What Do We Know About Neuropsychological Aspects Of Schizophrenia.pdf

8/10/2019 What Do We Know About Neuropsychological Aspects Of Schizophrenia.pdf

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REVIEW

What Do We Know About Neuropsychological Aspects

Of Schizophrenia?

Barton W. Palmer &Sharron E. Dawes &

Robert K. Heaton

Received: 25 March 2009 /Accepted: 2 July 2009 /Published online: 30 July 2009# The Author(s) 2009. This article is published with open access at Springerlink.com

Abstract Application of a neuropsychological perspective

to the study of schizophrenia has established a number ofimportant facts about this disorder. Some of the keyfindings from the existing literature are that, while neuro-cognitive impairment is present in most, if not all, personswith schizophrenia, there is both substantial interpatientheterogeneity and remarkable within-patient stability ofcognitive function over the long-term course of the illness.Such findings have contributed to the firm establishment ofneurobiologic models of schizophrenia, and thereby help toreduce the social stigma that was sometimes associated with

purely psychogenic models popular during parts of the 20thcentury. Neuropsychological studies in recent decades haveestablished the primacy of cognitive functions over psy-chopathologic symptoms as determinants of functionalcapacity and independence in everyday functioning. Al-though the cognitive benefits of both conventional and evensecond generation antipsychotic medications appear mar-ginal at best, recognition of the primacy of cognitivedeficits as determinants of functional disability in schizo-

phrenia has catalyzed recent efforts to develop targetedtreatments for the cognitive deficits of this disorder. Despitethese accomplishments, however, some issues remain to beresolved. Efforts to firmly establish the specific neuro-cognitive/neuropathologic systems responsible for schizo-

phrenia remain elusive, as do efforts to definitivelydemonstrate the specific cognitive deficits underlyingspecific forms of functional impairment. Further progressmay be fostered by recent initiatives to integrate neuropsy-

chological studies with experimental neuroscience, perhaps

leading to measures of deficits in cognitive processes moreclearly associated with specific, identifiable brain systems.

Keywords Psychoses . Cognitive . Heterogeneity.

Activities of daily living . Historical

Introduction

Schizophrenia is now almost universally recognized as aneurobiological disorder with a strong neurocognitivecomponent (Harrison and Weinberger2005; Keshavan etal. 2008). In contrast to earlier cognitive studies ofschizophrenia that were frequently focused on distinguish-ing schizophrenia from brain damage (reviewed inHeaton et al.1978), or on the description of schizophrenicthinking on a strictly psychological level (e.g., Bolles andGoldstein1938; Cameron1939a,1939b; Payne et al.1959;Vigotsky 1934), an enormous and still growing body ofneuropsychological research on schizophrenia over the lastfew decades has been based largely on either of two

premises: (a) specification of the neurocognitive pattern(s)associated with schizophrenia may help clarify the neuro-anatomic and/or neurophysiologic systems that underlieexpression of schizophrenia (Levin et al. 1989), and/or (b)recognition that identifying cognitive strengths and weak-nesses within persons with schizophrenia, and the relation-ship of such cognitive abilities/deficits to psychosocial orindependent living functions, might prove clinically usefulin developing effective placement and rehabilitative plans(Green1996; Heaton1976; Heaton and Pendleton1981).

In this paper, we consider the recent empirical literatureto inform an overview of the neuropsychological aspects ofschizophrenia. Following some brief historical comments,

B. W. Palmer (*) :S. E. Dawes : R. K. HeatonUniversity of California, San Diego,9500 Gilman Drive 0603V,La Jolla, CA 920930603, USAe-mail: [email protected]

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we will focus the remainder of our review on thefollowing questions: (1) What cognitive domains areaffected by schizophrenia? (2) How much intragroupheterogeneity exists? (Do all persons with schizophreniahave cognitive impairment, and are there reliable cognitivesubtypes?) (3) What is the premorbid, peri-onset, andlong-term course of cognitive functioning in schizophre-

nia? (4) What is known about neuropathological systemswhich may underlie cognitive dysfunction in schizophre-nia? (5) What are the effects of general and specificcognitive deficits on patients independence in everydayfunctioning? and (6) What is the effectiveness of current

pharmacologic treatments for cognitive deficits in schizo-phrenia? (We also briefly describe recent efforts todevelop non-pharmacologic interventions for the cognitivedeficits of schizophrenia; however, see Medalia and Choi(2009), this volume, for a comprehensive review ofcognitive remediation in schizophrenia.)

Historical Evolution of Neurocognitive Models

of Schizophrenia

There is now overwhelming empirical evidence thatschizophrenia is fundamentally a neurobiologic disorder(Harrison and Weinberger2005; Keshavan et al.2008), andone that is at least usually (albeit, as discussed below,

perhaps not invariably) accompanied by neurocognitivedeficits (Dickinson et al. 2007; Fioravanti et al. 2005;Heinrichs and Zakzanis 1998). Nevertheless, this contem-

porary view of the disorder represents a relatively recentresolution of a sometimes heated debate over the pastcentury about the functional versus organic nature ofschizophrenia (Babcock 1933; Bleuler 1930; Leonberger1989; May1931; Paris2005; Spielmeyer1930; Walker andTessner2008).

Emil Kraepelin, the first to distinguish schizophrenia(dementia praecox) from other forms of serious mentalillness, held a strongly neurobiologic conceptualization ofthis disorder. As early as 1899 he commented that Fromthe known clinical and anatomical facts [of dementia

praecox] I cannot doubt that we have to do here with asevere and as a rule markedly retrogressive process in the

brain cortex (as translated and cited by May (1931)p. 408). In the 1913 edition of his classic textbook,Kraepelin (1971/1919/1913) discussed possible biologicalas well as psychosocial causes of dementia praecox,including a number of potential factors which anticipatecontemporary neurodevelopmental models of schizophrenia(cf. Rapoport et al.2005), such as hereditary predispositionand injury to the germ (prenatal injury), as well ascommenting on minor facial and other physical anomalieswhich exist with striking frequencyamong such patients

(p. 236). (The latter are currently thought to reflect parallelprenatal aberrations in neurodevelopment (Weinberg et al.2007).)

Anticipating that regions of interest in contemporaryneuroanatomic theories of schizophrenia would be focused,in part, on the frontal-subcortical and temporal loberegions or systems (Harrison 2004; Ragland et al. 2007;

Shad et al. 2006; Winterer et al. 2003); Kraepelin (1971/1919/1913) noted that If it should be confirmed that thedisease attacks by preference the frontal areas of the brain,the central convolutions, and the temporal lobes, thisdistribution would in a certain measure agree with our

present views about the site of the psychic mechanismswhich are principally injured by this disease (p. 219).Kraepelin also characterized dementia praecox as adysfunction in what would today be labeled executivefunctions,particularly in regard to deficits ofvolitionorwill(see Zec1995).

Despite such strong beginnings toward a neurobiologic

model of schizophrenia, the first half and even early secondhalf of the 20th century evidenced considerable debateregarding psychogenic (or functional) versus biological(organic) models of schizophrenia (Babcock 1933;Bleuler 1930; Leonberger 1989; May 1931; Paris 2005;Spielmeyer1930; Walker and Tessner2008). There were anumber of empirical reports documenting cognitive deficitsamong persons with schizophrenia, particularly in regard todeficits in abstraction, conceptualization, or a tendencytoward overgeneralization (e.g., Bolles and Goldstein1938;Cameron 1939b; Fey 1951; Payne et al. 1959; Rawlings1921; Vigotsky 1934). With some exceptions (e.g.,Babcock 1933; e.g., Rawlings 1921; Wittman 1937), thelatter tended to be focused on a purely psychological levelof description of the structure of schizophrenic thinking,i.e., with limited presumption or reference to neuropatho-logic mechanisms (see reviews by Lothrop (1961) andWright (1975)).

