Dopamine receptors and schizophrenia :
contribution of molecular genetics and clinical
neuropsychology
Ge! rard Emilien1, Jean-Marie Maloteaux1,2, Muriel Geurts1 and Michael J. Owen3
Departments of " Pharmacology and # Neurology, UniversiteT Catholique de Louvain, Cliniques Universitaires Saint Luc, B-1200
Brussels, Belgium
$ Departments of Psychological Medicine and Medical Genetics, University of Wales College of Medicine, Cardiff, CF4 4XN, UK
Abstract
Family, twin and adoption studies suggest that genetic factors play an important role in the aetiology of
schizophrenia. The mode of inheritance, however, is complex and non-Mendelian. Although the aetiology of
schizophrenia is unknown, it has been hypothesized that the necessary conditions for developing the disease
are environmental stress and a vulnerability to psychosis. The implication of dopamine receptors to
schizophrenia has been greatly studied. Several linkage and association studies have been performed in an
attempt to establish the involvement of dopamine receptors in schizophrenia. However, although no
conclusive evidence of linkage or association to any gene has been established, some results, suggestive of
linkage for chromosomes 6, 22 and 13, await confirmation from other studies. Concerning association studies,
it is also of interest that some studies support an association between schizophrenia and homozygosity at D .
$
More work in larger samples is required before conclusive linkage hypothesis or association to a dopamine
receptor may be established.
Schizophrenic patients have been shown to have significant deficits in a wide range of cognitive processes,
including memory, attention, reasoning ability and language. Since cognitive deficits are significant symptoms
of schizophrenia which require effective treatment, their assessment in schizophrenic patients and during
clinical trials of new potential antipsychotics is highlighted. Cognitive impairment in schizophrenia impedes
psychosocial performance and is therefore an especially relevant target variable in the development of new
therapeutic approaches. It is most prominent in tasks involving attention, memory and executive functions
which are thought to reflect involvement of prefrontal and left-temporal brain areas. Semantic networks in
schizophrenic patients with a younger age of onset are observed to be more disorganized and differ
significantly to those of control subjects. The need to use broader approaches such as neuropsychologicalrelated measures to identify pertinent phenotypes in non-affected subjects carrying vulnerability genes is also
emphasized.
Since dopamine receptors are the primary targets in the treatment of schizophrenia, improved therapy may
be obtained by drugs that selectively target a particular subtype of dopamine receptor. In the development of
novel antipsychotics, D and D receptors have received much attention and this is partly related to the fact
$
%
that these receptors have a high abundance in brain areas associated with cognitive and emotional functions,
such as parts of the limbic system and cortex. Recent studies suggest that atypical neuroleptics may
significantly improve the cognitive deficits observed in schizophrenic patients and that atypical neuroleptics
such as risperidone appear to improve memory and alertness suggesting that further clinical studies are needed
to determine the precise influence of antipsychotics on the cognitive system of schizophrenic patients. Such
studies could lead to useful insights as to the potential advantages of the newer antipsychotics which appear
to have a sparing or beneficial effect on various components of cognitive function. However, the observation
that cortical D receptors are important sites of action for antipsychotics, that the cerebral cortex may harbour
#
the common sites of actions of antipsychotics and that the balancing of the opposing actions of D and D
"
#
receptor regulation may be an appropriate drug treatment suggests that the adjustment of D receptor levels
"
in the cortex may become an important goal of future antipsychotic generation. Such antipsychotics will be
able to treat the positive, negative and cognitive deficits of schizophrenia.
Received 1 October 1998 ; Reviewed 29 November 1998 ; Revised 3 February 1999 ; Accepted 10 February 1999
Key words : Schizophrenia, dopamine receptors, clinical neuropsychology, neuroleptics, antipsychotics,
molecular genetics, cognition, memory.
Address for correspondence : Dr Ge! rard Emilien, 127 rue Henri Prou, 78340 Les Clayes Sous Bois, France.
Tel. : 33 1 41 02 7464 Fax : 33 1 30 54 02 47 E-mail : GEmilien!aol.Com
R E V I E W A RT I C LE
International Journal of Neuropsychopharmacology (1999), 2, 197–227. Copyright # 1999 CINP
198
G. Emilien et al.
Contents
1. Introduction
2. Role of dopamine in schizophrenia
2.1. Structure and characteristics of dopamine
receptors
2.2. Symptoms of schizophrenia
2.3. Implications of dopamine receptors
2.4. Dopamine receptors and cognitive function
2.5. Issues and criticisms
3. Molecular genetics of schizophrenia
3.1. Linkage studies
3.2. Genome scanning studies
3.3. Association studies
3.4. Criticisms and perspectives
4. Cognitive impairment in schizophrenia
4.1. Attention
4.2. Language and information processing
4.3. Executive function and memory
4.4. Cognitive deficits and negative symptoms
4.5. Neuropsychological deficits as markers of
vulnerability
5. Methodological issues and testing
5.1. Computerized neuropsychological test battery
5.2. Mini-mental state examination
6. Effects of neuroleptics on cognitive deficits
6.1. Clozapine
6.2. Risperidone
6.3. New generation of antipsychotic drugs
7. Discussion and conclusion
8. Acknowledgements
9. References
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1. Introduction
Schizophrenia, the most severe of the mental illnesses, is
a psychotic disorder characterized by late-adolescent or
early adult onset and has, in most cases, a chronic course.
While the average lifetime prevalence, regardless of race
or country, is about 1 %, in the siblings of patients it is
8–10 %, and in the children of patients it is 12–15 %
(Regier et al., 1988 ; Gottesman, 1993) ; 10 % of patients
die from suicide (Caldwell and Gottesman, 1992). A
recent study of the genetic epidemiology of schizophrenia
in a Finnish twin cohort suggests that there is a marginally
higher prevalence of schizophrenia in men (2n2 %) than
women (1n8 %) (Cannon et al., 1998 ; Kringlen, 1990). The
aetiology of schizophrenia is still unknown, but current
research suggests that the necessary conditions for
developing psychosis are environmental stress and a
vulnerability to psychosis (McGue et al., 1983 ; McGuffin
et al., 1994). It has been suggested that the transmission of
liability to schizophrenia could be accounted for by
genetic factors only and that environmental factors may
be idiosyncratic and random. These important idiosyncratic effects could contribute as much as 26 % to the
variance in total liability to definite schizophrenia. In
another study, when the population risk of schizophrenia
was fixed at 0n6 %, model fitting indicated that the
maximum-likelihood of heritability was 87n5 % (McGuffin
et al., 1994). The use of a second model to attempt to
estimate simultaneously the genetic and residual components plus the population risk increased the heritability
to 89 %, with a population risk of 0n3 %.
Endophenotypes are traits that are associated with the
expression of an illness and are believed to represent the
genetic liability of the disorder among non-affected
subjects. Endophenotypes can include neurophysiological
or neuropsychological and cognitive measures. To meet
the criteria for a marker trait, an endophenotype must
occur before the onset of illness and must be heritable. If
a marker is a vulnerability trait for an illness then the
genes that are important for the expression of this
endophenotype will allow the identification of genes that
increase the susceptibility for the illness. When similar
perturbations at a given test are observed both in clinically
stable schizophrenics and their non-schizophrenic firstdegree relatives, this test could be qualified as an indicator
of the vulnerability to schizophrenia. This appears to be
the case for several neuropsychological tasks, exploring
attentional abilities such as the Continuous Performance
Task (CPT), Span of Apprehension Task (SAT) and
Wisconsin Card Sorting Test (WCST) (Franke et al., 1992 ;
Kremen et al., 1994 ; Nuechterlein et al., 1994). This
vulnerability is probably genetic but is not usually active
or expressed until the late-adolescent developmental
phase. The deficient processes involved in this order are
clinically silent until the onset of prodromal or psychotic
symptoms, at which time neuropsychological testing
demonstrates the presence of cognitive deficits that are
often chronic and apparently irreversible (Goldberg et al.,
1993). Thus, cognitive impairment is a central manifestation of the schizophrenic illness that impacts on the
quality of life of the patient and the cost of the illness to
society. Apart from the potential utility of indicating the
degree or severity of neuropsychological deficiency, the
measurement of cognitive processes and its impairment
may also serve as an indicator or marker of vulnerability
to schizophrenia in normal individuals at high risk of
schizophrenia.
