Treating cognitive dysfunction in patients

with

schizophrenia

Cherrie A. Galletly, MB ChB; C. Richard Clark, BA(Hons), PhD;

Alexander C. MacFarlane, MD
Galletly
The Queen Elizabeth Hospital and the Cognitive Neuroscience Laboratory and School of Psychology, Flinders
University of South Australia, Adelaide, South Australia; Clark
Cognitive Neuroscience Laboratory and School of
Psychology, Flinders University of South Australia; MacFarlane
Department of Rehabilitation and Community Psychiatry,
University of Adelaide, Adelaide, South Australia
Cognitive dysfunction is a common, chronically disabling component of schizophrenia. It has been proposed
that many of the symptoms of schizophrenia can be understood as a result of disruption of fundamental
cognitive processes. This paper reviews treatment strategies aimed at improving cognitive function in
patients with schizophrenia. Nonpharmacologic interventions include instruction in the performance of
tasks such as the Wisconsin Card Sorting Test. Mixed results have been achieved, but it appears that
instruction methods involving reinforcement of information held in working memory are more successful.
Computer-aided remediation has also been used with variable success. Novel antipsychotic drugs appear
to have an advantage over conventional antipsychotic drugs in terms of their effect on cognitive function.
The development of more precisely tailored methods of remedial teaching, along with optimal pharmacologic treatment, may lead to more effective treatment of cognitive dysfunction in patients with schizophrenia.

La dysfonction de la cognition est un element courant de la schizophrenie qui est cause d'incapacite
chronique. On a soutenu qu'il est possible de comprendre un grand nombre des sympt6mes de la schizophrenie comme le resultat d'une perturbation des m6canismes fondamentaux de la cognition. Ce document passe en revue des strat6gies de traitement qui visent a ameliorer la fonction cognitive chez les
patients atteints de schizophrenie. Les interventions non pharmacologiques comprennent 1'enseignement
de l'execution de tiches comme la classification categorielle de cartes (test Wisconsin). On a obtenu des
resultats mitig6s, mais il semble que les methodes d'enseignement qui comportent le renforcement de
l'information detenue dans la memoire de travail donnent de meilleurs resultats. On a aussi utilise la correction assistee par ordinateur avec des resultats variables. Les neuroleptiques nouveaux semblent offrir
un avantage sur les equivalents conventionnels par leurs effets sur la fonction cognitive. La mise au point
de m6thodes d'orthopedagogie plus pr6cises, conjuguees a un traitement pharmacologique optimal, peut
deboucher sur un traitement plus efficace de dysfonctions de la cognition chez les patients atteints de
schizophr6nie.

Correspondence to: Dr. C. Richard Clark, Cognitive Neuroscience Laboratory and School of Psychology, Flinders University of South
Australia, GPO Box 2100, Adelaide, SA 5001; fax 61 8 8201 3877, richard.clark@flinders.edu.au
Medical subject headings: antipsychotic agents; cognition; schizophrenia
J

Psychiatry Neurosci 2000;25(2):1 17-24.