Even Kurt Goldstein, one of the pioneers of neuropsy-chology and the use of psychometric tests to study theeffects of brain damage (see historical reviews by G.Goldstein 1990a, 2009), and someone well aware of theeffects brain damage can have on abstraction ability(Goldstein 1949; Goldstein and Scheerer 1941), empha-sized the psychological, not neurobiologic, aspects of whathe called the impairment in abstract attitude among

persons with schizophrenia (Bolles and Goldstein 1938;Goldstein 1939, 1959). Some of his musings about the

potential neuropathology underlying schizophrenia appearremarkably contemporary. For example, he wrote thatThere is no doubt that the clinical picture of schizophreniacontains symptoms which may best be understood asexpressions of a disturbed function of some apparatus ofthe brain, particularly of the frontal lobes and the

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subcortical ganglia... (Goldstein 1939, p. 582). Yet, hisemphasis in describing and explaining cognitive concrete-ness in schizophrenia remained solidly on the psycholog-ical/psychodynamic level. Indeed, in a later commentary, K.Goldstein (1959) noted his opinion that the abnormalconcreteness in schizophrenia is not the effect of anorganic defect (italics in original; p. 147), but rather a

protective mechanism against anxiety which originated inearly youth(italics in original; p. 147).

As noted above, the other primary impetus in early andmid-20th century studies of cognitive test performance inschizophrenia was to identify test performance patterns thatwould reliably discriminate patients with documented brainlesions (true organicity) from those with schizophrenia(reviewed in Heaton et al. 1978). Commenting on thedifficulties in finding useful discriminatory patterns,Watson et al. (1968) wrote It would appear that the chronicschizophrenics motivational deficits and thought disorders,coupled with the recovery shown by some organics, eliminate

many of the test differences psychologists have expected toseparate members of the two groups (p.679). The latter quotedemonstrates that, even through the late 1960s, at least someresearchers interpreted deficient performance by patients withschizophrenia on neuropsychological tests as reflectingdeficits engaging in the tasks (due to psychotic symptomsand motivation problems), rather than reflecting genuineneurocognitive impairment.

Finally, in the last quarter of the 20th century,neuropsychology began to take more frequent, albeitinitially somewhat diffident, steps in asserting the factthat schizophrenia is fundamentally a brain disorder. Forinstance, Strauss and Silverstein (1986) commented thatRecent evidence has raised a question of a centralnervous system basis for schizophrenic psychopathology[underline added for emphasis] (p. 35). Although the

potential role of psychosocial stress in the phenotypicmanifestation of schizophrenia is still generally recog-nized (Walker and Tessner2008; Zubin and Spring1977),the last quarter century brought a clear, empiricallygrounded change in the zeitgeist away from purely

psychogenic models of schizophrenia and other forms ofserious mental illness (Paris 2005; Walker and Tessner2008). This change included an exponential growth in theempirical study of schizophrenia from a neuropsycholog-ical perspective (Levin et al. 1989).

Level and Domains of Cognitive Impairment

The extant neuropsychological literature relevant to estab-lishing the level of cognitive impairment associated withschizophrenia is truly enormous. Fortunately, there have

been a number of excellent meta-analytic reviews published

over the past decade, integrating the literature comparingtest performance among schizophrenia patients and healthycomparison subjects (Dickinson et al. 2007; Fioravanti etal. 2005; Heinrichs and Zakzanis1998; Mesholam-Gatelyet al.2009). In addition to their own meta-analytic reviewof individual studies, Dickinson et al. (2007) provided aTable (i.e., their Table 4, p. 538) that serves as a summary

of meta-analytic reviews (see also Reichenberg and Harvey2007). The general conclusion that can be drawn from thisliterature is quite clear: schizophrenia is best characterizedas involving broad neurocognitive deficits across mostcognitive domains.

The average cognitive deficit associated with schizo-phrenia appears to be approximately one standard deviation(SD) below the mean of healthy comparison subjects(Dickinson et al. 2007). In regard to specific cognitivedomains, the general trend in the literature seems to bethat the strongest effect sizes are associated with tests ofepisodic memory (particularly free recall), and processing

speed, with the least (but still medium to large effect sizedifferences) associated with measures of crystallizedverbal knowledge and visual-spatial skill. For instance,among studies reviewed by Heinrichs and Zakzanis(1998), the lowest mean effect sizes were seen with theWechsler Block Design (d=0.46) and Vocabulary (d=0.53)subtests; the strongest mean effect size was seen on tests ofGlobal Verbal Memory(d=1.41). Similarly, among studiesreviewed by Fioravanti et al. (2005), the largest effect sizeswere associated with tests of memory (d=1.18), and thelowest with tests of language function (d=1.01) and globalcognitive function or IQ (d=1.01). In their recent meta-

analysis of studies of persons in their first-episode ofschizophrenia, Mesholam-Gately et al. (2009) also foundthe largest effect sizes, on average, to be associated with testsin the domain of auditory memory (d=1.20); althoughamong individual tests, the largest effect size was that forDigit Symbol (d=1.59). The smallest effect sizes were in thedomain of motor speed and dexterity (d=0.64); althoughon the level of individual test scores, some of the smallesteffect sizes were those associated with specific aspects ofCalifornia Verbal Learning Test Performance, particularlystorage (d=0.34). Dickinson et al. (2007) also found thestrongest effect sizes were those from the Digit Symbol task(d=1.57), and auditory episodic memory tests tended tohave the next highest effect sizes (ds=1.09 to 1.25). Someof the smallest effect sizes among studies reviewed byDickinson et al. (2007) were Block Design (d=0.84), LineOrientation (d=0.62), and Word Reading (d=0.59). Yet,note that even at the lower end, the effect size ranges inthese various reviews are near the cut-off of d=0.50commonly labeled a medium effect, while many othersare above the d=0.80 cut-off commonly labeled as alargeeffect size (Cohen1988).

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In addition to memory impairment, there has beenconsiderable interest in the neuropsychological literaturefocused on working memory and executive functions.Among the meta-analyses reviewed by Dickinson et al.(2007), the mean effect sizes for executive function tests(Wisconsin Card Sorting Test, Stroop Color Word Interfer-ence, and Trail Making Part B) range from d=0.53 to d=

1.06; for letter and category fluency (which were listedseparately), the effect sizes ranged from d=0.99 to 1.41;and for working memory (including Digit Span forward and

backward, mental Arithmetic, Letter Number Sequencing,and other measures of verbal or visual-spatial workingmemory), the effect sizes ranged from 0.61 to 1.18. (Forsake of consistency, we have labeled the effect sizes withd from Cohens d, but Dickinson et al. used amodification which adjusts for small sample sizes,Hedgesg). In short, although executive functions andworking memory are typically affected by schizophrenia,the empirical data do not point to differential impairment in

these ability areas (Braff et al.1991).From the pattern of effect sizes reviewed above, one

might be tempted to conclude that episodic memory deficitsare in some sense an especially important or corecognitive deficit in schizophrenia. However, the perennialinterpretive problem, brought by a lack of established

psychometric equivalence in sensitivity and specificity ofmeasures of different cognitive constructs, remains largelyunresolved (Chapman and Chapman 1973). Moreover, asalso is true of attention and executive functions, theterm memoryis non-specific (Squire2004). For instance,it appears that the bulk of test scores contributing to thelarge mean effect size formemory,reported in the studiesreviewed by Heinrichs and Zakzanis (1998), consisted offree recall scores on tests of verbal episodic memory. Instark contrast to the pattern seen with Alzheimer disease(Trster et al. 1993) patients with schizophrenia do nottypically show rapid forgetting of information actuallylearned (Heaton et al. 1994; Paulsen et al. 1995). In ameta-analysis specifically focused on memory test results,Aleman et al. (1999) found an effect size for total recall ofd=1.21, whereas that for recognition scores was only halfas strong (d=0.64).