Drug development for schizophrenia has previously
relied almost exclusively on laboratory animal models.
Since pathophysiological mechanisms remain obscure,
this strategy has led to many ‘ me-too ’ drugs but no new
treatment strategies. Advances in molecular genetics offer
the possibility of more rational approaches to the
Dopamine receptors and schizophrenia
treatment of schizophrenia by leading to insights into the
pathophysiology of the disorder, helping to identify
patients at high risk of developing the disease to whom
early treatment could be targeted, and allowing the
identification of subgroups of patients who may be
particularly responsive to a particular type\class of drug
treatment.
A recent comprehensive survey of the content and
quality of 2000 controlled trials in schizophrenia over the
last 50 yr indicates several important issues which suggest
that half a century of studies of limited quality, and clinical
utility leave much scope for well planned and well
conducted clinical trials (Thornley & Adams, 1998).
Among the objectives for a novel antipsychotic drug is an
expanded efficacy profile. More often, the primary
objective of treatment is the improvement of negative
symptoms which respond poorly to most current antipsychotic drugs. The ability to either prevent further
cognitive deterioration or improve performance are
equally important targets. An important criticism in the
above report was that since it is important to assess
normal cognitive functioning in schizophrenia studies,
proper measurement of this aspect was largely neglected.
Often, the lack of statistical power was reflected in the use
of an extraordinary number of non-validated tests and
rating scales and that it is often possible to achieve
significance on these measures with a small number of
patients. As low-quality scores were associated with an
increased estimate of benefit, these schizophrenia trials
may well have consistently overestimated the effects of
experimental interventions. Distinctive research progress
in molecular genetics and neuropsychology has brought
significant contributions to the area of neuropsychiatric
disease and the effect of neuropharmacological interventions, particularly in pharmacological treatment of
schizophrenia. Considering research advances during the
last few years, it may be suggested that significant and
continuous advancement in these two scientific areas
which, though at first instance seem unrelated, has
considerably increased our understanding of the genetics
and cognitive processes involved in the aetiology and
treatment of schizophrenia. Since neuropsychological
deficits are significant variables to be considered and
assessed in schizophrenia, there is some evidence that
atypical neuroleptics may, owing to their novel mechanisms of action, have the capacity to remediate cognitive
impairment in schizophrenia. This paper critically reviews
the importance and significance of neuropsychological
deficits in schizophrenia and argues for the inclusion of the
assessment of cognitive parameters in clinical trials of new
investigational drugs for the treatment of schizophrenia.
It is hypothesized that the assessment of neuropsychological variables in vulnerable schizophrenic popu-
199
lations will further increase our understanding of the
genetics of schizophrenia. Further advances in our understanding of the dopaminergic receptors and the genetics
of schizophrenia are also included in this discussion ;
outlining the potential, limits and future perspectives of
our comprehension of the pharmacological possibilities
for the effective treatment of schizophrenia. Finally, this
paper assembles two areas of research, which are often
published separately in various journals, to carefully
consider the possibility and perspective of producing a
superior future pharmacological treatment of schizophrenia.
2. Role of dopamine in schizophrenia
2.1. Structure and characteristics of dopamine
receptors
At present, five subtypes of dopamine receptors have
been characterized (Seeman, 1987 ; Seeman and Van Tol,
1993). The human genes corresponding to these different
subtypes were cloned and assigned to chromosomes
5q35 . 1 (D ), 11q22 . 23 (D ), 3q13 . 3 (D ), 11p15 . 5 (D ),
"
#
$
%
and 4p16 . 1 (D ), respectively (Civelli, 1995). Two D -like
&
"
receptor subtypes (D , D ) couple to the G protein Gs and
" &
activate adenylyl cyclase. The other receptor subtypes
belong to the D -like subfamily (D , D , D ) and are
#
# $ %
prototypic of G-protein-coupled receptors that inhibit
adenylyl cyclase and activate K+ channels.
The genomic organization of the dopamine receptors
supports the concept that they derive from the divergence
of two gene families that mainly differ in the absence or
the presence of introns in their coding sequences. The D
"
and D receptor genes do not contain introns in their
&
coding regions, a characteristic shared with most Gprotein-coupled receptors (Dohlman et al., 1987). In
contrast, the genes encoding the D -like receptors are
#
interrupted by introns so that the D receptor coding
#
region contains 6 introns, the D receptor coding region
$
5 and the D receptor 3 (Monsma et al., 1989 ; Sokoloff et
%
al., 1990 ; Van Tol et al., 1991). The presence of introns
within the coding region of D -like receptors allows the
#
generation of splicing variants. Indeed, the D receptor
#
has two main variants, called D s and D L, which are
#
#
generated by alternative splicing of a 87 bp exon between
introns 4 and 5. Both variants share the same distribution
pattern, with the shorter form less abundantly transcribed
and both isoforms revealing the same pharmacological
profile, even if a marginal difference in the affinity of some
substituted benzamides has been reported (Castro and
Strange, 1993 ; Malmberg et al., 1993 ; Neve et al., 1991).
Splice variants of the D receptor encoding non-functional
$
proteins have also been identified (Fishburn et al., 1993).
200
G. Emilien et al.
A recent study which examined the anatomical distribution of D receptor mRNA expression at different
$
levels of the human brain showed that the most abundant
D mRNA expression levels were found in the islands of
$
Calleja and discrete cell cluster populations within the
striatum\nucleus accumbens region (Suzuki et al., 1998).
High levels were also evident within the dentate gyrus
and striate cortex. This study also confirmed previous
reports that D receptors may play a significant role in
#
limbic-related functions such as cognition and emotion.
The study of the physiological functions mediated by
the D receptor indicate that several mutations and
%
polymorphisms change the D receptor structure (Seeman
%
and Van Tol, 1994 ; Van Tol and Seeman, 1995). These
include an insertion-deletion of a 4-amino-acid sequence
immediately upstream from transmembrane 1 (TM1), a
frame-shift mutation in TM2, a single nucleotide substitution that converts Val194 into Gly194, and a variable
number of a 48-bp tandem repeat (VNTR) in the third
cytoplasmic loop (Lichter et al., 1993 ; Van Tol et al.,
1992). In addition, it has been observed that translation
initiation of the D receptor can occur within the TM
%
region and individuals with 2–10 tandem repeat units
(called D . , D . , D . , etc.) have been described. These
%# %$ %%
different units can be found at various positions and
frequencies within the VNTR and to date more than 27
polymorphic variants of the D receptor have been noted
%
(Asghari et al., 1994 ; Lichter et al., 1993 ; Van Tol et al.,
1992). At the amino acid level, this has resulted in the
identification of at least 20 different polymorphic forms of
the D receptor with respect to this sequence. Unlike the
%
unstable trinucleotide repeat polymorphisms that underlie
various genetic disorders and confer genetic anticipation,
this VNTR is transmitted in a normal Mendelian pattern.
This polymorphism appears to be primate-specific and has
not been observed in rodents. The 4-repeat form (D . ) is
%%
predominant in the human population (60 %). The D .
%(
variant is present in 14 % of the population and the D .
%#
in 10 % (Seeman and Van Tol, 1994 ; Van Tol and Seeman,
1995). The functional significance of these variants has
not been elucidated. They display a slightly different
affinity for the neuroleptic clozapine, but none of them has
been related to an increased incidence of schizophrenia
(Seeman and Van Tol, 1994 ; Van Tol and Seeman, 1995).
