Neurocognitive Impairments

Richard S. E. Keefe, Ph.D.

Charles E. Eesley, B.S.

Dr. Richard Keefe

Associate Professor
Duke University
Box 3270
Duke University Medical Center
Durham, NC 27710 USA
Fax: 1-919-684-2632
richard.keefe@duke.edu

Charles E. Eesley, B.S.

Duke University
Box 3270
Duke University Medical Center
Durham, NC 27710 USA
919-471-0054
eesle001@mc.duke.edu

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Neurocognitive Impairments Chapter

I. What is the cognitive impairment in schizophrenia?

A. Cognition as a Core Feature of Schizophrenia
B. Profile and Magnitude of Cognitive Impairment Associated with Schizophrenia
1. 7 divisions of cognition

II. What is the natural history of neurocognitive impairment?

A. Deficits in children at risk for schizophrenia and follow-back studies
B. The course of cognitive impairment from prodrome to end-stage illness.
Prodrome Studies
First Episode of Psychosis Studies
Cognitive Changes in Patients Recovering from Acute Exacerbation
Longitudinal Change in Cognitive Function
Cognitive Functioning in Elderly Patients
C. Summary

III. Relationship of neurocognitive impairment to positive, negative and extrapyramidal

symptoms.
A. Pseudospecificity
B. Cross-sectional studies.
C. Longitudinal studies.

IV. Clinical importance of neurocognitive impairment.

A. Cross-sectional correlations with function
B. Relationship of Neurocognitive Impairment to Functioning

V. Conclusion

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 SECTION I. Cognitive Impairment in Schizophrenia

Cognition as a Core Feature of Schizophrenia

Cognitive impairment associated with schizophrenia is now viewed as a potential

psychopharmacological target for treatment (Hyman and Fenton 2003). While cognition is not a

formal part of the current diagnostic criteria for schizophrenia, the Diagnostic and Statistical

Manual of Mental Disorders, volume IV (DSM-IV-TR 2000) includes seven references to

cognitive dysfunction in the description of the disorder. Diagnostic and scientific experts have

increasingly expressed the idea that neurocognitive impairment is a core feature of the illness,

and not simply the result of the symptoms or the current treatments of schizophrenia.

Profile and Magnitude of Cognitive Impairment Associated with Schizophrenia

Severely impaired performance on cognitive tests is the strongest evidence for the

importance of cognitive deficits in schizophrenia. In several cognitive domains, the average

impairment can reach 2 standard deviations below the healthy control mean (Harvey and Keefe

1997; Heinrichs and Zakzanis 1998; Saykin et al. 1991). While only about 27% of patients with

schizophrenia (and 85% of the general population) are not rated as “impaired” by clinical

neuropsychological assessment (Palmer 1997), these patients tend to have the highest levels of

premorbid functioning (Kremen 2000), and demonstrate cognitive functioning that is

considerably below what would be expected of them based upon their premorbid levels and the

educational level of their parents. Recent analyses of data from 150 patients with schizophrenia

suggest that up to 98% of patients perform more poorly on cognitive tests than would be

predicted by their parents level of education (Keefe, Eesley, and Poe submitted for publication).

In addition, comparisons of monozygotic twins discordant for schizophrenia suggest that almost

all affected twins perform worse than their unaffected twin on cognitive tests (Goldberg et al.

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1990). Therefore, it is likely that almost all patients with schizophrenia are functioning below the

level that would be expected in the absence of the illness.

Neurocognitive tests often assess more than one domain of functioning, and many tests

do not fit neatly into a single domain. Thus, descriptions of the profile of cognitive deficits in

schizophrenia have varied across literature reviews. The domains that are most consistently cited

as being severely impaired in schizophrenia are verbal memory, executive functions, attention or

vigilance, verbal fluency, and motor speed (Harvey and Keefe 1997). Deficits in social cognition

also appear to be severe, but this is a relatively new area of research, with fewer studies to

support this finding (Pinkham et al. 2003). The opinion of a group of experts who served on the

Neurocognition Subcommittee for the Measurement and Treatment Research to Improve

Cognition in Schizophrenia (MATRICS) Project is that the most important domains of cognitive

deficit in schizophrenia are: working memory, attention/vigilance, verbal learning and memory,

visual learning and memory, reasoning and problem solving, speed of processing, and social

cognition (Green et al., in preparation www.matrics.ucla.edu).

The most striking aspect of the profile of cognitive deficits in patients with schizophrenia

is that so few cognitive functions remain similar to healthy controls (Harvey and Keefe 1997;

Saykin et al. 1994). In fact, an estimate of the severity of neurocognitive impairment in patients

with schizophrenia, based upon an examination of the most methodologically sound studies

completed, suggests that many important cognitive functions are in the severely impaired range

(2 to 3 standard deviations below the normal mean) or moderately impaired range (1 to 2

standard deviations below the normal mean). A review and meta-analysis of 204 studies shows a

consistent and stable difference between patients with schizophrenia (N = 7420) and healthy

controls (N = 5865) in a wide range of domains of cognitive functioning (Heinrichs and Zakzanis

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1998). Examples of tests that measure the most important components of cognitive impairment

in schizophrenia are briefly reviewed here.

Attention/Vigilance. Many neurocognitive tests require vigilance functions, even if the

test itself is not a measure of “pure” vigilance. Vigilance refers to the ability to maintain

attention over time. A standard vigilance test used in many studies is the Continuous

Performance Test, or CPT. The “A-X” version of the CPT, requires that patients attend to a

series of letters presented one at a time on a computer screen at a rate of one per second. Patients

respond with a button-press on the computer mouse or keyboard each time an “A” is followed by

an “X”. This type of CPT reveals severe vigilance impairments in patients with schizophrenia

(Cornblatt and Keilp 1994).