Further reason for caution in drawing conclusions aboutdifferential coredeficits was provided by Fioravanti et al.(2005), who noted the considerable heterogeneity in effectsizes seen between studies. (A similar observation wasmade by Mesholam-Gately et al. (2009) in regard to studiesof first episode patients.) Fioravanti et al. (2005) attributedthe inter-study heterogeneity in effect sizes to both a lack ofcross-study consistency in methodology (including varia-tion in the sensitivity of the specific measures employed tooperationalize various constructs, and variation in the

procedures for selecting and matching of healthy compar-

ison subjects), and to differences in the characteristics ofthe patient samples. In regard to the latter, Fioravanti etal. asserted that Our analysis of heterogeneity indicatesthat there has been a widespread failure to consider themultidimensional nature of this patient population(p. 90).Thus, rather than endeavoring to establish the deficits of anon-existent average patient with schizophrenia, it may

be more fruitful to consider the issue of cognitiveheterogeneity in level and pattern of impairment and thefactors which do or do not coaggregate with better/worse ordifferent patterns of impairment.

Heterogeneity

Do all persons with schizophrenia have cognitive impair-

ment? In the mid-1980s, there were several reportsindicating some patients with schizophrenia are neuro-

psychologically intact (Bryson et al. 1993; Silverstein

and Zerwic1985; Strauss and Silverstein1986), and morerecent studies indicate that approximately 15% to 30%(with most estimates between 20% to 25%) of schizophre-nia patients have neuropsychological profiles in the normalrange (Allen et al. 2003; Goldstein 1990b; Heinrichs andAwad 1993; Holthausen et al. 2002; Ilonen et al. 2004;Kremen et al. 2000; Leung et al. 2008; Liu et al. 2006;Palmer et al. 1997; Weickert et al. 2000). For instance,using a previously validated procedure for systematicclinical ratings of results from an expanded Halstead-Reitan battery (Heaton et al. 1981), we found 47 of the171 (27.5%) people with schizophrenia had neuropsycho-logically normalprofiles (Palmer et al.1997). By way ofcomparison, Kremen et al. (2000) used a similar clinicalrating procedure, albeit with a different neuropsychologicaltest battery, and classified 17 of 75 (22.7%) schizophrenia

patients as neuropsychologically within normal limits.The larger literature examining the association between

severity of cognitive deficits and psychopathologic symp-toms is consistent in showing a significant but modestassociation between severity of cognitive deficits andnegative symptoms, but no discernable association betweencognitive deficits and positive symptoms, such as halluci-nations and delusions (see de Gracia Dominguez et al.2009). Comparisons of neuropsychologically normal versusneuropsychologically impaired patients with schizophreniayield results generally consistent with this overall pattern.For instance, relative to neuropsychologically impaired

patients, the neuropsychologically normal patients in ourstudy had significantly less negative symptoms andextrapyramidal symptoms, and reported more frequentsocial contacts, as well as being less likely to have had a

psychiatric hospitalization in the year preceding evaluation(Palmer et al. 1997). Other than the preceding variables,



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however, the neuropsychologically normal and impairedpatient groups were comparable in most of the demograph-ic, symptomatic/clinical, and functional characteristics.Similarly, Kremen et al. (2000) found that, relative toneuropsychologically impaired patients, those who wereclassified as neuropsychologically within normal limitshad a trend (p


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those who were neuropsychologically normal showed betterscores on a performance-based measure of social compe-tence and a measure of overall functional capacity, andwere more likely to have independent living status. On theother hand, there were no group differences in employmentor marital status. Note that findings regarding the lack ofeffects of neuropsychologically normal profiles on work

status are consistent with those of Heinrichs et al. (2008),described previously. We also obtained similar findingsfrom a study of predictors of functional status amongmiddle-aged and older patients with schizophrenia (Palmeret al.2002), i.e., there were significant correlations betweencognitive test performance and level of independence ineveryday functioning, but no significant correlation be-tween cognitive performance and work history. Suchfindings warrant follow-up through replication of the study,

but may indicate that work functioning is particularlyvulnerable to a variety of non-cognitive as well as cognitiveinfluences (cf. Green et al.2000). The general issue of the

association of neuropsychological deficits with everydayfunctioning is considered in greater detail in a separatesection to follow.

Cognitive subtypes: Another approach to the question ofcognitive heterogeneity in schizophrenia has been to usecluster analyses to identify general cognitive subgroups.Most cluster analytic studies (e.g. Allen et al. 1998;Goldstein et al. 1998; Heinrichs and Awad1993; Hill etal. 2002; Horan and Goldstein 2003; Seaton et al. 1999)find approximately four clusters that usually contain oneneuropsychologically normal cluster and one severely and

broadly impaired cluster. The other two clusters vary intheir profiles but are usually impaired (with differingdegrees of severity), and show perhaps one or two areasof neuropsychological functioning as stand out impair-ments (e.g., motor, verbal memory, or executive function-ing). For example, Horan and Goldsteins (2003) middletwo clusters included one described as moderate overallimpairment with severe motor impairment and the otherwith moderate impairment in all areas, whereas Heinrichsand Awad (1993) found five clusters with the threeintermediate clusters being described as (1) especiallyimpaired executive functioning, (2) especially impairedexecutive functioning and motor abilities, and (3) especiallyimpaired motor abilities. Such findings are usually based onsome iterative procedure (e.g., Wards (1963) method) ondata that may have been reduced in some manner (e.g.,

principal components analysis) int o neurocognitivedomains (e.g., abstraction/executive functioning, attention,verbal and visual memory, verbal and visuospatial abilities,motor skills, and working memory). However, there aresome interpretive limitations associated with cluster analy-ses. The cluster determination may be arbitrary, depending

on the methods employed. Methods are varied and there islittle consensus as to the best method to employ, which maylead to differing results (Lange et al. 2002). Also, theclusters derived are often based upon overall level of

performance rather than pattern based, which in somerespects may not be very helpful in identifying differencesin kind(Lange et al.2002). There are ongoing advances in

analytic techniques and approaches such as finite mixturemodeling or factor mixture modeling which have not beenwidely applied to cognitive heterogeneity in schizophrenia

but may yield additional insights (McLachlan and Basford1988).