2.2. Symptoms of schizophrenia
Schizophrenia tends to present two clusters of symptoms,
positive and negative. Positive symptoms include delusions, hallucinations, excitement, grandiosity, suspiciousness and hostility. Negative symptoms include
inability to focus on relevant issues, paucity in speech,
distractibility, emotional flattening, lack of spontaneity,
and stereotyped thinking. Patients often manifest one
cluster more than another, though relative predominance
of the two frequently changes over time. This twosyndrome concept of schizophrenia with Type 1 patients
having mostly positive symptoms and Type 2 negative
symptoms is now widely regarded as being very simplistic
(Crow, 1980 ; McGlashan and Fenton, 1992). Indeed,
recent data from factor analyses suggests that at least
three orthogonal factors underlie the symptoms of
schizophrenia which can be described as follows : psychomotor impoverishment (mostly negative symptoms),
disorganization (thought disorder), and reality distortion
(delusions and hallucinations) (Lenzenweger and Dworkin,
1996 ; Rowe and Shean, 1997).
Cognitive deficits in abstract reasoning and attention,
together with structural brain abnormalities such as
enlargement of the ventricular system and reductions in
cortical (prefrontal) and mesotemporal volume are also
common findings (Hirsch and Weinberger, 1994). Disorders of attention in schizophrenia were reported as
early as 1919 by Kraepelin who noted ‘ a certain
unsteadiness of attention ’ as well as ‘ a rigid attachment of
attention ’. Subsequent studies suggest that schizophrenic
patients appear incapable of focusing their attention
(Goldberg and Gold, 1995). The difficulties of schizophrenic patients are characterized by difficulties in maintaining attention to relevant information while disregarding unimportant material. Furthermore, the speed
with which they process information is compromised. A
potential approach to clarifying such constructs is through
neuropsychological indices and cognitive assessment.
To further understand and categorize the symptoms of
schizophrenia, several symptom-rating scales, such as the
Positive and Negative Syndrome Scale (PANSS) have
been developed (Kay et al., 1987). PANSS consists of 30
items (7 items for positive subscale, 7 items for negative
subscale and 16 items for general psychopathology
subscale) with strict criteria for definition and evaluation.
PANSS is currently widely used in clinical and therapeutic
trials in its three-dimensional form. Recently, PANSS has
been revised and 5 subscales have been proposed
(negative, positive, excited, depressive and cognitive
factors) which need to be validated (Kay and Sevy, 1990).
Due to the various cognitive difficulties encountered by
schizophrenic patients, it has become important to include
a cognitive subscale in PANSS.
2.3. Implications of dopamine receptors
In recent years, a modified dopamine hypothesis of
schizophrenia has been introduced. While the standard
dopamine hypothesis attributes schizophrenic psychopathology to elevated dopamine levels, several authors
Dopamine receptors and schizophrenia
have proposed that negative symptoms in schizophrenia
are due to a decrease in dopaminergic activity (Davis et
al., 1991 ; Heritch, 1990). It was suggested that negative
symptoms are caused by low prefrontal dopamine
activity, which leads to excessive dopamine activity in
mesolimbic dopaminergic neurons, and may eventually
lead to positive symptoms (Davis et al., 1991). It was
argued that schizophrenia patients suffer from a diminished ‘ tonic ’ striatal dopamine release, consecutive upregulation of striatal postsynaptic dopamine receptors
and, hence, increased responses to ‘ phasic ’ striatal dopaminergic activation due to environmental stress (Grace,
1991). This would result in both low dopaminergicnegative symptoms and stress-related hyperdopaminergic-positive symptoms. The hypothesis that negative
symptoms in schizophrenia are due to a decrease in
dopaminergic activity, rather than an increase, was also
supported by various other authors (Crow, 1980 ; Davis et
al., 1991 ; Grace, 1991).
A study in which personality traits (Karolinska scales of
personality) and D receptor density (PET) in the putamen
#
were measured in normal subjects indicated that the
density of D receptors strongly correlated with a
#
detached personality (r lk0n68, p 0n001) (Farde et al.,
1997). It was pointed out that detachment can encompass
social isolation, indifference to other individuals and lack
of intimate friendships, traits which are included among
the category of ‘ negative symptoms ’ that commonly
characterize patients with schizophrenia. It was proposed
that D receptor density may be a useful neurochemical
#
measure for relating the genetic endowment to human
personality traits.
Anatomical substrates for the clinical efficacy of D
#
receptor antagonism in improving positive symptoms,
including auditory hallucinations, in schizophrenia were
investigated in tissues obtained post-mortem from
schizophrenics (Goldsmith et al., 1997). A modular
organization of D receptors unique to the temporal lobe
#
was reported ; the dense bands of D receptors showed
#
highest frequency in auditory and speech association
cortices (Brodmann areas 22, 39, 42) and auditory–visual
association areas (Brodmann areas 20, 37). It was hypothesized that blockade of D receptors in auditory and
#
auditory–visual association cortices is a likely mechanism
for the clinical efficacy of D antagonists in reducing
#
hallucinations. An in vivo evidence for a dysregulation of
striatal dopamine release in schizophrenia has also been
demonstrated (Abi-Dargham et al., 1998). Patients with
schizophrenia exhibited a significantly larger reduction in
D receptor availability following acute amphetamine
#
challenge than the comparison group. While the mechanism, specificity and significance of this increased
dopaminergic response in schizophrenia remains to be
201
clarified, this observation is consistent in documenting an
excessive neurochemical response and provides evidence
to support the hypothesis of a dysregulation of central
dopamine transmission in schizophrenia.
The examination of the expression of the transcripts
encoding the dopamine receptors in cortical and striatal
regions of post-mortem schizophrenic brains shows a
focal abnormality of dopaminergic circuitry in the schizophrenic prefrontal cortex (PFC) suggesting that prefrontal
cortical dopaminergic activity is diminished in this illness
(Meadow-Woodruff et al., 1997). These data indicate that
cortical dopaminergic neurotransmission may be disrupted in schizophrenia at the level of receptor expression.
These changes were restricted to the D and D receptors
$
%
and localized to Brodmann area 11 (orbitofrontal cortex).
It also appears that the down-regulation of D and D
$
%
mRNA in Brodmann area 11 is probably related to
schizophrenia itself and not to the medication. Schmauss
et al. (1993) found a selective loss of D mRNA expression
$
in the parietal and motor cortices of post-mortem,
schizophrenic brains. This phenomena may be due to
either the course of the disease or the therapy given to the
patient during the course of the disease.
Of the other dopamine receptor gene products, D
%
demanded immediate attention because of its high affinity
for clozapine, its remarkable allelic variability and its
cortical and limbic distribution (Seeman & Van Tol, 1994 ;
Van Tol et al., 1991 ; Van Tol & Seeman, 1995). Seeman et
al. (1993) measured indirectly the density of D receptor
%
binding sites in striatal homogenates using two ligands
[$H]emonapride which detects D , D and D receptors
# $
%
and [$H]raclopride in the presence of guanine nucleotide
which detects D and D receptors. The difference in
#
$
binding between the two ligands was used as an estimate
of D receptor density. A 6-fold increase in D receptors
%
%
in the basal ganglia from deceased schizophrenic patients
was noted (Seeman et al., 1993). However, Reynolds and
Mason (1994) using a competitive (rather than subtractive) method were unable to confirm the existence of
D receptor in human striatal tissue from schizophrenic
%
patients. Regardless of the methodology employed, it
remains to be established whether elevations in D -like
%
receptors in schizophrenia are partially or wholly an effect
of neuroleptic treatment. Overall, the importance of D
%
receptor involvement in schizophrenia remains unclear.
