The paradox of normal neuropsychological function in schizophrenia

Journal of Abnormal Psychology2000. Vol. 109, No. 4, 743-752

Copyright 2000 by the American Psychological Association, Inc.0021-843X/00/S5.00 DOI: 10.1037//002I-843X.109.4.743

The Paradox of Normal Neuropsychological Function in Schizophrenia

William S. KremenUniversity of California, Davis, School of Medicine

and Napa State Hospital

Larry J. Seidman, Stephen V. Faraone,Rosemary Toomey, and Ming T. Tsuang

Massachusetts Mental Health Center,Brockton-West Roxbury Veterans Affairs Medical Center, and

Harvard Institute of Psychiatric Epidemiology and Genetics

Mounting evidence suggests that compromised neurocognitive function is a core feature of schizophre-

nia. However, some studies have found neuropsychologically normal schizophrenia patients. To address

this apparent contradiction, we blindly rated individual neuropsychological profiles of 75 schizophrenia

patients and 91 control participants on the basis of methods developed by L. J. Seidman, S. V. Faraone,

W. S. Kremen, J. R. Pepple, M. J. Lyons, and M. T. Tsuang (1993). Almost one-quarter of the patients

were classified as neuropsychologically within normal limits (WNL). Despite significantly worse

neuropsychological performance, WNL patients had higher estimated premorbid ability than did controls.

Compared to a subset of controls matched on overall neuropsychological function, WNL patients had

higher estimated premorbid ability and current IQs. Our results favor the view that even neuropsycho-

logically normal schizophrenia patients have compromised cognitive function relative to their presumed

expected or premorbid level of intellectual ability.

Neuropsychological function ranging from apparently normal to

widespread and dementia-like impairment is widely observed in

schizophrenia (Goldstein & Shemansky, 1995: Seidman, 1990;

Seidman, Cassens, Kremen, & Pepple, 1992). Multiple neuropsy-

chological impairments have been observed even in the context of

approximately average general intellectual functioning (Braff et

al., 1991; Elliott, McKenna, Robbins, & Sahakian, 1998; Gold-

William S. Kremen, Department of Psychiatry, University of California,

Davis, School of Medicine and TJC Davis-Napa Psychiatric Research

Center, Napa State Hospital. Larry J. Seidman, Stephen V. Faraone,

Rosemary Toomey, and Ming T. Tsuang, Harvard Medical School Depart-

ment of Psychiatry at Massachusetts Mental Health Center and Brockton-

West Roxbury Veterans Affairs Medical Center, and Harvard Institute of

Psychiatric Epidemiology and Genetics.

Portions of this article were presented at the 7th biennial meeting of the

International Congress on Schizophrenia Research, Santa Fe, New Mexico,

April 17 to 21, 1999. Preparation of this article was supported in part by

National Institute of Mental Health Grants MH43518-01 (MERIT Award)

and MH46318, the Veteran's Affairs Medical Research and Health Ser-

vices Research and Development Programs, and a National Alliance for

Research on Schizophrenia and Depression (NARSAD) Young Investiga-

tor Award.

We thank Gwen Barnes, Mimi Braude, Deborha Cart, Jo-Ann Donatelli,

Tova Ferro, Lisa Gabel, David Goldfinger, Robin Green, Lynda Jacobs,

Denise Leville, Cathy Monaco, Anne Shore, Rob Trachtenberg, Judith

Wides, John Pepple, Keith Hawkins, and Theresa Pai for their contribu-

tions to the projects. We also thank Anna Mitchell, David Osser, and Larry

Albert for assistance in recruiting participants at Taunton State Hospital;

Sue Thiemann for statistical consultation; and Anne Hoff for helpful

comments.

Correspondence concerning this article should be addressed to William

S. Kremen, Department of Psychiatry, University of California, Davis,

School of Medicine, 4430 V Street, Sacramento, California 95817. Elec-

tronic mail may be sent to [email protected].

stein, 1986; Seidman, 1983), but various proportions of schizo-

phrenia patients also have been found to be neuropsychologically

unimpaired (Golden et al., 1982; Palmer et al., 1997; Silverstein &

Zerwic, 1985). Neuropsychologically normal schizophrenia pa-

tients tend to have fewer negative symptoms, more paranoid symp-

toms, and better psychosocial functioning and to receive less

anticholinergic medication than their neuropsychologically im-

paired counterparts (Palmer et al., 1997; Seidman et al., 1992;

Silverstein & Zerwic, 1985).

