Parsing Schizophrenia with Neurocognitive Tests: Evidence of Stability and Validity

35, 207–224 (1997) BR970938

BRAIN AND COGNITION ARTICLE NO.

Parsing Schizophrenia with Neurocognitive Tests: Evidence of Stability and Validity R. Walter Heinrichs, Lesley Ruttan, Konstantine K. Zakzanis, and Danielle Case York University The stability and validity of a neurocognitive typology for schizophrenia were studied in 55 chronic patients who met DSMIII-R criteria for the illness. Subtypes were based on an earlier cluster analytic study by Heinrichs and Awad (1993) that utilized the following variables: IQ (WAIS-R), categories (Wisconsin Card Sorting Test), free recall intrusions (California Verbal Learning Test), and bilateral motor performance (Purdue Pegboard). Stability was examined by analyzing subtype assignment at the original assessment and 3 years later at follow-up. Stability over this interval was variable with an overall kappa of .45 and individual kappas from .12 to .66. Adjunct cognitive and clinical data gathered at follow-up provide evidence for the validity of several subtypes, especially in terms of their cognitive and functional differences. There was no evidence of symptom differences in this relatively asymptomatic medicated sample of patients. The results are discussed in terms of the possibility that several patterns of neurocognitive dysfunction may underlie schizophrenia, with implications for understanding the heterogeneity of the illness and its variable functional outcomes.  1997 Academic Press

No psychological or biological abnormality is shared by all individuals with a diagnosis of schizophrenia. This lack of coherence is a major obstacle to understanding the illness and may reflect the existence of several distinct disorders with different causes and behavioral features (Bellak, 1994; Carpenter, Buchanan, Kirkpatrick, Tamminga, & Wood, 1993; Heinrichs, 1993). Numerous attempts have been made to identify more homogenous groups of patients by analyzing symptoms to create typologies and subclassifications (e.g., paranoid/nonparanoid, positive/negative). Some traditional subtypes Data collection was supported by grants from the Ontario Mental Health Foundation to R. Walter Heinrichs and a graduate assistantship from York University to Lesley Ruttan. Appreciation is expressed to Ed Janiszewski and Queen Street Mental Health Centre for support and assistance with the study. We also thank Michael Friendly for statistical advice. Address correspondence and reprint requests to R. Walter Heinrichs, Department of Psychology, York University, 4700 Keele Street, North York (Toronto), Ontario, Canada M3J 1P3. 207 0278-2626/97 $25.00 Copyright  1997 by Academic Press All rights of reproduction in any form reserved.

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like paranoid/nonparanoid have received partial validation (Nicholson & Neufeld, 1993). However, most efforts at symptomatic subtyping have yielded unclear boundaries between subtypes, weak validity, and stability, and questionable empirical justification (Carpenter, Heinrichs, & Wagman, 1985; Helmes, 1991). This suggests that alternative ways of parsing and organizing schizophrenia should be considered. Neurocognitive test data offer a number of advantages over symptom ratings as a basis for subtyping. Neurocognitive tests are more objective and neurologically valid than symptom ratings, reflecting a long history of research on the cerebral basis of cognition (Frith, 1992; Strauss & Sommerfeldt, 1994). Although the temporal stability of neurocognitive performance needs further demonstration, test performance is not reducible readily to medication effects (Cassens, Inglis, Appelbaum, & Gutheil, 1990; Spohn & Strauss, 1989) or to chronicity of illness (Cleghorn, Kaplan, Szechtman, Szechtman, & Brown, 1990). Moreover, there is suggestive evidence that neurocognitive and neurobiological subtypes exist in the schizophrenia population. Subgroups of patients have been found that are intact while others are impaired in executive cognition (Levin, Yurgelun-Todd, & Craft, 1989). Similarly, Clark, Kopala, James, Hurwitz, & Li (1993) found evidence for prefrontal and diffuse cortical metabolic subtypes of schizophrenia. Many of the neural sites under study show abnormalities that fail to replicate consistently. These sites include the fronto-striatal system (Buchsbaum, 1990; Farde et al., 1987; Wong et al., 1986), the left medial temporal lobe (Crow, 1990; Roberts, 1991; Suddath, Christison, Torrey, Casanova, & Weinberger, 1990; Volkow, Brodie, & Bendriem, 1991), and the corpus callosum (Bigelow, Nasrallah, & Rauscher, 1983; Craft, Willerman, & Bigler, 1987; but see Woodruff, McManus, & David, 1995), as well as diffuse pathological features like ventricular dilation and atrophy (Raz & Raz, 1990). Cognitive functions associated with these sites, including verbal memory in the case of the hippocampus and medial temporal lobe, also show a pattern of variable impairment within and across samples (Heinrichs, 1994; McKenna et al., 1991; Paulsen et al., 1995; Yurgelun-Todd & Waternaux, 1991). Taken together, the findings provide considerable support for taking a neurocognitive approach to the problem of subdividing schizophrenia. These considerations formed the basis of a search for subtypes using cluster analysis of selected neurocognitive variables (Heinrichs & Awad, 1993). Four tasks were chosen based on executive function (Wisconsin Card Sorting Test; Heaton, 1981), verbal memory (California Verbal Learning Test; Delis et al., 1987), motor function (Purdue Pegboard; see Lezak, 1985, pp. 682– 683), and general intellectual ability (Wechsler Adult Intelligence ScaleRevised; Wechsler, 1981). The logic underpinning the choice of these tasks was that each one indexed neurobehavioral functions implicated as being defective in at least a proportion of schizophrenia patients (see Heinrichs, 1993; Levin et al., 1989).