When studies have examined the associations betweenclinical or demographic factors and cluster membership,most found that clinical characteristics (e.g. dose ofantipsychotic or positive or negative symptoms; Reich-enberg and Harvey2007) were not related, whereas somedemographics (e.g., education) were different betweenclusters (Seaton et al. 1999). Heinrichs et al. (1997)

examined differences between cognitive cluster groups ona modified version of the Sickness Impact Profile (SIP).The SIP is a self-report measure that provides ratings ofself-perceived health, quality of life, sleep and rest, homemanagement, social interaction, and recreation activities.The authors found that persons in the normative(generally intact) cognitive group had better sleep and restrelative to those in an executive-motor subtype (charac-terized by impaired WCST and Purdue Pegboard scores),whereas the selective executive group (characterized byisolated impairment only on the WCST) reported betterhome management, social interaction, and recreation thanthe executive-motor group, as well as better socialinteraction relative to those with generalized cognitiveimpairment. However, the sample sizes for these analyseswere relatively small (total N=55); there is clearly a needfor additional research that is sufficiently powered to detectfunctionally relevant differences and that employs multiplemeasures of functional capacity and functional status. (Theissue of the association between cognitive deficits andeveryday functioning is considered in greater detail below.)

Allen et al. (2000) examined the relationship ofcognitive and symptom cluster subgroups to brain struc-ture, measured with computerized tomography (CT) scans.They found no significant differences among the cognitivecluster groups in reference to ventricular size; however,global sulcul widening was highest among patients in theseverely impaired cognitive cluster. In contrast, whencomparisons were made among symptom-based clusters,

participants in the predominantly negative symptomscluster had larger third ventricle diameters relative tothose in the mixed and positive symptom clusters. Allen etal. concluded that symptom and cognitive abnormalities inschizophrenia may have different neuropathological cor-



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relates. As also noted by Seaton et al. (2001): Ultimately,the most likely typology to be successful will involve acombination of cognitive, symptom, and neuroimagingvariables(p. 47).

Course

Premorbid cognitive functioning: There is compelling evi-dence that schizophrenia is associated with early premorbidcognitive deficits. For example, Bilder et al. (2006) compared

premorbid school transcripts, as well as college aptitude testscores, from first-episode inpatients with schizophreniarelative to those of healthy comparison subjects. Comparisonof the available school transcripts suggested that, even in thefirst grade, children who later developed schizophreniamanifested an average grade equivalent score approximately0.8 year lower than healthy comparison subjects (selected to

have a similar distribution of age and gender) who did notdevelop schizophrenia. Comparison of college aptitude testscores (administered in grades 11 or 12) also indicated a

premorbid deficit, relative to healthy comparison subjects, ofalmost one SD.

One caveat in interpreting Bilder et al.s(2006) resultsregarding school transcript and college aptitude test com-

parisons is that the healthy comparison groups had highermean parental social class scores than the patient group(based on the Hollingshead-Redlich Index (Hollingsheadand Redlich1958); also the healthy comparison group had ahigher proportion of Caucasians (approximately 49% of

patients and 83% of healthy comparison subjects were ofCaucasian background). The degree to which these socio-economic and demographic differences affect the validity ofthe archival scores in establishing premorbid cognitivefunction is uncertain. Nonetheless, the overall pattern inthe literature is generally consistent with the findings fromBilder et al.

Results of two meta-analytic reviews of studies doc-umenting premorbid IQ among persons who subsequentlydeveloped schizophrenia suggest presence of at least a mild

premorbid cognitive deficit, with an average premorbid FullScale IQ of 90 to 95 compared to the population mean of100, with SD of 15 (Aylward et al. 1984; Woodberry et al.2008). For instance, Woodberry et al. (2008) reviewed 18studies in which people who later developed schizophrenia,as well as healthy comparison subjects, had receivedstandardized IQ or similar psychometric tests (studiesfocused on achievement tests were excluded) and found alower premorbid IQ with a medium effect size (d=0.54)among people who later developed schizophrenia. Woodberryet al. noted that this effect size is approximately half theeffect size found in comparison of IQ when measured

among post-onset schizophrenia patients relative tohealthy comparison subjects (Dickinson et al. 2007;Heinrichs and Zakzanis 1998). It is also lower than themean effect sizes for WAIS Full Scale IQs among firstepisode patients when compared against normal controls,d=1.01 (Mesholam-Gately et al. 2009). But there was noevidence of an age-related decline in IQ during the

premorbid period, and there was no significant differencein the pattern of intellectual skills when considered in termsof Verbal versus Performance IQ.

As noted by the previous discussion of cognitiveheterogeneity, much of the literature on premorbidcognitive deficits among persons with schizophrenia hasfocused on group averages, yet schizophrenia is typified

by substantial interpatient heterogeneity in virtually everydimension along which this disorder may be characterized.Thus it is not at all clear that the presence of premorbidcognitive deficits typifies all persons who later developschizophrenia. Indeed, as previously noted in the discus-

sion of neuropsychologically normal persons with schizo-phrenia, there may be some persons who functioned wellabove average in premorbid cognitive abilities (Keefe etal. 2005; Kremen et al. 2000; Wilk et al. 2005). Also,generally consistent with theories of brain or cognitivereserve (Satz1993; Stern 2002), it is quite possible thatlower premorbid cognitive functioning, rather than reflect-ing the influence of genetic or other schizophrenicvulnerability, may represent a second hit to thosegenetically at risk for schizophrenia, making the pheno-typic expression of that risk as clinical schizophrenia morelikely (cf. Mednick and Hollister1995).

Peri-onset cognitive changes: Data documenting the courseof cognitive deficits before and after onset of clinicalsymptoms are relatively rare. One approach to examiningthis issue is to study subpopulations who received pre-morbid testing (such as aptitude tests administered as partof enlistment in the military), and then to re-administer thesame tests at a post-onset period to people who did and whodid not develop schizophrenia or other neuropsychiatricconditions. One of the earliest examples of this approachwas a study by Schwartzman and Douglass (Schwartzmanand Douglas 1962; Schwartzman et al. 1962), whocompared the premorbid Army enlistment test scores, aswell as 10-year re-test scores, of Canadian World War IIveterans, including 50 who developed schizophrenia some-time after enlistment and 30 psychiatrically healthy veter-ans, matched to the patient group in terms of test scores atthe time of enlistment. The authors found that the groupthat developed schizophrenia evidenced a premorbid to

post-onset decline equivalent to approximately six IQpoints. A detailed review of this and other early longitudi-nal studies is available in Heaton and Drexler (1987).



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A more recent study relevant to establishing the degreeof premorbid to post-onset cognitive decline associatedwith schizophrenia is that of Seidman et al. (2006), whoexamined changes in IQ of persons with schizophreniawhose intellectual functioning had originally been assessedat age seven as part of the final visit in the NationalCollaborative Perinatal Project (NCPP). The latter was a

prospective national study in which 50,000 people werefollowed periodically from the prenatal period through thefirst seven years of life. Seidman et al. contacted a subset of

part icipants approximat ely 28 years later and re -administered intelligence tests. Their report provides alongitudinal comparison of IQ test performance from ageseven to an approximate 28-year follow-up among 38

people who developed schizophrenia or schizoaffectivedisorder and 62 non-schizophrenic controls. Consistentwith findings reviewed above regarding premorbid func-tioning, persons who developed schizophrenia had lowerIQ scores when tested as children relative to the non-

schizophrenic controls; moreover, the persons with schizo-phrenia, on average, showed a decline of approximately 10IQ points (adjusted for changes seen in the control group)from age seven to the time when they were re-tested in their30s. One interpretive caution regarding the latter finding,however, is that when comparing childhood to adult IQscores, it can be difficult to disentangle a failure to shownormative maturation/development of cognitive skills froman actual within-person decline in cognitive efficiency(Wechsler1939).

Taken together, the admittedly limited longitudinalpremorbid to postmorbid cognitive comparisons suggestthat, on average, schizophrenia illness onset may beassociated with one-third to one-half SD decline in generalcognitive functioning.