In apparent contradiction with the existence of neuropsychologi-

cally normal schizophrenia patients is the idea thai neuropsycho-

logical compromise is a core feature of schizophrenic illness. We

refer to core features as dysfunctional features that reflect under-

lying processes, as opposed to secondary consequences of symp-

toms or treatment. Such features thus would be primary dysfunc-

tions that should be present in anyone with the disorder. Evidence

from several areas of research supports the notion that neuropsy-

chological dysfunction is a core feature of schizophrenia. First,

neuropsychological abnormalities exist prior to and at the onset of

illness (Aylward, Walker, & Bettes, 1984; Hoff, Riordan,

O'Donnell, Morris, & DeLisi, 1992; Jones, Rodgers, & Murray,

1994; Kremen et al., 1998). Second, compromised neuropsycho-

logical function similar to deficits found in patients (although

milder) is found in nonpsychotic biological relatives of schizo-

phrenia patients (Cannon et al., 1994; Faraone et al., 1995; Gold-

berg et al., 1993; Keefe et al., 1994; Mirsky et al., 1992). Com-

promised function occurring prior to the onset of illness or in

family members cannot simply reflect the effects of illness or

treatment. Third, it is reasonable to postulate that a core dysfunc-

tional feature would tend to be more treatment resistant than would

other illness characteristics. Although neuropsychological perfor-

mance may fluctuate with changes in clinical state, impairment

still usually persists even when symptoms are relatively remitted

743

744 KREMEN, SEIDMAN, FARAONE, TOOMEY, AND TSUANG

(Gold & Harvey, 1993). Taken together, this evidence is consistent

with the notion that at least some neuropsychological performance

reflects a core dysfunctional feature of schizophrenia. Despite

well-documented heterogeneity, if compromised neuropsycholog-

ical function is indeed a core feature, one must ask how it is

possible—as suggested in the aforementioned studies—to have

schizophrenia but still be neuropsychologically normal.

The clinical tradition in neuropsychology, which emphasizes the

careful description of individual cases, has advantages for discern-

ing heterogeneity but is not readily amenable to large-group data

(Marshall & Newcombe, 1984). This research-clinical distinction

is analogous to the nomothetic—idiographic distinction in person-

ality research (Allport, 1942). We have emphasized the importance

of the case study as the essence of clinical neuropsychology

(Kremen, Seidman, Pepple, Lyons, Tsuang, & Faraone, 1994;

Seidman, 1990; Seidman et al., 1993). In particular, Seidman

(1990) and Seidman et al. (1993) suggested that examination of

individual neuropsychological profiles could be a useful alterna-

tive to group analysis for making sense of heterogeneity in schizo-

phrenia. Toward the same end, Shallice, Burgess, and Frith (1991)

have characterized the individual neuropsychological profiles of a

few patients,

In this study, we used a hybrid approach involving individual

case ratings and analysis of group data derived from those ratings.

A similar approach was used in an elegant study by Palmer et al.

(1997), who identified a subgroup of schizophrenia patients as

neuropsychologically normal. We blindly rated individual neuro-

psychological profiles and compared patients rated as within nor-

mal limits (WNL) to normal control participants and to patients

rated as abnormal. Consistent with the idea of compromised neu-

rocognitive function as a core feature of the illness, we tested

whether, in comparison to controls, there would be evidence of

poorer cognitive function even in WNL schizophrenia patients.

If compromised neuropsychological function is a core feature of

schizophrenia, then those with apparently normal neuropsycholog-

ical function may have above-average levels of expected or pre-

morbid ability. The same reasoning applies to educational attain-

ment, which is likely to be attenuated by schizophrenic illness.

Indeed, we showed that chronic schizophrenia patients who were

matched one-to-one on education with controls tended to have

higher estimated premorbid ability than the controls (Kremen et

al., 1996). Therefore, we predicted that schizophrenia patients

classified as neuropsychologically WNL in this study would have

higher estimated premorbid intellectual ability in comparison to

the general intellectual ability of the controls. We also examined

the clinical and demographic correlates of neuropsychologically

normal and abnormal schizophrenia patients.

Method

Participants

All participants gave informed consent and were paid to participate.

Patients were from three Boston area public hospitals. Inclusion criteria for

patients were diagnosis of schizophrenia according to the Diagnostic and

Statistical Manual of Mental Disorders (3rd ed., rev.; DSM-IU-R; Amer-

ican Psychiatric Association, 1987), age 18 or older, English as the primary

language, and a minimum of 8 years of formal education. Exclusion criteria

were neurologic disease or damage, any insulin shock or greater than 25

lifetime electroconvuls;ve treatments, current substance abuse (within the

past 6 months), history of head injury with loss of consciousness of greater

than 5 min or with documented neurocognitive sequelae, menial retarda-

tion, and medical illnesses that may be associated with significant neuro-

cognitive impairment. Data were gathered from interviews and medical

records.

Control participants were recruited from nonprofessional hospital staff

and advertisements in the community. Except for psychopathology or

family history of psychosis, selection criteria were the same as for patients.

Controls were screened for current psychopathology with a short form of

the Minnesota Multiphasic Personality Inventory (MMPI-168; Vincent et

al., 1984) and were excluded if the score on any clinical or validity scale,

except for Masculinity-Femininity, was above 70. Further details about

ascertainment of controls are provided in previous reports (Faraone et al.,

1995; Kremen et al., 1995).

We tested 76 schizophrenia patients and 92 controls. One patient and one

control were excluded from these analyses because of incomplete neuro-

psychological profiles. Patient subgroups were as follows: 21 (28%) para-

noid, 11 (15%) disorganized, 1 (1%) catatonic, 1 (1%) residual, 41 (55%)

undifferentiated, 25 (33%) inpatients, and 50 (67%) outpatients. Demo-

graphics are shown in Table 1.

Procedures and Instruments

Assessment of psychopathology. Consensus lifetime DSM-IIl-R diag-

noses for patients were determined from interviews conducted with the

Schedule for Affective Disorders and Schizophrenia (SADS; Endicott &

Spitzer, 1978), medical record reviews, and consultation with clinicians.

As noted, in place of the interview, controls were screened for current

psychopathology with the MMPI-168.