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A five cluster solution suggested the following subtypes: (1) an ‘‘executive’’ subtype with selective Wisconsin Card Sorting Test (WCST) impairment in categories achieved; (2) a ‘‘normative’’ subtype with generally intact cognition; (3) an ‘‘executive-motor’’ subtype with impaired card sorting and poor Purdue Pegboard motor function; (4) a ‘‘dementia’’ subtype with general impairment; and (5) a ‘‘motor’’ subtype with impairment only on the Purdue Pegboard. These tentative subtypes differed in age, length of illness, and extent of hospitalization, which provided limited evidence of clinical validity. Moreover, the subtypes were consistent with findings in the neurobiological and neuropsychological research literature (e.g., Clark et al., 1993; Goldstein, 1990). At the same time, this provisional typology was based on a limited number of tasks and measures and raised questions of stability and validity. Hence, one purpose of the present study was to assess the temporal stability of the neurocognitive subtypes by comparing subtype assignment at index and at follow-up after a significant time interval. The second purpose was to examine the validity of the subtypes more closely and to clarify putative underlying neurocognitive functions. One of the subtypes identified by Heinrichs and Awad (1993) was labeled dementia, but no independent tests of intellectual ability or memory were available in the original study to confirm the accuracy of the label. Accordingly, the present study examined the possibility of subtype differences in general intellectual ability, with the expectation that the Dementia subtype would demonstrate the lowest performance in this area, especially in comparison with the Normative subtype. Memory impairment was also implicated selectively in the Dementia subtype, so the question asked was whether features characteristic of organic memory disorder exist in this subtype. In addition, three subtypes included a bilateral psychomotor deficit. Such deficits may reflect genuine motor control problems, medication, or other problems including intermanual conflict and poor coordination caused by corpus callosum dysfunction (Bogen, 1993, pp. 337– 408), a structure that has been implicated in schizophrenia (e.g., Craft et al., 1987). Hence, it was considered important to compare the subtype groups on tests of unilateral motor function and on tests sensitive to interhemispheric transfer. Moreover, subtype descriptions such as ‘‘Executive-Motor’’ or ‘‘Dementia’’ are tentative and may require revision as additional neurocognitive differences between subtypes are discovered. Thus we investigated subtype differences with a variety of tasks not used in the original cluster analysis. Finally, although the original study sample was composed of medically stable outpatients, it is important to relate neurocognitive subtypes to clinical characteristics including current symptoms, history, and personal and social adjustment to the illness. Definitive validation of any neurocognitive typology requires neurobiological as well as behavioral support. However, clinical validity is evidence that a typology captures a major source of variability

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TABLE 1 Demographic and Clinical Characteristics of Follow-up Patients (n 5 55) Variable

M

SD

Age (years) Education (years) Age at first hospitalization (years) Months in hospital CPZ-equivalent daily dose in mg Brief Psychiatric Rating Scale (total) Male/female Socioeconomic status (parent) 1. High executive, major professional 2. Administrative personnel, small business 3. Clerical, sales, technician, farmer 4. Skilled manual employee 5. Unskilled manual employee Receiving anti-Parkinsonian medication

40.0 10.4 23.6 20.2 394.5 38.2

10.3 2.5 6.2 27.6 331.0 11.6

n

36/19 2 9 15 10 19 32

Note. Means and standard deviations are presented for the first six variables; frequencies are presented for sex, socioeconomic status, and anti-Parkinsonian medication.

between schizophrenia patients, and one that has implications for understanding the expression and severity of illness. The present study provides a preliminary indication of the typology’s clinical as well as cognitive validity. METHOD