Submitted July 3, 1999

Revised Dec. 16, 1999
Accepted Dec. 20, 1999
2000 Canadian Medical Association

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Introduction
Cognitive dysfunction is common in patients with
schizophrenia, with deficits reported in a range of functions including memory, attention, executive processes,
language and motor skills.1L2 The severity of cognitive
dysfunction has been shown to be an important predictor of social and occupational outcome.-5 Indeed, outcome measures have been found to correlate more
closely with the extent of cognitive dysfunction than
with the severity of psychotic symptoms. Improvement
in cognitive functioning is increasingly acknowledged
as an important treatment goal in the management of
schizophrenia.
Besides cognitive dysfunction, the symptoms of
schizophrenia include disorders of perception, thought,
motivation and social behaviour. This diversity of
symptoms might be understood as the result of a disturbance in a single, fundamental cognitive process. A
number of models have been developed, which explain
the symptoms of schizophrenia as manifestations of an
underlying problem in perceiving, evaluating and
retaining information. Braff6 has suggested, on the basis
of both clinical and neurophysiological abnormalities,
that patients with schizophrenia have difficulty with
the allocation of attentional resources to relevant tasks.
Goldman-Rakic and Selemon7 have proposed that the
fundamental disturbance in schizophrenia is a defect in
working memory, such that the ability to hold and utilize internal representations of the external world is
impaired. A failure of the processes of perception and
memory is implicated in the hypothesis of Hemsley,8
which proposes that schizophrenia results from a
breakdown in the normal relationship between current
sensory input and stored material, so that information
from past experience is not used effectively to understand the present environment. Andreasen et al9 have
suggested that impaired connectivity between frontal,
thalamic and cerebellar regions produces "cognitive
dysmetria," which results in the person with schizophrenia not being able to coordinate functions such as
the perception, encoding, retrieval and prioritization of
experience and information.
Green and Nuechterlein'0 have developed a model
that links neurocognitive deficits in patients with schizophrenia with treatment interventions and functional
outcome. The model describes the impact of treatment
factors, including conventional and novel antipsychotic
drugs, anticholinergic drugs and cognitive-behavioural

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interventions, on cognitive function in patients with

schizophrenia. Some treatment interventions have been
found to produce an improvement in performance on
neuropsychological tests, and it is important to understand the processes by which these performance gains
can be translated into long-term reduction in disability.
Green and Nuechterlein'0 suggest that social cognition,
which includes emotional perception, insight and coping strategies, may be the mediator between basic neurocognition and functional outcome.

Nonpharmacologic treatment
of cognitive dysfunction
Approaches to cognitive remediation in patients with
schizophrenia have ranged from teaching patients how
to improve their performance on a single neuropsychological test11 to provision of a comprehensive, intensive
remediation program.12 Computer programs as well as
more traditional teaching methods have been used.13
The areas of cognitive function addressed with nonpharmacologic treatments include attention, cognitive
flexibility, planning and memory. The simplest method
of outcome evaluation is to measure changes in neuropsychological test performance, although more recent
studies have investigated whether undertaking some
form of cognitive remediation is associated with an
improved level of social functioning.12

The starting point for this research was to establish

whether it is possible to achieve any improvement in
cognitive function in patients with schizophrenia using
nonpharmacologic methods. Goldberg et all" attempted
to teach patients with schizophrenia to improve their
performance on the Wisconsin Card Sorting Test
(WCST). They found patients could improve their performance when explicit card-by-card instructions were
given, but their performance dropped to baseline when
the test was repeated without instructions. However,
Bellack et al'4 reported that providing detailed instructions plus rehearsal and feedback, resulted in improved
performance that was maintained the following day
when the test was repeated without instructions.
Contingent or noncontingent monetary reinforcement
did not affect performance. Several other studies also
reported success in teaching patients with schizophrenia to perform better on the WCST.1516 The next step in
this line of research was to try to identify the most effective teaching methods. Goldberg et all' did not require
patients to describe their plan with regard to each card.

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ate the effectiveness of a program specifically designed