Neuropsychological assessment. We administered a battery of neuro-

psychological tests assessing several domains of cognitive function. Be-

cause our goal was to minimize state-dependent effects and to capture

performance at its optimum level, patients were tested when they were

judged to be relatively stable clinically (i.e., at their "baseline") by the

clinical staff who were familiar with them.

Over the course of the study, some changes were made in the test

battery. Tests included in the present analyses are those given to most of

the participants. For general verbal ability, we used the Wechsler Adult

Intelligence Scale—Revised (WAIS-R; Wechsler, 1981) Vocabulary

subtest and the Wide-Range Achievement Test—Revised (WRAT-R; Jas-

tak & Wilkinson, 1984) Reading and Spelling subtests. For general visual-

spatial ability, we used the WAIS-R Block Design subtest, the Hooper

Visual Organization Test (Hooper, 1983), and Judgment of Line Orienta-

tion (Benton, Hamsher, Vamey, & Spreen, 1983). For verbal declarative

memory, we used the Wechsler Memory Scale (WMS; Wechsler, 1945) or

the Wechsler Memory Scale—Revised (WMS-R; Wechsler, 1987) Logical

Memories subtest. The WMS-R was published after the study began, and

the decision was made to switch from the WMS to the WMS-R. Conse-

quently, not all participants were administered the same version. We

calculated each participant's score as a percentage of the maximum pos-

sible score because the stories composing the Logical Memories subtest

differ slightly on the two test versions. These scores were calculated for

immediate recall, delayed recall, and the percentage retained from imme-

diate to delayed recall. For abstraction-executive function, we used the

number of perseveration and categories on the Wisconsin Card Sorting

Test (Heaton, 1981) and the number of total misses on the Visual-Verbal

Test (Feldman & Drasgow, 1981). For executive-motor function, we used

the total score and number of perseverations on Graphic Sequencing and

the Manual Position Sequencing total score. For perceptual—motor speed,

we used the WAIS-R Digit Symbol subtest and the time on Parts A and B

of the Trail Making Test (War Department, 1944). For mental control-

encoding, we used the WAIS-R Digit Span subtest and the WRAT-R

Arithmetic subtest. For sustained attention-vigilance, we used die number

of digits detected (regardless of ear of report accuracy) and number of

digits correct (based on ear of report) on the Dichotic Listening Test

NEUROPSYCHOLOGICAL FUNCTION IN SCHIZOPHRENIA 745

Table 1

Demographic Characteristics, 1Q, and Psychosocial Functioning of Schizophrenia Patients and Control Participants

Schizophrenia patients

Controls (C)

Variable

Age (years)Education (years)

Parental education (years)Premorbid IQ estimate3

Current IQ estimate11

Global Assessment Scalec

SexMale

FemaleEthnicity

Caucasian

Other

(n =

M

42.1113.51

10.96102.12

106.7189.05

n

41

50

79

10

91)

SD

15.14

2.502.19

12.9814.014.16

%

45

55

8911

WNL

(« =

M

42.0613.2911.92

110.411 10.9466.22

n

12

5

14

3

17)

SD

12.112.142.957.07

10.94

8.66

%

71

29

8218

ABN

(n =

M

44.29

11.6611.6097.1192.91

47.26

n

49

9

47

11

'58)

SD

12.262.162.85

17.1312.5114.41

%

84

16

8119

P

.63

.0001

.17

.003

.0001

.0001

.001

.40

Pairwise comparisons

C = WNL > ABN

WNL > C> ABN

WNL = C> ABNC > WNL > ABN

C < WNL = ABN(male/female ratios)

Note. WNL = neuropsychologically within normal limits; ABN = neuropsychologically abnormal.a Based on the Wide-Range Achievement Test—Revised Reading subtest. Missing data for 1 ABN participant. b Based on the Wechsler Adult IntelligenceScale—Revised Vocabulary and Block Design subtests (Brooker & Cyr, 1986). c Includes only a subset of participants: 88 control, 9 WNL, and 23 ABN .participants. Scores range from 0-100, with higher scores representing better functioning.

(Kimura, 1967) and the number of correct hits on the Auditory Continuous

Performance Test (CRT; Weintraub & Mesulam, 1985).

Individual profile ratings. Profiles consisting of the eight neuropsy-

chological functions were plotted for each participant. As described in our

previous work (Faraone et al, 1995), regression equations based on con-

trols only were used to predict neuropsychological test scores, given an

individual's age, sex, and parental education. Using parameters from those

regressions, we generated residual (observed minus predicted) scores for

all participants. Each neuropsychological function score is the mean of the

standardized residual scores for tests comprising that function; the direc-

tion of some individual scores was changed so that higher scores always

reflected better performance. Through restandardizatioii of the neuropsy-

chological function scores such that each had M = 0 and SD = I in die

control group, each individual's score represented how many standard

deviations above or below the control mean he or she was.

Individual neuropsychological profiles were rated by one of us (William

S. Kremen) without knowledge of any other participant characteristics.

Possible bias toward guessing that profiles showing a great deal of impair-

ment were those of the schizophrenia patients was reduced by the inclusion

of profiles for 15 chronic bipolar disorder patients; schizophrenia and

bipolar disorder profiles are compared elsewhere (Seidman et al., 2000).

Interrater reliability based on 20 randomly selected profiles rated by two of

us (William S, Kremen and Larry J. Seidman) was excellent, intraclass r

(ICC) = .96, p< .0001.

