Copyright Blackwell Munksgaard 2007 Bipolar Disorders 2007: 9: 7192

BIPOLAR DISORDERS

Original Article

Neuropsychological symptom dimensions in bipolar disorder and schizophrenia

Czobor P, Jaeger J, Berns SM, Gonzalez C, Loftus S. Neuropsychological symptom dimensions in bipolar disorder and schizophrenia. Bipolar Disord 2007: 9: 7192. Blackwell Munksgaard, 2007 Background: While neurocognitive (NC) impairments have been well documented in schizophrenia (SZ), there is limited data as to whether similar impairments are present in other persistent mental illnesses. Recent data indicate that NC impairments may be manifested in bipolar disorder (BPD) and that they persist across disease states, including euthymia. An important question is whether a comparable structure of NC impairments is present in the 2 diagnostic groups. Objective: In a previous factor analytic study, we identied 6 factors to describe the basic underlying structure of neuropsychological (NP) functioning in SZ: Attention, Working Memory, Learning, Verbal Knowledge, Non-Verbal Functions, Ideational Fluency. The goal of this study was to investigate whether this factor structure is generalizable for BPD. Methods: The BPD sample included patients (n 155) from an ongoing longitudinal study evaluating BPD at the time of hospitalization for relapse and at multiple time points over the following 2 years. The SZ sample included patients (n 250) from a 3-year study. For the current examination the baseline NP evaluations were selected for both samples. Results: Exploratory and conrmatory factor analyses in the BPD sample yielded factors similar to those identied in the SZ sample. The coecients of congruence ranged between 0.660.90 for the individual factors, indicating a good overall correspondence between the factor structures in the 2 diagnostic groups. Analysis of covariance (ANCOVA) analysis with education level, full scale-IQ, gender and ethnicity as covariates indicated that SZ patients had markedly worse performance on the Attention and Non-Verbal Functioning factors compared to the BPD patients. Conclusions: Together, these data suggest that while the same underlying factor structure describes NP functioning in both groups, the prole of impairments appears to vary with the diagnosis.

l Czobora,b, Judith Jaegerc,d, Pa Stefanie M Bernsc, Cristina Gonzalezc and Shay Loftusc
DOV Pharmaceutical Inc., Hackensack, NJ, Nathan Kline Institute for Psychiatric Research, Orangeburg, cThe Center for Neuropsychiatric Outcome and Rehabilitation Research, The Zucker Hillside Hospital, North Shore Long Island Jewish Health System, Glen Oaks, dDepartment of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA
b a

Key words: bipolar disorder commonality in factor structure neuropsychological symptom dimensions schizophrenia Received 1 July 2005, revised and accepted for publication 17 August 2006 Corresponding author: Judith Jaeger, PhD, MPA, AstraZeneca Pharmaceutical Company, FOC W2-651, 1800 Concovel Plaza, Wilmington, DE 19803, USA. Fax: +1 302 886 4803. e-mail: jaeger.ju@gmail.com

Controversy exists over whether bipolar disorder (BPD) and schizophrenia (SZ) are best characterized as separate disorders or along a continuum (1). The classical position assumes a categorical view based on Kraepelins proposition from more

The authors of this paper do not have any commercial associations that might pose a conict of interest in connection with this manuscript.

than a century ago (2); it considers dierences between psychotic symptoms across diagnoses as qualitatively dierent. Current diagnostic systems such as DSM (3) and ICD-10 (4) operationalized this view, and try to separate bipolar illness (excluding recurrent major depression, which Kraepelin had grouped with manic depression) and SZ in a categorical fashion by requiring the presence or absence of certain symptoms for the purpose of diagnosis. However, since symptoms

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may overlap, sometimes for extended periods, the dierential diagnosis of BPD and SZ frequently poses a problem in clinical practice. In response to this, an alternative, dimensional view is often invoked in contrast to the prevailing categorical approach, which posits that BPD and SZ do not represent a discrete illness entity. For example, Crow proposed that psychosis might vary along a continuum, extending from unipolar aective disorder through bipolar aective disorder and schizoaective disorder to typical SZ (1, 5). Recently, the dimensional view has gained favor in a rapidly growing literature emphasizing shared abnormalities that cut across the current diagnostic divide. For example, shared morphometric ndings, such as enlarged ventricles (6), and white matter volume reductions in the left frontal and temporoparietal regions were found in both disorders (7). Furthermore, common cellular and molecular patterns were observed, including a decrease in cell density in the GABAergic interneurons in SZ as well as in BPD (8). At the intracellular level, both diagnostic groups showed abnormalities in intracellular molecules (e.g., PSD95) that provide a physical link between multiple neurotransmitter systems (including the glutamatergic and dopaminergic systems) which are potentially involved in the neurobiology of SZ and aective disorders (9). Since these studies do not systematically exclude cases that are diagnostically challenging (e.g., share substantial features of both disorders) ndings of shared pathophysiology may be confounded by the incorrect classication of cases. Recent studies have also reported apparent overlap in the genetic susceptibility between BPD and SZ. For example, family studies show a substantial degree of familial co-aggregation between bipolar illness and SZ (10). Moreover, systematic whole genome linkage studies raised the possibility of some common chromosomal regions shared by BPD and SZ, although various metaanalyses yielded inconsistent results with regard to the strength of the evidence for each of the potential candidate regions (1113). Additionally, in candidate gene studies, specic genes have been identied in which variation appears to confer the risk to both BPD and SZ (with the strongest evidence shown for G72/G30, in the 13q candidate region, but common susceptibility was raised for example for BDNF, COMT, DISC1, neuregulin 1, and dysbindin) (11, 14). In addition, results from the rst diagnostically unrestricted twin study indicate that the common shared additive genetic variance is substantially higher for mania and SZ (49% and 68%, respectively) than the diagnosis-

specic additive genetic variance (19% for mania and 33% for SZ) (15). Similar to studies examining pathophysiology, studies of genetic susceptibility for the most part suer from design challenges that bias against ndings that would distinguish the groups as Kraepelin had proposed (e.g., the diculty of blinding the co-twins diagnosis during the diagnostic process, the practice of including cases with overlapping features which increases the chance of diagnostic error and the exclusion of recurrent major depression from the bipolar group). To address the question of disease boundaries, there is growing interest in identifying more precisely dened quantitative traits, which would represent more direct downstream biological consequences of genes than the symptoms. Such traits, or endophenotypes could serve as an alternative (or complement) to the categorical disease phenotypes, and potentially underlie a more accurate diagnostic classication. Based on their heritability and the fact that they can be measured objectively and reliably, certain domains of neurocognitive (NC) performance have been considered as candidate endophenotypes in major mental disorders including BPD and SZ. In the case of SZ, general NC decits and decits in various specic tasks indexing broader cognitive domains have been demonstrated, particularly in tasks of Attention, Long-Term Memory, Working Memory, and Executive Functioning (16). With regard to BPD, in the earlier literature, a common misconception was that, in contrast to SZ, bipolar aective disorder is not associated with general cognitive impairment independent of illness episodes, or in the premorbid state (6). However, newer literature challenged this view, and converging evidence suggests that persons with BPD exhibit persistent cognitive impairment across a range of tasks of Attention, Memory and Executive Function during remission (1721). Furthermore, cognitive dysfunctions seem to be present in BPD patients not only during acute symptom exacerbation but both in prodromic and residual phases (14). Some of the authors concluded that particularly poor performance on tests of Verbal Memory was consistently found as a characteristic of BPD (17, 22). Glahn et al. (23) recently suggested that Verbal Learning and Memory and Executive Function/Working Memory may represent the most salient endophenotypic components of neurocognition in BPD because these domains appear heritable, co-segregated within families, associated with the disease, and impaired during periods of symptom remission.

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Neuropsychological symptom dimensions An important theoretical question regarding NC functions as potential candidate endophenotypes is their diagnostic specicity. A recently conducted meta-analysis of all comparative studies indicated that patients with BPD generally perform better than patients with SZ, but the distribution of eect sizes revealed a large degree of heterogeneity (24). In particular, this investigation compared NC performance in patients with BPD and SZ in 11 NC domains. The 11 domains comprised: Verbal Fluency, Verbal Working Memory, Executive Control, Visual Memory Delayed, Mental Speed, Verbal Memory Immediate, IQ, Verbal Memory Delayed, Concept Formation, Visual Memory Immediate, and Fine Motor Skills. The metaanalysis (24) showed signicantly worse performance in the patients with SZ in 9 out of 11 cognitive domains. The only areas in which performance of the 2 patient groups were not statistically signicant were delayed Visual Memory and Fine Motor Skills. Another recently published meta-analytic review of the literature (16), dened only 4 major NC domains, which included IQ, Attention (Sustained, Selective), Memory, and Executive Functions (Cognitive Flexibility, Working Memory, Verbal Fluency). This review concluded that BPD patients exhibit extensive cognitive abnormalities with a pattern of decits that is not unique to this disease. The study by Seidman et al. (22) focused specifically on a comparison of proles of NC abnormalities between BP and SZ in 8 domains, including Verbal Ability, Visuo-Spatial Ability, Abstraction/Executive, Verbal/Declarative Memory, Perceptual-Motor Functions, Mental Control, and Sustained Attention/Vigilance. Similar to the above 2 meta-analyses, this study concluded that while the level of impairments was higher in patients with SZ, the prole shape did not dier between BPD and SZ. Overall, Abstraction, Memory, Perceptual-Motor Functions, and Vigilance showed the largest impairments in both groups, with a higher level of impairment in patients with SZ in this study (22). Using a standardized test battery (Repeatable Battery for the Assessment of Neuropsychological Status; RBANS), Hobart et al. (25) showed that patients with SZ were more impaired than patients with BPD in terms of general functioning [medium eect size (0.55) for the total score], and that among 5 NC domains including Visuospatial/ Constructional, Language, Attention, Delayed Memory and the Immediate Memory only the latter (Immediate Memory, eect size 0.65) obtained a signicant dierence between the groups. The dierence in terms of attention functioning did not reach signicance (eect size 0.33). However, it is dicult to evaluate the validity of these results since it is conceivable that the group dierences were confounded by the extent to which the NC domains represented dierent underlying constructs (factors) across diagnoses. In general, the above literature that compared NC in patients with BPD and SZ had certain limitations. The majority of studies used only a relatively small set of tasks, and the composition of tasks was vastly dierent across studies. This makes the comparisons dicult, and limits the interpretability of the ndings since the various components of the NC proles across diagnoses were assembled from data derived from dierent studies. A potential research strategy to overcome this problem and to compare patterns of NC decits in BPD and SZ is to administer a comprehensive neuropsychological (NP) battery consisting of several measures tapping into each of several putative NC domains. However, those studies that investigated multiple areas simultaneously, focused on a dierent number of domains, and applied dierent denitions. Since component measures were arbitrarily selected, the domains (construct) validity may not generalize to dierent samples, or within the same sample over time. The 2 large recent meta-analyses published only a few months apart from each other (16, 24; see above), considered 11 and 4 domains, respectively, whereas the study by Seidman et al. (22) dened 8 domains for the comparison of respective NP proles. To our knowledge, no empirical evidence has been shown to demonstrate that the various denitions of the underlying NC domains were valid in a particular diagnostic group, and generalizable across diagnoses. Obtaining such evidence is a logical prerequisite of further group comparisons, and as stated by Horn and McArdle (26, p. 117) without such evidence, the basis for drawing scientic inference is severely lacking. Factor analysis provides 1 way to obtain this evidence based on the analysis of interrelationships among various NC measures. Surprisingly, despite the fact that a substantial research eort has been spent to demonstrate that BPD and SZ share specic domains of psychopathology in terms of factor analytic structure, as far as we know, no previous studies compared the NC factor structure derived from the same instrument in both bipolar and schizophrenic patients. In our previous factor analysis of patients with SZ, on the basis of the analysis of a comprehensive NC test battery, we derived 6 clearly identiable factors that had good psychometric properties with excellent construct,