Impairments in vigilance can result in difficulty following social conversations, inability

to follow important instructions regarding treatment, therapy or work functions, and simple

activities like reading or watching television become labored or impossible. Reviews of the

literature have suggested that vigilance deficits in patients with schizophrenia are related to

various aspects of outcome, including social deficits, community functioning, and skills

acquisition (Green 1996; Green 2000).

Verbal Learning and Memory. Several different types of abilities involved in memory

functioning include, but are not limited to, abilities associated with learning new information,

retaining newly learned information over time, and recognizing previously presented material. In

general, patients show larger deficits in learning than in retention. The findings for recognition

are more equivocal, with most studies suggesting relatively mild deficits (Calev 1984; Saykin et

al. 1991) yet large deficits have also been reported (Mohamed et al. 1999). The tests used to

measure learning typically involve the ability to learn lists of words or written passages. Verbal

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list learning tasks usually require the patient to listen to 12 to 16 words, then immediately recall

as many of the words as possible. Using the California Verbal Learning Test, normal controls

can recall about 8 of 16 words after the first trial; patients with schizophrenia can recall only

about 5 (Paulsen et al. 1995). After 5 consecutive trials of the same word list, most controls can

recall at least 13 of the words, while patients with schizophrenia, on average, can recall only 9.

Thus, patients are not only impaired in their ability to immediately recall verbal material, they

are also impaired compared to controls in their ability to learn over time. Patients are also

impaired in recalling more interesting verbal material, such as stories (Hoff et al. 1992).

Much empirical evidence points to the connection between verbal memory impairment

and social deficits in patients with schizophrenia (Green 1996).

Visual Learning and Memory. Since visual information is not as easily expressed as

verbal information, fewer tests sensitive to the deficits of schizophrenia have been developed,

and this area of cognitive function has generally been found not to be as impaired as verbal

memory (Heinrichs and Zaksanis 1998). Most tests require subjects to draw figures from

memory or to indicate which among an array of figures was previously presented.

Studies of the relationship between poor visual memory and functional outcome have

yielded mixed findings. Visual memory has been found to correlate modestly with employment

status (Gold et al. 2003), job tenure (Gold et al. 2002), psychosocial rehabilitation success

(Mueser et al. 1991), social functioning (Dickerson et al. 1999), quality of life ratings (Buchanan

et al. 1994), and strongly with functional capacity (Twamley et al. 2003). Other studies have

reported no significant correlations (Addington and Addington 2000; Addington et al. 1998;

Ertugrul and Ulug 2002; Velligan et al. 2000).

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 Reasoning and Problem-solving. While there are numerous tests of reasoning and

problem solving, the most well-known and most frequently utilized in schizophrenia research is

the Wisconsin Card Sorting Test (Heaton 1981). In this test, patients are given a deck of cards

with various numbers of colored shapes on them, and are asked to match their cards to four

“key” cards that have shapes on them that differ by color, form, and number. The first principle

to which the subject needs to learn to sort the cards is color. After a patient demonstrates that he

has learned that color is the correct sorting principle, the principle changes to form without

warning. Repeated sorting attempts by the previously correct principle are referred to as

perseverations, and patients with schizophrenia, like patients with frontal lobe damage, often

make many of these errors. In fact, the very poor performance of patients with schizophrenia on

the Wisconsin Card Sorting Test (Goldberg et al. 1987), and the reduced activity of the

dorsolateral prefrontal cortex during performance of this test (Weinberger et al. 1987) led to

widespread pursuit of the hypothesis of frontal hypoactivation in schizophrenia. It is important to

note, however, that the Wisconsin Card Sorting Test measures a variety of cognitive functions

and is not a “pure” measure of executive functions (Keefe 1995)

The rules of society and the workplace change regularly, and success in these arenas is

often measured by one’s ability to adapt to changes. Patients with schizophrenia who are

impaired on measures of executive functions have difficulty adapting to the rapidly changing

world around them.

Speed of processing. Many neurocognitive tests require subjects to process information

rapidly and can be compromised by impairments in processing speed. A standard example of this

type of task is the Wechsler Adult Intelligence Scale Digit Symbol Test (Wechsler et al. 1997).

Each numeral (1 through 9) is associated with a different simple symbol. Subjects are required to

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copy as many of the symbols associated with the numerals as possible in 90 seconds. This

nonspecific cognitive impairment has been found to correlate with a variety of clinically

important features of schizophrenia, such as daily life activities (Evans et al. 2003), job tenure

(Gold et al. 2002), and independent living status (Brekke et al. 1997). It is also sensitive to

medication side effects such as somnolence and extrapyramidal symptoms (Galletly et al. 2000).

Reduced processing speed can impair ability to keep in step with the task-oriented jobs

that are frequently held by patients with schizophrenia. Increased response latency in social

settings may hamper social relationships.

Verbal Fluency. Most cognitive assessments in treatment studies of schizophrenia have

included measures of verbal fluency as a separate domain of functioning (Harvey and Keefe

2001; Keefe et al. 1999; Meltzer and McGurk 1999). Most of these tests measure either

phonological fluency (also referred to as letter fluency) or semantic fluency. Phonological

fluency refers to a patient’s ability to produce as many words as possible beginning with a

particular letter within for instance 60 seconds. Semantic fluency refers to the ability to produce

words within a particular meaning-based category, such as “vegetables.” Not only do

schizophrenia patients produce fewer words than normal controls, but they often produce

inappropriate examples, such as examples of fruits instead of vegetables. Impaired verbal fluency

can damage functioning in social and vocational settings by making communication difficult and

awkward.