Our quasi-clinical method was originally developed by one of us (Larry

J. Seidman) as a way of making individual case ratings that could be

applied easily to large-group data. Standardizing test scores and adjusting

for relevant demographic variables enabled us to rate individual profiles

fairly rapidly without having to look up additional information. Scores

were adjusted for age because neuropsychological performance is often

associated with age. Controlling for parental education served as a way of

adjusting for differences in socioeconomic background. Parental education

was preferred over a socioeconomic index because the former allows for

greater variability than most socioeconomic classifications. Adjusting for

the participant's own education was specifically avoided because educa-

tional attainment is likely to be attenuated by schizophrenic illness. That is,

education may represent a "background" variable associated with general

intellectual level for controls; however, for schizophrenia patients, it likely

reflects a combination of a background variable and deleterious effects of

the illness (Kremen et al., 1995, 1996). We also adjusted for the sex of the

participant because the sex ratio was significantly different for patients and

controls, ^(2, N= 166) = 23.47, p < .001. Moreover, we wished to avoid

generating subgroups that were simply old versus young or more versus

less educated because these characteristics tend to be associated with

neuropsychological performance regardless of schizophrenic illness.

Examining each profile individually enabled us to assess both the

absolute level of performance in each domain of function and the extent of

within-subject variability across domains, analogous to the way in which

one would clinically evaluate individual neuropsychological profiles.

Within-subject variability is particularly difficult to capture in typical

group analyses. Guidelines for rating profile severity and type along the

lines of traditional neuropsychological case assessment were articulated by

one of us (Larry J. Seidman) on the basis of various approaches to clinical

neuropsychological assessment (Kaplan, 1990; Reitan & Davison, 1974)

and then refined by two of us (Larry J. Seidman and William S. Kremen).

These ratings were previously applied to the relatives of schizophrenia

patients (Seidman et al., 1993). Specific guidelines for severity ratings—

the subject of this article—are shown in the Appendix, For purposes of this

study, we combined individuals with overall normal or borderline-normal

ratings to create a WNL group and combined those with overall abnormal

or severe ratings into a single abnormal group.

A single function was defined as abnormal or impaired when it was more

than 2 SDs below the control mean. A profile was generally considered

abnormal when at least two functions were more than 2 SDs below the

control mean, analogous to the 2-point codes used in MMPI interpretation

(Graham, 1977). However, this guideline was modified slightly in order to

balance concerns about both false-positive and false-negative classifica-

tions. A profile with only a single impaired function could be rated as

abnormal if that function was extremely impaired (i.e., >3 SDs below the

control mean). As noted by Palmer et al. (1997), it is generally agreed upon


that there are likely to be too many false positives if overall cognitive

abnormality is based on only a single impaired function (American Acad-

emy of Neurology, 1991; American Psychiatric Association, 1987; Heaton,

Grant, & Matthews, 1991; McKhann et al.. 1984), On the other hand, we

believed that 3 or more SDs below the control mean reflected impairment

that was extreme enough to warrant classification as abnormal. We also

considered sizable discrepancies between domains of function to indicate

compromised neuropsychological function, even if neither function was

more than 2 SDs below the control mean. Such discrepancies also had to

be considered neuropsychologically meaningful. For example, verbal

memory function that was only slightly below the control mean but that

was 2 or more SDs below a person's general verbal ability would be

considered to reflect compromised verbal memory function. By these

definitions, performance may be compromised without being technically

abnormal or impaired.

Estimating change from expected or premorbid level of function. In

accord with our definition of terms, the performance of patients with no

functions greater than 2 SDs. below the control mean might still be judged

to reflect decline or compromised functioning relative to their expected or

premorbid level of ability. It should also be noted that premorbid ability

was not used in making profile severity ratings. On the basis of previous

work by our group and others, we used WRAT-R Reading scores as an

estimate of premorbid intellectual ability (Dalby & Williams, 1986; Kre-

men et al., 1995, 1996). The discrepancies between standardized scores on

the WRAT-R Reading and current IQ based on age-scaled Vocabulary and

Block Design subtests (Brooker & Cyr, 1986) served as one index of

decline from premorbid level of function. Because educational attainment

is likely to be attenuated by schizophrenic illness, we also examined

discrepancies between standardized scores on WRAT-R Reading and

education.

Tf schizophrenia is conceptualized as a neurodevelopmental disorder

(Feinberg, 1982; Seidman, 1990; Weinberger, 1987), then premorbid may

not be an entirely appropriate construct. We use the term to refer to the

period prior to the onset of florid psychotic symptoms. Premorbid ability

thus refers to the putative expected level of ability had the individual not

had schizophrenia or genes predisposing him or her to schizophrenia (for

a more detailed discussion, see Kremen et al., 1995, 1996).

Substance use ratings. We rated substance use on a 0-4 scale derived

from relevant sections of the SADS, with questions modified for rating

both lifetime (prior to the past 6 months) and current (past 6 months) use.

Individuals with current alcohol ratings of 3 (abuse, with duration of 6

months to 5 years) or higher or current drug ratings of 2 (regular use) or

higher were excluded, fnterrater reliability based on 20 cases was excellent,

ICCs ̂ .95, ps < .0001. There was too little variability in current drug use

to compute a meaningful ICC; ratings were 0 in all cases, except for one

participant, who received ratings of 0 and 1. See Faraone et al. (1995) for

additional details about these ratings.