Subjects We successfully recruited 55 of the 104 subjects included in the original cluster analysis by Heinrichs and Awad (1993). Each subject met DSMIII-R criteria for schizophrenia based on the structured clinical interview for DSMIII-R (Spitzer, Williams, & Gibbon, 1987) and independent diagnoses by hospital psychiatrists at a large mental health facility affiliated with the University of Toronto. Descriptive information regarding the follow-up sample is presented in Table 1. The follow-up sample was compared with subjects who did not participate in the present study. Reasons for not participating included direct refusal or disinterest (42%), illness or death (8%), and unavailability due to migration, discharge, or failure to respond to inquiries from research staff (49%). The follow-up and drop-out groups differed (p , .05) in age, but not in years of education, length of illness, time spent in hospital, parental socioeconomic status (Andreasen, 1987), neuroleptic medication dose, gender composition, or intelligence (WAIS-R IQ). The modal follow-up patient was in early middle age, with a history of chronic illness. Study patients were relatively asymptomatic as a group and were receiving neuroleptic medication. They were primarily outpatients (91%) affiliated with hospital-linked community mental health clinics and case management services. Patients with histories of mental retardation or current substance abuse had been excluded from the original study (see Heinrichs & Awad, 1993).

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Measures Neurocognitive tests available from the original study and readministered in the present study included the Vocabulary and Block Design subtests of the WAIS-R (Wechsler, 1981), the California Verbal Learning Test (CVLT; Delis et al., 1987), the WCST (Heaton, 1981), and the Purdue Pegboard (Purdue Research Foundation, 1948). Adjunct neurocognitive tasks administered at follow-up to assess subtype validity included the release from proactive inhibition paradigm (Craik & Birtwhistle, 1971; Moscovitch, 1982; Wickens, 1970). This involves successive presentations of word lists from the same taxonomic category, with recall trials after each presentation. Recall typically declines over these trials with the build-up of proactive inhibition. A final trial involves a new taxonomic category and subsequent improvement in recall for most subjects. Hence this task provides an index of verbal encoding and mental flexibility. Patients with frontal lobe pathology often fail to ‘‘release’’ from proactive inhibition on the final trial despite having relatively intact verbal recall (Moscovitch, 1982). In the present study performance was separated into primary and secondary memory components, with the difference between fourth and fifth (‘‘release’’) trials constituting the dependent measure of interest (see Moscovitch, 1982, p. 351). Raven’s Standard Progressive Matrices (Raven, 1960) was included to index reasoning and general intellectual ability with nonverbal material (see Lezak, 1995, pp. 612–616). The Grooved Pegboard test (Matthew’s & Klove, 1964) was included as an alternate motor control and dexterity task requiring unilateral manual performance. Unlike the Purdue Pegboard, the Grooved Pegboard stimuli are rotated prior to insertion, and target holes are in random array rather than in linear sequence. Pegs inserted per second was used as the dependent variable. In addition to these tasks, a modified version of Geffen et al. (1985) tactile tests to detect interhemispheric transfer problems was included (Case, 1994). These tests require subjects to localize touch in the ipsilateral and contralateral limbs under conditions of occluded vision, a process that is sensitive to corpus callosum dysfunction. Callosal dysfunction can also cause intermanual conflict and hence may contribute to bilateral Purdue Pegboard performance. Accordingly, a callosal transfer task assesses whether putative motor aspects of a subtype are true motor problems, like those associated with basal ganglia dysfunction, or due to interhemispheric transfer problems. Both neural sites have been implicated in at least a proportion of schizophrenia subjects (Bigelow et al., 1983; Buchsbaum, 1990; Craft et al., 1987). Measures of clinical and functional status at follow-up included a 24-item version of the Brief Psychiatric Rating Scale (BPRS; Lukoff, Nuechterlein, & Ventura, 1986; Overall & Gorham, 1962; Woerner, Mannuzza, & Kane, 1988; Zakzanis, 1994). An abbreviated version of the Sickness Impact Profile (SIP; Awad, 1990; Bergner, Bobbitt, Carter, & Gilson, 1976) with self-report ratings of present health, quality of life, sleep and rest, home management, social interaction, and recreational activities was included to index everyday life functioning. Finally, medical records were reviewed to provide information regarding illness history and treatment variables like medication. A shortened Drug Attitude Inventory (DAI; Hogan & Awad, 1992) was included to measure subjective response to medication effects.