Immediate / Working Memory. Immediate memory refers to the ability to hold a limited

amount of information "on-line" for a brief period of time (usually a few seconds). Repeating a

string of digits (Digits Forwards) is an example of immediate memory. The definition of working

memory, on the other hand, is more complex and varies across studies. Some investigators

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consider working memory to be synonymous with immediate memory, whereas others describe

that it should require some manipulation of the information being held on-line. For example,

repeating a series of digits in the reverse order than they were presented (Digits Backward)

requires an active manipulation because the information needs to be both held on-line and then

subsequently re-ordered. Patients typically show deficits on both tasks. These visual tasks

involve keeping a visuospatial stimulus, such as a dot on a computer screen, or series of visual

objects in mind while working on a related or unrelated task (reviewed in Keefe 2001).

Working memory has been described by various authors as a core component of the

cognitive impairment in schizophrenia (Goldman-Rakic 1994; Keefe 2001; Silver et al. 2003),

and is related to functional outcomes such as employment status (McGurk and Meltzer 2000),

and job tenure (Gold et al. 2002). Much of the clinical relevance of working memory deficits in

schizophrenia comes from strong correlations that working memory measures have with a

variety of other cognitive domains impaired in schizophrenia, such as attention, planning,

memory (reviewed in Keefe 2001), and intelligence (Baddeley 1992), as well as the advanced

understanding of the neuroanatomy of working memory functions in human and non-human

primates. This neuroanatomical work has suggested that neural circuitry that includes prefrontal

cortical regions mediates aspects of working memory functions (Callicott et al. 1999; Goldman-

Rakic 1987), and that this circuitry may be impaired in schizophrenia (Callicott et al. 1999).

Social Cognition. Theory-of-mind skills and social perception have been the general

focus of the literature on social cognition in schizophrenia. Theory-of-mind is the ability to infer

about another’s intentions and/or to represent the mental states of others. Individuals with

schizophrenia perform poorly on measures of theory-of-mind abilities (Corcoran, Mercer, and

Frith 1995; Drury, Robinson, and Birchwood 1998; Sarfati et al. 1997). The evidence regarding

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whether impairments in theory-of-mind skills are independent of a general cognitive deficit is

mixed (Doody et al. 1998; Pinkham et al. 2003). Facial affect recognition and social cue

perception are the two general areas into which studies of social perception in schizophrenia can

be broken down. Reviews of the literature on facial affect recognition (Morrison, Bellack, and

Mueser 1988; Penn et al. 1997) suggest that individuals with schizophrenia have stable deficits

on tests of facial affect perception compared with healthy controls and psychiatric controls, and

that perception of negative emotions and fear may be particularly impaired (Addington and

Addington 1998; Edwards et al. 2001; Gaebel and Wolwer 1992). Tests of social cue perception

use more dynamic stimuli that require multiple sensory modalities, such as watching videotapes

of persons interacting. Patients with schizophrenia show consistent impairments on these tasks

(Bell, Bryson, and Lysaker 1997; Corrigan, Davies-Farmer, and Stolley 1990). In particular, they

have more difficulty discerning other individuals’ goals and intentions than what they are

wearing or saying.

A variety of reports have described the strong relationship between cognitive function

and social deficits in schizophrenia (reviewed by Trumbetta and Meuser 2000). Even so, there is

growing evidence that social cognition is related to social impairments in schizophrenia, even

after controlling for performance on neurocognitive tasks (Penn et al. 1996).

Summary

Experts in cognition and schizophrenia have come to a clear consensus that cognitive

impairment is a core feature of the illness. The profile of deficits is broad, severe, and is likely

present in most if not all patients. Neurocognitive impairment has clear clinical relevance, as

cognitive impairment interferes with the everyday lives of patients in various important ways,

from limiting social relationships to reducing the likelihood of employment.

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SECTION II. Natural History of Neurocognitive Impairment

Evidence shows that the time course of the development of cognitive deficits in

schizophrenia patients appears to follow a predictable pattern. Some deficits may be present in

childhood, followed by a decline in cognitive function prior to the first episode. The severity of

neurocognitive impairments becomes even more severe once psychosis develops. The long-term

stability of neurocognitive impairment over time is not clear, but evidence for progression in

non-elderly patients is lacking.

Deficits in Children at Risk for Schizophrenia and Follow-back Studies

Individuals who are genetically vulnerable to schizophrenia have notable cognitive

impairments (Cornblatt and Keilp 1994), while individuals who are examined with cognitive

assessments before they develop schizophrenia are found to have impairments in a variety of

areas (Davidson et al. 1999). High-risk studies of children with one or two biological parents

with schizophrenia (Cornblatt et al. 1999) have suggested that attention deficits can predict

which children will develop schizophrenia in the future.

Several studies have utilized the “follow-back” method of identifying adult patients with

schizophrenia, and then linking these patients with their records of cognitive assessments

performed while they were children or adolescents (Fuller et al. 2002; Jones et al. 1994;

Davidson et al. 1999). In the UK National Survey of Health and Development study, data from

5,362 people indicated that children who went on to develop schizophrenia as adults differed

significantly from the general population in a wide range of cognitive and behavioral domains

(Jones et al. 1994). Low educational test scores in verbal, non-verbal, and

mathematics/arithmetic at all ages assessed were significant risk factors. Similar findings were

generated from a population-based study that investigated the risk of schizophrenia in a sample

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of 50,000 18-year-old males conscripted into the Swedish Army between 1969 and 1970 (David

et al. 1997). In the U.S., scores from grades 4, 8, and 11 on the Iowa Tests for 70 children who

later developed schizophrenia show no significant differences from controls at grades 4 and 8.

