the same brain areas, mechanisms, and pathways can be impaired across multiple disorders. Therefore, studying perseveration as a dimensional impairment may provide more information by allowing for the examination of questions such as why one should become perseverative with a range of psychiatric disorders. Is it an issue of limited cognitive resources, mental stiffness or a reduced range of behaviors? Approaching diagnosis and impairment dimensionally forces one to think outside the box and develop hypotheses that cut across diagnoses, especially as diagnostic assessment moves toward a continuum of impairment. Role of funding source The original study was funded by an NIMH MERIT Award, but the current analyses were not funded. Contributors Rachel Waford, as first author, conceptualized the hypothesis, conducted the data analysis, and prepared the manuscript. Richard Lewine supervised the data collection, coding and management, supervised data analysis, and oversaw all manuscript revisions. Conflict of interest There are no conflicts of interest for either author. Acknowledgments The collection of the original data was supported by an NIMH MERIT Award, (RL).
Appendix A Mean % perseverative errors for schizophrenia groups and healthy controls.
Morice (1990) Perry and Braff (1998) Rossi et al. (2000) Saoud et al. (2000) Keri et al. (2001) Liu et al. (2003) Szoke et al. (2008)
Schizophrenia
Healthy controls
34.7 43.6 17.54 48.6 22.0 25.8 26.8
15.5 13.5 8.81 28.16 10.0 14.8 9.7
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