Procedure Prospective subjects from the original study were contacted by telephone or through case managers at community mental health clinics. Informed consent was obtained and subjects were paid for participation. The average time between initial and follow-up assessment was 36.5 (SD 5 8.0 months). The neurocognitive test battery was administered by three trained psychometrists using standard administration and scoring instructions under the supervision of a clinical neuropsychologist (R.W.H.). The tactile transfer tests are not standard neurocognitive measures and hence more detail on testing procedure is provided as follows. Subjects were seated and blindfolded with palms

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facing up. The psychometrist applied light stimulation by depressing the skin of either two or three fingers in sequence with the tip of a pencil. Subjects had to indicate which fingers had been touched by immediately touching the thumb of the same hand (ipsilateral condition) to the fingers stimulated in the touch sequence. In the contralateral condition the subject responded with the thumb of the opposite hand to indicate the corresponding fingers that had been touched. Before each trial subjects were given practice with the ipsilateral and contralateral stimulation conditions until they indicated comprehension of the task. Each subject responded to 16 ipsilateral and 16 contralateral two-finger sequences and the same number of three-finger sequences, with alternating laterality of presentation. A finger localization transfer score was derived by calculating the difference between ipsilateral and contralateral trials. A sequence transfer score indexed the same difference with respect to correct finger sequence identifications. Both scores therefore reflected the mediating influence of information transfer between the cerebral hemispheres. A randomly selected subset of 16 of the 55 study subjects was rated by two psychometrists who had received training in the use of the BPRS. This provided an index of interrater reliability, with a mean intraclass correlation of .89 across subscales, reflecting a high degree of agreement. Three summary scores were used from the BPRS: the Total Pathology score, which sums ratings across 24 seven-point item scales, a negative symptom score derived from ratings of self-neglect, motor retardation, blunted affect, and emotional withdrawal, and a positive symptom score, derived from ratings of suspiciousness, unusual thought content, grandiosity, and hallucinatory behavior. The Sickness Impact Profile and Drug Attitude Inventory were self-administered questionnaire-type measures (see Bergner et al., 1981; Hogan & Awad, 1992).

Neurocognitive Subtype System The original study by Heinrichs and Awad (1993) produced clusters of subjects with similar patterns of neurocognitive performance on four test variables. However, the follow-up sample was too small (n 5 55) to justify the use of clustering algorithms employed previously. Therefore, a nonparametric version of the discriminant function approach to subject classification used by Massman, Delis, Butters, Dupont, & Gilin (1992) and Paulsen et al. (1995) was adopted for present purposes. A nonparametric method, k nearest neighbor analysis, was used because nonparametric methods can employ the same metric as the original cluster analysis (i.e., Euclidean distance based on standardized scores) but do not require multivariate normal distributions for the classification variables (see Morrison, 1976). Normality is difficult to achieve with cluster analysis-generated groups because, by definition, cluster analysis aggregates cases with similar scores. The rationale underlying our approach was that a discriminant function could be used to replicate the original subtypes with data from the first assessment. The same function could then be applied to the follow-up data to determine classification agreement at two separate points in time. Accordingly, as a first step, a k nearest neighbor discriminant analysis was conducted on the original sample of 104 patients using standardized test scores (based on sample mean and standard deviation) on the four classification tasks (WAIS-R IQ, WCST categories, Purdue scores, and CVLT free recall intrusions). This was essentially an attempt to replicate the original subtypes with a different method. A value of 8 was set for k after comparison of classification error at larger and smaller values and in consideration of the likely subtype sample sizes based on Heinrichs and Awad’s (1993) results. The accuracy of the function was approximately 95%, with five cases being classified into alternate subtypes. These cases were reclassified to yield a somewhat more refined typology. Next, a two-stage k nearest neighbor analysis was again carried out on the original sample of 104 patients from the first assessment, but with the follow-up sample of 55 patients specified as a cross-validation sample for the nearest neighbor function. This yielded joint subject classification into subtypes

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TABLE 2 Neurocognitive Subtype Assignment at First and Second Assessment, n, (%) First assessment

Second assessment 1. 2. 3. 4. 5.

Executive 10 (18) Normative 12 (22) Executive Motor 12 (22) Dementia 12 (22) Motor 9 (16)

1. Executive 11 (20)

2. Normative 10 (18)

3. Executive Motor 10 (18)

4. Dementia 13 (24)

5. Motor 11 (20)

3 (27) 3 1 3 1

2 6 (60) 0 1 1

1 0 8 (80) 1 0

2 1 3 7 (54) 0

2 2 0 0 7 (64)

Note. Numbers on the diagonal are patients assigned to the same subtype at first and second assessments, with numbers in parentheses indicating the percentage. Horizontal and vertical data show prevalence of each subtype relative to the total sample (n 5 55) at first and second assessments.

based on initial and follow-up data for the 55 patients in the study and allowed us to address subtype stability and generate subtype membership for the follow-up sample and to examine questions of validity and subtype comparisons. For validity analysis only the follow-up subtype assignments were used in this study.