Symptom ratings. Symptoms were assessed with the Scale for the

Assessment of Negative Symptoms (SANS; Andreasen, 1983) and the

Scale for the Assessment of Positive Symptoms (SAPS; Andreasen, 1984).

We examined Negative, Reality Distortion (Delusions and Hallucinations),

and Disorganization (Positive Formal Thought Disorder and Bizarre Be-

havior) dimensions from global SANS and SAPS scores (Arndt, Alliger, &

Andreasen, 1991; Liddle, 1987; Toomey et al., 1997). The Inattention

subscale was omitted because of its redundancy with cognitive function.

Psychosocial functioning. The Global Assessment Scale (GAS; Endi-

cott, Spitzer, Fleiss, & Cohen, 1976) was used as a general index of

psychosocial functioning.

Data Analysis

Controls and patient subgroups were compared by means of univariate

analyses of variance (ANOVAs). Significant ANOVAs were followed by

r tests for pairwise comparisons. For demographic and clinical character-

istics that were categorical variables, chi-square tests were used. Neuro-

psychological functions were also analyzed with Kruskal-Wallis tests

followed by Wilcoxon rank sum tests for pairwise comparisons. All sig-

nificant differences remained significant with these nonparametric tests

(results available on request), thus eliminating any concerns about distri-

butional properties of the measures or unbalanced designs in which group

sizes differ substantially. Given the consistency of results, we report only

the results of the parametric tests. All tests were two-tailed.

Results

Neuropsychological Profiles

Seventeen (23%) of the schizophrenia patients and 84 (92%) of

the controls were classified as having neuropsychological profiles

that were WNL, )f(\, N = 166) - 83.70, p < .001. Note that the

analyses reported here are based on the entire control group,

including the seven controls (8%) who were classified as neuro-

psychologically abnormal. Figure 1 depicts the mean neuropsy-

chological profiles for controls, WNL schizophrenia patients, and

neuropsychologically abnormal schizophrenia patients (n — 58;

77%). Differences in each of the eight neuropsychological func-

tions, as determined by univariate ANOVAs, were significant at or

beyond the .0001 level.1 These differences (and those for the

nonparametric results) would remain significant even with a con-

servative Bonferroni correction.

Pairwise comparisons showed that neuropsychologically abnor-

mal schizophrenia patients were substantially impaired on all

neuropsychological functions compared with controls or WNL

patients, all ps < .004. Comparisons of controls and WNL patients

revealed highly significant differences in abstraction-executive

function, 1(106) = 4.19, p < .0001, and perceptual-motor speed,

((106) - 3.71, p < .0003. General verbal ability was nearly

significantly different, r(l06) = -1.97, p < .052, but in the

opposite direction; that is, WNL patients scored somewhat higher

than controls.2

Correlates of Neuropsychological Performance

Demographics, IQ, and psychosocial functioning (control and

patient subgroups) (Table I). In considering these comparisons,

it should be recalled that neuropsychological test scores were

adjusted for age, sex, and parental education. There were no

differences in age, F(2, 163) = 0.47,^ = .63, parental education,

F(2, 163) = 1.77, p = .17, or ethnicity, j^(2, N = 164) = 1.82,

p — .40. As indicated in the Method section, there was a signifi-

cantly higher proportion of men in the patient groups than in the

control group, but the sex ratio was not significantly different

between the patient groups. There were highly significant differ-

ences in participants' own education. F(2, 163) = 11.33, p <

.0001. Educational attainment was lower in the abnormal schizo-

phrenia group than in either of the other two groups, /?s < .02, but

it did not differ between controls and WNL schizophrenia patients.

1 Raw scores for individual tests composing each function are available

on request.2 Controls and WNL patients did not differ in declarative memory, p =

.26. As suggested by an anonymous reviewer, inclusion of the percent

retained score could have obscured group differences, but the results were

essentially unchanged for immediate recall alone, p = .21.


^Normal Controls (n=91)

eWNL Schizophrenia Patients (n=17)

1 •Abnormal Schizophrenia Patients (n=58)

Neuropsychological Functions

Figure I. Neuropsychological profiles of control participants, neuropsy-

chologically normal schizophrenia patients (within normal limits [WNL]},and neuropsychologically abnormal schizophrenia patients.

Only a subset (43%) of the schizophrenia patients had ratings on

the GAS index of overall level of functioning. Nevertheless, there

were significant group differences in GAS scores, F(2, 117) =

293.97, p < .0001; t tests showed that all pairwise comparisons

were highly significant as well, ps < .0001.

Current IQs were significantly different among the three groups,

F(2, 163) = 23.92, p < .0001; t tests indicated significantly lower

IQs in the abnormal schizophrenia group than in either of the other

two groups, ps < .0001. WNL schizophrenia patients had nonsig-

nificantly higher IQs than did controls. There was also a significant

overall effect for WRAT-R Reading scores, our estimate of pre-

morbid intellectual ability, F(2, 162) = 6.19, p < .003; however,

in this case, all pairwise comparisons were significant, ps < .04.