More recent research has shown that the simple strategies of requiring subjects with schizophrenia to verbalize the matching criterion before card sorting"5 or to verbally describe their actions,16 results in improved performance. There are several possible explanations for
this finding. Stratta et all5 hypothesized that requiring
verbal expression of the matching criterion drives a cognitive strategy that allows conceptual organization of
incoming information. Earlier research has shown that
teaching patients with schizophrenia to verbalize a
behavioural strategy reduces their distractibility."7 Also,
numerous studies have shown that working memory is
implicated in WCST performance."'20 Describing aloud
the thoughts and actions involved in performing the
test may provide reinforcement of information held in
working memory.
More sophisticated methods of teaching the WCST
have also been used. Scaffolding, a process whereby
assistance is given for those aspects of the task not yet
learnt and gradually removed in the areas that have
been mastered, and a similar method, errorless learning, have been found to be effective, with improved
performance persisting at 4 weeks' follow-up.21'22
Clinically, it is important to know whether better performance on a neuropsychological test such as the
WCST generalizes to other situations. This is unclear,
since the results of 2 studies evaluating whether training effects across similar problem-solving tasks are generalizable, were contradictory.213
Wiedl24 has used the ability to improve performance
on the WCST as a predictor of rehabilitation readiness.
He found that individuals with schizophrenia who
were able to leam to improve their performance on the
WCST and retain this information, gained more benefit
from skills-training groups (teaching medication selfmanagement techniques and problem-solving skills)
than patients who could not learn to perform better on
the WCST or could not retain this information.
Several recent studies have attempted to show the
effects of cognitive remediation on measures of functional outcome. Corrigan et al25 evaluated a memory
and vigilance training program for patients with schizophrenia. The memory training included semantic elaboration, where patients retold, in their own words, the
story of a social situation presented to them. The training program produced an improvement in their ability
to recognize social cues in a video of a social situation.
Wykes et a126 used a more comprehensive measure of
social function, the Social Behaviour Schedule, to evalu.U

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for remediation of frontal/executive impairments in

patients with schizophrenia.27 Compared with patients
receiving intensive occupational therapy, the group
remediation improved more on
tests of cognitive flexibility and memory and gained in

receiving cognitive

self-esteem. Although no group difference in social

functioning was found, patients who reached a certain
threshold of improvement in cognitive flexibility tasks
showed improved social functioning.
Computer programs that have been shown to be effective in retraining attentional deficits in patients with
closed-head injury have been used with patients with
schizophrenia. Again, results have been mixed, with
some studies reporting improvement on measures of
attention"3,' and others finding no change.290 The computer-aided rehabilitation programs used in these studies were designed for patients with disorders such as
stroke and head injury. Programs that are specifically
developed to optimize remediation of cognitive deficits
in patients with schizophrenia may be more successful.
In conclusion, much of the research into cognitive
remediation in patients with schizophrenia has
involved teaching patients to perform particular tests
more effectively, and, generally, some improvement
has been found. Further research is needed to develop
maximally effective teaching methods. Recent work has
focussed on identifying the patients who will benefit
most from cognitive remediation.12 As yet, limited information is available regarding the persistence and generalizability of gains made in cognitive remediation
programs and this will be crucial in evaluating their
clinical utility.

The effects of conventional antipsychotic

drugs on cognitive function
The effects of conventional antipsychotic drugs on cognitive function in patients with schizophrenia are complex. Performance has been shown to improve on some
cognitive and motor tasks and to worsen on others.
Potential confounding factors include differences
between patient groups, such as variations in phase of
illness and symptom severity. Conventional antipsychotic drugs have a range of adverse effects besides their
antipsychotic action, and these side-effect profiles differ
among drugs. Sedation may affect attention and motivation, and extrapyramidal side effects can impair performance on tasks requiring fine motor coordination or

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induce slowing of mentation,

along with the motor manifestations of parkinsonism.
The effect of anticholinergic agents is important as
many conventional antipsychotic drugs either possess
intrinsic anticholinergic activity or require the coadministration of anticholinergic agents to control
extrapyramidal side effects. Anticholinergic drugs produce significant impairment in short-term memory and
new learning in normal subjects.3- Similar effects have
been found in patients with schizophrenia, with an
inverse correlation being reported between memory
performance and serum anticholinergic levels.32
However, Perlick et alP3 found that this effect applied to
verbal recall but not to recognition memory and proposed that the anticholinergic activity might influence
factors such as motivation, attention and the ability to
initiate and maintain goal directed activity rather than
impact directly on primary memory functioning.
In a comprehensive review of the literature concerning the effects of antipsychotic drugs on cognitive function in patients with schizophrenia, Cassens et alm concluded that acute administration of these drugs impairs
performance on some, but not all, tasks requiring vigilance and attention, and on some motor tasks. Longterm administration improved performance on some
tasks requiring sustained attention and visuomotor
problem solving skills, depending on the dose and
length of administration. It appeared that long-term
administration did not impair neuropsychological function, apart from some effects on motor function. A more
recent review observed that changes in cognitive function appear to be independent of changes in clinical
state.35 This point is important in considering the effects
of the novel antipsychotic drugs on cognitive function,
given that some studies have reported both clinical
improvement and improved cognition-6'7
In summary, conventional antipsychotic drugs have
not been shown to improve cognitive function in
patients with schizophrenia, apart from some enhancement of attention. The extrapyramidal and anticholinergic side effects of the drugs can have detrimental effects
on cognition.
may