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divergent and predictive validity, and stability over time in a longitudinal study (factors included Attention, Working Memory, Learning, Verbal Knowledge, Non-Verbal Functions, and Ideational Fluency). The principal objective of the current study was to extend this research further, by investigating whether the same underlying factor structure of NC functions that characterized patients with SZ would generalize to patients with BPD.
Methods

The data for the research reported here were collected in 2 longitudinal clinical studies investigating predictive and concurrent associations between neurocognitive performance and disability in life (psychosocial) functioning (LF) in individuals with serious mental illnesses [see companion paper (27) in this issue for further details of this research]. The 2 studies represented subsequent phases of the research project. The goal of the rst (Study 1: Schizophrenia Study) was to test the longitudinal relationship between NC decits and life functioning (disability) in patients with SZ or schizoaective disorder; the aim of the second (Study 2: Bipolar Study) was to investigate the above relationship in patients with BPD. Both studies collected a large number of NC variables and aimed to conduct factor analyses for the purpose of data (dimensionality) reduction. This aim was previously accomplished in the rst study in a subset comprised of the rst 156 patients enrolled (see below for further details). The core results, including details concerning the NC factors that were identied, have been published (28). Since the principal purpose of Study 2 was similar to that of Study 1, and dimensionality reduction was an important tool to achieve a reduction in Type I error arising from multiple repeated testing of individual variables, an essential question was whether the same factor structure that we found in the SZ sample is applicable to the bipolar sample. Hence, the question of generalizability of the NC factors across diagnoses served as a principal practical motivating problem for the current investigation.
Subjects

received a comprehensive NC test battery and Positive and Negative Symptom Scale (PANSS) (29) ratings at baseline (used for the present report) and again after 6, 18 and 36 months (not included in this report). Sta administering NC tests were previously trained and observed in test battery administration to assure uniformity. The PANSS raters had demonstrated interrater reliability compared to an expert (ICC 0.80). For the present analyses, the nal dataset from this study was used; subjects were included in the analyses if they had completed the baseline NC assessment. Baseline NC testing was conducted whenever possible when patients were optimally stabilized after hospitalization for the index episode. A total of 250 patients, with the diagnosis of SZ (n 185; 74%) or schizoaective disorder (n 65; 26%) were enrolled in the study. Study 2: Bipolar sample. The subjects for the analyses that we report here are consenting patients from an ongoing 24-month study investigating predictive and concurrent associations between NC decits and disability in life functioning in individuals with BPD. The objective of this naturalistic longitudinal study is to evaluate approximately 200 individuals aged 18 to 54 years with BPD [diagnosed using SCID (3)] at the time of hospitalization for relapse and at multiple time points over the following 24 months. For the present analyses, an interim dataset from this ongoing study was cleaned and frozen (i.e., no further changes were made in the database); subjects from this database were included in the analyses, if they had completed the baseline NC assessment. Baseline NC data from a total of 155 subjects were used for the purpose of the current investigation. Using cut-o scores for the Clinician-Administered Rating Scale for Mania (CARS-M; 15 items) (30) of 07 for questionable and 815 for mild mania and, for the Hamilton Depression Rating Scale (HAM-D; 17 items) (31), 06 for not depressed and 717 mildly depressed, we found that the majority (approximately 54%) of the sample had no or mild symptoms on both scales. Approximately 30% had moderate to high mania with no or low depressive symptoms, and, conversely, approximately 11% of the sample had moderate to high depression with no or mild mania at the time of neurocognitive testing. Approximately 5% of the sample had active mixed symptomatology at the time of testing (e.g., moderate or greater symptoms on both mania and depression rating scales). Altogether, 11% (n 17) of the subjects in the primary dataset (n 155) evidenced symptoms on

Study 1: Schizophrenia sample. Subjects were consenting patients in a 3-year study of SZ and schizoaective disorder [diagnosed using the Structured Clinical Interview for DSM-IV (SCID)] which involved repeated neurocognitive testing. Subjects were enrolled within 6 months of symptom exacerbation requiring hospitalization, and

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Neuropsychological symptom dimensions Delusions involving Replacement of Will (Delusions of Control, Thought Insertion, Thought Deletion, Thought Broadcasting) and Hallucinations, reecting the overlapping boundaries of BPD with the SZ spectrum in terms of symptom presentation. In secondary analyses, we investigated whether the inclusion of these subjects in the sample had an impact on the principal results.
Comparison of the 2 samples

The demographic characteristics of the bipolar (n 155) and SZ (n 250) samples are shown in Table 1. As Table 1 shows, the 2 groups were essentially identical in terms of age, onset of illness, and age at which they received the rst psychiatric treatment. The groups, however, were signicantly dierent (p < 0.05) in their ethnicity and gender distributions. In particular, a signicantly higher proportion of patients from the white ethnic group were present in the bipolar as compared to the SZ sample. Furthermore, as expected on the basis of
Table 1. Descriptive and demographic characteristics in the bipolar and the schizophrenia (reference) sample Bipolar sample (n 155a) Mean 35.4 19.1 21.2 14.1c 86.4c 13.0 10.6 (SD) (10.9) (8.4) (8.8) (2.4) (11.9) (8.9) (6.4) Schizophrenia sample (n 250a,b) Mean 36.3 19.1 20.6 12.0c 82.7c 18.9 20.1 (SD) (9.1) (6.5) (6.8) (2.5) (10.3) (5.5) (5.8)

Characteristics

Age Onset of illness Age rst treated Education Full scale-IQ CARS-Md/PANSS POSe HAM-Dd/PANSS NEGe Gender, n (%) Male Female Race, n (%) White Black Hispanic Other
a

demographic prevalence data, the proportion of female patients was higher in the bipolar as compared to SZ group. In addition, the bipolar sample demonstrated a signicantly higher full scale-IQ and more years of education, although the former dierence was quite modest (3.7 points in full scale-IQ). The 2 groups evidenced mild levels of symptom severity as shown by the respective psychometric ratings in each group, CARS-M (30) and the HAM-D scale (31) for the bipolar patients; the PANSS positive and negative symptom subscale for the schizophrenics (Table 1). In the bipolar sample, at the time of the current analyses, medication data were available for a total of 142 patients (91.6% of 155). The distribution (%) of the most common treatments was the following: lithium (69.0%), anticonvulsants (67.3%), neuroleptics (typical and atypical neuroleptics combined: 65.5%), valproic acid (60.6%), antidepressants (38.0%), benzodiazepines (22.4%), and anxiolytics (18.3%). Overall, the analysis of the medication data indicated that all patients received polypharmacy in the bipolar sample. In the SZ sample, while polypharmacy was common, the overwhelming majority of the patients (93% of the sample) were taking at least 1 neuroleptic medication at baseline. The distribution of atypical and typical agents in the sample was 68% and 32%, respectively. In addition to the neuroleptics, in the SZ sample, many patients were taking another class of psychotropic medication as well including mood stabilizers, anxiolytics, and antidepressants.
Measures

67 (43.2f) 88 (56.8) 113 29 7 6 (72.9f) (18.7) (4.5) (3.9)

156 (62.4f) 94 (37.6) 99 106 28 17 (39.6f) (42.4) (11.2) (6.8)

Sample size may vary due to missing data. Diagnostic distribution: schizophrenia 74% (n 185) versus schizoaffective disorder 26% (n 65). c Signicant mean difference (p < 0.05) between the two samples (ANOVA). d In the bipolar sample, symptom severity was indexed by the total score on the Clinician-Administered Rating Scale for Mania (CARS-M) and the Hamilton Rating Scale for Depression (HAMD; 17-item version), respectively. e In the schizophrenia sample, symptom severity was indexed by the total score on the positive (POS) and negative symptom (NEG) subscale of the Positive and Negative Symptom Scale (PANSS), respectively. f Signicant difference in proportions (p < 0.05) between the two samples (chi-square test).
b