Moreover, WNL patients had significantly higher Reading scores

than did controls, with an effect size (ES) of .69, based on Cohen's

(1988) d. Reading-IQ discrepancies were significantly different

among the three groups, F(2, 162) = 8.85, p < .0002, but these

were accounted for primarily by lower IQ relative to reading in the

abnormal schizophrenia group. WNL patients had nonsignificantly

larger Reading-TQ discrepancies than did controls, p < .13, with

the difference being of moderate ES (.40).3 The Reading-

education discrepancy was highly significantly different among

the three groups, F(2. 162) = 50.4, p < .008, and between WNL

patients and controls, p < .009, (ES = .72).

Clinical characteristics (Table 2). There was a significantly

higher proportion of paranoid subtype patients in the WNL schizo-

phrenia group than in the abnormal schizophrenia group, but these

groups were not significantly different in terms of inpatient versus

outpatient status. Substance use ratings did not differ between

these patient groups. Neuroleptic dose (in chlorpromazine equiv-

alents) was higher in the abnormal schizophrenia patient group

than in the WNL patient group, and a higher proportion of neuro-

psychologically abnormal patients was receiving anticholinergic

medications, but these were only trend-level differences, p < .08.

Age at first psychiatric hospitalization was substantially later and

length of illness was significantly shorter for the WNL group than

for the abnormal group. Because the patient subgroups did not

differ in age, one would expect that age at first hospitalization and

length of illness would be highly redundant. Interestingly, these

were rather weakly correlated in the full patient sample, r(72, N =

74) = — .13, p = .29, indicating that they contribute relatively

independent information regarding neuropsychological status.

Symptom ratings were available for only 10 of the 17 WNL

schizophrenia patients and 48 of the 58 neuropsychologically

abnormal schizophrenia patients. The WNL group tended to have

lower symptom ratings than the abnormal group. Differences were

nearly significant for negative symptoms, p < .06, but not for

reality distortion or disorganization symptoms.

One-to-One Matched WNL Schizophrenia Patients Versus

Controls

Although WNL patients were neuropsychologically WNL, most

were below the control mean. Perhaps a more stringent comparison

would be to examine differences between WNL patients and a

subgroup of controls matched for overall neuropsychological func-

tion.4 We therefore created a global neuropsychological score by

averaging the eight neuropsychological function scores. For each

WNL patient, we selected a control with the global score closest to

that of the patient. This one-to-one matching was carried out

without knowledge of any other participant characteristics. Mean

global scores for WNL patient and control subgroups were —.31

(SD = .38) and -.30 (SD = .38), respectively; the largest differ-

ence between any patient-control pair was only .012. WNL pa-

tients again performed significantly worse on abstraction-

executive function and perceptual-motor speed, ps < .03, but now

performed significantly better than the closely matched controls on

general verbal ability, p < .002. General visual-spatial ability,

executive-motor function, mental control—encoding, and sustained

attention-vigilance scores were higher (albeit slightly and nonsig-

3 As suggested by an anonymous reviewer, we also estimated current IQwith all four of the WAIS-R subtests that we administered (Vocabulary,

Block Design, Digit Span, and Digit Symbol). This estimate resulted in ahighly significant Reading-IQ discrepancy between controls and WNLpatients, p < .00001 (ES = 1.37). The two-subtest IQ estimate has beenvalidated (Silverstein, 1990), has been widely used, and thus can be

compared with the results of other published studies. We are unaware ofany short form that has been validated with these four subtests. Moreover,the Digit Symbol subtest strongly tends to be the lowest IQ subtest in

schizophrenia patients (Heaton & Drexler, 1987), and the scores for thissubtest were well below those of the other subtests in WNL patients. Withonly four subtests, the Digit Symbol subtest is likely to have an undueinfluence in the direction of reducing the IQ estimate. The "true" current IQof the schizophrenia patients may lie somewhere between these two esti-mates. Although it provides more conservative results, we retained thetwo-subtest estimate for our analyses because it also provides greatercomparability with previous studies.

4 This comparison was suggested by an anonymous reviewer.


Table 2

Clinical Characteristics of Neuropsychologically Normal and

Impaired Schizophrenia Patients

Schizophrenia patients

WNL(n = 17)

ABN

(n = 58)

Variable M SD M SD

Substance use history*Alcohol 1.59 1.54 1.93 1.35 .22Drug 0.53 1.01 2.18 1.31 .18

Age at first psychiatrichospitalization (years)6 29.18 8.04 22.58 5.28 .005

Length of illness (years)1" 14.11 11.94 22.21 10.50 .009Symptom ratings6

Negative 1.07 1.30 1.80 1.05 .06Reality Distortion 1.90 1.45 2.18 1.51 .60Disorganization 0.90 0.88 1.44 1.05 .14

Neuroleptic dosed 378.13 269.25 659.65 600.84 .08

Paranoid subtypeOutpatientsReceiving anticholinergicse

n

9

144

%

538224

n

12

3627

%

21

6248

.009

.12

.08

Note. WNL — neuropsychologically within normal limits; ABN = neu-ropsychologically abnormal.a Substance use ratings were from 0 (never or occasional) to 4 (heavyor sustained abuse). h Missing data for 1 ABN participant. c Basedon the Scale tor the Assessment of Negative Symptoms (SANS) and theScale for the Assessment of Positive Symptoms (SAPS) and includingonly a subset of participants: 10 WNL and 48 ABN participants.Negative - mean of SANS subscales except Inattention; Reality Dis-tortion = mean of SAPS Delusions and Hallucinations subscales;Disorganization — mean of SAPS Bizarre Behavior and Positive FormalThought Disorder subscales. d Measured in milligrams of chlorprom-azine equivalents. Missing data for 1 WNL participant and 1 ABNparticipant. Results are based on the Kruskal-Wallis chi-square test; theI test was significant at the .01 level, but the distribution of dosagevalues deviated substantially from normality. c Missing data for 2ABN participants.