However, for children who developed schizophrenia, test scores dropped significantly between

grades 8 and 11, corresponding to the onset of puberty (Fuller et al. 2002). Yet limitations of

this study including small sample size and a non-random sample restrict the generalizability of

these results.

Several studies have utilized a link between the Israeli Draft Board Registry and the

National Psychiatric Hospitalization Case Registry. Israeli law requires that all adolescents

between the ages of 16-17 undergo pre-induction assessment to determine their intellectual,

medical, and psychiatric eligibility for military service. This assessment is compulsory and is

administered to the entire, unselected, population of Israeli adolescents. It includes individuals

who will be eligible for military service, as well as those who will be excused from service based

on medical, psychiatric, or social reasons. The results suggest that cognitive functions are

significantly impaired in those adolescents who are later hospitalized for schizophrenia. These

deficits thus precede the onset of psychosis in young people destined to develop schizophrenia,

and along with social isolation and organizational ability, cognitive deficits are a significant

predictor of which young people will eventually develop a psychotic disorder (Davidson et al.

1999). One study from this series examined the cognitive performance of 44 patients with a first

episode of schizophrenia who had previously undergone cognitive assessment as part of their

registration with the Israeli Draft Board. The stability of the deficits in these patients suggests

that most of the cognitive impairment seen occurs prior to the first psychotic episode (Caspi et al.

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2003). These follow-back studies consistently demonstrate that cognitive impairment precedes

the onset of illness in schizophrenia and schizoaffective illness.

Prodrome Studies

Cognitive deficits are also found in individuals who are identified as being at “ultra-high”

risk (Yung and McGorry 1996) for schizophrenia by virtue of their family history of

schizophrenia and/or the manifestation of mild signs and symptoms consistent with the

prodromal symptoms of schizophrenia. While several research groups are gathering data on this

question, results have only recently begun to be reported (Brewer et al. 2003; Hawkins et al.

2004). Preliminary data also suggests that olfactory identification deficits predict which

individuals at ultra-high risk will develop schizophrenia (Brewer et al. 2003).

First Episode of Psychosis Studies

Once psychosis develops, cognitive deficits are severe (Mohamed et al. 1999; Bilder et

al. 2000; DeLisi et al. 1995; Hoff et al. 1999; and Stirling et al. 2003). Patients with a first

episode of schizophrenia who have never taken antipsychotic medication, already exhibit

cognitive impairment (Brickman et al, in press; Mohamed et al. 1999; Saykin et al. 1994). Motor

functions and language functions may be more mildly impaired prior to medication treatment

(Brickman et al, in press). Initial treatment with first-generation antipsychotic medications does

little to change these cognitive deficits (Bilder et al. 2000).

Cognitive Changes in Patients Recovering from Acute Exacerbation

Several studies have investigated the longitudinal course of cognitive deficits in

schizophrenia by repeatedly assessing cognition in samples that combine first episode patients

and those who have had an acute exacerbation of their symptoms. Patients recovering from an

acute exacerbation of illness do not appear to demonstrate substantial changes in the severity of

13
their cognitive impairment despite clear improvements in symptoms with treatment (Hughes et

al. 2003; Nopoulos et al. 1994; Gold S. et al. 1999; Sweeney et al. 1991).

Longitudinal Change in Cognitive Function

There are many age-related changes in cognitive functioning in the normal population,

especially in motor speed and memory functions (Moss and Albert 1988). The magnitude of

change in long-term memory and ability to access and utilize previously learned material is more

modest. Reading and vocabulary are tests of “old learning” therefore baseline functioning can be

estimated from performance on these tests which show minimal aging-related changes. The

possibility of detecting cognitive decline with aging is diminished due to floor effects on

numerous tests. The types of cognitive functions that change with normal aging, such as new

learning and recall, attention, and processing speed are related to the deficits most commonly

observed in schizophrenia patients early in life. Thus, aging-related changes are likely to affect

those functions that are already severely impaired in adults with schizophrenia (Harvey

1999).The notion of neurodegeneration in schizophrenia has been controversial. Evidence has

been presented suggesting that schizophrenia is a neurodegenerative process, and some have

concluded that schizophrenia is progressive (Lieberman 1999). Supportive evidence for this

theory derives from the greater cognitive impairment reported in chronic patients compared with

first episode patients (Saykin et al. 1994). However, with a few notable exceptions (Bilder et al.

1992; Davidson et al. 1995; O’Donnell et al. 1995), cross-sectional studies generally have not

found evidence of increased cognitive impairment in association with duration of illness, and

older non-elderly patients do not manifest greater impairment than younger patients (Goldberg et

al. 1993b; Heaton et al. 1987; Hyde et al. 1994; Zorrilla et al. 2000). Definitive answers to

questions regarding possible progression of cognitive impairment in schizophrenia must come

14
from longitudinal studies. The available studies, however, have a variety of methodological

limitations such as small or unrepresentative samples, no controls, limited assessment, or

relatively short follow-up periods. One recent longitudinal study traced 111 first-episode

schizophrenia patients over 10-12 years and finding that Visuospatial function while spared in

the first episode may deteriorate over time while executive deficits do not (Stirling et al. 2004).

These longitudinal studies of neurocognitive impairment suggest that it is a stable, enduring

feature of the illness, with very little change in chronic patients between assessment periods of

up to 5 years duration (Heaton et al. 2001; Rund 1998)

Cognitive Functioning in Elderly Patients

There is some evidence that neurocognitive impairment in schizophrenia may worsen

over time in at least a subgroup of elderly patients with schizophrenia. In older schizophrenic

patients with a lifetime of poor functional outcome, prominent cognitive impairments resembling

dementia have been reported (Arnold et al. 1995; Davidson et al. 1995; Harvey et al. 1997).