Psychopathology. Psychometric assessments of symptom severity in each study were conducted at baseline and each of the follow-up visits including neuropsychological testing. The rating instruments in each study were specic to the population targeted in that study. In Study 1, which focused on patients with SZ and schizoaective disorder, the principal measures of psychopathology were the PANSS and the Brief Psychiatric Rating Scale (BPRS) (32). In Study 2, which focused on patients with BPD, the principal measures of psychopathology were the CARS-M (30) and the HAM-D (31). The raters for each of these rating instruments in our study had demonstrated interrater reliability compared to an expert (ICC > 0.80). Neurocognitive performance. The NC battery was designed to examine functional domains previously considered important by virtue of their demonstrated impairment in people with major mental

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Table 2. Neuropsychological tests used in the present study Neuropsychological tests Wechsler Adult Intelligence Scale-Revised (WAIS-R) (57) Wechsler Memory Scale Revised (WMS-R) (58) Letter Number Span (46) Complex Ideational Material (47) Concentration Endurance Test (D2) (48) Stroop Test (49) Wisconsin Card Sorting Test (128-card manual version) (50) Trail Making Test (A&B) (51) Controlled Oral Word Association Test (COWAT) (52) Animal Naming Test (51) Ruff Figural Fluency Test (53) Grooved Pegboard Test (54) Finger Tapping Test (55) Edinburgh Handedness Inventory (56)

disorder and their relations to functional outcomes. It includes 14 tests focused on measures of General Ability, Attention, Working Memory, Verbal Knowledge, Learning, Non-Verbal Functions, Ideational Fluency, Executive Functions, and Motor Skills (Table 2). The specic tests used have been previously described by us and others; thus, we provide only a brief description in the Appendix. Sta administering NP tests were previously trained and observed in test battery administration to assure uniformity. As mentioned above, the same neuropsychological test battery was administered in both studies; however, we note that 3 of the variables were not obtained in the bipolar study due to the fact that our preliminary analyses indicated that they displayed a high degree of overlap with variables in their respective factors, and that the omission of these variables had essentially no impact on the internal consistency of these factors (change in Cronbach alpha was <0.05 for these factors). These variables were the Visual Memory Span Forward [Wechsler Memory Scale-Revised (WMS-R); included in the Attention factor based on Study 1]; Wechsler Adult Intelligence Scale-Revised (WAIS-R) Information (included in the Verbal Knowledge factor); and the WAIS-R Object Assembly variables (included in the Non-Verbal Functions factor). At the time of the previous publication, Study 1 was ongoing and data were available only from a subset of 156 subjects. By the time of the current analyses, the data were available from the entire SZ sample; thus, we used all available data for the current study of the replicability of the NC factor structure across the 2 diagnostic samples.
Conceptual framework of the statistical analyses

NC test batteries typically yield a large number of variables, hence a fundamental goal in NC

research is dimensionality reduction to nd a suitable representation of such multivariate data (i.e., to identify, based on the pattern of relationships among the observed variables, a relatively low number of basic underlying dimensions that provide the most ecient description of the variation in the data). This goal, in general, can be achieved by various multivariate techniques, including factor and principal component analyses (PCA), which view the observed variables as manifestations of some underlying, latent set of factors (dimensions). However, when applied to NC data, traditional multivariate methods, including PCA run into serious diculties because of the extremely high number of variables in the data relative to the number of observations. Even if the geometric properties of PCA remain valid, and numerical techniques yield stable results, the covariance matrix on which the analysis is carried out is sometimes a poor estimate of the real population covariance. Thus, the analysis under these conditions fails to provide a robust, generalizable solution. To deal with this problem, in our previous study to identify the basic NC dimensions in patients with SZ, a 2-stage procedure was designed to implement the PCA in a stratied way. Briey, in Stage 1, the neuropsychological variables were divided into blocks based on a priori knowledge about their observed associations. The 10 a priori blocks comprised Sustained Vigilance, Short-Term Memory Capacity/Span, Working Memory, Set Shifting/Cognitive Flexibility, Ideational Fluency, Verbal Learning, Non-Verbal Learning, Verbal Knowledge, Non-Verbal Reasoning/Problem Solving, and Motor Functioning. In Stage 2, the variables in each block were subjected to factor (principal component) analysis to identify the basic underlying NC constructs (factors) that explained most of the variation within such a block of variables. The factor analysis was based on the principal component method, and the PROMAX rotation (33) was applied in order to obtain a conceptually interpretable simple structure. The PROMAX rotation is an oblique rotation technique which allows for correlation between factors. Since there are conceptual as well as clinical reasons to presume a substantial correlation between the NC factors, this technique provides a more realistic representation of the data than the orthogonal solution which assumes independence. Further details of our procedures are described elsewhere. We note here, however, that a technique called block principal component analysis (BPCA) has

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Neuropsychological symptom dimensions been described recently in the literature (34), which analogous to the 2-stage procedure employed in our study, relies on variable stratication. Using multivariate statistical theory, it has been demonstrated that BPCA is as ecient as ordinary principal component analysis for dimensionality reduction (34). Based on the above approach, in our previous study (28), 6 factors were extracted as having good construct, divergent and predictive validity, and stability over time over an 18-month period of observation. The 6 factors were Attention, Working Memory, Learning, Verbal knowledge, NonVerbal functions, and Ideational Fluency (Table 3). An additional 5 NC measures, which have been widely studied in SZ, could not be reliably combined with any of these factors or with each another, indicating the need to examine them separately. These include: Wisconsin Card Sorting
Table 3. Six neurocognitive factors derived from the schizophrenia sample Neurocognitive factor Attention Neurocognitive measure included in factor D2 letters minus errors Stroop - words only Stroop - color only Trails A WMS-R Visual Memory Span Forwarda WAIS-R Digit symbol D2 uctuation WAIS-R Digit span forward LNS, number correct LNS, longest WAIS-R Arithmetic WAIS-R Digit Span Backward WMS-R Log Mem Immed WMS-R Verbal Pair I WMS-R Verbal Pair II WMS-R Visual Pair I WMS-R Visual Pair II WAIS-R Vocabulary WAIS-R Informationa WAIS-R Comprehension WAIS-R Similarities WAIS-R Block Design WAIS-R Object Assemblya WAIS-R Picture Completion WAIS-R Picture Arrangement WCST Number of Perseverative Errors Ruff Figural Fluency Unique Designs COWAT Animal Naming

Test Perseverative Errors, Stroop Interference, Trails B-Trails A/Trails A, Grooved Pegboard Preferred plus Non-Preferred Hand, Finger Tapping Preferred plus Non-Preferred Hand.
Statistical analyses

Working memory

Learning

Verbal knowledge

Non-verbal functions

Ideational uency

For the purpose of the current investigation, generalizability was considered as factorial invariance, i.e., constancy in the structure of the underlying NC constructs across diagnoses (BPD versus SZ). The concept of factorial invariance was based on Thurstones notion of simple structure (35), which states that the pattern of salient (nonzero) and non-salient (zero or near-zero) loadings denes the structure of a psychometric construct. In terms of factorial invariance, the principle of simple structure entails congurational invariance; items comprising the same construct are expected to exhibit the same conguration of salient and non-salient factor loadings across the 2 diagnostic groups. The analyses were conducted in multiple steps. First, the homogeneity of the correlation matrices across the 2 diagnostic samples was tested. Second, the empirical data from the bipolar sample were subjected to unrestricted exploratory factor analysis (EFA) to examine whether model modications were necessary in terms of the number of the factors and item composition of the underlying constructs derived in the SZ sample. Third, conrmatory factor analyses (CFA) (33) were conducted to statistically test the congurational invariance of the hypothesized factor structure, i.e., to examine whether the items have the same relationship to the same underlying factor as posited on the basis of the earlier analyses in the SZ sample. Fourth, since the CFA addresses the congurational invariance of factors across samples but does not directly investigate the extent of similarity, a factor analysis with conrmatory Procrustes rotation was performed to examine the extent of similarity between the BPD and SZ samples with regard to each of the individual factors. Finally, in Step 5, the psychometric properties (reliability and construct validity) of the NC factors derived in the bipolar sample were examined. Step 1: Homogeneity of correlation matrices. In Step 1, we tested the null-hypothesis of no-dierence in the correlation matrices between the BPD and the SZ sample. The analysis was based on the likelihood ratio approach, using nested hierarchical models of the data as implemented by the SAS PROC MIXED procedure (36). In particular, using the maximum likelihood estimation, rst we

D2 Concentration Endurance Test; Stroop Stroop ColorWord Interference Test; Trails Trailmaking Test; LNS Letter Number Span Test; Log Mem Immed Logical Memory (immediate recall); WCST Wisconsin Card Sorting Test; COWAT Controlled Oral Word Association Test. a Variables not available in the bipolar sample included: Wechsler Memory Scale Revised (WMS-R) Visual Memory Span Forward; Wechsler Adult Intelligence Scale-Revised (WAIS-R) Information; and the WAIS-R Object Assembly.