RESULTS

Subtype Stability and Prevalence Cross-tabulation results for neurocognitive subtype assignment at first and follow-up assessments are presented in Table 2. Percentages in the diagonal indicate the proportion of patients that were classified in the same subtype at both assessment times. The overall kappa for the five-part typology is .45. Individual kappas were: .12 (Executive), .43 (Normative), .66 (Executive-Motor), .43 (Dementia), and .64 (Motor). These values indicate a range of reliability from low to moderate with the typology as a whole showing a moderate degree of stability and two of five subtypes showing at least moderate stability. There was considerable movement between subtypes but it is difficult to discern a clear pattern in this movement. Normative, Executive-Motor, and Motor subtype patients were unlikely to change into the Dementia subtype, while Dementia and Executive-Motor patients were unlikely to ‘‘improve’’ into less impaired subtypes like the Normative or Motor groups. The Executive patients appeared equally likely to deteriorate into the Dementia or improve into the Normative subtype. This Executive subtype is clearly the least stable, most dynamic of the patient groups. In terms of prevalence, the patients distributed themselves fairly evenly across the subtypes at initial and follow-up assessments, with little evidence of major disparities.

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TABLE 3 Subtype Classification Rates for Actual and Simulated Assessments Classification agreement (%) Subtype pair Executive–executive Normative–normative Executive motor–executive motor Dementia–dementia Motor–motor

Actual time 1–time 2 Actual time 1–simulated time 2 27 60 80 54 64

80 94 90 94 89

Note. Figures in the first column are the same percentages reported in Table 2 for the initial and follow-up assessments. Figures in the second column are percentages of classification agreement between the first assessment and a simulated second assessment derived by averaging five trials where random numbers were added to the first assessment subtyping variables.

Random patient movement and associated classification error rather than true neurocognitive evolution from one subtype to another may account for the changes observed between initial and follow-up assessments. To estimate this possibility a reanalysis was carried out by using the existing initial assessment data and simulating a second assessment that reflected only the addition of random error to the initial data. This was done with a computergenerated algorithm that added random numbers to the initial classification variables while preserving the psychometric characteristics of standard scores (i.e., M 5 0, SD 5 1). Five trials were carried out and subjected to the same nonparametric nearest neighbor program employed in the actual study. The results were cross-tabulated and percentage classification agreement calculated between initial and simulated follow-up assessments. The percentages averaged over trials are presented in Table 3 along with the agreements obtained in the actual study for comparison. A nonparametric test revealed a significantly higher median agreement rate for the actual– simulated assessments than for the actual–actual assessments (p , .05). This suggests that more movement between subtypes took place in the actual study than seems probable on the basis of mere classification error and random score fluctuations. To evaluate further the stability of the subtypes, intraclass correlations were calculated between assessments (initial and follow-up) for the component test variables that comprised the subtypes. The highest correlation was for prorated IQ (.84), followed by free recall intrusions (.73), Purdue Pegboard (.64), and WCST categories (.53). Hence, three of four component scores show at least adequate test–retest reliability. The WCST index is the only one with questionable reliability. Recent data provided by Heaton, Chelune, Talley, Kay, & Curtiss (1993) indicate that normal subjects also show only modest test–retest reliability on this task, even at much shorter time intervals. This modest reliability may underlie the weak stability of