The fact that different dopamine ligands and selective
antagonists are currently available from many sources
means that further investigations with these tools will
probably help to further clarify the role of these dopamine
receptors in schizophrenia (Lie! geois et al., 1988). Nevertheless, from the recent observation that a selective D
%
receptor antagonist (L745,870) was ineffective as an
antipsychotic for the treatment of neuroleptic-responsive
202
G. Emilien et al.
in-patients with acute schizophrenia may suggest the
limited implications of D receptor in schizophrenia
%
(Kramer et al., 1997). In fact, in this 4-wk, placebocontrolled, double-blind study the patients became worse
after treatment with L745,870 and a greater percentage
receiving the drug compared to placebo discontinued the
treatment due to insufficient therapeutic response (32 vs.
16 %).
2.4. Dopamine receptors and cognitive function
Preclinical studies provide some useful hints about the
implications of dopamine receptors in cognitive processes.
Dopamine plays an important role in both working and
long-term memory (LTM) (Goldman-Rakic, 1995). In
LTM, dopamine is involved specifically in the mechanisms
of reinforcement (Schultz et al., 1993). A study investigating the role of dopamine on short-term memory
(STM) and LTM in rats with cannulae implanted in the
dorsal CA1 region of the hippocampus or the entorrhinal
cortex, trained in one-trial step-down inhibitory avoidance, and tested 1n5 or 24 h later, indicated that STM and
LTM are differentially modulated by D receptors in the
"
CA1 and entorrhinal cortex (Izquierdo et al., 1998). The
D antagonist SCH23390 (0n5 µg) enhanced STM with"
out affecting LTM when implanted in CA1, and blocked
LTM without affecting STM when implanted in the
entorrhinal cortex. D receptors in the PFC are involved in
"
working memory processes other than just the short-term
active retention of information and also provide direct
evidence for dopamine modulation of limbic-PFC circuits
during behaviour (Seamans et al., 1998). Further animal
studies also suggest that supranormal D receptor stimu"
lation in the PFC is sufficient to impair PFC working
memory function and that the impairment may be
reversed by pretreatment with a D receptor antagonist,
"
SCH23390, consistent with drug actions at D receptors
"
(Zahrt et al., 1997). Since D receptor which is highly
"
expressed in the PFC has been implicated in the control of
working memory, and memory dysfunction is a prominent
feature of schizophrenia, it is therefore, important to
understand how dopamine affects cognition in schizophrenia. The hypothesis that the dependence of working
memory on D receptor activity can be described as an
"
inverted U-shaped function in which there is an optimal
range of dopamine concentration and cortical D receptor
"
for normal cognitive performance was suggested (Lidow
et al., 1998). Too little or too much D receptor activation
"
leads to a deficient operation of the neural systems
necessary for working memory thus resulting in deficient
cognitive performance. Therefore, depending on how
antipsychotics regulate cortical D receptors in relation to
"
the optimal dose range, they may either have a beneficial,
detrimental or absence of effect on cognitive function in
schizophrenia (Lidow et al., 1998).
Regarding the role of other dopamine receptors in
cognition, it was noted that the D receptor has a
$
restricted expression in brain limbic areas, associated with
cognitive functions and motivated behaviour (Griffon
et al., 1995). A recent study in the rat showed that the
D agonist R(j)-7-hydroxy-N,N-di-n-propyl-2-amino$
tetralin (7-OH-DPAT, 0n1–100 µg\kg, s.c.) administered
before training, immediately after training, and before
retention significantly shortened step-down latency of
passive avoidance learning, indicating the amnesic effects
of 7-OH-DPAT (Ukai et al., 1997). Neither the D
"
receptor antagonist SCH23390 (2n5, 5 µg\kg, i.p.) nor the
D receptor antagonist sulpiride (10, 100 mg\kg, i.p.)
#
markedly influenced the 7-OH-DPAT-induced amnesia. It
was hypothesized that the amnesic affects of the D
$
receptor agonist 7-OH-DPAT are not mediated via D or
"
D receptors in the brain.
#
A recent study using positron emission tomography
(PET) to examine the distribution of D and D receptors
"
#
in brains of drug-naive and drug-free schizophrenic
patients reported that binding of radioligand to D
"
receptor was reduced in the PFC of schizophrenics (Okubo
et al., 1997). This decrease was related to the severity of
the negative symptoms such as emotional withdrawal and
to poor performance in the WCST. It was suggested that
dysfunction of D receptor signalling in the PFC may
"
contribute to the negative symptoms and cognitive
deficits seen in schizophrenia. In another clinical investigation, the association between dopamine activity with
cognitive and motor impairment was studied in healthy
volunteers (Volkow et al., 1998). All subjects underwent a
neuropsychological test battery. Correlations between D
#
receptors and neuropsychological test performance were
strongest for the motor task (finger tapping test) and were
also significant for most tasks involving frontal brain
regions, including measures of abstraction and mental
flexibility (WCST) and attention and response inhibition
(Stroop Colour-Word Test, interference score). These
relationships remained significant after control for age
effects. It was concluded that dopamine activity may
influence motor and cognitive performance irrespective of
age and that interventions that enhance dopamine activity
may improve cognitive performance and quality of life in
individuals such as elderly subjects or schizophrenic
patients.
2.5. Issues and criticisms
Dopamine may be critical for working memory and other
cognitive functions (Gabrielli, 1998). Associations between working memory, reasoning, and strategic memory
Dopamine receptors and schizophrenia
occur in many clinical studies and all three capacities
appear to depend on dopaminergic fronto-striatal
systems. The extent to which these associations reflect
shared vs. neighbouring processes in both normal individuals and schizophrenic patients needs to be assessed.
Another important question of whether reductions in one
capacity are causal or merely correlated with changes in
other capacities remains also to be determined.
3. Molecular genetics of schizophrenia
Two methods often employed in molecular genetic
studies are the linkage and association approaches.
Currently, five chromosomal regions 5q, 6p, 8p, 13q and
22q have been intensely investigated by the linkage
analysis methodology.
3.1. Linkage studies
Linkage in molecular genetic studies refers to the fact that
a gene is located near a specific DNA marker on the
chromosome. Linkage analyses are based on family and
pedigree studies in which families with ill members are
tested by genotyping the variable sequences at DNA
marker loci, which are unrelated to the disease. Linkage
analyses determine whether ill relatives have inherited the
same marker allele more often than expected by chance.
Genetic linkage to illness is present when ill relatives share
alleles at one or several genetic loci ; however, at any
linked locus, the shared allele need not be the same in
different families. Detectability depends on the magnitude
of the risk imparted by a given locus and the size of the
sample of families studied. Genetic markers are polymorphic, with multiple genetic variants and with known
location on the genome. Maximum lod scores (MLS) are
a measure of the strength of an association with values
between 1n9 and 3n3 being suggestive of linkage and
values above 3.3 being evidence for linkage. A lod score
of k2 or lower excludes linkage.
Linkage studies have identified several chromosomal
regions as candidates for containing a schizophrenia
susceptibility locus. The strongest support is for 6p24–22,
where at least four groups have reported results suggestive of positive linkage (Antonarakis et al., 1995 ; Moises
et al., 1995 ; Schwab et al., 1995 ; Straub et al., 1995 ; Wang
et al., 1995) (see Table 1). A linkage analysis was
performed in 186 families (567 individuals classified as
affected which included typical schizophrenia, simple
schizophrenia, schizoaffective disorder, schizotypal personality disorder, schizophreniform disorder, delusional
disorder, atypical psychosis and mood incongruent psychotic affective disorder) and under a model with partially
203
dominant inheritance, moderately broad disease definition
and assuming locus homogeneity, a lod score of 3n2 was
reported for D6S260 on chromosome 6p23 (Wang et al.,
1995). After combinations of two marker loci simultaneously, a maximum multipoint lod score of 3n9 was
noted, after allowing for locus heterogeneity at a map
position of 5 cM distal to D6S260, in an analysis using
this marker and F13A1. These positive results do not
include HLA region (6p21;3) which was shown previously to be possibly linked or associated with schizophrenia (Kendler and Diehl, 1993). In a large study (14
research groups using 14 markers in a new sample of
403–567 pedigrees per marker), no evidence for linkage
on chromosome 3 was noted (Schizophrenia Linkage
Collaborative Group for Chromosomes 3, 6 and 8, 1996).