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derived a null-model likelihood by positing an unstructured homogeneous correlation matrix for the empirical data across the 2 diagnostic groups. Second, we relaxed the homogeneity condition (posited a heterogeneous correlation matrix by diagnostic group) and examined whether the resulting improvement in the likelihood reached statistical signicance. Test of improvement in model t was based on chi-square statistics. Step 2: Exploratory factor analyses. A failure to reject the null-hypothesis with regard to the homogeneity of the correlation matrices across the 2 diagnostic groups may be a reection of low statistical power. Thus, in view of the fact that we had a relatively small sample size, it is possible that the 2 groups have certain systematic dierences which would not result in the rejection of the null-hypothesis in our study. For example, it is conceivable that the number of interpretable factors is dierent in the 2 samples, or that most but not all of the factors are replicable (i.e., partial versus full factorial invariance). Therefore, before we proceeded with the CFA, we performed EFA to investigate whether the theoretically-postulated factor structure derived from the SZ sample represents an adequate representation of the pattern of observed associations among a group of variables in the BPD sample. More specically, in these preliminary analyses, we investigated whether model improvements were necessary in terms of the number of factors that need to be retained for further analyses, and in terms of the factor structure of the individual factors based on the distribution of salient and non-salient loadings. Similar to our previous study, we used the principal component method for factor extraction. The PROMAX rotation was applied in order to derive a simple structure to facilitate the interpretation. In order to examine the dimensionality in an EFA, we used the KaiserGuttman eigenvalue >1 criterion (37) and Cattells Scree plot (38). Items were allocated to factors according to their highest loading; the threshold loading of 0.5 was chosen to indicate saliency. Step 3: Conrmatory factor analyses. The relationship between the observed variables and the hypothesized underlying constructs can be investigated by CFA. The CFA techniques used in this investigation set a priori denitions of the factor structure (measurement model) based on the ndings from the SZ sample and based on our preliminary EFA ndings in the BPD sample. In the structural part of the CFA models, 2 theoretically possible alternatives were tested against each

other. In model 1, the basic assumption was that the 6 NC factors represent 6 distinct constructs with no relationship (correlation) between them. In model 2, all factors were considered interrelated constructs and a correlation was therefore allowed between any of the 6 factors. In the CFA, estimates of loadings of the individual neuropsychological items were obtained for their hypothesized factors. Values of t-statistics were used to test whether the individual items were signicantly related to their specic factors. The Root Mean Square Error of Approximation (RMSEA) and the Goodness of Fit Index (GFI) were used to assess model t for the entire CFA model. The RMSEA indicates the t of the model to the covariance matrix (or correlation matrix, as in our study). It represents the square root of the average amount that the sample covariances dier from their estimates derived on the basis of the posited factor model. As a guideline, RMSEA values below 0.1 are generally considered to indicate an adequate t, whereas values of <0.05 represent a close t. For GFI, values above 0.90 are considered as an indication of an adequate model t. Step 4: Generalizability across samples. As described above, following Thurstone (35), the most basic conceptualization of a construct is the pattern of non-zero and zero loadings, not the particular magnitude of the non-zero loadings. In this theoretical framework, in order to establish whether a construct can be conceptualized in the same way across diagnoses, the requirement is that the same pattern of (zero and non-zero) factor loadings is found in the individual groups. For this reason, in a multi-group CFA no cross-sample constraints are imposed on the magnitude of the salient factor loadings; the non-salient loadings are (implicitly) specied to be equal (i.e., zero). Therefore, whereas the CFA addresses the congurational invariance of factors across samples, it does not indicate the extent of similarity (generalizability), since it does not take the particular magnitude of the loadings into account. For the current study, conrmatory Procrustes rotation (39) was applied to investigate the extent of similarity (generalizability) between the SZ and the BPD samples (maximum congruence). This conrmatory procedure rotates empirically extracted principal components to a theoretically specied target matrix of factor loadings to maximize their similarity. The theoretical factor-loading matrix species the number of components to be tted and the factor-loading pattern of the test items. Unlike the CFA method, the Procrustes

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Neuropsychological symptom dimensions approach estimates loadings for all items (including items that are considered non-salient). The model t was evaluated by the coecient of congruence (CC) (38), normed between +1 and )1. Values of CC of 0.80 and above are considered to indicate sucient similarity between the empirically Procrustes-rotated and theoretically postulated factors. The sampling variation of the CC was estimated using the bootstrap/resampling approach (40). In order to do this, we rst randomly selected 1,000 samples with replacement from the original database; then, each of these samples, whose size was identical to the size of original dataset, was subjected to factor analysis with Procrustes rotation. Step 5: Reliability, construct validity. Scale (factorial) reliability was examined through the internal consistency reliability. Internal consistency for each of the 6 NC factors was determined by the use of Cronbach alpha (41). External (criterion-related) validity of the NC factors derived in the bipolar sample was investigated through the convergent, discriminant and concurrent validity. In particular, in order to establish convergent validity, we examined the degree to which the NC factors yielded convergent information with other, external measures that they would theoretically be expected to be similar to. For the purpose of the analyses reported here, 2 of the items of the CARSM, including Distractibility (Item 6, which excludes distractibility due to intrusions of visual and/or auditory hallucinations or delusions and rates whether attention is too easily drawn to unimportant or irrelevant external stimuli) and Disordered Thinking (Item 11) were investigated. Since, apart from such selected items, NC functioning and psychopathology may represent separate dimensions, for discriminant validity, we examined the degree to which the 6 NC factors overlapped with psychometric ratings of clinical symptoms. In particular, discriminant validity was examined via bivariate correlations between the components of the NC factors and the overall severity score of clinical symptoms, indexing mania and depression, respectively. To examine concurrent validity we assessed the ability of the 6 NC factors to distinguish between the 2 diagnostic groups. Table 4. Comparison of the 2 groups on the individual measures indicated a signicantly better performance in the BPD as compared to the SZ sample for 15 of 30 measures (corrected for multiple testing using the Hochberg procedure), although the magnitude of the dierence was generally modest.
Homogeneity of correlation matrices

The null-hypothesis of no-dierence between the correlation matrices from the BPD and the SZ sample was tested by the likelihood ratio test. In particular, rst we derived the null-model likelihood by positing an unstructured, homogeneous correlation matrix across the 2 diagnostic groups. Second, the homogeneity condition was relaxed (i.e., a heterogeneous correlation matrix was posited across the 2 groups), and we examined whether the resulting improvement in the modellikelihood over the null-model likelihood reached statistical signicance. The null-model likelihood indicated chi-square 5130.5 (df 350, p 0.0001), whereas the heterogeneous correlation model resulted in chi-square 5330.5 (df 701, p 0.0001). The likelihood ratio chi-square statistic for the improvement in model t did not reach statistical signicance (p > 0.1), indicating that the homogeneous correlation structure provides adequate t to the data across the 2 diagnostic groups.
Exploratory factor analysis

Results

Demographic and basic descriptive data at baseline

Descriptive neuropsychological data on all individual NC variables of interest are shown in

Overall, similar to our published ndings in the SZ sample, results of the exploratory factor analysis (principal component method with PROMAX rotation) in the bipolar sample indicated 6 factors based on both the KaiserGuttman eigenvalue criterion (i.e., eigenvalue > 1 for factors retained for further analyses) and on Cattells scree-plot criterion based on the breakpoint of the curve. Together, the 6 factors explained approximately 68.0% of the total variance in the neuropsychological dataset in the bipolar sample. The distribution of the amount of variance explained across the 6 factors was: Working Memory (12.6%), Attention (12.5%), Verbal Knowledge (12.0%), Non-Verbal Functions (11.6%), Ideational Fluency (11.1%), and Learning (9.2%). These results in the bipolar sample were similar to what we found in the expanded sample of schizophrenic patients that we used for the purpose of the current analyses [n 250, including the subsample of patients used for our previous

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Table 4. Descriptive statistics for individual neurocognitive measures Bipolar sample (n 155a) Neurocognitive measure D2 letters minus errors Stroopwords only Stroopcolors only Trail Making A Time WAIS-R Digit Symbol Raw D2 Fluctuations WMS-R Digit Span Forward LNS Total Correct LNS Longest Item Passed WAIS-R Arithmetic Raw WMS-R Digit Span Backward WMS-R Log Mem Immed Ruff Figural Fluency Unique Designs COWAT Total Correct Animal Naming Total Correct WAIS-R Vocabulary Raw WAIS-R Comprehension Raw WAIS-R Similarities Raw WAIS-R Block Design Raw WAIS-R Picture Completion Raw WAIS-R Picture Arrangement Raw WMS-R Verbal Paired Association I WMS-R Verbal Paired Association II WMS-R Visual Paired Association I WMS-R Visual Paired Association II WCST Number of Perseverative Errors Finger Tapping Preferred Finger Tapping Non-Preferred Grooved Pegboard Preferred Grooved Pegboard Non-Preferred Mean (SD) 358.5c 89.6c 59.7c 43.7c 44.3c 16.2 7.3 12.0c 4.7 8.9c 5.8 19.9c 66.8 33.7 18.9c 40.2c 15.9c 16.1 22.6 11.7 8.6 16.2 6.6 12.0c 4.8 21.0c 47.5c 43.6c 99.0 116.7 (98.5) (17.5) (13.8) (19.3) (13.6) (7.0) (2.1) (4.1) (1.1) (3.4) (2.4) (8.0) (24.9) (12.4) (6.8) (12.7) (5.6) (4.7) (10.5) (3.9) (4.5) (5.0) (1.6) (5.0) (1.7) (16.9) (9.8) (8.9) (37.1) (53.2) Q1Q3b 297429 76.5102.0 49.069.0 31.052.0 34.555.0 12.020.0 6.09.0 10.015.0 4.05.0 6.011.0 4.07.0 13.025.0 46.582.0 24.043.0 15.022.0 30.049.0 11.020.0 13.019.0 15.029.0 9.015.0 5.012.0 13.020.0 6.08.0 8.017.0 4.06.0 7.033.0 41.053.6 38.149.5 73.5114.5 80.0136.0 Schizophrenia sample (n 250a) Mean (SD) 321.2c 79.1c 53.7c 51.0c 38.8c 15.7 7.1 10.5c 4.4 7.8c 5.2 16.1c 60.2 31.7 16.5c 34.1c 13.9c 15.3 19.7 11.3 7.4 15.5 6.5 10.1c 4.5 31.2c 42.6c 39.4c 111.1 125.4 (96.7) (18.5) (14.7) (22.9) (12.6) (7.2) (2.0) (4.1) (1.3) (3.4) (2.0) (7.1) (21.0) (11.4) (5.8) (14.9) (5.7) (5.4) (9.7) (4.1) (4.4) (4.7) (1.6) (4.6) (1.7) (22.8) (9.9) (9.4) (62.4) (69.0) Q1Q3b 251395 68.091.0 43.064.0 34.061.0 30.046.0 10.019.0 6.08.0 8.013.0 3.05.0 5.010.0 4.06.0 11.021.0 45.073.0 24.039.0 13.020.0 21.045.0 9.018.0 12.019.5 12.025.0 9.014.0 4.010.0 13.019.0 6.08.0 7.014.0 3.06.0 16.038.0 36.050.3 33.346.0 77.0119.0 90.0133.0