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several subtypes because all depend, in part, on WCST score reliability even though highly reliable scores like IQ are also included in the subtype criteria. In sum, the data indicate a very modest degree of stability in this neurocognitive typology over a 3-year time interval, with greatest instability occurring in the Executive subtype. There is some suggestion in the data that more impaired subtypes (Dementia, Executive-Motor) are unlikely to evolve into less impaired subtypes (Normative, Motor) and that less impaired subtypes are unlikely to evolve into the most impaired subtype (Dementia). In terms of component test variables three of four showed adequate to high reliability. There is no evidence of inherent unreliability of neurocognitive performance in this population, although WCST performance shows a relative weakness compared to the other measures. Subsidiary analyses showed that the most and least stable subtypes did not differ in terms of hospital admissions and stays during the test interval (Kruskal–Wallis, nonparametric test, n.s.). To assess the possibility that changes in medication during the test interval play a role in stability, neuroleptic doses (in chlorpromazine equivalent units) were compared at initial and follow-up assessments for each patient. This yielded a dose change score that was subjected to a one-way analysis of variance. The ANOVA indicated no differences between subtypes at follow-up in terms of neuroleptic medication changes (F 4,50 5 .87, p . .05). There were also no differences in the use of anti-Parkinsonian medication across the test interval (F 4,50 5 .92, p . .05). Finally, each patient’s neuroleptic dose change between assessments was correlated with their standardized scores on the neurocognitive tasks used in the subtype classification. There were no significant correlations between the magnitude of medication change and neurocognitive performance on any of the four tasks. Overall, there was a mild trend toward lower doses of neuroleptic medication at the follow-up relative to the initial assessment (medication change M 5 2178.0, SD 5 554.0 in cpz equivalent units at follow-up). Accordingly, there is little evidence that the clinical state of the patient, including medication changes, mediates stability/reliability differences between subtypes in any direct or obvious way. Neurocognitive Validity Raw scores on the component variables describing each subtype group are presented in Table 4. The subtype groups differed in age (F 4,50 5 3.26, p , .05) but not education (F 4,50 5 .97, n.s.). Significant (p , .05) product– moment correlations were obtained between age and both the dominant and nondominant hand trials of the Grooved Pegboard test. Inspection of correlations within each group suggested that use of covariance techniques was justified. Hence, covariate-adjusted F ratios for these two variables and unadjusted F ratios for the remaining neurocognitive variables are presented along with group descriptive statistics in Table 5.

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TABLE 4 Raw Scores of Subtype Groups on Defining Variables 1. Executive (n 5 20)

WAIS-R IQ WCST CVLT Purdue PB

2. Normative (n 5 12)

3. Executive Motor (n 5 12)

4. Dementia (n 5 12)

5. Motor (n 5 9)

M

SD

M

SD

M

SD

M

SD

M

SD

89.9 1.8 0.5 10.6

10.8 1.8 1.3 1.4

86.9 5.9 2.4 11.2

10.0 0.3 3.4 1.5

81.8 0.9 1.1 7.7

8.6 1.4 1.1 1.0

80.0 1.2 9.6 8.8

15.3 1.0 3.3 1.4

107.2 4.1 1.4 8.9

11.3 1.7 1.4 1.3

Note. WAIS-R IQ, IQ prorated from Vocabulary and Block Design subtests (see Silverstein, 1982); WCST, categories score on the Wisconsin Card Sorting Test; CVLT, free recall intrusions, California Verbal Learning Test; Purdue PB, bilateral trial, Purdue Pegboard test.

Pair-wise group comparisons were carried out using Tukey’s (1953) method to control experiment-wise error in the case of unadjusted group means, and the Bonferroni method was used in the case of covariate (age)adjusted means. The subtype groups differed in terms of general intellectual ability and reasoning (Raven Matrices) although the Executive-Motor rather than the Dementia group had the lowest scores. Differences approached significance between the Dementia and Normative groups. In terms of memory, three verbal memory variables from the CVLT that were not included in the original cluster analysis revealed differences between subtypes. The Dementia subtype demonstrated the lowest score in each case. However, there was no evidence of a failure to ‘‘release’’ from proactive inhibition in any subtype group, although the Executive-Motor group evinced a trend toward attenuated release. The subtype groups did not differ significantly in ipsilateral or contralateral tactile processing (Table 6). However, motor tests revealed differences for both dominant and nondominant hand function even when performance was adjusted for age. The Executive-Motor and Dementia groups were more impaired than the Normative group on the Grooved Pegboard dominant hand trials. On the nondominant trials, Motor and Executive-Motor groups showed significant differences relative to the Normative group. This provides validation for the motoric aspect of the Executive-Motor subtype and also indicates that the dysfunction is not an artifact of bilateral coordination tasks like the Purdue Pegboard, but also occurs on unilateral tasks. Some validation for the Motor subtype is also provided by the results, although this is limited to nondominant hand performance. Overall, the neurocognitive data provide evidence that the Normative, Dementia, Executive-Motor, and Motor patients represent relatively distinct subtypes in terms of several aspects of cognition, at least on a cross-sectional basis. This can be seen in differences on intellectual, memory, and motor

11.7 2.9 7.9 1.0

42.6 8.7 92.0 b 2.0

42.8 9.3 90.2 b 2.5

12.9 3.9 9.0 2.2

11.6

32.2 a

11.7

28.0 33.7 6.6 86.7 0.7

19.0

M

12.4 3.2 7.5 2.2

8.9

SD

3. Executive Motor (n 5 12)

28.8 5.8 73.8 2.1

24.6

M

14.5 3.0 18.4 2.4

8.4

SD

4. Dementia (n 5 12)

39.7 8.7 88.7 b 1.8

39.5 a,b

M

5. Motor (n 5 9)

9.4 2.3 8.7 1.6

5.9

SD

F 4,50

2.79* 2.80* 4.72** 1.4

6.76***

Note. CVLT, California Verbal Learning Test; long delay, Long Delay Free Recall trial; Release from PI, release from proactive inhibition. a Different from the Executive-Motor group at p , .05 using Tukey test. b Different from the Dementia group at p , .05 using Tukey test. * p , .05. ** p , .01. *** p , .001.