Clozapine
The majority of studies of the effect of novel antipsychotic drugs on cognitive function in patients with
schizophrenia have involved clozapine. Most of these
studies are not double blind and report on relatively
small numbers of patients. Typically, measurements are
undertaken before, then during treatment with the
study drug, so there are potential problems with both
order and practice effects. Comparisons between studies are limited by differences in baseline medication
regimens, patient populations and the neuropsychological tests selected.
Studies evaluating the effects of clozapine on cognitive
function in patients with schizophrenia are summarized
in Table 1 337A3 The neuropsychological tests used have
been grouped into categories.49 The investigators frequently used more than 1 test to evaluate a particular
cognitive function. Change in neuropsychological test
performance was defined by comparing baseline results
when patients were generally receiving typical antipsychotic drugs, with results when patients were receiving
the study drug. The investigators' definitions of significant change were used, although there was some variability in the rigour of the tests of significance. In studies

The effects of novel antipsychotic drugs

on cognitive function
It has been suggested that 1 of the advantages of the
novel antipsychotic drugs, compared with the typical

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antipsychotics, may be a more beneficial effect on cognitive function.'"' If so, there would be major implications for the management of schizophrenia. It is apparent from both clinical and psychopharmacologic studies that the novel antipsychotic drugs differ considerably from one another, so it can be anticipated that their
effects on cognitive function will also vary. This has
been confirmed in animal studies in which significant
differences between the novel antipsychotic drugs were
evident on tests of spatial learning, memory and motor
function.'410 It would appear, therefore, that these drugs
must be considered individually in evaluating their
effect on cognition.
There are relatively few studies of the effects of novel
antipsychotic drugs on cognitive function in normal
subjects. Saletu et a142 compared zotepine, clozapine and
placebo and found that both drugs produced deficits in
attention and concentration, and increases in reaction
time. Clozapine also adversely affected memory.
However, given that the effects of conventional antipsychotic drugs can differ between normal and schizophrenic subjects,6 it cannot be assumed that these
results can be generalized to a patient population.

motor speed. It is also possible that dopamine blockade

in the basal ganglia

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Some studies have found a correlation between

improved cognitive function and reduction in negative
symptoms during clozapine treatment, but overall the
pattern of association between change in psychopathology and change in cognitive function is variable.-"-`52 This
suggests that clozapine has a range of effects on the distributed neural systems, which are dysfunctional in
patients with schizophrenia, that would be consistent
with the diversity of neuroreceptor affinities of clozapine.

involving repeated measures, the change between baseline and the longest follow-up period was used. The
duration of treatment varied from 12 weeks to 3 years.
As shown in Table 1, verbal fluency showed the most
consistent improvement with clozapine treatment.
Results on at least half the tests of general intelligence,
verbal memory, attention, construction, concept formation and reasoning, and performance on maze tests,
also improved. Verbal skills, visual recognition and
maze tests were generally unchanged, and visual memory tended to be unchanged or significantly worse. The
amount of change in neuropsychological test performance was relatively small, and patients' test scores
during clozapine treatment typically indicated persisting cognitive dysfunction. It has been suggested that
the apparent improvement in cognitive function with
clozapine is due to an increase in response speed, related to the lack of extrapyramidal side effects.45 However,
it has been reported that clozapine does not improve
motor speed in simple reaction time tasks, compared
with either fluphenazine or placebo.5O Mazes require
both visuomotor skills and executive functions, and
treatment with clozapine is associated with improvements in passage time and maze route but not in motor
errors.51 It, therefore, appears that clozapine does not
simply increase motor speed compared with typical
antipsychotic drugs but is associated with improvement in complex timed tasks, which require both motor
skills and executive functions.