D2 Concentration Endurance Test; Stroop Stroop Color-Word Interference Test; LNS Letter Number Span Test; Log Mem Immed Logical Memory (immediate recall); WAIS-R Wechsler Adult Intelligence Scale-Revised; WMS-R Wechsler Memory Scale-Revised; COWAT Controlled Oral Word Association Test. a Sample size may vary due to missing data. b Q1Q3 Interquartile range. c Signicant mean difference (p < 0.05, with Hochbergs adjustment for multiple testing) between the 2 samples (ANOVA).

analyses (n 156)]. In particular, the 6-factor solution in the SZ sample explained 67.8% of the variance. Furthermore, the individual factors explained a similar amount of variance in the SZ as in the BPD sample, with the exception of the ideational uency factor which was associated with a smaller amount of explained variance in the SZ sample. The distribution of explained variance across the 6 factors in the SZ sample was: Attention (15.0%), Working Memory (12.5%), Verbal Knowledge (11.7%), Non-Verbal Functions (11.5%), Learning (10.7%) and Ideational Fluency (3.4%). In addition to the above EFA analyses that focused on the same set of variables that we included in our previous analyses in the SZ sample, similar to our published study, we explored whether a separate motor factor can be derived in the BPD sample. For the purpose of this investigation, we added the 4 motor measures

(Table 4, last 4 rows) to the set of NC variables that we used above, and repeated the exploratory factor analysis that we performed for the more limited set of measures that did not include the motor variables. Similar to our previous analyses, the results indicated that the motor variables did not load on any of the 6 basic NC factors described above. In addition, a single motor factor could not be derived. Instead, based on the 4 variables that we used for the analysis 2 independent small factors (containing 2 related variables only) emerged, 1 for motor speed (Finger Tapping Preferred and Non-Preferred hand, respectively) and 1 for dexterity (Grooved Pegboard Preferred and Non-Preferred hand, respectively).
Conrmatory factor analysis

As mentioned in the methods, the CFA analysis set a priori denitions of the factor structure based on

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Neuropsychological symptom dimensions our earlier ndings from the SZ sample. In particular, the CFA assumed a simple structure: observed NC variables were allowed to assume a non-zero estimate only for 1 of the 6 underlying constructs, for which they were considered as indicators. In other words, estimates of loadings of the individual NC variables were obtained for their hypothesized factors only; loadings outside the underlying construct were not estimated (restricted to be 0). Results of the CFA analysis indicated that the correlated factor model (Model 2) which allowed correlations between the 6 underlying factors provided a signicantly better t to the data than the independent factor model (Model 1) (BPD sample: chi-square 164.4, df 15, p < 0.0001; SZ sample: chi-square 663.3, df 15, p < 0.0001). Indices of overall model t showed that GFI did not reach the recommended level in either of the 2 samples (BPD sample GFI 0.69; SZ sample GFI 0.82); the RMSA values were 0.094 and 0.074 in the BPD and the SZ samples, respectively. Table 5 displays the estimated factor loadings for Model 2 (correlated factors) based on the CFA
Table 5. Conrmatory factor analysis estimates of factor loadings Bipolar sample Factor Attention Neurocognitive measure D2 letters minus errors Stroop-words only Stroop-colors only Trail Making A Time WAIS-R Digit Symbol Raw D2 Fluctuations WMS-R Digit Span Forward LNS Total Correct LNS Longest Item Passed WAIS-R Arithmetic Raw WMS-R Digit Span Backward LMI Ruff Figural Fluency Unique Designs COWAT Total Correct Animal Naming Total Correct WAIS-R Vocabulary Raw WAIS-R Comprehension Raw WAIS-R Similarities Raw WAIS-R Block Design Raw WAIS-R Picture Completion Raw WAIS-R Picture Arrangement Raw WMS-R Verbal Paired Association I WMS-R Verbal Paired Association II WMS-R Visual Paired Association I WMS-R Visual Paired Association II Loading (SE) 0.69 0.58 0.70 0.69 0.79 0.34 0.63 0.95 0.87 0.52 0.65 0.40 0.80 0.56 0.66 0.86 0.68 0.65 0.70 0.64 0.73 0.61 0.76 0.78 0.68 (0.11) (0.12) (0.11) (0.11) (0.11) (0.12) (0.11) (0.09) (0.10) (0.12) (0.11) (0.12) (0.11) (0.12) (0.11) (0.11) (0.12) (0.12) (0.11) (0.12) (0.11) (0.12) (0.11) (0.11) (0.11) t-statistic* 6.19 4.98 5.95 6.24 7.41 2.83 5.74 10.58 9.00 4.53 5.86 3.37 7.32 4.70 5.78 7.74 5.78 5.52 6.18 5.51 6.43 5.19 6.97 7.18 5.95 Schizophrenia sample Loading (SE) 0.75 0.78 0.81 0.65 0.75 0.23 0.59 0.95 0.93 0.95 0.63 0.41 0.75 0.76 0.84 0.85 0.81 0.80 0.79 0.72 0.74 0.75 0.74 0.74 0.72 (0.06) (0.06) (0.06) (0.06) (0.06) (0.07) (0.06) (0.05) (0.05) (0.06) (0.06) (0.07) (0.07) (0.07) (0.05) (0.06) (0.06) (0.06) (0.06) (0.06) (0.06) (0.06) (0.06) (0.06) (0.06) t-statistic* 12.18 12.88 13.69 10.21 12.31 3.26 9.16 18.48 17.85 10.36 10.03 6.14 10.02 9.74 7.96 14.43 13.58 13.31 12.62 11.24 11.64 11.87 11.58 11.63 11.15

analysis conducted in the BPD and in the SZ samples, respectively. As Table 5 shows, the results were similar in both samples, suggesting congurational invariance across the 2 samples. In particular, the estimated loading coecients reached statistical signicance for each of the indicators (observed NC variables) for each of the hypothesized factors in both samples. We note, however, that for 2 of the variables [Concentration Endurance Test (D2) Fluctuations and Logical memory immediate recall (LMI)] the coecients were low (loading estimate <0.45) in both samples. Since these ndings suggested low indicator reliability for these variables with respect to their underlying construct (Working Memory, for both D2 Fluctuations and LMI), the above 2 variables were omitted from our nal CFA model. The CFA results based on this model indicated an improvement in the model t indices. In the BPD sample, the GFI and the RMSA were 0.72 and 0.086 respectively; in the SZ sample, the analogous values were 0.84 (GFI) and 0.064 (RMSA), respectively. Although the GFI indices failed to reach the recommended threshold, our nal factor model was based on the restricted set of variables

Working memory

Ideational uency

Verbal knowledge

Non-verbal functions

Learning

D2 Concentration Endurance Test; Stroop Stroop Color-Word Interference Test; LNS Letter Number Span Test; LMI Logical Memory (immediate recall); WAIS-R Wechsler Adult Intelligence Scale-Revised; WMS-R Wechsler Memory Scale Revised; COWAT Controlled Oral Word Association Test. *p < 0.05 for all values in the column.

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(i.e., not including D2 Fluctuations and LMI) since this set provided a closer t to the empirical data.
Procrustes matching

As described in the Methods, conrmatory Procrustes rotation was applied to investigate the extent of congruence between the factor structures derived in the bipolar and the SZ sample. This method is suitable for maximizing the similarity between a matrix of factor loadings and an assumed underlying structure by means of theory-based expectations as targets. Unlike the CFA, the Procrustes approach estimates for each factor the loadings for all variables used in the analysis (including items that are considered non-salient for a particular factor). For the purpose of the current study, the Procrustes analysis used the theoretically postulated target structure based on the factor structure derived in the nal factor model from the CFA analyses. Similar to our previous analysis, the factor analysis was based on the principal component method, and the PROMAX approach was used to allow for correlation among the 6 NC factors. Table 6 displays the estimated coecients of congruence between the corresponding factor pairs from the BPD and the SZ samples, respectively. As shown in Table 6, for 5 of the 6 factors including Attention, Working Memory, Verbal Knowledge, Non-Verbal Functions, and Learning, there was a high level of similarity between the set of loadings derived in the BPD and the SZ samples, respectively. For 1 of the factors (Ideational Fluency), the congruence was moderate. The factor loading estimates yielded by the Procrustes analysis are depicted in Figs 16 for each of the 6 NC factors, respectively. Consistent with coecient of congruence estimates, Figs 16 indicate a good correspondence between the set of
Table 6. Coefcient of congruence (CC) between factors derived in the bipolar and the schizophrenia samplea 95% Condence limitsb Factor Attention Working memory Ideational uency Verbal knowledge Non-verbal functions Learning
a

loadings derived in the BPD and the SZ samples, respectively, for all factors except for Ideational Fluency. An inspection of Fig. 3 indicates that this relative lack of congruence for this factor is due to the fact that, in the BPD sample, only 2 of the constituting items whereas in the SZ sample all 3 of the items reached saliency (in particular, in the bipolar sample, the loading for the Ru Figural Fluency Unique Designs was close to zero). As mentioned before, approximately 26% of the sample in the Schizophrenia Study was diagnosed with schizoaective disorder, and 11% in the Bipolar Study evidenced some symptoms of Delusions or Hallucinations. Inclusion of these subjects in the analyses increased diagnostic heterogeneity and phenomenological overlap across diagnoses, which may have served as a major contributing factor to the similarity of the factor structures across diagnoses. To investigate this possibility further, in additional secondary analyses, we excluded the aforementioned subjects, and recomputed the coecient of congruence for the factor structure across diagnoses. Results indicated that the 6 NC factors were replicable with the more homogeneous samples; the values of CC remained almost unchanged between the 2 diagnostic samples (Attention 0.863, Working Memory 0.805, Ideational Fluency 0.601, Verbal Knowledge 0.797, Non-Verbal Functions 0.821 and Learning 0.890).
Reliability, validity

Construct reliability. Table 7 displays the Cronbach alpha estimate (measuring internal consistency) for each factor in each of the 2 samples. As Table 7 shows, the internal consistency for the individual factors was generally good, with the exception of the Ideational Fluency factor for which the internal consistency estimate in each sample was only of moderate magnitude. Overall, no meaningful dierences were observed between the 2 samples in terms of construct reliability of the 6 NC factors. Convergent validity. For convergent validity, we examined the degree to which the NC factors provided convergent information with measures that they would theoretically be expected to be overlapping. The analyses focused on 2 items of the CARS-M, including Distractibility (Item 6) and Disordered Thinking (Item 11). In particular, association between the above 2 items (i.e., Distractibility, Disordered Thinking) and the 6 NC factors, respectively, was examined by logistic regression analysis. Results of the logistic regressions analyses are shown in Table 8.