Post-onset cognitive course: Neither the presence of pre-morbid cognitive deficits nor the occurrence of an initialfurther decline in overall cognitive functioning around thetime of clinical onset of schizophrenia has generated

particular controversy. There has been somewhat lessconsensus regarding the long-term course of cognitivedeficits after onset of illness, but even in that regard, ageneral agreement appears to be emerging that, contrary toKraepelins initial suggestion that dementia praecox ischaracterized by a course of progressive decline, thecognitive deficits in schizophrenia tend to stabilize (Heatonet al. 2001; Kurtz 2005; Rund 1998), and may even

partially improve during the initial stabilization phaseimmediately after first onset (Albus et al.2002; S. KristianHill et al.2004; Klingberg et al. 2008).

Longitudinal as well as cross-sectional studies of non-institutionalized patients consistently demonstrate stablecognitive deficits after illness onset (Heaton et al. 1994,

2001; Kurtz 2005; Rund 1998). An example of theremarkable stability in neurocognitive functioning associ-ated with schizophrenia was provided in a longitudinalstudy from our research group (Heaton et al. 2001) inwhich 142 patients with schizophrenia and 209 healthycomparison subjects were re-tested with an expandedHalstead-Reitan test battery for an average of three years

(and up to 10 years). We found no evidence of cognitivedecline in any of seven neurocognitive ability areasexamined. Moreover, there were no differences in stabilityof cognitive functioning when considered in reference toshorter versus longer-term follow-up, lower versus higher

baseline functioning, age of onset, elderly versus non-elderly baseline age, or when patients were categorized bystability or change in severity of positive or negativesymptoms.

A possible exception to the general rule of cognitivestability in schizophrenia is the case of elderly persons whohave experienced long-term institutionalization for schizo-

phrenia (reviewed in Kurtz2005; Rajji and Mulsant2008;White et al.2006). There does seem to be a greater declinein general cognitive functions than can be attributed tonormal agingin a subgroup of such patients. This declinedoes not seem to be attributable to a comorbid neurode-generative condition such as Alzheimers disease (Friedmanet al.1999). One difficulty in interpreting such findings isthat the effects of institutionalization alone are difficult todisentangle from the specific effects of schizophreniarequiring institutionalization. That said, an association

between chronic institutionalization for schizophrenia andcognitive decline was observed even in some of the earliestlongitudinal studies of cognitive changes in schizophrenia(e.g., Schwartzman et al.1962). Nonetheless, as the bulk ofcontemporary patients with schizophrenia have not beenchronically institutionalized (Cohen et al.2000; Vahia et al.2007), i t appears that the modal pattern is one ofremarkable long-term cognitive stability in the post-onset

period.

Neuropathology

Precise delineation of the neuropathology underlyingschizophrenia in general, or its associated neurocognitivedeficits in particular, have both remained elusive despiteefforts extending back over a century. There are somegeneral patterns reviewed below.

Brain MRI studies of schizophrenia have found lowergray matter volumes (especially in the superior temporalgyrus and in medial temporal lobe and limbic structuresincluding the amygdala, hippocampus, and parahippocam-

pal gyrus), volume reductions in the frontal and parietal



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lobes, lack of normal asymmetries, enlargement of thecaudate (perhaps related to medication), and developmentalabnormalities such as presence of cavum septum pelluci-dum [thought to reflect aberrations in neurodevelopment;

patients with larger cavum septum pellucidum may showworse performance on learning and other cognitive meas-ures (Flashman et al. 2007)]. There are also frequent

abnormalities in the size or shape of the corpus callosum(Price et al. 2007; Walterfang et al. 2008), supporting theview of schizophrenia as a disconnection syndrome (Fristonand Frith1995) and, as with earlier CT findings, there areenlarged ventricles (DeLisi2008; Shenton et al.2001).

Functional imaging studies have found lower activity inthe prefrontal cortex and abnormal activation in thetemporal lobes during performance of both verbal andvisual tasks (Eyler et al.2004,2008; Keshavan et al.2008).This finding is also true for PET and SPECT, where theliterature suggests problems in the prefrontal and temporalregions of the brain (Lawrie et al. 2008). In resting state

network studies using fMRI, results are mixed as to theeffect that schizophrenia has on connectivity (Greicius2008). Overall, the main areas that are implicated in bothresting state and activation-based fMRI studies on anassortment of cognitive-based tasks include parts of thecerebral cortex (i.e., prefrontal, cingulate and temporalareas), the limbic system (specifically the hippocampus,striatum and thalamus), and the cerebellum (McGuire et al.2008).

Additional information has come through studies employ-ing Diffusion Tensor Imaging (DTI), which measures thefractional anisotropy of white matter tracts (i.e., how intact thetracts are). In schizophrenia, rather consistent findings areabnormalities in these tracts, leading to increased diffusivity inthe prefrontal and temporal lobes, corpus callosum, uncinatefascicules, cingulum bundle, and arcuate fasciculus (Assaf andPasternak 2008; Kubicki et al. 2007). The white matterfindings of Wexler et al. (2009), described above in thesection on neuropsychologically normal schizophrenia, sug-gested abnormalities of functional connectivity in participantswith schizophrenia and cognitive impairment, but not inhealthy controls or participants with schizophrenia and nocognitive impairment.

Other significant central nervous system findings inschizophrenia are in neurochemical dysfunction (e.g.,reduced N-acetyl aspartate in the frontal and temporallobes, hypercortisolemia and hypothalamopituitaryadre-nal axis dysregulation, and an increase in D2 receptors inthe striatum), neurophysiological dysfunction (includingabnormal prepulse inhibition, decreased P300 amplitudes,and REM sleep abnormalities), and at autopsy, decreaseddendritic density accompanied by normal or increasedneuron density and an absence of gliosis (Keshavan et al.2008).

Effects on Everyday Functioning

There has been long-standing interest in the functionalimportance of neurocognitive deficits in schizophrenia.More than 30 years ago, the senior author of the presentreview (RKH) noted The clinical value of neuropsycho-logical evaluation would be increased considerably if it

could also provide some reliable information regarding thepatients abilities to meet the demands of his [or her]everyday life(Heaton1976, p. 11). A wealth of empiricalresearch relevant to establishing such clinical value inmultiple clinical and nonclinical populations has arisen inthe subsequent three and a half decades (Green1996; Greenet al. 2000; Heaton and Pendleton 1981; Kurtz2006). In

particular, the empirical literature is quite clear andconsistent in demonstrating that, whereas the positivesymptoms of schizophrenia have little or no demonstrableeffect on everyday functioning, the neurocognitive deficits,and to lesser degree negative symptoms, are significant

correlates of functional capacity, and (perhaps less directly)levels of manifest everyday functioning.

The issue of whether there are differential effects ofimpairment in specific cognitive domains on overall function-al capacity or status is less clear. In Greens(1996) classicreview of this literature, he divided the types of functionalcapacity, status, or outcome variables into three categories:(a) independence in community functioning, (b) social

problem solving, and (c) skill acquisition. The strongestevidence for significant cognitive correlates was with tests ofauditory episodic memory (which Green labeled secondaryverbal memory), for which at least some studies foundsignificant correlations with community functioning, social

problem solving, and skill acquisition. The evidence regard-ing an association with executive functions (as assessed withWisconsin Card Sorting Test [WCST]) was strong forcommunity functioning, weaker for skill acquisition, andnon-significant for social problem solving. The evidence forvigilance (as measured with a Continuous Performance Test)was strong for social problem solving and skill acquisition,

but absent (not assessed) for community functioning. Greenconcluded that auditory memory and vigilance appear to benecessary for adequate functional outcome.