However, the results, although inconclusive, were
suggestive of linkage for chromosome 6 [MLS of 2n19
(new sample) and 2n68 (combined sample)] and chromosome 8 [MLS of 2n22 (new sample) and 3n06 (combined
sample)]. Although others have failed to find linkage to
schizophrenia in regions of chromosome 6 (Daniels et al.,
1997 ; Gurling et al., 1995 ; Mowry et al., 1995 ; Riley et
al., 1996), these studies do not necessarily constitute a
refutation as only 15–30 % of the schizophrenia families in
the positive linkage studies were estimated to carry a
vulnerability locus (Schizophrenia Linkage Collaborative
Group for Chromosomes 3, 6 and 8, 1996).
Another chromosome of strong interest is 22q, where
several groups have reported support for linkage [Coon et
al., 1994 ; Gill et al., 1996 ; Moises et al., 1995 ; Pulver et
al., 1994 ; Schizophrenia Collaborative Linkage Group
(Chromosome 22), 1996]. Other regions for which there is
some suggestions for linkage include 8p (Kendler et al.,
1996 ; Pulver et al., 1995 ; Schizophrenia Linkage Collaborative Group for Chromosome 3, 6 and 9, 1996), 13q (Lin
et al., 1995 ; Pulver et al., 1995) and 5q (Schwab et al.,
1997 ; Straub et al., 1997).
3.2. Genome scanning studies
Genome scanning has become a sensible strategy for
detecting biologically important genetic derangements.
The major strength of genome scanning is that it covers
all possible biological mechanisms of inherited disease,
including possibilities that the investigator has not
thought of. If a mutation is present, the biology of a
disease can be elucidated rapidly. In a large study,
genome-wide scanning for a schizophrenia locus was
carried out in three phases (Moises et al., 1995). In the first
stage, only five family lines with a total of 37 affected
individuals from Iceland were used. Screening with 413
markers produced 26 potential loci, of which 10 were
204
G. Emilien et al.
Table 1. Some linkage studies of chromosome implicated in schizophrenia.
Chr.
MLS
5q
1n8
6p
No. of
families
sample
44
3n35
265 (Irish)
3n51
265 (Irish)
Markers
Comments
Ref.
D5S642, 666, 393, 399, 500,
658, 438, 210, 434, IL-9,
CSF1R
D5S815, 1467, 421, 489,
2055, 818, 804, 642, 666,
393, 399, 500, 658, IL-9
In sample I (14 families), a lod score of 1n8 by two-point lod score analysis was noted
for the marker IL-9. In sample II (44 families), a lod score of 1n8 around the marker
D5S399 was obtained by multipoint analysis.
Strongest evidence for linkage occurred under the narrow phenotypic definition and
recessive genetic model, with a peak at marker D5S804 (p l 0n0002).
Schwab et al.
(1997)
MLS was 3n51 (p l 0n0002), assuming locus heterogeneity, with D6S296. C test also
supported linkage with the strongest results obtained with D6S296 (p l 0n00001),
D6S274 (p l 0n004) and D6S285 (p l 0n006).
1n17
57
0n05–1n0
23
D6S477, 296, 277, 470, 443,
259, 260, 274, 285, 422,
299, 105, 276, 273, 291,
F13A1
D6S477, 296, 277, 259, 260,
285, 276, 1011
D6S296, 285
0n23–0n34
45
D6S296, 470, 259, 285
1n0–1n1
0–0n261
211
19
(African*)
GATA23E10, GAAT12F07,
SCAI, D6S477, 309, 277,
296, 470, 1058, 259, 469,
260, 289, 1676, 288, 285,
422
D6S296, 277, 470, 259, 285
Straub et al.
(1997)
Straub et al.
(1995)
The most significant results were obtained for D6S296 using the recessive model,
giving a lod score of 1n17. However, this linkage does not extend to the HLA region.
No evidence of linkage. Failed to confirm Straub et al. study.
Antonarakis et al.
(1995)
Gurling et al.
(1995)
No evidence of linkage. Slightly positive lod scores occurred near D6S259.
Mowry et al.
(1995)
Despite the use of 17 polymorphic markers spanning a 37 cM region, neither two-point Daniels et al.
(1997)
nor multipoint non-parametric analyses reached significance at a level less than 0n01
for any markers examined and lod score analyses were not suggestive of linkage.
Therefore, there was no evidence of linkage to chromosome 6.
No evidence to support linkage in this region of chromosome 6.
Riley et al.
(1996)
2n19, 2n68
0n192
8p
403–567
86
3n2
186
2n35
57
2n00, 2n52,
2n08
265
2n22, 3n06
403–567
D3S1293, D3S1283,
D3S1266, D3S1298,
D6S296, D6S277, D6S470,
D6S259, D6S285, D8S261,
D8S258, D8S133, D8S136,
D8S283
D6S309, 296, 470, 259, 260,
285, 461, 276, 291
D6S277, 259, 260, 285, 273,
F13A1
Fourteen collaborative groups studying chromosomes 3, 6 and 8 in independent
samples. No evidence for linkage on chromosome 3. Results were interpreted as
inconclusive but suggestive of linkage in the latter two regions.
SLCG (1996)
No evidence for linkage\MLS of 0n192 was for D6S309.
Daniels et al.
(1997)
Wang et al.
(1995)
A lod score of 3n2 was obtained for D6S260 on chromosome 6p23. A multipoint score
of 3n9 was achieved when the F13A1 and D6S260 loci were analysed, allowing for
locus heterogeneity.
Genome-wide search\520
markers
D8S552, 511, 1731, 261,
1715, 258, 282, 298, 133,
1733, 136, 1752, 1739,
137, 283
D8S261, 258, 133, 136, 283
MLS occurred using the ‘ affected only ’ models for markers D8S136 (Zmax, dominant
Pulver et al.
l 2n35 ; recessive l 2n20) and for D8S133 (Zmax, dominant l 1n34 ; recessive l 2n02). (1995)
According to two-point heterogeneity lod scores, the strongest evidence for linkage
Kendler et al.
was for markers D8S1731 (2n08), D8S1715 (2n52) and D8S133 (2n08)
(1996)
Fourteen collaborative groups studying chromosomes 3, 6 and 8 in independent
samples.
SLCG (1996)
1n62
13
D13S175, 232, 192, 120,
260, 263, 126, 119, 144,
160, 121, 122, 128, 64,
173, 285, 71, HTR2A
Under the assumption of homogeneity, most of the markers gave negative total lod
scores, although with a narrow model marker D13S119 gave a total lod score of
1n62 and marker D13S144 gave a total lod score of 1n48.
Lin et al.
(1995)
22q
2n82–1n54
39
Genome scan\240
randomly distributed
markers
D22S278
Pairwise linkage analyses suggest a linkage (MLS l 1n54) for region 22q12–q13n1.
Reanalyses, varying parameters in the dominant model, maximized the MLS to 2n82.
Pulver et al.
(1994)
Results are suggestive of a susceptibility locus for schizophrenia near to the D22S278
locus on chromosome 22.
SCLG (1996)
na
574
MLS, Maximal lod score ; SLCG, Schizophrenia Linkage Collaborative Group ; * Southern African Bantu-speaking black population ; na, not available ; SCLG, Schizophrenia
Collaborative Linkage Group for Chromosomes 3, 6 and 8.