Observed CC value 0.883 0.878 0.658 0.818 0.837 0.903

Lower 0.787 0.794 0.467 0.704 0.675 0.813

Upper 0.979 0.962 0.850 0.932 0.999 0.993

Factor analysis was based on the PROMAX method using Procrustes rotation. b Bootstrap/resampling estimates, based on 1,000 samples drawn randomly from the original observed dataset.

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Attention factor
1.00

Factor loadings

0.50

0.00

Digit Sp. Forw.

LNS, Correct

LNS, Longest

Arithmetic

Digit Sp. Back.

Ruff Uniq.Des.

COWAT Total

Anim. Naming

WAIS Block D.

WAIS Pict.Cp.

Stroop, Words

Stroop, Colors

WAIS Pict.Arr.

Trails A, Time

D2 Lett.-Error

Digit Symbol

WAIS Compr.

Verb. Paired I

Verb. Paired II

WAIS Vocab.

WAIS Similar.

Visual Paired I

Visual Paired lI

Bipolar SCH/SCA

Fig. 1. Attention: comparison of factor loadings obtained in the bipolar and schizophrenia samples. The factor analysis was based on the principal component method applying Procrustes rotation. Factors from the 2 samples were matched (paired) on the basis of their congruence. On the horizontal axis, individual neuropsychological variables entering the factor analysis were grouped according to the 6 factors identied on the basis of previous study (28). D2 Concentration Endurance Test; Stroop Stroop Color-Word Interference Test; LNS Letter Number Span Test; COWAT Controlled Oral Word Association Test; WAIS Wechsler Adult Intelligence Scale.

Working memory factor

1.00

0.50

Factor loadings

0.00

Digit Sp. Forw.

LNS, Longest

LNS, Correct

Arithmetic

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Stroop, Words

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Ruff Uniq.Des.

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Visual Paired I

D2 Lett.-Error

Trails A, Time

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WAIS Pict.Cp.

WAIS Pict.Arr.

Verb. Paired I

Verb. Paired II

Visual Paired lI

COWAT Total

Anim. Naming

Bipolar SCH/SCA

Fig. 2. Working memory: comparison of factor loadings obtained in the bipolar and schizophrenia samples. See Fig. 1 for complete description and abbreviations.

As Table 8 indicates, the clinical rating of Distractibility was associated with poorer functioning on the Attention and Non-Verbal Functions factors (and to a lesser extent on Learning). As expected, the largest eect size was observed for the association with the Attention factor. Disordered Thinking had a more general relationship with NC functioning, as indexed by the NC factors. In particular, a statistically signicant association was observed for 5 of the 6 factors including Attention, Working Memory, Ideational Fluency, Verbal Knowledge, Non-Verbal Func-

tions. The association did not reach signicance for Learning. Discriminant validity. For discriminant validity, we investigated the degree to which the 6 NC factors overlapped with psychometric ratings. In particular, discriminant validity was examined via bivariate correlations between the neurocognitive factors and the overall severity score of clinical symptoms, indexing mania (total score on the CARS-M scale) and depression (total score on HAM-D scale, 17-item version), respectively.

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Ideational fluency factor
1.00

0.50

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0.00

Ruff Uniq.Des.

COWAT Total

Anim. Naming

Verb. Paired I

Verb. Paired II

Visual Paired I

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Stroop, Words

Stroop, Colors

Trails A, Time

D2 Lett.-Error

Digit Sp. Forw.

LNS, Correct

LNS, Longest

Digit Symbol

Arithmetic

Digit Sp. Back.

WAIS Compr.

WAIS Block D.

WAIS Pict.Cp.

WAIS Pict.Arr.

WAIS Vocab.

WAIS Similar.

Bipolar SCH/SCA

Fig. 3. Ideational uency: comparison of factor loadings obtained in the bipolar and schizophrenia samples. See Fig. 1 for complete description and abbreviations.

Verbal knowledge factor

1.00

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0.50

0.00

Ruff Uniq.Des.

Anim. Naming

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Trails A, Time

WAIS Vocab.

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WAIS Similar.

Bipolar SCH/SCA

Fig. 4. Verbal knowledge: comparison of factor loadings obtained in the bipolar and schizophrenia samples. See Fig. 1 for complete description and abbreviations.

Results of these analyses revealed no statistically signicant association between the total score on the HAM-D scale and any of the 6 NC factors. Analyses of the total score on the CARS-M scale indicated 2 signicant, but modest associations including the Working Memory (n 148, r )0.20, p 0.017) and the Non-Verbal Knowledge factors (n 148, r )0.16, p 0.047), respectively. Concurrent validity. To examine concurrent validity we assessed the ability of the 6 NC factors to distinguish between the 2 diagnostic groups. The analyses were based on the analysis of covariance (ANCOVA) model using the NC factors as dependent variables, with a separate analysis

performed for each of the factors. Diagnostic group served as an independent variable in the ANCOVA analysis; full-scale IQ, education, gender and ethnicity were used as covariates. Results of the comparisons between the 2 diagnostic groups are summarized in Table 9. As shown in Table 9, patients in the BPD sample displayed a signicantly better functioning on each of the NC factors than patients in the SZ sample. However, after adjustment for the covariates, a signicant group dierence was detectable only on the Attention and Non-Verbal Functions factors. Since age, onset of illness, and the age at rst treatment may have a dierential impact on NC functioning in the 2

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Non-verbal functions factor
1.00

0.50

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0.00

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Arithmetic

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Digit Symbol

WAIS Compr.

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Verb. Paired II

WAIS Vocab.

WAIS Similar.

Visual Paired I

Visual Paired lI

Bipolar SCH/SCA

Fig. 5. Non-verbal functions: comparison of factor loadings obtained in the bipolar and schizophrenia samples. See Fig. 1 for complete description and abbreviations.
Learning factor
1.00

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0.50

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WAIS Block D.

WAIS Pict.Cp.

WAIS Pict.Arr.

Trails A, Time

Bipolar SCH/SCA

Fig. 6. Learning: comparison of factor loadings obtained in the bipolar and schizophrenia samples. See Fig. 1 for complete description and abbreviations.

diagnostic groups, in additional ANCOVA analyses, these variables were introduced in order to test the possibility of a dierential relationship. None of the analyses indicated a signicant eect (i.e., p > 0.10 in all analyses for the main eect or for the interaction of the above variables with the diagnosis).
Discussion

To our knowledge, this is the rst study that compared the factor structure across diagnoses including SZ and BPD. The results, taken together, indicated that the factor structure is generalizable across the 2 diagnostic samples. In particular, the coecient of congruence between the individual

factors derived from the 2 samples was high, and the CFA showed that the items loaded on the factors that were theoretically stipulated on the basis of measurement model based on our prior SZ study. Furthermore, the congruence between the factor structures remained essentially unchanged with the more homogeneous samples (i.e., after excluding subjects who had schizoaective disorder in Study 1; or evidenced DSM-IV symptoms of delusions and hallucinations in Study 2). It is noteworthy that similar factor structures emerged in spite of sample dierences on some demographic characteristics and IQ. Specically, the bipolar sample had a higher proportion of females and white ethnicity than the SZ sample, as well as more years of education and higher full

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Table 7. Internal consistency reliability (Cronbach alpha) and item composition of each neurocognitive factor Standardized alpha Neurocognitive factor Attention Neurocognitive measure included in factor D2 letters minus errors Stroop-words only Stroop-color only Trails A WAIS-R Digit symbol WAIS-R Digit Span Forward LNS, number correct LNS, longest WAIS-R Arithmetic WAIS-R Digit Span Backward Ruff Figural Fluency Unique Designs COWAT Animal Naming WAIS-R Vocabulary WAIS-R Comprehension WAIS-R Similarities WAIS-R Block Design WAIS-R Object Assembly WAIS-R Picture Completion WAIS-R Picture Arrangement WMS-R Verbal Pair I WMS-R Verbal Pair II WMS-R Visual Pair I WMS-R Visual Pair II Bipolar sample 0.83 Schizophrenia sample 0.86

Working memory

0.83

0.87

Ideational uency

0.65

0.65

Verbal knowledge

0.80

0.86

Non-verbal functions

0.70

0.80

Learning

0.80

0.82

D2 Concentration Endurance Test; Stroop Stroop Color-Word Interference Test; LNS Letter Number Span Test; COWAT Controlled Oral Word Association Test; WAIS-R Wechsler Adult Intelligence Scale-Revised; WMS-R Wechsler Memory ScaleRevised. Table 8. Criterion-related validity: bipolar sample (n 155)a Distractibility Characteristic Attention Working memory Ideational uency Verbal knowledge Non-verbal functions Learning
a