Raven matrices CVLT Trials 1–5 Long delay Discriminability Release from PI

SD

M

M

SD

2. Normative (n 5 12)

1. Executive (n 5 10)

TABLE 5 Intellectual and Memory Results at Follow-up

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15.50 9.20 .33 .29

14.00 6.90 .07 .07

14.08 6.42 .34 .32

6.85 4.40 .07 .06

18.40 8.33 .25 a .22 a

M 10.80 4.44 .07 .08

SD

3. Executive Motor (n 5 12)

15.70 7.40 .27 a .24

M 11.30 5.00 .09 .07

SD

4. Dementia (n 5 12)

13.20 8.00 .31 .24 a

M

SD 5.04 3.90 .06 .06

5. Motor (n 5 9)

.40 .48 3.46 b,* 2.73 b,*

F 4,50

Note. FLTS, finger localization transfer score; FSTS, finger sequence transfer score; Grooved PD, grooved pegboard dominant hand pegs/s; Grooved PN, grooved pegboard nondominant hand pegs/s. Due to peripheral manual disabilities one patient in the Dementia group was unable to complete the tactile tests and two patients in the Executive-Motor group were unable to complete the motor tests, reducing the sample sizes accordingly. a Different from the Normative group at p , .05 with Bonferonni adjustment. b Co-variate (age) adjusted F ratio df 5 5.47. * p , .05.

FLTS FSTS Grooved PD Grooved PN

SD

M

M

SD

2. Normative (n 5 12)

1. Executive (n 5 10)

TABLE 6 Tactual and Motor Results at Follow-up

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tasks. There is no evidence for the distinctiveness of the Executive group or of the executive component of the Executive-Motor group although there is a tendency for Executive-Motor patients to show diminished release from proactive inhibition. Clinical Validity Results of the clinical validation analysis are presented in Table 7. There was no evidence of subtype differences in positive or negative symptoms, or in general psychopathology scores on the BPRS. The mean values indicate low levels of symptom severity, and the standard deviations suggest limited dispersion around the means. Analysis of variance revealed significant differences on all four sections of the Sickness Impact Profile, with the ExecutiveMotor and Dementia groups more disabled and socially maladjusted than the Normative and/or Executive groups. There was no evidence of medicationrelated group differences or gender composition disparities between subtype groups. The clinical and social data provide evidence primarily in support of the validity of the Dementia, Executive-Motor, and Normative subtypes. These patients are distinguished from each other in everyday life functioning despite the lack of evidence for symptomatic differences between subtypes. DISCUSSION

In a recent award address Bellak (1994) argued forcefully in favor of a multiple illness view of schizophrenia, suggesting that samples of 500 patients will be required in future to encompass the aetiological diversity. A multiple illness view holds that it is meaningless to treat all patients with schizophrenia as exemplars of a single disease entity. Inevitably, findings will pertain to only a subset of patients or fail to replicate, reflecting the inherent heterogeneity of the schizophrenic disorders (see also Heinrichs, 1993). In several respects the data presented in our study are consistent with this multiple illness view. An original sample of 104 patients and a follow-up sample of 55 patients fell fairly evenly into five distinct subtypes based on neurocognitive performance at index and at follow-up 3 years later. Two of the subtypes were at least moderately stable over a 3-year period. There is no single pattern of neuropsychological functioning that characterizes the sample, or schizophrenia, as a whole. Indeed, one subtype represents essentially intact performance on neurocognitive measures while another represents a dementia-like picture with impaired general intellectual ability, the kind of memory deficits seen in organic amnesia, deficits in mental flexibility and poor motoric skills. Moreover, the follow-up data show that these subtypes differ in social and personal adjustment to the illness. Although the findings support primarily the validity of the Dementia, Executive-Motor,

40.3 10.5 4/10 398.7 7 7.8 5.3 5.8 5.2 8.8 a 15.7a,b 6.1 a

Age (years) Education (years) Gender (male/m) Cpz dose (mg) Anti-Park (n) DAI Positive BPRS Negative BPRS SIP sleep/rest SIP home SIP social SIP recreation 1.8 3.1 2.4 2.0 1.4 2.9 2.4