Based upon cross-sectional studies, elderly patients with schizophrenia appear to show

some decline in cognitive function toward the end of life. However, this decline may be

restricted to those patients who had an early onset of illness followed by a lifetime of poor

functioning (Heaton et al. 1994; Hyde et al. 1994; Jeste et al. 1995; Zorrilla et al. 2000). Some of

the inconsistency of these results may derive from the subject selection processes in these

studies. Finally, cognitive decline in some elderly patients with schizophrenia has been found to

be associated with tardive dyskinesia (Waddington and Youssef 1996) and neurological

dysfunction (Goldstein and Zubin 1990).

Summary

Several studies have demonstrated that neurocognitive impairment is present in a mild

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form prior to the onset of psychosis in young people destined to develop schizophrenia.

Neurocognitive impairment is severe in patients who have experienced their first psychotic

episode, even before antipsychotic treatment is initiated. While some early phase patients may

demonstrate a slight improvement in neurocognitive impairment with treatment, many patients

do not improve at all. Following this early phase, neurocognitive impairment appears to be

remarkably consistent, even in the presence of positive and negative symptom change, although

few longitudinal studies have had follow-up periods of longer than 5 years. The course of

neurocognitive impairment in elderly patients in uncertain, but some studies suggest that patients

with the most chronic courses of illness may manifest a further, albeit gradual, cognitive decline

in the latest years of life.

Early treatment with second generation antipsychotics could potentially improve long

term cognitive and functional outcome and change the longitudinal course of illness described

above. We will return to this topic of a greater cognitive enhancing effect of second generation

antipsychotics in the section entitled Impact of Second Generation Antipsychotics on Cognition.

III. Relationship of Neurocognitive Impairment to Schizophrenia Symptoms

Overview and Introduction of Pseudospecificity

This section will address the relationship between neurocognitive impairment and

symptoms. If neurocognitive deficits were the result of the symptoms of the illness, then the

deficits would disappear when the symptoms do. However, this is usually not the case in patients

with schizophrenia. In contrast to patients with psychotic bipolar illness whose performance on

cognitive tests may improve when their psychotic symptoms remitted, the performance of the

patients with schizophrenia does not change when psychosis remits (Harvey et al. 1990).

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 The impact of first generation antipsychotics on cognition is very weak (Blyler and Gold

2000). The recalcitrance of neurocognitive impairment in the context of substantial symptom

improvement is one of the most compelling lines of evidence of the independence of these

symptom domains. However, recent studies investigating second-generation antipsychotics raise

an important question about the potential “pseudospecificity” of cognitive improvement: If

second-generation antipsychotics improve cognition and symptoms, is the cognitive

improvement explained by the improvement in symptoms? While substantial improvements in

symptoms and mild improvements in cognition may be found with some second-generation

drugs, the correlations between these two domains of improvement have largely been found not

to be statistically significant (Bilder et al. 2002).

Cross-sectional Studies of the Relation to Symptoms of Schizophrenia

Neurocognitive deficits are largely separate from both the positive and negative

symptoms of the disorder. Cross-sectional relationships between neurocognition and positive

symptoms, particularly for hallucinations and delusions, are usually quite weak (Addington and

Addington 2000; Hughes et al. 2003; Strauss 1993). Generally, the variance shared by these

variables is less than 10 percent. Relationships tend to be slightly stronger between

neurocognition and negative or ‘deficit’ symptoms (Addington and Addington 2000; Buchanan

et al. 1997; Hughes et al. 2003; Tamlyn et al. 1992).

Positive Symptoms

It has been repeatedly reported that neurocognitive ability is not strongly correlated with

severity of psychotic symptoms in patients with schizophrenia (Addington et al. 1991; Bilder et

al. 1985; Strauss 1993). In acute exacerbation, the severity of positive symptoms has been found

to be significantly correlated with better performance on select domains of cognitive function.

17
Although some exceptions exist, such as isolated reports of significant correlations of positive

symptoms with working memory (Bressi et al. 1996; Carter et al. 1996), source monitoring

(Keefe et al. 2002), and auditory distractibility (Walker and Lewine 1988), the overall trend is

for general neurocognitive impairment not to be correlated with positive symptoms. This low

correlation across various patient samples, including first episode (Mohamed et al. 1999),

chronic (Addington, Addington, and Maticka-Tyndale 1991; Tamlyn et al. 1992), and elderly

(Davidson et al. 1995) samples, suggests that positive symptoms are clearly not the sole cause of

the cognitive impairment found in patients with schizophrenia.

The low reliability of positive symptom assessment is a crucial factor (Strauss 1993). The

subjective report of a psychotic patient may not reflect the true level of the patient’s psychosis.

Another factor may be that the exclusion of patients who are too psychotic to be tested may serve

to weaken any potential correlation between the severity of psychosis and neurocognitive

impairment. Finally, those patients who have more intact cognitive abilities may be better able to

recall and express their internal state including detailed delusions and hallucinations. These

patients would thus receive higher scores on positive symptom rating scales, resulting in a

reduction in any potential correlation between positive symptoms and neurocognitive

impairment. Clearly, there are limitations to the assessment of positive symptoms, and the

absence of cross-sectional correlations between positive symptoms severity and neurocognitive

impairment is complex.

Negative Symptoms

Cognitive dysfunction is significantly correlated with various types of negative symptoms

(Addington, Addington, and Maticka-Tyndale 1991; Cuesta et al. 1995; Morris et al. 1995;

Strauss 1993; Summerfelt et al. 1991; Tamlyn et al. 1992). The greater variance shared between

18
neurocognition and negative symptoms compared with positive symptoms may result from

measurement overlap. For instance, the neurocognitive variable verbal fluency and the negative

symptom variable poverty of speech both measure the speed at which a patient generates speech.