Disordered thinking ORb 2.0 1.8 1.8 1.9 1.8 1.3 (1.23.3) (1.22.9) (1.22.8) (1.23.0) (1.22.9) (0.82.0) Chi-square (p)c 7.8 6.5 8.5 7.6 7.6 1.4 (0.0054) (0.011) (0.0035) (0.006) (0.0058) (0.24)

ORb 1.6 1.4 1.4 1.4 1.5 1.4 (1.02.5) (0.92.1) (0.92.0) (0.92.1) (1.02.3) (0.92.2)

Chi-square (pc) 4.2 2.3 2.8 2.4 4.0 2.0 (0.040) (0.13) (0.10) (0.12) (0.046) (0.087)

Sample size may vary due to missing data. OR odds ratio statistics, indicating the odds ratio increase for higher symptom severity for each SD unit of decrease in functioning on a particular neurocognitive factor. c Based on logistic regression analysis with symptom severity (Disordered Thinking, Distractibility) as a dependent variable and neurocognitive factor as an independent variable.
b

scale-IQ (although full scale-IQ was generally low in both samples). However, in contrast to the above variables, the 2 diagnostic groups were almost identical in terms of age and age at onset of illness. This is consistent with the fact that SZ and bipolar illness share a number of characteristics, including their onset starting in early adult life (42). The factor analyses yielded a similar structure across diagnoses both in terms of the number of factors and congurational invariance (salience of the loadings). With respect to the number of factors,

the exploratory factor analysis indicated 6 factors based on the KaiserGuttman eigenvalue >1 criterion and Cattells scree plot. The total amount of variance explained by the 6 NC factors in the 2 samples, respectively, was essentially identical. Specically, the 6 factors, together, explained approximately 68.0% and 67.8% of the total variance in the NC dataset in the BPD sample. In addition to the total variance explained, the distribution of the explained variance across the individual NC factors was also similar in the 2 samples.

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Table 9. Neurocognitive factor scores in the bipolar and the schizophrenia samples Neurocognitive measure Bipolar sample Mean (SD) 0.45 0.27 0.27 0.33 0.27 0.26 (0.75) (0.79) (0.92) (0.74) (0.81) (0.85) Schizophrenia sample Mean (SD) )0.01 )0.03 )0.03 )0.03 )0.02 )0.01 (0.82) (0.81) (0.75) (0.87) (0.85) (0.80) Group difference F (p)a 7.8 0.1 2.2 0.0 6.7 1.2 (0.006) (0.80) (0.14) (0.94) (0.01) (0.28)

Attention Working Memory Ideational Fluency Verbal Knowledge Non-Verbal Functions Learning
a

p-values are based on the analysis of covariance model and were adjusted for full-scale IQ, years of education, gender and ethnicity as covariates; a signicant group difference between groups was observed on each factor without the adjustment for the covariates. Higher mean values indicate better functioning. Since the schizophrenia sample was used as a reference, means in this sample were essentially identical to zero.

In general, the individual factors accounted for approximately 1015% of the variance in each of the samples, with the exception of the Ideational Fluency which explained a substantially smaller amount of the variance in the BPD (3.4%) than in the SZ sample (11.1%). Consistent with this nding, the coecient of congruence based on the Procrustes analysis showed only a moderate agreement between the 2 samples for the Ideational Fluency factor, in contrast to the high level agreement observed for all other factors. As shown in Fig. 3, the relatively lower congruence for this factor is due to the fact that in the bipolar sample only 2 of the 3 constituting items reached saliency (whereas in SZ sample all 3 of these items provided high loadings on the factor). Since all subjects in this study received medication (typically polypharmacy; see above), it is conceivable that the high degree of similarity across factor structures in the 2 samples was to due to medication eects. However, while this possibility cannot be excluded, we think that this explanation is unlikely since the distribution of treatments in the 2 diagnostic groups showed marked dierences in the current investigation. Overall, whereas the CFA results indicated that the estimated loading coecients obtained statistical signicance for each of the indicators (observed NC variables) for each of the hypothesized factors that they were considered part of, for 2 variables (D2 Fluctuations and LMI) the coecients were low (loading estimate <0.45) in both samples. Since these ndings suggested low indicator reliability for these variables with respect to their underlying construct, they were omitted from our nal model. In addition, the motor variables were not included in nal CFA model because, similar to our previous ndings, the current results failed to provide empirical support for combining motor speed and dexterity measures into a single motor factor (28). Instead, the analyses yielded 2 independent small factors, 1 for motor speed (Finger Tapping Preferred and Non-Preferred hand,

respectively) and 1 for dexterity (Grooved Pegboard Preferred and Non-Preferred hand, respectively). Consequently, in future studies, the set of 6 NC factors needs to be supplemented by additional measures if these abilities are of specic interest (e.g., motor variables, Wisconsin Card Sorting). In addition to generalizability across diagnoses, the set of 6 NC factors showed favorable psychometric properties in both samples. More specically, the internal consistency for the individual factors was generally good (typically 0.80 or above), with the exception of the Ideational Fluency factor for which the internal consistency estimate in each sample was of moderate magnitude (0.65 in each sample). The internal consistency was similar across the samples, with only minor dierences between the 2 diagnostic groups. With regard to external validators, the NC factors provided convergent information with measures that they would theoretically be expected to be overlapping. Logistic regression analyses indicated that the CARS-M Distractibility rating was related to poorer functioning on the Attention and Non-Verbal Functions factors, with the largest eect size observed for the association with the Attention factor. Disordered Thinking had a more general relationship with neurocognitive functioning; a signicant association was present for 5 of the 6 factors including Attention, Working Memory, Ideational Fluency, Verbal Knowledge, NonVerbal Functions. Overall, these results revealed a remarkable consistency between the NC factors and the clinicians observations. The fact that there was only a minimal overlap between the 6 NC factors and the overall severity on symptoms of mania and depression, respectively, indicates that these factors have good discriminant validity as compared to clinical symptoms. The CARS-M total score showed only 2 statistically signicant (p < 0.05), but clinically modest associations, 1 with the Working Memory (r )0.20) and with the Non-Verbal Knowledge

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factors (r )0.16), respectively. Furthermore, there was no signicant association between the HAM-D total score and any of the 6 NC factors. These results are consistent with the notion that clinical symptoms and NC functioning constitute independent dimensions. In the current investigation, concurrent validity was supported by the nding that the NC factors distinguished the 2 diagnostic groups. Overall, the results showed a general dierence among the 2 groups: without an adjustment for the covariates, patients in the BPD sample displayed signicantly better functioning on each of the NC factors than patients in the SZ sample. Thus, these results, at face value, are consistent with the view that patients with BPD suer less severe cognitive impairments than do patients with SZ (22, 43). However, we note that after an adjustment for the observed group dierences in the covariates, a signicant dierence between the 2 samples was detectable only on the Attention and Non-Verbal Functions factors. Because it can be argued that dierences in IQ and education may be a consequence of the illness and therefore the adjustment for these covariates is hard to justify in a study of NC dierences, we repeated the analyses by controlling for the demographic variables, but not for IQ and education. The results indicated that in addition to Attention and Non-Verbal Functions, the dierence in Ideational Fluency reached signicance. Thus, together, these ndings indicate a specic prole of dierence, instead of a general dierence in the overall NC functioning between the 2 diagnostic groups. Nonetheless, it should be noted that in terms of statistical eect size (Cohens d) the dierence between the 2 diagnoses was relatively modest. In particular, the eect sizes, after adjusting for the covariates, fell in the moderate range for the Attention and Non-Verbal Functions (0.41 and 0.38, respectively); for factors that failed to obtain statistical signicance the eect size was small (0.2 for Ideational Fluency, and <0.15 for the 3 remaining factors after correcting for the covariates). Eect sizes of this magnitude are associated with a large degree of overlap in terms of the underlying distributions. Specically, an eect size of approximately 0.4 (Attention) indicates a 73% overlap for the factor score distributions between the 2 diagnostic groups, whereas an eect size of approximately 0.20 (Ideational Fluency) shows an 85% overlap. Such a large degree of overlap can be indicative of a dimensional rather than a categorical transition between the 2 diagnoses, and may be explained by shared genetic susceptibility, and/or common underlying neurobiological substrates.

However, in addition to the possibility that NC functions serve as common endophenotypic markers across diagnoses, alternative explanations are conceivable [e.g., iatrogenic eects such as use of medication; confounding factors such as drug and alcohol abuse; NC impairment (e.g., impairment in attention) represent non-specic of brain dysfunction; imprecision of diagnoses]. Future studies need to investigate these possibilities further.
Limitations

There were a number of limitations in this study. First, despite the large sample size, the number of observations for the multivariate analyses was relatively small, and therefore sampling variance may have aected the results. Second, whereas the CFA showed high loadings for the individual NC variables with respect to their hypothesized factors, the overall t indices in the CFA analysis did not demonstrate a close t for the entire model. The lack of close t in the current investigation is consistent with the fact that approximately 1/3 the total variance of the observed empirical variables remained unaccounted for by the factors (i.e., the 6 factors together explained 68% of the variance). While the aforementioned proportion of explained variance appears low, we note that this proportion (68%) is higher or comparable to those described for widely used psychometric scales, such as the BPRS (44) and PANSS (45). This value is also comparable with the amount of variance (74%) explained by 6 factors in the analyses of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (25) (despite that the factors in the analyses of the RBANS were retained if their eigenvalue was >0.7 as opposed to >1, the KaiserGuttman rule that was adopted for our study). Third, the investigation of the generalizability of the factor structure was based on cross-sectional data; such data have the potential to confound state and trait eects. Since the factor structure may changeovertime,theanalysisoflongitudinalchanges in NC functioning and their impact on the factor structure in the BPD sample is essential. However, we note that the theoretical factor structure that we tested in this study was derived based on both crosssectional and longitudinal approaches, using data from an on-going longitudinal study of SZ. Finally, the analyses were conducted in bipolar patients only; additional studies should therefore address the issue of broader diagnostic generalizability (e.g., with regard to major depressive disorder).