290.3

8.6 2.9

SD 34.0 10.8 8/12 283.5 6 4.7 8.0 5.2 5.7 a 7.2 13.8 4.3

M

4.4 5.0 1.6 1.4 2.3 2.9 2.4

308.4

7.5 2.6

SD

2. Normative

42.7 10.2 10/12 367.5 7 3.5 9.7 8.0 3.6 5.4 9.8 2.8

M

4.4 5.2 4.0 1.9 2.7 5.4 1.6

348.8

9.8 2.0

SD

3. Executive Motor

46.3 9.3 7/12 441.2 10 5.7 8.7 5.9 4.4 6.2 9.2 4.2

M

3.4 6.3 2.2 1.5 2.3 4.5 2.4

415.7

9.2 2.9

SD

4. Dementia

44.8 11.3 7/9 502.0 5 6.2 8.1 6.3 4.1 7.4 12.8 3.5

M

2.5 5.0 2.9 2.1 2.9 3.7 2.5

293.0

10.4 1.5

SD

5. Motor

2.23 1.1 1.7 2.53* 3.28* 5.10** 3.16*

3.26* 0.97

F4,50

Note. Cpz, neuroleptic dose in chlorpromazine equivalent units; BPRS, Brief Psychiatric Rating Scale; DAI, Drug Attitude Inventory; SIP, Sickness Impact Profile (lower scores indicate greater disability); anti-Park., anti-Parkinsonian medication (on/off). a Significantly different ( p , .05) from the Executive-Motor group using Tukey test. b Significantly different (p , .05) from the Dementia group using Tukey test. Chi-squared tests on frequency of anti-Parkinsonian medication by subtype group and gender distribution by subtype group were not significant. Kruskal–Wallis nonparametric test on cpz dose by subtype groups nonsignificant. * p , .05.

M

Variables

1. Executive

TABLE 7 Clinical and Demographic Results at Follow-up

220 HEINRICHS ET AL.

PARSING SCHIZOPHRENIA WITH NEUROCOGNITIVE TESTS

221

and Normative subtypes, a simple impaired/unimpaired dichotomy does not capture all of the diversity in the patient data. For example, one subtype, the Motor subtype, is distinguished solely by reduced motor speed and manual dexterity, especially with the nondominant hand, in the presence of normal intellectual functioning and no medication or age-related differences relative to the other subtypes. The evidence is qualified by the low stability of the Executive subtype, which may be attributable in part to the modest test–retest reliability of the Wisconsin Card Sorting Test when compared to the other test variables. The limited information available on the reliability of the WCST (e.g., Heaton et al., 1993, pp. 40–41) as well as the good to excellent reliability of the Purdue, CVLT, and IQ scores, suggests that this instability may be a property of the WCST itself rather than a reflection of changes in clinical state or a peculiarity of the schizophrenia population. This issue requires clarification in future subtyping research with neurocognitive tasks. The WCST may be an inappropriate executive function measure if it is unreliable. Alternative tasks with high test–retest reliability will be needed to track the evolution or stasis of executive defect in schizophrenia. Nonetheless, the modest overall stability of the typology suggests that patients ‘‘progress’’ into other subtypes over time to a limited degree, although it is rare for patients in more impaired subtypes to ‘‘normalize’’ and improve their cognitive status. Perhaps neurocognitive function in schizophrenia reflects several neurological events that wax and wane over time rather than a more static kind of encephalopathy (see Andreasen, 1989; Goldberg, Hyde, Kleinman, & Weinberger, 1993). Finally, it is not surprising that the subtypes were indistinguishable on symptomatic grounds because the groups comprised patients who were responsive to medication and had been receiving treatment on an outpatient basis for many years. On the other hand, it is important to relate neurocognitive profiles to symptom patterns and this may require the use of a more acute, medication-free sample of schizophrenia patients. Moreover, the data suggest that neurocognitive profiles may be useful in predicting social and personal adjustment to the illness. Indeed, it is here that neurocognitive subtyping may have its greatest clinical relevance if the issues of stability and test reliability can be clarified. Do neurocognitive measures provide a better typology for schizophrenia than symptom ratings? Our study suggests that both approaches may produce data that reflect distinct but gradually evolving rather than static neurobehavioral conditions. The stability of neurocognitive subtypes is comparable but not superior to the stability of symptomatic subtypes (e.g., McGlashan & Fenton, 1993). One possibility for future research is to base neurocognitive subtype criteria only on measures that have a high demonstrated reliability. This would also help resolve the issue of whether subtype progression reflects a changing illness state or an unreliable behavioral task.

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