nificantly) in WNL patients than in controls.5 Educational attain-

ment was slightly higher in WNL patients, p = .10, and both

current IQs (110.9 vs. 98.6), p < .004, and WRAT-R Reading

scores (110.4 vs. 95.8), p < .002, were significantly higher in

WNL patients than in controls. GAS scores were substantially

lower in WNL patients than in the matched controls, p < .0001.

Discussion

Neuropsychologically Normal Status Does Not Preclude

Compromised Neurocognitive Function

Despite being classified as neuropsychologically WNL, the

WNL patients still manifested poorer overall neuropsychological

performance than did controls, with deficits accounted for primar-

ily by abstract!on-executive function and perceptual-motor speed.

In contrast to the neuropsychological differences, both groups had

similar levels of educational attainment, and WNL patients had

significantly higher estimated premorbid intellectual ability than

did controls. Compared with a subgroup of controls who were

matched one-to-one on global neuropsychological function, WNL

patients had both significantly higher estimated premorbid intel-

lectual ability and current IQ but still had significantly poorer

abstraction-executive function and perceptual-motor speed.

Suggestive of a decline from premorbid level of function,

schizophrenia patients in a previous study by our group (which

included a subset of participants in this study) had significantly

larger Reading-IQ discrepancies than did controls (Kremen et al.,

1996).6 These discrepancies were nonsignificantly larger in WNL

patients than in controls, although there was a moderate ES of .40.

Consistent with our argument that educational attainment is atten-

uated by schizophrenic illness (Kremen et al., 1996), WNL pa-

tients had higher Reading scores than did the control group as a

whole, relative to their level of education (ES = .72). When WNL

patients were compared with a subset of matched controls, there

were even greater differences in educational attainment, [Q, and

WRAT-R Reading scores; all of these were higher in WNL pa-

tients, despite the persistence of the abstraction-executive and

perceptual-motor speed deficits. Differences in discrepancy scores

for these matched groups were reduced for Reading-IQ (ES = .24)

but not for Reading-education (ES = .70). Thus, WNL patients

may have relatively little decline in general intellectual function,

but they still appear to have attenuated educational attainment and

compromised neuropsychological function relative to expected or

premorbid ability.

On the basis of studies of both schizophrenia patients and their

biological relatives, we have argued that even prodromal symp-

toms are likely to result in reduced educational attainment or

neuropsychological deficits or both (Faraone et al., 1995; Kremen

et al., 1995, 1996). In contrast, Palmer et al. (1997) reasoned that

onset of illness after the completion of typical formal education

meant that the illness was unlikely to have interfered with educa-

tional attainment. However, even with age of onset that was much

later than that in the neuropsychologically abnormal patients, our

data strongly suggest that WNL patients still had reduced educa-

tional attainment.

Elliott et al. (1998) also found significantly impaired perfor-

mance on a variety of neuropsychological tests in schizophrenia

patients of similar age and with similar current and estimated

premorbid IQs as our WNL patients. Even genetically at-risk

individuals (including discordant monozygotic twins) manifest

neuropsychological deficits relative to controls or to estimates of

expected intellectual ability based on WRAT-R Reading scores

(e.g., Faraone et al., 1995; Goldberg et al., 1990; Kremen et al.,

1995). Thus, schizophrenia without at least some degree of com-

promised neurocognitive function relative to expected or premor-

bid ability seems unlikely.

5 Simple CPTs are prone to ceiling effects in controls, but it was the

more difficult Dichotic Listening Test that accounted for most of the

variance in the attention-vigilance function.6 There were 44 schizophrenia patients and 44 controls in the previous

study of Kremen et al. (1996), and these individuals are also included in

this study. However, neuropsychological function was not examined in the

earlier article.


Other Clinical and Demographic Correlates of

Neuropsychological Performance

Essentially, the pattern of clinical and demographic correlates is

consistent with WNL patients having a milder illness than neuro-

psychologically abnormal patients. Consistent with this view, the

WNL patients had much later age of onset and shorter duration of

illness than did the abnormal patients. Sex differences might

impact the age-of-onset findings (cf. Goldstein, 1995), but this

notion is difficult to gauge because a majority of the patients were

men and the scores were adjusted for sex.

The difference in the proportions of paranoid subtype patients in

our neuropsychologically abnormal and WNL schizophrenia

groups is consistent with several (e.g., Kremen, Seidman, Gold-

stein, Faraone, & Tsuang, 1994; Seidman et al., 1992; Silverstein

& Zerwic, 1985), but not all (Palmer et al., 1997), studies suggest-

ing better functioning in paranoid patients. Symptom differences

between WNL and abnormal patients were relatively weak, but

GAS ratings were quite different. This finding is consistent with

other data showing that cognitive function tends to be a better

predictor of psychosocial functioning than does symptomatology

(Green, 1996).