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Conclusion
specic and generic brain structural endophenotypes. Arch Gen Psychiatry 2004; 61: 974984. Woo TU, Walsh JP, Benes FM. Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch Gen Psychiatry 2004; 61: 649657. Clinton SM, Meador-Woodru JH. Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropsychopharmacology 2004; 29: 13531362. Craddock N, ODonovan MC, Owen MJ. Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull 2006; 32: 916. Craddock N, ODonovan MC, Owen MJ. The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005; 42: 193204. Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 405411. Segurado R, Detera-Wadleigh SD, Levinson DF et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: bipolar disorder. Am J Hum Genet 2003; 73: 4962. Maier W, Zobel A, Wagner M. Schizophrenia and bipolar disorder: dierences and overlaps. Curr Opin Psychiatry 2006; 19: 165170. Cardno AG, Rijsdijk FV, Sham PC et al. A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry 2002; 159: 539545. Daban C, Martinez-Aran A, Torrent C et al. Specicity of cognitive decits in bipolar disorder versus schizophrenia. A systematic review. Psychother Psychosom 2006; 75: 7284. Johnson MH, Magaro PA. Eects of mood and severity on memory processes in depression and mania. Psychol Bull 1987; 101: 2840. Thompson JM, Gallagher P, Hughes JH et al. Neurocognitive impairment in euthymic patients with bipolar aective disorder. Br J Psychiatry 2005; 186: 3240. van Gorp WG, Altshuler L, Theberge DC et al. Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. A preliminary study. Arch Gen Psychiatry 1998; 55: 4146. Tabares-Seisdedos R, Balanza-Martinez V, Salazar-Fraile J et al. Specic executive/attentional decits in patients with schizophrenia or bipolar disorder who have a positive family history of psychosis. J Psychiatr Res 2003; 37: 479486. Martinez-Aran A, Vieta E, Colom F et al. Neuropsychological performance in depressed and euthymic bipolar patients. Neuropsychobiology 2002; 46 (Suppl. 1): 1621. Seidman LJ, Kremen WS, Koren D et al. A comparative prole analysis of neuropsychological functioning in patients with schizophrenia and bipolar psychoses. Schizophr Res 2002; 53: 3144. Glahn DC, Bearden CE, Niendam TA et al. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar aective disorder. Bipolar Disord 2004; 6: 171182. Krabbendam L, Arts B, van Os J et al. Cognitive functioning in patients with schizophrenia and bipolar disorder: a quantitative review. Schizophr Res 2005; 80: 137149. Hobart MP, Goldberg R, Bartko JJ et al. Repeatable battery for the assessment of neuropsychological status as a screening test in schizophrenia, II: convergent/discriminant validity and diagnostic group comparisons. Am J Psychiatry 1999; 156: 19511957.

Together, the results of this study indicate that while the same underlying factor structure describes NC functioning in both diagnostic groups, the prole of impairments may vary with the diagnosis. The group comparisons revealed dierences between patients with BPD and SZ in the neurocognitive domains of Attention and Non-Verbal Functions, which may indicate that NC factors operate in a dierent way in the 2 illnesses. The large degree of overlap between the respective distributions of NC variables across diagnoses can be interpreted as reection of a dimensional rather than a categorical transition between the 2 diagnoses. It may be underlied by shared genetic susceptibility, although alternative explanations are conceivable including (but not restricted to) iatrogenic eects due to medication and confounding factors such as drug and alcohol abuse. Overall, the nding of similar factor structure is consistent with the hypothesis that the same cognitive processes are involved in both disease entities; however, the nature of these processes appears to be dierent in the 2 disorders.
Acknowledgements
The authors are grateful for the valuable advice and support provided by Dr Samuel Gershon, Dr Anil Malhotra, and Estelle Douglas, as well as the diligence in data collection and quality management provided by Drs Sara Davis-Conway, Scott Greisberg, Rebecca Iannuzzo, Pradeep Nagachandran and Sarah Uzelac and by Mr Sherif Abdelmessih, Ms Claudia Salazar, Ms Marilyn Mejia, Ms Pam DeRosse, Ms Priya Matneja and Ms Donna OShea. The authors owe enormous gratitude to the study participants who give generously of their time and without whose eorts and patience this work would never be possible. Funding Source: NIMH R01 MH 60904, Stanley Medical Research Institute.

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Appendix: Neuropsychological tests used in the battery

Wechsler Adult Intelligence Scale-Revised (WAIS-R) (57)

The goal of this scale is to provide an overall evaluation of intellectual functioning. The scale is composed of 11 subtests, 6 verbal and 5 performance oriented, which yield, respectively, the verbal IQ (VIQ), the performance IQ (PIQ), and the full scale IQ (FSIQ; representing the composite of VIQ and PIQ). The verbal subtests are the Information, Digit Span (forward and backward tasks), Vocabulary, Arithmetic, Comprehension and Similarities; the performance subtests are the Picture Completion, Picture Arrangement, Block Design, Object Assembly, and Digit Symbol. The analyses that we conducted for the purpose of this study included each of the verbal and performance subtests.
Wechsler Memory Scale Revised (WMS-R) (58)

The WMS-R test investigates various aspects of memory functioning, verbal and non-verbal learning and attention. In the current study, the verbal and visual paired associates tasks were included as putative indices of Verbal and Non-Verbal learning. Logical Memory I (immediate recall) was included as part of the of the Working Memory factor; the Visual Memory Span subtest (tapping forward) was used for the Attention factor.
Letter Number Span (46)

In the Letter-Number Span test, the subject is asked to order short sequences of randomly presented letters and numbers. In order to perform this task, the information needs to be maintained

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Neuropsychological symptom dimensions over a short delay and transformed. Since the test requires both memory storage and processing, it is considered an index of working memory functions. The current investigation adopted the number of correct trials and the longest sequence as the measures of interest for the analyses.
Concentration Endurance Test (D2) (48)

the color and word reading conditions were reliable indices of the Attention factor.
Wisconsin Card Sorting Test (WCST; 128 card manual version) (50)

The purpose of this test is to assess sustained attention and visual scanning ability. This paperand-pencil test is modeled after other cancellation tasks; the subject is asked to detect as many target letters as possible in a matrix of letters consisting of 14 lines. For the purpose of the present study, the total score minus errors (letters minus errors) and the uctuation (dierence between the row with the highest rate of production and the lowest rate of production) were selected for the analyses.
Trail Making Test (A & B) (51)

This test has been extensively described in the literature and seems to be cognitively polyfactorial, reecting Set Shifting, Working Memory Ideational Fluency, Abstraction, Hypothesis Testing, and Responsiveness to Feedback. Based on previous literature and our prior factor analyses, the principal variable of interest for this study was the number of perseverative errors that occurred during a given trial.
Controlled Oral Word Association Test (COWAT) (52)

Visual motor speed and set shifting were assessed using the Trail Making Test with 2 parts: A and B. The time to complete each test part (A and B) was recorded for each patient, with a maximum of 5 min allowed per part. In part A, patients were asked to connect in sequential order 25 numbers randomly distributed on a test page. In part B, the test items included both numbers and letters, and the sequence connection was numeric-alphabetic in an alternating sequence. Based on our previous factor analytic study (28), the time to completion in seconds in part A of the test was the principal variable of interest for this task.
Stroop Test (49)

Controlled Oral Word Association Test was used for the assessment of verbal uency within phonemic (letter) constraints. For this task, patients were given one letter of the alphabet at a time and instructed to say aloud as many words beginning with that letter as they could within 1 min, for a total of 3 letters in 3 min. The variable of interest for the current analyses was the total number of correct responses (words provided) for the 3, 1-min trials.
Animal Naming Test (51)

The Animal Naming Test is part of the Boston Diagnostic Aphasia Examination. It is a generative naming task employing semantic constraints. Subjects are instructed to name as many dierent animals as possible in 90 s, and the most productive 60 s are scored.
Ruff Figural Fluency Test (RFFT) (53)

The Stroop Test is considered a measure of selective attention and cognitive exibility (response inhibition). In the conict condition, the test requires subjects to inhibit automatic responses by naming the color of ink in which color words are presented. Patients are asked to read word names or name colors as quickly as possible. The number of correct responses within a 60-s trial was used as the measure of interest. The test consists of 3 conditions: presenting color names in black ink (labeled as words) and presenting a block of xs in colored ink, the task being to name the color of each block and nally a conict condition in which color names are printed in text having a dierent color (e.g., the word green printed in red ink). Our previous work showed that while the conict condition did not reliably correlate with any of the cognitive factors,

Figural uency tests have been developed to provide a non-verbal analogue of the word (verbal) uency tasks; the RFFT measures the production of novel designs under both graphical and time constraints. Ru et al. (53) suggested that the task reects uid and exible thinking and the ability to create novel responses without repetition.
Grooved Pegboard Test (54)

Fine motor skills including motor speed, visualmotor coordination, and single-hand dexterity were tested using the Grooved Pegboard Test. Patients were asked to use one hand to put 25 pegs in a 5 by 5 grooved pegboard. The holes of the

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pegboard have slots and the pegs have a key on one side that must be rotated to match the hole in the board. The number of completed rows, number of pegs dropped, and time to complete the test was recorded for each hand. A maximum of 5 min was allowed for testing each hand.
Finger Tapping Test (55)

Complex Ideational Material (47)

Language comprehension was assessed with 8 yes/ no questions from the Test of Complex Ideational Material (CIM) from the Boston Diagnostic Aphasia Exam (47).
Edinburgh Handedness Inventory (EHI) (56)

The Finger Tapping Test was adopted as a measure of motor speed. Subjects tap on a lever for 5, 10-s trials with their dominant and nondominant hand. The total number of taps for each hand was used for statistical analysis.

The EHI, a standard test of manual dexterity, was used for determining which hand would be considered preferred hand for motor tests.

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