Dopamine receptors and schizophrenia
13q
205
206
G. Emilien et al.
selected for the second stage and tested in a total of 65
families from numerous populations. This material revealed some evidence for linkage to four loci. When
results from the first and second stage were combined and
analysed, the statistical evidence for linkage increased
slightly for loci on chromosomes 6p, 8p and 20. The most
stringent significance level could be reached only for 6p.
A genome scan of cortical-evoked potential (P50)
abnormality was performed in members of schizophrenia
pedigrees, without respect to affection status with
schizophrenia (Freedman et al., 1997). Linkage was
observed to be present, using a single-locus model of the
trait, to markers on chromosome 15, very close to the
gene for the α -subunit of the nicotinic cholinergic
(
receptor. This work is an innovative approach in choosing,
as a phenotype, not the illness but a component of the
illness that can also be found in clinically unaffected firstdegree relatives. Although the relationship of P50 and the
chromosome 15 region is indicated by the results of this
study, a relationship of the genetic finding to schizophrenia and to the nicotinic cholinergic receptor is only
suggested.
Recent study on genome scan of schizophrenia does
not support the hypothesis that a single gene causes a
large increase in the risk of schizophrenia (Levinson et al.,
1998). A genome scan of 43 schizophrenia pedigrees
including 126 patients with schizophrenia-related psychoses did not show any genome-wide, statistically
significant or suggestive linkage result. However, nominally significant results were observed in five regions.
There were p values less than 0n01 at chromosomes 2q
and 10q, and there were p values less than 0n05 at
chromosomes 4q, 9q and 11q. This study is the largest
schizophrenia genome scan published to date and the
results failed to produce significant evidence for linkage.
However, a major gene could exist in certain populations,
in a chromosomal region not well covered in the map used
in this study or in an undetermined subgroup of families.
Detection of these genetic effects could require larger
samples than has been currently used (e.g. 500–1000
pedigrees). At this time there are no strong candidate
genes for schizophrenia within the regions identified by
linkage studies. Contradicting results in this area may
often simply be due to the possible genetic heterogeneity
of the sample selected for study. Controlling for the
effects of medication usage and other factors such as sex
and age, all present significant challenges to the investigator.
3.3. Association studies
Association studies attempt to determine whether a
genetic variant is more common among affected than
among non-affected individuals. Therefore, association
studies are case-control studies. In association, a particular
allele or mutation in the candidate gene is found more
frequently in patients than controls. Association studies
have also their limitations. Given a gene with a major or
a modest effect size, genetic markers have substantially
less coverage in association studies than in linkage studies.
Associations between schizophrenia and the
Ser311Cys polymorphism in exon 7 of the D receptor
#
gene as well as a polymorphism Ser9Gly in exon 1 of the
D receptor gene have been reported (Crocq et al., 1992).
$
However, recent investigation by a European multicentre
association study of schizophrenia suggest that there is no
evidence for allelic association between schizophrenia and
the Cys311 variant of the D receptor gene (Spurlock et
#
al., 1998). Therefore, it appears that the rare Cys311
variant in exon 7 of the D receptor gene does not play a
#
role in the pathogenesis of schizophrenia in European
populations. This finding was not confirmed in Japanese
population either (Fujiwara et al., 1997).
Evidence of an association between schizophrenia and
homozygosity for a Ser to Gly polymorphism in exon 1
of the dopamine D receptor gene has been reported
$
(Crocq et al., 1992). This polymorphism creates a BalI
restriction endonuclease site and brings about an aminoacid change (Gly-Ser) in the N-terminal extracellular
domain of the receptor. Several studies have subsequently
confirmed this finding in independent samples and using
a family-based design (Asherton et al., 1996 ; Mant et al.,
1994 ; Williams et al., 1998). A number of negative studies
have also been reported (Durany et al., 1996). However,
a meta-analysis of all available results, now comprising
over 5000 individuals showed a small (OR l 1n23) but
significant (p l 0n0002) association between homozygosity and schizophrenia, which is unlikely to be the
result of publication bias, has also been reported (Williams
et al., 1998). We have also screened all six exons that
make up the coding region of the gene using singlestranded conformational polymorphism analysis (SSCP)
(Asherton et al., 1996). No other mutations were found
that altered protein structure in a total of 36 schizophrenics and the same number of controls. We are
currently following up these results with cell culture
studies on the functional significance of the D poly$
morphism and by sequencing the D promoter and
$
screening it for polymorphisms. A second meta-analysis
(29 independent samples, from 24 different association
studies so far published ; 2619 schizophrenic patients and
2517 controls) also reported an excess of homozygosity
and 1–1 genotype in schizophrenic patients in African and
Caucasian groups (p 0n05) (Dubertret et al., 1998).
Clearly more work is needed to establish the relevance of
homozygosity of the D receptor to schizophrenia.
$
Table 2. Examples of some association studies
Populations (sample size)
Hypothesis and method
Schizophrenic Spanish patients, ICD-10 F20 (107)
Healthy matched controls (100)
No statistically significant differences between the
To test an association between D receptor gene
$
patients and control group were detected with
mutation and the liability to develop schizophrenia
respect to either allele frequencies or genotype
by comparing allele frequencies and genotype
distribution in patients and controls. For genotyping, distribution. However, if not corrected for
multiple testing a correlation was noted between
genomic DNA was extracted from whole blood
homozygosity and early age of onset of
of each individual. PCR amplification of DNA was
schizophrenia and between A1 allele frequency
conducted with primers flanking the gene region
and disorganized and undifferentiated
containing the polymorphism of interest.
schizophrenia.
Schizophrenia DNA samples\DSM-III-R (51 from
living patients, 7 from post-mortem tissues of
patients who died with schizophrenia)
Controls (296)
To test for possible abnormalities in the coding
region of the genomic DNA sequence for the
dopamine D receptor in control and schizophrenia
%
tissues. The genomic DNA was extracted from
blood samples and in some cases from postmortem brain tissues. Genomic DNA was
amplified in vitro by the PCR using Taq
polymerase.
Twenty-three out of 183 control blacks (12n6 %) and
3 out of 24 (12n5 %) schizophrenic blacks revealed a
replacement of T by G, suggesting a substitution
of valine by glycine at amino-acid position 194
(variant D Gly194). The identical prevalence in
%
the two groups indicate that the variant is not
associated with schizophrenia. However, none of
the caucasians in the study (113 controls, 34
schizophrenics) revealed the D Gly194 variant.
%
Seeman et al.
(1994)
Schizophrenic patients, DSM-III-R (78 unrelated
schizophrenic individuals were selected for an
initial detailed examination of D5 gene)
To determine whether mutations in the D receptor
&
gene are associated with schizophrenia, the gene
(78 patients\156 D alleles) was first examined to
&
identify sequence variations affecting protein
structure or expression. Sequence changes of likely
functional significance then were tested for an
association with disease via case-control and
family-based analyses.
Five different sequence changes (C335X, N351D,
A269V, S453C, P330Q) that would result in
protein alterations were identified. However, no
statistically significant associations were noted
with schizophrenia or other neuropsychiatric
diseases. There also were no significant
associations between any one measure of
neuropsychological function. However, a post-hoc
analysis of combined measures of frontal lobe
function hinted that heterozygotes for C335X
may have a vulnerability to mild impairment.
Sobell et al.
(1995)
115 Japanese patients and controls (52 patients
met the ICD-10 and DSM-III-R criteria for
schizophrenia)
Using four loci (D2, D3, D4 and DAT) as candidate
genes, the association between these markers and
neuropsychiatric diseases was tested. Genomic
DNA was isolated from lymphocytes with a DNA
extractor WB kit (Wako, Osaka) and analysed by
PCR with oligonucleotide primers specific for part
of each dopamine receptor or DAT sequence.