One might be tempted to interpret these reviewedfindings as indicative of differential importance of specificcognitive dimensions, but Green (1996) himself was carefulto note that his conclusions were limited by the infrequencywith which specific associations had actually been assessedand reported in the empirical literature. Moreover, in asubsequent updated review of the literature, Green et al.(2000) found that the largest amount of variance (between20 and 60 percent) in functional outcome was predicted byglobal or composite cognitive (rather than domain-specific)measures of neurocognition. This is not surprising because,



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as discussed above, schizophrenia is typically associatedwith multiple deficits in varying patterns, rather than withany single isolated cognitive impairment. In addition, withthe larger number of studies available in the 2000 review,Green et al. (2000) found further evidence that the strengthof documented associations may be influenced by thefrequency with which the associations have been examined

in the literature. For example, the updated review foundstudies in which executive functions (WCST scores) wereassociated with social problem solving, in addition to skillacquisition and community functioning.

Results of several studies from our research group andothers suggest that the association between cognitivedeficits and impairments in functional capacity or statusare generally non-specific (Evans et al.2003; Palmer et al.2002; Palmer and Jeste2006; Twamley et al.2002; Velliganet al. 2000). Such findings do not necessarily mean thatthere are no differential relationships between specificcognitive deficits and specific functional tasks. However,

efforts to unequivocally document the presence and natureof such relationships are hampered by the multi-factorialnature of standard neurocognitive tests (Dickinson andGold 2008; Gladsjo et al. 2004; The PsychologicalCorporation 1997), the multifactorial nature of mosteveryday tasks and activities, the lack of neurocognitive(as well as functional outcome) tests of different domainsthat have documented psychometric equivalence (Chapmanand Chapman1973), the above mentioned heterogeneity ofcognitive profiles of schizophrenia, and differences inopportunity of patients to perform certain everyday tasksand activities (Bellack et al. 2007).

The last decade also brought increased interest in thedegree to which the association between the cognitivedeficits and functional disability associated with schizo-

phrenia might be exceeded or partially mediated by deficitsin what has been called social cognition (Green et al.2000; Green and Leitman2008; Kee et al. 1998), a termwhich in the context of schizophrenia research has beendefined as referring to the following constructs: theory ofmind (requiring inferences about the mental states ofothers), social perception, social knowledge, attributional

biases, and emotional processing (see Green et al. 2008). [Itshould be noted that such use of the term social cognitionis narrower than originally developed within the field ofsocial psychology, wherein it includes a broader array ofconstructs such as perceived self-efficacy, outcome expec-tancies, and perceived locus of control (e.g., Bandura1986;Mischel 1973; Rotter 1966)]. Accumulating evidencesupports the contention that persons with schizophrenia,and even first-degree relatives, may show deficits in at leastsome of these social cognitive dimensions (Bora et al.2009; Eack et al. 2009; Marwick and Hall 2008), and thatthey do indeed affect functional outcome (Couture et al.

2006). Research is ongoing, but the body of publishedresearch in which identical constructs have been examinedis presently too small to draw firm conclusions regardingthe degree to which social cognitive deficits supplement,supplant, or mediate the effects ofgenericneurocognitionon everyday function (Bowie et al.2008; Pijnenborg et al.2009; Vauth et al. 2004). It appears likely that some of the

effects of cognition on outcome will be mediated throughsocial cognitive abilities, but that not all aspects ofeveryday functioning depend on social efficiency or skill.

Treatment

Pharmacologic: The era of conventional neuroleptics be-gan when the antipsychotic properties of chlorpromazinewere first identified in France in 1952; chlorpromazinereceived FDA approval two years later in March 1954(Crilly 2007). Although chlorpromazine and other subse-

quently developed neuroleptic medications were eventuallyfound to have serious potential side-effects such as tardivedyskenisia (reviewed in Jeste et al. 1999), they weregenerally thought to have minimal effects on cognition(either positive or deleterious), with the possible exceptionof partial normalization of some aspects of attention (e.g.,Cassens et al. 1990; Spohn and Strauss 1989). However,Mishara and Goldberg (2004) noted that this generalwisdom about the lack of beneficial effects of conven-tional neuroleptic medications on cognitive deficits inschizophrenia was based exclusively on narrative reviewsof the empirical literature, i.e., there was no extantquantitative/meta-analytic review. The latter authors con-ducted a meta-analyses of the available empirical literatureand found, contrary to conventional wisdom, that thatthere might indeed be some beneficial neurocognitiveeffects of conventional neuroleptic medications which,while modest in size (mean effect size d=0.22), at leastwarrant further empirical inquiry (Mishara and Goldberg2004).

The era of atypical or second generation antipsy-chotic medications is a long and circuitous one dating backto the late 1950s (Crilly 2007; Hippius 1999), butsystematic study of the effects of second generationantipsychotic medications on the neuropsychological defi-cits in schizophrenia began in the early to mid-1990s. Thesubsequent decade brought some suggestions that secondgeneration antipsychotic medications might partially im-

prove cer tain aspects of neurocognitive functioning(Harvey and Keefe 2001; Keefe et al. 1999; Meltzer andMcGurk1999; Woodward et al. 2005). However, whetheratypical antipsychotic medications actually produce func-tionally relevant degrees of cognitive benefit remains a

point of debate (Carpenter and Gold2002).



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The largest and most comprehensive investigation of thecognitive effects of antipsychotic medications was provided

by the NIMH-sponsored Clinical Antipsychotic Trials ofIntervention Effectiveness (CATIE) schizophrenia study(Keefe et al.2007). The CATIE study involved a randomizeddouble-blind comparison of schizophrenia treatment for up to18 months with any of five medications, including four

second generation antipsychotics (olanzapine, quetiapine,risperidone, or ziprasidone) and one conventional neuroleptic(perphenazine). The cognitive effectiveness analyses were

based on 817 patients who completed at least a baseline and 2-month follow-up assessments. There was a significantimprovement in overall cognitive performance within eachof the treatment groups, and there were no significantdifferences between the treatment groups in terms of changesin any of five specific cognitive domains. Similar findingswere seen in the subset of participants for whom 6- or 18-month follow-up data were available. The difference incognitive scores from 2- to 18-months was negligible,

suggesting the bulk of improvement occurred in the first twomonths of treatment. Overall changes in each of the groups,while statistically significant, were small and of questionablefunctional importance, and given the absence of an untreatedgroup, could at least partially reflect practice effects. Ifanything, however, participants randomized to the conven-tional neuroleptic manifested greater improvement in cogni-tive performance than did those randomized to secondgeneration antipsychotics. Specifically, exploratory pairwisecomparisons of 18-month change scores suggested thatimprovement in the neurocognitive composite score was

better in the group randomized to treatment with theconventional neuroleptic (perphenazine) relative to thoserandomized to treatment with olanzapine or risperidone.