A patient who generates speech at a slow rate will do so during a test of verbal fluency as well as

in an interview during which he is being rated for poverty of speech.

Empirical studies suggest that motor functions are strongly correlated with negative

symptoms (Cuesta et al. 1995; Manschreck et al. 1985), job success (McGurk et al. 2003) and

outcome (Bilder et al. 1985). Deficient motor skills are represented in both the negative symptom

and the cognitive dysfunction domain, since symptoms such as blunted affect and motor

retardation are observational measures of motor functioning (Alpert 1985; Andreasen 1989).

Thus, impaired motor skills in many ways lie at the core of negative symptoms in schizophrenia.

Whether the negative symptom of reduced motivation underlies the poor performance of

patients with schizophrenia on cognitive tests is controversial. Though monetary reinforcement

has been shown to improve performance on effortful cognitive tests such as the WCST in some

studies (Summerfelt et al. 1991), especially in less difficult tasks, others have not (Green et al.

1990). Increases in pupil size are associated with increased cognitive processing demands

(Granholm et al. 1996). Therefore, pupillary response can measure engagement in a task. If the

cognitive deficits of schizophrenic patients were due to lack of interest or motivation, their

pupillary response would be low throughout the period of cognitive assessment. Only during

high processing conditions do patients have abnormal pupillary responses, suggesting they put

forth a normal amount of effort when being given cognitive tests, yet their decreased processing

capacity leads them to be unable to engage in difficult tasks (Granholm et al. 1997).

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 On the contrary, cognitive deficits may cause reduced motivation. Individuals with

cognitive deficits are less likely to be motivated to have goals and pursue them (reviewed by

Deci and Flaste 1996). Patients with neurocognitive impairment are likely to be met with failure

if they attempt to pursue employment, social, and even recreational avenues that require

cognitive skill. Repeated failures are likely to cause discouragement and reduced motivation in

people with schizophrenia.

In sum, a cross-sectional correlation of negative symptoms and neurocognitive

impairment has been consistently reported, but the magnitude of this relation is modest.

Formal Thought Disorder

Deficits in semantic memory may lie at the heart of the cognition—thought disorder

relation (Elvevag et al. 2002). This argument has recently been supported by empirical data

suggesting that the difference between semantic fluency (the number of names of animals

produced in 60 seconds) and phonological fluency (the number of words beginning with “F”

produced in 60 seconds), an indication of the severity of the impairment of the “semantic

network” in schizophrenic patients, predicted the severity of their formal thought disorder

(Goldberg et al. 1998). Thus, a patient’s ability to have verbal information available (referred to

as “semantic priming”) may be the most important cognitive factor in formal thought disorder.

Affective symptoms

Since many patients with schizophrenia also report depressed mood (Jin et al. 2001) if

not a full depressive disorder, and since depression is associated with some cognitive impairment

(Goldberg et al. 1993a), the role of depressed mood in neurocognitive impairment is important.

Very few studies have examined this relationship directly. Furthermore, the distinction between

depressive symptoms and negative symptoms is sometimes difficult for raters and clinicians to

20
make (McKenna et al. 1989; Goldman et al. 1992), yet factor analyses suggest that they are

separate dimensions of schizophrenia (Lindenmayer et al. 1995; Van der Does et al. 1995).

Higher depression scores were significantly correlated with worse verbal memory task

performance, which remained even when psychomotor retardation and processing speed

performance were controlled statistically (Brebion et al. 2001). Thus, depression may influence

the association between negative symptoms and cognitive impairments, and it may also have a

direct deleterious effect on some aspects of neurocognitive impairment.

In conclusion, the cross-sectional correlations between neurocognitive impairment and

symptoms are weaker than might be expected, and vary depending upon symptom domain. The

consistency of this finding strongly supports the idea that neurocognitive impairment is not

caused by psychosis.

Longitudinal Studies

The relative independence of neurocognitive impairment and symptoms in cross-

sectional studies appears to be supported by longitudinal studies. When patients with

schizophrenia are successfully treated with first-generation antipsychotics, the severity of their

symptoms is substantially reduced (Lieberman et al. 2003). However, if neurocognitive function

improves with first-generation antipsychotic treatment, the effects are small (Blyler and Gold

2000; DeLisi et al. 1995; Gold S. et al. 1999; Hoff et al. 1999).

It is important to emphasize here that the stability of neurocognitive impairment occurs in

the context of frequent variability of the symptoms of schizophrenia, especially the positive

symptoms (Bilder et al. 2000). For example, in a study of patients tested during a psychotic

exacerbation and then again when symptoms had improved considerably one to two years later,

cognitive function was found to be very stable over time (Nopoulos et al. 1994). In a longitudinal

21
study over a one-year interval, cognitive and negative symptoms were correlated at each of the

assessments, but there was no predictive relationship between these variables over time (Harvey

et al. 1996). If negative symptoms were somehow causing poor performance on cognitive tests,

then a longitudinal relationship between these variables would have been expected. Second,

when the differential relationship between cognitive and negative symptoms and adaptive

functioning deficits has been examined, cognitive impairments have been found to be more

strongly correlated with functional deficit than negative symptoms (Harvey et al. 1996; Harvey

et al. 1998). Third, in those patients whose functional status worsens over time, changes in

cognitive impairment predicts the level of change while changes in negative symptoms do not

(Harvey et al. 1998). These data suggesting a variable relationship of symptoms and

neurocognitive impairment provide yet another line of support for the relative independence of

these domains.