The frequency of each variant was not significantly
greater in the patient group than in the control
group, and there was no evidence for an
association of each variant with subtypes of
schizophrenia and reactivity to pharmacotherapy
with dopamine antagonists.
Fujiwara et al.
(1997)
Ref.
Durany et al.
(1996)
Dopamine receptors and schizophrenia
207
PCR, polymerase chain reaction ; DAT, dopaminergic transporter.
Results
208
G. Emilien et al.
The implication of D receptor in schizophrenia has
%
also been investigated (Seeman et al., 1994). This study
led to the identification of a single base substitution
occurring in exon 3 of the dopamine D receptor gene of
%
12n5 % of those of African descent in both control and
schizophrenic individuals. This substitution suggests a
replacement of Val by Gly at amino-acid position 194 and
this variant was termed D Gly194. Because the prevalence
%
of the D Gly194 was the same in controls and in
%
schizophrenics, this variant is probably not associated
with schizophrenia.
The role of the D gene as a candidate for involvement
&
in schizophrenia was studied (Sobell et al., 1995). The
gene was examined in a group of unrelated schizophrenic
patients to identify sequence variations affecting protein
structure or expression. Sequence changes of likely
functional significance were then tested for an association
with schizophrenia via case-control and family-based
analyses. No significant associations with schizophrenia
were detected. Considering results of neuropsychological
tests, among the heterozygotes for the C335X allele,
neuropsychological testing revealed a high rate of poor
performance on tests sensitive to the frontal lobe
impairment, but no individual measure was associated at
a statistically significant level with heterozygosity for the
variant allele. However, a post-hoc analysis of combined
measures of frontal lobe function (the Controlled Oral
Word Association Test and the Retroactive Interference
Index from the Rey Auditory Verbal Learning Test)
revealed a trend toward greater impairment among
C335X heterozygotes. However, the data must be
interpreted with caution given the post-hoc analysis and
the small size of the sample examined.
3.4. Criticisms and perspectives
Whether an alteration of dopaminergic function exists in
schizophrenia or not, it is tempting to speculate that a
genetic abnormality of dopamine receptors, either structural or affecting gene expression, might play a causative
role in the pathogenesis of schizophrenia. To date, studies
published have not found any unequivocal association of
schizophrenia with D –D receptor genes, although the
" &
data on D look promising (Kalsi et al., 1995 ; Liu et al.,
$
1995 ; Yang et al., 1993). Linkage strategy has not
produced replicable results of schizophrenia. Increased
understanding of complex inheritance has led to an
appreciation of the frequency of false positive results and
of the large sample size required to detect genes of small
effect (Hauser et al., 1996 ; Kruglyak and Lander, 1995).
Labelling patients as ‘ unaffected ’ when they are affected
can reduce the apparent penetrance, thus a larger sample
size is required to obtain significant results. Conversely,
labelling patients as ‘ affected ’ when they are unaffected
can mask the presence of linkage because it appears that
there is a recombination when there is none. This makes
detection of linkage more difficult and specific localization
of susceptibility genes almost impossible. In the light of
the numerous molecular genetic studies, many geneticists
favour an oligogenic hypothesis, according to which 2 or
3 genes together lead to a predisposition to schizophrenia
(Owen and McGuffin, 1993). Their effects may be
dependent on interaction with physical and psychosocial
environmental factors. Whatever the explanation, the
identification of a genetic association with schizophrenia
has several consequences. It provides a new and much
needed clue that may help unravel the pathophysiology
of the disease. Genetic variation may also identify
prognostic or therapeutic subgroups of patients. These
results also suggest a research strategy for an integrative
approach to the study of schizophrenia integrating
neuropsychiatric, genetic and neuropsychological studies
in the search to establish the origins, nature and treatment
of schizophrenia.
4. Cognitive impairment in schizophrenia
Cognitive impairment in schizophrenia is mostly defined
in terms of performance deficits on neuropsychological
tests (see Table 3). This deficit is present at the onset of the
illness, persists for most of the patient’s life without
periods of spontaneous remission and may precede the
development of psychotic symptoms (Hoff et al., 1992). In
terms of social adjustment, neuropsychological test
deficits reflect inabilities to carry out everyday tasks and
obtain employment. For many elderly schizophrenics,
cognitive deficits may lead to early admission in nursing
homes or long-term psychiatric institutions. Neuropsychological tests such as those measuring attention,
executive functions and information processing speed are
only a few of the neuropsychological tests on which
schizophrenic patients perform poorly. Although some
test results are more abnormal than others, cognitive
deficits in schizophrenia are generally believed to be
diffuse and heterogeneous and not limited to one discrete
function (Gold and Harvey, 1993). Interest in sex
differences in neuropsychological functions suggest that
women with schizophrenia may be less vulnerable to
particular cognitive deficits, especially those involving
verbal processing, than schizophrenic men (Goldstein et
al., 1998). Further observations on the cognitive dysfunctions of schizophrenia also point out that poor social
functioning in schizophrenia might be related to
attentional and cognitive deficits in combination with
Dopamine receptors and schizophrenia
dysfunctional reactions to social or environmental
stressors, and further highlight the usefulness of neuropsychological assessment in the study of schizophrenia
(Bellack, 1992 ; Brenner et al., 1992).
In a recent study investigating which variables best
identify geriatric patients with chronic schizophrenic
illness and which variables are more typical of those who
are community residents, it was noted that in patients
with either persistent or episodic symptoms of schizophrenia, the severity of cognitive impairment was a
stronger predictor of adaptive deficits than was the
severity of either positive or negative schizophrenia
symptoms (Harvey et al., 1998). The results suggest that
adaptive-functioning deficit is correlated with overall
functional status and that cognitive impairment is an
important correlate of adaptive skills. Therefore, this
study underscored the importance of cognitive functioning in the outcome of schizophrenia and recommended that treatment of cognitive impairment in
schizophrenia should be a focus of intervention.
4.1. Attention
Taylor et al. (1996) examined the procedure of the wellknown Stroop Colour-Word Test (colour-words written
in various colours are presented to subjects, who must
name the colour in which the words are written ; the
colours and the colour-words may be the same or
different), a test usually interpreted as showing an
individual’s ability to use selective attention. This function
is believed to be impaired in schizophrenic individuals,
showing the greater interference effects in patients,
relative to normal individuals. After correction for
generalized slowing in the schizophrenia group, it was
noted that the two groups did not differ in the degree of
interference on the incongruent condition although the
patients exhibited significantly greater facilitation on the
Stroop test compared to the normal controls (81 vs.
12 ms). It was concluded that attentional dysfunction
theories did not account sufficiently for the Stroop
performance in patients with schizophrenia.
4.2. Language and information processing
Language disturbances in schizophrenia can be grouped
into a number of broad categories, two of which are the
most important. The first may be referred to as negative
thought disorder, consisting of reduced verbosity, reduced syntactic complexity and increased pausing (Alpert
et al., 1994). The second dimension which may be
considered as discourse coherence disturbances includes a
subset of the classic subtypes of formal thought disorder
(e.g. tangential responses, loss of goal, derailments, non-
209
sequitur responses, distractible speech) as well as vague or
ambiguous word meaning references (Berenbaum and
Barch, 1995). Numerous studies have demonstrated that
these types of language disturbances tend to covary
among schizophrenic patients (Andreasen, 1979 ; Harvey
et al., 1992). A reduction in the syntax complexity of
comprehended language and expressed langauge has
been observed in schizophrenia patients, though whether
this phenomenon was a failure to acquire, or a loss after
acquisition, has not been determined (Morice and
McNicol, 1985, 1986). Negative thought disorder appears
to reflect a disturbance in generating a discourse plan
which requires selecting ideas to be expressed, retrieving
concepts or ideas from LTM, and connecting such ideas to
a logical format (Levelt, 1989). Generating a discourse
plan is thought to involve the retrieval of conceptual
information from working memory and\or LTM (Levelt,
1989). Thus, one factor that could influence the generation
of a discourse plan is the ease of retrieving conceptual
information to be expressed in speech. Discourse coherence disturbances may reflect deficits in the ability to
maintain a discourse plan and to monitor the ongoing
content of speech. Both negative thought disorder and
disturbances in discourse coherence among schizophrenic
patients reflect deficits in specific components of language
production (Barch and Berenbaum, 1997). The presence of
structure improves the maintenance of a discourse plan
such as fewer discourse coherence disturbances but does
not improve the initiation of a discourse plan (e.g. no
decrease in negative thought disorder).