Risperidone
Treatment with risperidone has been found to be associated with improvement on tests of attention, executive function and working memory.5351 Green et al55
reported that risperidone had a more favourable effect
on verbal working memory than haloperidol, but performance of the risperidone-treated group was still
within the impaired range. Unlike clozapine, risperidone has no anticholinergic activity, and rarely causes
sedation. Daniel et all6noted these differences when
comparing the clinical characteristics of these drugs, but
they did not find a consistent pattern of differences
when comparing performance on standard neuropsychological tests.
Gallhofer et al,57 using mazes specifically designed to
assess changes in cognitive function in patients with
schizophrenia, reported differences between the effects
of risperidone and clozapine. The clozapine group were

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accuracy, making more motor errors, whereas, the
risperidone-treated patients were relatively slower but
more accurate. Both groups performed better than
unmedicated patients and patients taking conventional
antipsychotic drugs.

Other novel antipsychotic drugs

There have been a limited number of studies reporting
the effects of other novel antipsychotic drugs on cognitive function. These studies have small subject numbers
but support the possibility that some improvement in
cognitive function is achievable with the novel antipsychotic drugs, and also that there may be significant differences among drugs. For example, in patients with
schizophrenia, a comparison of the effects of clozapine
and zotepine in a maze task showed that performance
improved with both drugs, but the improvement was
more pronounced in the zotepine-treated group.51 Two
preliminary reports have suggested that, compared
with a baseline placebo condition, treatment with quetiapine was associated with significant improvements
on a range of neuropsychological tests.58-9 Preliminary
data from a study comparing ziprasidone and risperidone showed more trends to improvement in the
patients receiving ziprasidone.w Meltzer and McGurk3
found that, compared with treatment with typical
antipsychotic drugs or thioridazine, treatment with
olanzapine had a significant effect on some measures of
reaction time, executive function, verbal learning and
memory, and verbal fluency.
In summary, the novel antipsychotic drugs do appear
to produce a modest but patchy improvement in cognitive function. However, there are methodologic shortcomings in much of the research in this area.

Conclusions
Cognitive dysfunction in patients with schizophrenia
did not respond readily to treatment, and none of the
strategies described above were able to produce dramatic improvements. However, it appears that treatment with either risperidone or clozapine, and possibly
other novel antipsychotic drugs, may be associated
with beneficial effects on cognition. Use of novel
antipsychotic drugs along with cognitive remediation,
social skills training or more general rehabilitation programs may be a useful strategy. A pilot study reported

jW,

positive results from the combination of clozapine and

social skills training.6' In addition, Wykes et all2 noted
that patients taking novel antipsychotic drugs tended to
gain more benefit from cognitive remediation.
Further work is needed to identify the most effective
methods for teaching new information and skills to
patients with schizophrenia, to enable the benefits of
psychoeducational and rehabilitation programs to be
optimized. The development of new tools for assessment of cognition in patients with schizophrenia, in
place of tests developed for other purposes, may enable
better outcome evaluation and comparison between
studies. Further research is also needed in carefully
defined clinical subgroups, as there has been little
emphasis on differences in patient populations, such
as first episode patients. There is also a need for
hypothesis-driven studies, linking cognitive models of
schizophrenic psychopathology with their neurobiological and neurochemical correlates. These models could
be further developed to enable prediction of the effects
of various antipsychotic drugs on cognition. Functional
imaging can be expected to play an increasingly important role in such investigations.

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