Another way to investigate the longitudinal relationship between neurocognitive

impairment and symptoms is to calculate the correlation between change in neurocognitive

impairment and symptom change. This approach addresses the issue of ‘pseudospecificity’.

Several studies have performed such analyses and though results are mixed, the findings have

generally suggested that symptom change does not contribute substantially to cognitive change

(Addington, Addington and Maticka-Tyndale 1991; Hoff et al. 1999).

Impact of Second Generation Antipsychotics on Cognition

Patients with schizophrenia were treated with excessive doses of conventional

antipsychotic medication for years. This may have had direct adverse cognitive effects and led

clinicians to use anticholinergic medications to control side effects. Lowering dosages of

conventional antipsychotic medications has some modest cognitive benefit (Seidman, Pepple,

22
and Faraone 1993) which suggests that use of excessive doses may have led to some of the

failures of conventional medications to improve cognition (Harvey et al., in press).

When compared with first generation antipsychotics, second generation antipsychotics

have some cognitive benefits (Harvey and Keefe 2001; Keefe et al. 1999). This issue is still

controversial as many of the studies are methodologically limited. For instance, many

comparisons of the cognitive benefit of second generation and first generation antipsychotics

include excessive doses of first generation antipsychotic medication, which may unfairly inflate

the benefits attributable to second generation antipsychotics by confusing them with dose effects.

Further, there is evidence that unlike first generation antipsychotics, second generation

medications may allow patients to benefit from practice-related improvements (Harvey et al.

2000). However, recent studies of first episode patients on lower doses of first generation

antipsychotics suggest that second generation antipsychotics have a greater cognitive enhancing

effect (Keefe et al, in press; Harvey et al, submitted).

Summary

In conclusion, the literature on neurocognitive impairment consistently demonstrates that

cognitive impairment is not caused by the symptoms of schizophrenia. Most impressive is the

zero-to-mild cross-sectional correlations between neurocognitive impairment and the positive

symptoms of the illness. While other aspects of schizophrenia, such as negative symptoms,

appear to correlate with neurocognitive impairment, there is as much or more evidence

supporting the idea that neurocognitive impairment causes negative symptoms as there is

evidence that negative symptoms cause neurocognitive impairment. While there is limited

evidence of a relationship between changes in neurocognitive impairment and changes in

symptoms over time, there is certainly no clear evidence that improvements in neurocognitive

23
impairment are caused by improvements in symptoms. In fact, most data point to the relative

independence of these two targets of treatment in schizophrenia.

IV. Clinical Importance of Neurocognitive Impairment.

Cross-sectional Correlations with Function

Although the literature on neurocognitive impairment suggests that it is not strongly

correlated with symptoms, it has proven to be consistently related to a variety of other important

aspects of the illness, such as social functioning (Liberman, Mueser, and Wallace 1986;

Spaulding et al. 1986), functional impairments, unemployment (Brekke et al. 1997; Lysaker and

Bell 1995; McGurk and Meltzer 2000; Velligan et al. 2000), quality of life (Fujii and Wylie

2003), relapse prevention (Fenton, Blyler, and Heinssen 1997; Jarboe and Schwartz 1999),

medical status and economic cost (Knapp 1997; Sevy and Davidson 1995). Neurocognitive

impairment also has considerable power to predict functional status years later.

Relationship of Neurocognitive Impairment to Functioning

Functional outcome in schizophrenia is difficult to define and measure. The three types of

functional outcome that most studies of neurocognitive deficits have examined are: community

(social and occupational) outcome, the ability to solve simulations of interpersonal interactions,

and success in psychosocial rehabilitation programs. Strong support for associations between key

areas of neurocognition and functional outcome are offered by two reviews of the literature

(Green 1996; Green et al. 2000).

The connection between actual community functioning and cognition has been weaker

than the strong link between laboratory measures of community functioning or skills acquisition

and cognition (Green 1996). In a one-year follow-up study of patients with first episode

24
psychosis, the size of the correlations between the number and quality of actual social relations

and various cognitive measures were found to be in the .25 to .35 range (Malla et al. 2002).

Across the studies reviewed by Green (2000), all of the key neurocognitive constructs

(secondary memory, immediate memory, vigilance, and executive functioning / card sorting) had

significant relationships to functional outcome and effect sizes in the medium range. Cognitive

impairments are also correlated with deficits in the performance of specific skills critical for

independent living (Evans et al. 2003; Patterson et al. 2001).

Neurocognitive Impairment and Unemployment

Several studies of cognitive performance and vocational functioning have been conducted

in rehabilitation settings (Bell and Bryson 2001; Lysaker and Bell 1995). Ratings of work

behavior/performance are related to baseline scores on verbal memory tests and the Wisconsin

Card Sorting Test. Additionally, improvement in patient work performance in a 6 month work

rehabilitation program was predicted by baseline performance on various cognitive tests.

A number of positive findings have been reported in studies examining correlates of

competitive employment (Beiser et al. 1994; Brekke et al. 1997; Velligan et al. 2000). Patients

enrolled in school full-time or holding competitive employment show superior performance

across measures of working memory, sustained attention, problem solving, and episodic memory

when compared to unemployed patients (McGurk and Meltzer 2000), with scores of part-time

workers falling between the other two groups. In addition, vocational functioning is significantly

associated with performance on speed of processing tasks such as Trailmaking A and B (McGurk

et al. 2003).

McGurk and Meltzer (2000) evaluated the relationship of cognitive functioning and work

status and concluded that neurocognitive performance plays a more important role than clinical

25
symptoms in the ability of patients with schizophrenia to work. The implication is that patients

with schizophrenia who have higher levels of cognitive impairment may require greater amounts

of vocational support than those with lower levels of impairment (McGurk et al. 2003).