One important interpretive caveat mentioned by Keefe etal. (2007) was that the majority of patients in the CATIEstudy were already receiving treatment with one or moreantipsychotic medications at the time of study entry. Theoverall pattern of results did not change even when theinvestigators adjusted the analyses to account for patientsreports of their baseline antipsychotic medication; nonethe-less, the possibility cannot be ruled out that acute cognitive

benefits of second generation antipsychotic medications mayhave been attenuated by prior treatment with the samemedication. Even so, such experience would not explain the(unexpected) finding of cognitive benefits from the conven-tional neuroleptic, perphenazine. The findings from morerecent report from the European First Episode SchizophreniaTrial also suggest no differential cognitive benefit of secondgeneration antipsychotics versus conventional neuroleptics(Davidson et al. 2009). In the latter study, 498 first episodeschizophrenia patients (each with less than 2 weeks exposureto antipsychotic medications in the year preceding studyenrollment) were randomly assigned to treatment with a

conventional neuroleptic (haloperidol) or one of four secondgeneration antipsychotic medications (amisulpride, olanza-

pine, quetiapine, or ziprasidone). Comparison of baseline to6-month follow-up assessments indicated statistically signif-icant improvements in overall cognitive test performance,

but there were no differences in the magnitude of thechanges among the five medication groups.

The question of differential cognitive benefits of secondgeneration versus conventional neuroleptic medications is notfully settled (Woodward et al. 2005, 2007). In light thedocumented effect sizes, however, there appears little reasonto be very enthusiastic about the cognitive benefits of eitherclass of medication. On the other hand, this conclusionrelates only to the potential cognitive effects of medicationsintended primarily to treat the psychotic symptoms. Effortsto develop more targeted pharmacologic treatments forcognition in schizophrenia are represented by the NIMH-sponsored Measurement and Treatment Research to ImproveCognition in Schizophrenia (MATRICS), Treatment Units

for Research on Neurocognition and Schizophrenia(TURNS), and Cognitive Neuroscience Treatment Researchto Improve Cognition in Schizophrenia (CNTRICS) projects(Buchanan et al. 2007; Carter et al. 2008; Green 2007;Marder 2006). Although development of drugs targetingcognitive deficits in schizophrenia remains in the earlystages, these initiatives represent an important step forwardtoward identification and development of promising com-

pounds or targets, to be tested by systematic efficacy andeffectiveness trials, and hopefully culminating in eventualregulatory approval of safe and effective medications for thiskey component of the illness.

Cognitive rehabilitation: In recent years, there has been anincreasing recognition of the need for psychosocial reha-

bilitative interventions for schizophrenia (Insel 2009). Inthat regard, recent efforts to develop cognitive training

programs for schizophrenia offer promise (Twamley et al.2003; Velligan et al. 2006). In general, these interventionstend to be most effective when focused on teaching patientscompensatory strategies (i.e., to help patients identify waysof minimizing the deleterious influence of cognitivedeficits, and to draw upon any cognitive or environmentalstrengths that may be available). For example, ElizabethTwamley, with other colleagues in our research group,recently developed a manualized 12-week cognitive reha-

bilitation program focused on teaching of compensatorystrategies and habit learning, and pilot tested its efficacy(relative to pharmacotherapy alone) through a randomizedcontrolled trial (Twamley et al.2008). At the post-treatmentassessment, those in the cognitive training group reportedfewer cognitive problems and more use of compensatorystrategies than those in the pharmacotherapy-alone group.Replication and refinement is needed, but this study



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illustrates the importance and viability of looking beyondpharmacologic interventions to address the functionaleffects of neurocognitive deficits in schizophrenia. (Pleasesee Medalia and Choi (2009), this volume, for a compre-hensive review of cognitive remediation in schizophrenia.)

Summary and Conclusions

Application of a neuropsychological perspective to thestudy of schizophrenia has established a number ofimportant facts about this disorder. Some of the highlightsand key conclusions that can be drawn from our review ofthis literature are summarized in Table1, top among whichare that there is (a) substantial interpatient heterogeneity incognitive function, (b) remarkable cognitive stability overthe course of the illness, and (c) that severity of cognitivedeficits, not psychopathologic symptoms, seems to be the

primary determinant of impairments functional capacity andfunctional status. The heterogeneity in cognitive function-ing provides tangible reason to express hope to patients andtheir families that schizophrenia is by no means typicallyaccompanied by profound cognitive deficits or by a lifelong

progressive decline in functioning. Thus contemporary dataprovide a substantially more optimistic picture than thatportrayed by the classic Kraeplinian notion of schizophre-nia as a dementia praecox. Recognition of the functionaleffects of cognitive deficits has been important in directingtreatment development efforts away from the previousexclusive focus on reduction or management of psychotic

symptoms, and toward a broader consideration of the needfor interventions that beneficially influence effects of thecognitive deficits and negative symptoms that may be moreimportant determinants of residual disability.

One other tangible benefit of this body of research is that itfurther establishes the view of schizophrenia as a neuro-

biologic disorder. Although neurobiologic models of schizo-phrenia date back to its earliest conceptualization, the 20thcentury also witnessed periods in which purely psychogenicmodels dominated the field. The latter models sometimes hadthe inadvertent effect of reinforcing the stigma experienced by

patients with this disorder and their families. For instance, theschizophrenogenic mothertheory was a particularly noto-rious psychogenic model that often contributed to unwarrant-ed guilt among family members about the affected personscondition (reviewed in Hartwell1996).

Where should the field go from here? One consistentissue that strikes us is the difficulty in firmly establishing the

presence of differential cognitive deficits in terms of specificcognitive domains or patterns. As noted in our introductorycomments, one of the key motivating factors or assumptions

behind much of the contemporary neuropsychological

research in schizophrenia has been the hope/assumption thatspecification of the neurocognitive pattern(s) associated withschizophrenia may help clarify the neuroanatomic and/orneurophysiologic regions or systems that underlie expressionof this disorder (Levin et al. 1989). While the data seem to

point to some degree to temporal and frontal-subcorticalbrain systems, these were among the regions Kraepelin

(1971/1919/1913) himself expressed interest in almost acentury ago, and which were reiterated by others, such as inthe previously cited quote from Kurt Goldstein in 1939(Goldstein1939). Judged from that perspective, the degreeof progress is unimpressive.

Closely related to the difficulty in establishing differen-tial cognitive deficits characterizing schizophrenia is thequestion of specificity. That is, given that one of the reasonsto consider the pattern(s) of neuropsychological strengthsand weaknesses associated with schizophrenia is to under-stand the underlying neurobiology associated with mani-festation of the clinical syndrome, it would be helpful to

discern the degree to which the level and pattern(s) ofneurocognitive deficits associated with schizophrenia aredistinct from those of other forms of serious mental illness,such as schizoaffective disorder or bipolar disorder. With afew isolated exceptions, most studies comparing level,

pattern, and frequency of neurocognitive deficits amongpatients with schizophrenia versus schizoaffective disordersuggest no reliable differences (reviewed in Palmer andSavla2009). [Recent reports on preparation of the DSM-V,scheduled for publication in 2012, indicate plans toeliminate schizoaffective disorder as diagnostic entityseparate from schizophrenia (Gever 2009).] Comparisons

of persons with schizophrenia to those with bipolar disorderhave led to a more complex pattern of results. In aninteresting contrast to schizophrenia, in which duration ofillness, symptom severity, and fluctuations of symptoms donot substantially influence severity of cognitive deficits(Heaton et al.1994,2001; Nayak et al.2006; Palmer et al.1997), a number of studies suggest that some cognitivefunctions are adversely affected by severity of currentmanic or depressive symptoms in bipolar patients (reviewedin Goldberg and Burdick (2008)). However, cognitivedeficits are also present during the inter-episode periodsof relative remission/euthymia among many persons with

bipolar disorder (Cavanagh et al.2002; Martinez-Aran et al.2004a,b; Torrent et al.2006). These deficits may be worseamong patients with a longer duration of illness and withhigher numbers of lifetime affective episodes (Bearden etal. 2001; Cavanagh et al. 2002; Denicoff et al. 1999;El-Badri et al. 2001; Lebowitz et al. 2001; Zubieta et al.2001). Yet, the primary finding in comparison of neuro-

psychological profiles among persons with schizophreniaversus bipolar disorder is that those with bipolar disordertend to have a similar profiles of impairment, but have a



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less severe degree of impairment (Depp et al. 2007;Schretlen et al.2007; Seidman et al. 2002).