Limitations

Because data for symptom and GAS ratings were available for

only a subset of participants, conclusions regarding these variables

must be considered more tentative than conclusions about other

variables. We could not include visual-spatial declarative memory

because during the study we began using an updated version of the

test that was not comparable to the older version. Although we

cannot be certain, on the basis of previous findings (Saykin et al.,

1991; Seidman et al., 1992), it seems unlikely that this addition

would have greatly altered the neuropsychological results.

A generalized deficit in the schizophrenia patients could lead to

misinterpretation of our results (Chapman & Chapman, 1978).

Relatively poorer performance on particular neuropsychological

functions compared with that of others might, for example, be a

reflection of differences in task difficulty rather than specific

abilities. We believe that several factors argue against this expla-

nation in this study. First, attention-vigilance was worse than

mental control-encoding in the neuropsychologically abnormal

patients but was slightly better than mental control-encoding in

the WNL patients. This pattern suggests a double dissociation of

function. Second, (he WNL group cannot be said to have a gen-

eralized deficit because they performed nonsignificantly better

than the controls on two functions (verbal ability and executive-

motor function). Compared with controls matched on global neu-

ropsychological performance, WNL patients had significantly bet-

ter verbal ability and nonsignificantly better performance on four

other neuropsychological functions. If differences are attributable

to task difficulty or other psychometric properties, the results

should be in the same direction in each group. Finally, in contrast

to our results, schizophrenia patients studied by Saykin et al.

(1991, 1994) showed their most prominent deficits in declarative

memory. Because we used very similar tests, we also should have

observed the most prominent relative deficiencies in memory if

that pattern were primarily a function of task difficulty or some

other psychometric property.

It should be noted that with a cross-sectional design, we can

only infer decline from expected or premorbid ability levels based

on the observed discrepancies. Although we cannot know when

declines may have occurred or whether score discrepancies have

always been present and do not reflect change over time, inferring

decline seems the most parsimonious explanation. Moreover, lon-

gitudinal studies in which premorbid cognitive data were available

have indicated declines after the onset of psychosis (Goldman et

al., 1999; Schwartzman & Douglas, 1962).

Although relatively stable, our patient sample was a very

chronic one. It is possible that some patients early in the course of

illness do not experience any neuropsychological decline from

premorbid levels. Goldman et al. (1999) recently studied first-

episode patients who had improved neuropsychological function

after 3 years of illness. Current functioning was average (.2 SD

below the control mean), but their grade school achievement test

scores averaged 2 grades above grade level. These longitudinal

results for young, nonchronic patients strongly suggest decline

from superior to approximately average levels of function. Thus,

results from both chronic and first-episode patients support our

contention that compromised neuropsychological function is in-

deed a core feature of schizophrenia. Moreover, most studies have

not found evidence of progressive neuropsychological deteriora-

tion (Hoff et al., 1999: Hyde et al., 1994; Rund, 1998), at least not

before age 50 (Fucetola et al., 2000).

Summary

Although we classified almost one-quarter of a group of chronic

schizophrenia patients as being neuropsychologically WNL, our

findings were consistent with the notion that even these apparently

unimpaired patifents had compromised neuropsychological func-

tion relative to their expected or premorbid level of intellectual

ability. These findings support the hypothesis that compromised

neuropsychological function is a core feature of illness that is

present in virtually all individuals with schizophrenia. Further

understanding of the neural underpinnings of compromised neu-

ropsychological function in schizophrenia will be necessary to

understand whether or not the same sort of neuropsychological

compromise underlies all cases of schizophrenia and the extent to

which neural substrates for neuropsychological dysfunction and

traditional signs and symptoms may overlap. Finally, longitudinal

studies will be necessary to fully understand if and how neuropsy-

chological function changes over the course of illness, how it may

influence psychosocial functioning, and how neuropsychological

change is affected by level of premorbid intellectual ability.

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(Appendix follows}


Appendix

Guidelines for Rating Severity of Individual Neuropsychologicai Profiles (Based on Eight Functions)

This information is based on that given by Seidman et al. (1993).

NormalExpect within-subject variability of up to 1 to 2 SDs across functionsExpect function scores that are down to 1 SD below the control meanA single function may be close to or equal to 2 SDs below the control mean

Borderline NormalA single function that is ^2 and ^3 SDs below the control meanTwo functions that are ^1.5 and ^2 SDs below the control meanA single function that is ^1.5 SDs and s2 SDs below the control mean but also well below all other functions (difference of ^2 SDs,)

Examples: Verbal score = I and verbal memory = -1.5; one function is 2.5 SDs below another, but the more impaired function is only 1.5 SDsbelow the control mean (suggests selective impairment in the context of a mild severity level)

AbnormalA single function that is >3 SDs below the control meanTwo or three functions that are >2 SDs below the control meanTwo or more functions that are >1 SD and ^2 SDs below the control mean, with at least 4 SDs between the highest and lowest functions

Examples: Both visual memory and visual-spatial functions are >2 SDs below the control means, but the rest of the profile is relatively flat andwell within the average range; abstraction = -1.5, attention-vigilance - -1.8, and verbal = 2.2, making a 4-5D difference between thehighest and lowest scores

SevereFour or more functions that are >2 SDs below the control mean

Received May 17, 1999

Revision received March 1, 2000

Accepted June 8, 2000 •

The paradox of normal neuropsychological function in schizophrenia

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Transcript of The paradox of normal neuropsychological function in schizophrenia