Neurocognitive Impairment and Quality of Life

Quality of life is often defined by the quality of social, occupational, and interpersonal

aspects of life and is related to cognitive function. Some evidence suggests that reductions in

quality of life are more strongly associated with cognitive deficits than other symptomatic

features of the illness. Specifically, the relationship between subjective experience and social

functioning has been shown to be mediated by executive functioning (Brekke, Kohrt, and Green

2001). Patients have less realistic impressions of their social functioning if they also have more

severe executive deficits.

The need for anticholinergic treatments is also associated with reductions in quality of

life. Reductions in quality of life and anticholinergic medications may be related to the EPS that

triggers anticholinergic medication prescriptions, nonetheless anticholinergic medications

reliably reduce cognitive functioning as well. In patients with schizophrenia, anticholinergic

medications impair attention and memory functions (Spohn and Strauss 1989). These

impairments can induce reductions in subjective quality of life. One study of patients with

schizophrenia that examined the relationship between coping abilities and cognitive dysfunction

suggested that more severe executive and memory deficits are related to decreased use of coping

mechanisms (Wilder-Willis 2002).

Fujii and Wylie (2003) studied the long-term effects of neurocognition on quality of life

in patients with severe schizophrenia. They found that neurocognition does, in fact, have long-

26
term predictive validity for quality of life and that therapeutics targeting neurocognition could

improve quality of life in this population.

Neurocognitive Impairment and Relapse Prevention

Cognitive functions have been shown to be the strongest predictors of patients' ability to

manage medications (Jeste et al. 2003). Cognitive deficits contribute to patterns of medication

mismanagement that are associated with poor adherence and risk of relapse (Fenton, Blyler, and

Heinssen 1997; Jarboe and Schwartz 1999). In one study, memory impairment was the best

predictor of partial compliance (Donohoe et al. 2001). Patients performing poorly in medication

management tests also had poor global scores on a dementia inventory (Patterson et al. 2002).

Decreased medication compliance in schizophrenic patients has been shown to be related to poor

performance on tests of attention and visual memory (Jarboe and Schwartz 1999).

Neurocognitive Impairment and Medical co-morbidity

Neurocognitive Impairment is also related to medical co-morbidities in schizophrenia.

Deficits in organization (executive skills) directly affects patients’ ability to seek treatment for

medical problems. In elderly patients with schizophrenia, cognitive and functional impairments

predicted the later incidence of new-onset medical problems, while medical problems did not

predict the subsequent worsening of cognitive and self-care deficits (Friedman et al. 2002).

Inability of patients with schizophrenia to reduce damaging habits such as smoking has been

correlated with deficits in memory and attention (Buchanan, Holstein, and Breier 1994; George

et al. 2000). Thus, cognitive impairments were shown to directly effect new-onset medical

problems in older patients.

The Costs of Neurocognitive Impairment

27
 A major factor in the costs (direct and indirect) associated with schizophrenia is cognitive

impairment (Sevy and Davidson 1995). Factors leading to the increased cost include loss of

ability for self-care, level of inpatient and outpatient care needed, and loss of productivity (for

both patient and caretaker). Although cognitive impairment by itself is rarely a reason for acute

hospitalization of a patient with schizophrenia, it may contribute to the overall length of

hospitalization. It may lead to early admission to nursing homes or long-term care facilities in the

case of elderly patients.

V. Conclusion

A consensus has developed amongst experts in cognition and schizophrenia that

cognitive impairment is a core feature of the illness. The course of neurocognitive impairment

follows a characteristic pattern and following the early phase, is consistent even when positive

and negative symptoms change. Consistent with the demonstration that cognitive impairments

are not a result of symptoms of schizophrenia, on the whole studies show the independence of

these two targets for treatment. Long term functional and cognitive outcome as well as the

longitudinal course of the illness could potentially improve with early treatment using second

generation antipsychotics. Functional status years later can be predicted with considerable

accuracy with the extent of neurocognitive impairments. The relationship has been established

between cognition and many other facets of schizophrenia from social functioning to

unemployment to relapse prevention. Indeed, improved understanding and treatment of

neurocognitive impairments in schizophrenia holds considerable promise for the field and for the

lives of patients with schizophrenia.

28
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Table 1. Cognitive Impairments in Schizophrenia and Their Severitya
Severe Impairments (2 to 3 SD below the meanb)
 Serial learning
 Executive functioning
 Vigilance
 Motor speed
 Verbal fluency
Moderate Impairments (1 to 2 SD below the mean)
 Distractibility
 Delayed recall
 Visuo-Motor skills
 Immediate memory span
 Working memory
Mild Impairments (0.5 to 1 SD below the mean)
 Perceptual skills
 Delayed recognition memory
 Confrontation naming
 Verbal and full-scale IQ
No Impairment
 Word recognition reading
 Long-term factual memory

aThe estimated average severity scores are corrected on the basis of age and relative education level.
b The “mean” refers to the average level of performance of normal individuals who are similar in age and
educational attainment.
FROM: Harvey and Keefe, CNS Spectrums, 1997

46
 Course of Cognitive Impairment in
Schizophrenic Patients Using Typical
Neuroleptics

0 Normal

–1
? Psychosis-Free
Patients
Standard
Deviations
–2

–3

Premorbid Onset Initial 2 Years 20 Years

Therapy After Start After Onset
of Therapy

10

Figure 1. Course of Cognitive Impairment in Schizophrenic Patients Using Typical

Neuroleptics.

From: Keefe RSE: Neurocognition. in Current Issues in the Psychopharmacology of

Schizophrenia. Breier A, Tran PV, Herrera J, Bymaster F, Tollefson G, eds. Lippincott

Williams & Wilkins Publishers. Baltimore, 2001

47