Much of the existing research on cognitive deficits inschizophrenia also was motivated by a general presumptionthat identifying cognitive strengths and weaknesses within

persons with schizophrenia, and the relationship of suchcognitive abilities/deficits to psychosocial or independentfunctions, would have clinical value in developing effective

placement and rehabilitation plans. While the relationship

between cognitive function in general and functional capacityis firmly established, the evidence for differential relationships

between specific cognitive dimensions and specific tasks ordemands of everyday living remains murky.

In part, the difficulties in making greater progress inestablishing the presence of differential cognitive deficitsand differential relationships with specific aspects ofeveryday functioning may reflect the heterogeneous natureof schizophrenia. Eugen Bleuler (1950/1911) appears tohave been wise in describing the disorder with the plural

(schizophrenias) rather than singular (schizophrenia)form. It is possible that further advances in neuroimaging,genomics, and epigenetics will help identify more homog-enous neurocognitive subtypes than are presently available.Also, Kremen et al. (2000) noted that examination ofindividual neuropsychological profiles could be a usefulalternative to group analysis for making sense of heteroge-neity in schizophrenia(p. 744). One patient may evidencedifficulty on a list learning task due to impairments in

memory consolidation associated with medial temporallobe dysfunction, whereas another patients poor perfor-mance on that same task may reflect deficits in frontal orfrontal-subcortical systems related executive functions, e.g.,resulting in choice and application of a suboptimalencoding strategy. In recognition of such possibilities, inclinical interpretation, neuropsychologists do not typicallyor automatically interpret tests as measures of their namedor standard cognitive constructs, but rather attempt to comeup with hypotheses of the latent deficit(s) that may explain

Table 1 Summary of key findings from the empirical literature on neuropsychological aspects of schizophrenia

Domain of inquiry Key findings

Level of impairment Heterogeneous findings between persons, between domains, and between studies, but on average, schizophrenia isassociated with a mild-to-moderate degree of cognitive deficit approximately one standard deviation below thenormative mean

Pattern Generalized impairment in most cognitive domains; some evidence of stronger effect sizes for aspects of immediate

recall on episodic declarative memory tasks, and for processing speed, with lower (but still medium to large) effectsizes in reference to crystallized knowledge and visual-spatial skills. There is little consistent evidence ofdifferential decline in working memory or executive functions, despite long-standing interest in these domains aspotential core deficits in schizophrenia.

Heterogeneity About 20% to 25% of patients with schizophrenia retain a psychometrically normal pattern of neurocognitivefunctions. Neuropsychologically normal status does not appear to represent differences in severity of illness, asreflected by psychotic symptoms. Cluster analytic studies also suggest the presence of a severely impairedsubgroup, which would be consistent with earlier notions of deficit syndrome, Type II, and/or negative symptomschizophrenia.

Course Mild (on average) premorbid cognitive deficits; further decline at the time of onset of clinical symptoms equivalentto about 5 to 10 IQ points (with partial recovery of cognitive functions during the stabilization phase after firstonset); a stable pattern of cognitive functions across all neurocognitive domains over the long-term chronic courseamong non-institutionalized patients

Neuropathology Precise delineation of the neuropathology underlying schizophrenia in general, or its associated neurocognitivedeficits in particular, has remained elusive despite efforts extending back over a century. However, general patternsinclude decreased gray matter volume (particularly in the temporal and limbic structures), as well as enlargedcaudate and ventricles. Functional imaging studies suggest decreased activity in the prefrontal cortex and abnormalactivation in the temporal lobes during both verbal and visual tasks. Diffusion Tensor Imaging (DTI) studiessuggest schizophrenia may be associated with increased diffusivity, in the prefrontal and temporal lobes, corpuscallosum, uncinate fascicules, cingulum bundle and arcuate fasciculus.

Effects on everydayfunctioning

Positive symptoms of schizophrenia have little effect on everyday functioning. Neurocognitive deficits, and to lesserdegree negative symptoms, are significant correlates functional capacity, and to a lesser degree levels of manifesteveryday functioning. Little compelling evidence of differential associations between specific cognitive deficits andimpairments in specific dimensions of functional capacity or status. Whether and the degree to which, or underwhat specific conditions, the association between cognitive deficits and deficits in everyday functioning aresupplemented by, supplanted by, or mediated by the effects on social competence related skills (social cognition)remains an open question.

Amenability to treatment Relative cognitive benefits of conventional versus second generation antipsychotic medications remains a point ofunresolved debate, but none has been shown to result in substantial (functionally relevant) levels of cognitive

improvement. Efforts are ongoing to develop pharmacologic agents that would directly target the cognitive deficitsassociated with schizophrenia, as well as to develop and validatenon-pharmacologiccognitive compensatory programs.



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the pattern of strengths and weaknesses across a set of tests.Yet in neurocognitive research there is a tendency to equatedeficits on specific test scores with their labeled ability. Theapparent diffuse or nonspecific nature that seems to bestcharacterize the averagepattern of neurocognitive deficitsin schizophrenia may, at least in part, reflect the fact that we(as a field) tend to blend apples and orangesand then try

to say something intelligent about average fruit. Furtheradvances in analytic methodology may enable researchersto more effectively apply process or idiographic interpreta-tion to large sets of cognitive data from schizophrenia

patients and their subgroups (cf. Barlow and Nock2009).In addition, there remains a need for better neurocognitive

measures that are more sensitive and specific to deficits indiscrete cognitive functions. Many of the commonly usedcognitive measures have shown relatively little modificationfrom their original forms over the past 50 to 100 years (Berg1948; Boake 2000, 2002; MacLeod 1991; Partington andLeiter1949; Wechsler1939). These are all well-established

tools, and remain valued components of the neuropsycho-logical armory, but it must also be recognized that they weregenerally developed and designed for uses quite distinctfrom establishing differential cognitive deficits in neuropsy-chiatric conditions. There is reason for optimism that the tideis turning in this regard. In particular, the Cognitive

Neuroscience Treatment Research to Improve Cognition inSchizophrenia (CNTRICS) initiative is a recent cognitiveneuroscience focused spin-off of the more widely known,clinically construct-oriented MATRICS project (Carter et al.2008). The aim of the CNTRICS is to identify promisingconstructs from cognitive neuroscience which may be usefulin identifying more specific or elementary cognitive process-es related to more specific brain systems involved inschizophrenia. Whether the products of this initiative willin fact lead to more sensitive and specific measures ofdifferential cognitive abilities/deficits in schizophrenia isuncertain, but it seems a timely and worthy attempt.

Acknowledgments This work was supported, in part, by NationalInstitute of Mental Health grants P30 MH080002, T32 MH019934,and R01MH064722.

Disclosures The authors have no conflicts of interest to report.

Open Access This article is distributed under the terms of theCreative Commons Attribution Noncommercial License which per-mits any noncommercial use, distribution, and reproduction in anymedium, provided the original author(s) and source are credited.

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