In a recent study designed to investigate what type of
cognition might be most strongly associated with thought
disorder in schizophrenia, the authors questioned whether
thought disorder resided in the semantic system or
elsewhere (Goldberg et al., 1998). All patients and normal
controls received tests of executive function and working
memory, including WCST and the Letter-Number Span
Test, a test of deployment of attentional resources, and
tests of semantic processing and language comprehension,
including the Peabody Vocabulary Test, the Speed and
Capacity of Language Processing Test, the Boston
Naming Test, and tests of semantic verbal fluency and
phonologic verbal fluency. The normal subjects were
compared with the schizophrenic patients who were rated
as high, having mild thought disorder or moderate to
severe thought disorder. While differences between the
schizophrenic subgroups and the comparison subjects
were observed on nearly all tests, a large difference in
effect size between the two schizophrenic subgroups was
apparent only in the verbal fluency difference score. Since
the fluency measure discriminated between the groups
with high and low levels of thought disorder, it was
hypothesized that clinically rated thought disorder in
210
Table 3. Some studies indicating the assessment of cognitive performance in schizophrenic patients
Duration of illness
Neuroleptic treatment
Results
Ref.
Monozygotic pairs of
individuals discordant for
schizophrenia, DSM-III-R
(24)
Normal pairs of monozygotic
twins (7)
Mean of 10n3 yr
(range : 1–24 yr)
Nineteen of the affected twins
were receiving neuroleptic
treatment.
On the declarative memory tasks, the affected group
performed significantly worse than the discordant
unaffected group on story recall, paired associate learning
and visual recall of designs. Effortful, volitional retrieval
from the lexicon, measured by verbal fluency, was also
compromised in the affected group. Comparisons of the
normal group and unaffected group indicated that the
latter group had very mild impairments in some aspects
of episodic memory. Significant correlations between
measures of memory and global level of social and
vocational functioning within the discordant group were
also observed.
Goldberg et al.
(1993)
DSM-II-R schizophrenic (12)
Age-matched controls (12)
na
Ten patients were taking
neuroleptics (5 on
risperidone, 1 on clozapine,
4 on conventional
neuroleptics) and 2 had been
off antipsychotic medication
for 1 wk.
In the Stroop task, the schizophrenic patients had slower
reaction times in all conditions. There was a significant
difference for facilitation between the schizophrenic and
control groups with the schizophrenics showing greater
facilitation (81 vs. 12 ms). Interference effects were not
significantly different.
Taylor et al.
(1996)
DSM-III-R schizophrenic (12)
Age-matched controls (7)
2 yr
Average dosage in
chlorpromazine equivalents
was 450 mg (100–2000 mg).
Patients showed essentially perfect recall with word lists of
up to 4 words. Beyond this, performance declined, with
the steepest fall in the impaired schizophrenic patients.
Patients with schizophrenia showed a failure in DLPFC
activation only in the face of diminished performance
measures, suggesting that a full characterization of taskrelated changes in DLPFC activation must consider
performance levels.
Fletcher et al.
(1998)
DSM-III-R schizophrenic (38)
Age-matched controls (39)
na
All patients were receiving
medication.
One subgroup of patients has a selective deficit in verbal
memory despite normal motivation, attention and general
perceptual function. A second group of patients has
deficits in multiple aspects of cognitive function suggestive
of deficiencies in early stages of information processing.
Wexler et al.
(1998)
G. Emilien et al.
Populations (sample size)
19 yr
(diagnosed when
less than 45 yr
old at onset)
All patients were treated with
either typical neuroleptic or
risperidone.
Cognitive impairment was the strongest predictor of
adaptive deficits for all 3 groups The data suggest that
interventions aimed at cognitive impairment may have
an impact on overall functional status.
Harvey et al.
(1998)
DSM-IV schizophrenic (6)
(patients served as their own
control in a within-subject
design)
Mean of 12 yr
(range : 3–19 yr)
Had been receiving atypical
neuroleptic treatment for at
least 1 month (mean dose
450 mg chlorpromazine
equivalents ; range, 250–750).
The severity of positive thought disorder was inversely
correlated with activity in areas implicated in the
regulation and monitoring of speech production.
Decreased activity in these regions may contribute to the
articulation of the linguistic anomalies that characterize
positive thought disorder.
McGuire et al.
(1998)
DSM-II-R schizophrenic (23)
Normal controls (23)
Mean of 17n1 yr
(.. l 8n6)
All patients were receiving
neuroleptics during study
[clozapine, 9 ; risperidone, 4 ;
others (haloperidol,
fluphenazine or loxapine),
10].
Thought disorder may be associated with semantic
processing abnormalities. In particular, patients with more
severe thought disorder may have difficulty accessing
semantic items because of disorganization of the semantic
systems or possible lack of a semantic knowledge
base.
Goldberg et al.
(1998)
DSM-III-R schizophrenic (73)
First-degree relatives (33
siblings, 28 parents)
Age-matched controls (35)
na\consecutively
admitted in-patients
No neuroleptics or
antidepressants or
benzodiazepines within the
last 2 wk or depot
neuroleptics within the last
2 months.
Performance of schizophrenic patients was worse than
those of controls in all variables of WCST (including
perseverative and non-perseverative responses). Healthy
siblings of schizophrenic probands showed more
perseverative responses than controls, but did not show
any difference with respect to the non-perseverative
responses.
Franke et al.
(1992)
DLPFC, dorsolateral region of prefrontal cortex.
Dopamine receptors and schizophrenia
DSM-III-R geriatric
schizophrenic patients as
follows
Chronically hospitalized
residents (97)
Nursing home residents
(37)
Acute admissions
211
212
G. Emilien et al.
schizophrenia may result from semantic processing abnormalities and that language disorder present in schizophrenia may occupy an important place in the treatment
of cognitive processes of schizophrenic patients.
In a within-subject design study performed to further
understand the pathophysiology of thought disorder
using positron emission tomography (PET), regional
cerebral blood flow was measured while six schizophrenic
patients described a series of 12 ambiguous pictures
[drawn from the Thematic Apperception Test (Murray,
1943) and comprised grey scale whole-body representations of people in scenes whose interpretation was
ambiguous] which elicited different degrees of thoughtdisordered speech (McGuire et al., 1998). The total score
for positive ‘ Thought Language and Communication
Index ’ (TLCI) (Liddle, 1998) items (e.g. looseness, peculiar
word usage, peculiar sentence construction, peculiar logic
and distractibility) was used as an index of verbal
disorganization or positive thought disorder. The results
showed that the severity of positive thought disorder was
inversely correlated with activity in the inferior frontal
and cingulate cortices. The negative correlations in these
regions may reflect a failure to engage areas which
normally control the production of speech. Pathophysiological changes in these areas might also account
for the association between positive thought disorder and
the disorganization of emotion and cognitive behaviour
in schizophrenia (Liddle and Morris, 1991).
Recent findings suggest that early age of onset in
schizophrenia may be associated with more impaired
cognitive functions (Hoff et al., 1996). The later the age of
onset, the better the performance. Earlier age-of-onset
patients have more impaired language function. Performance in receptive and expressive speech is relatively
poor. The poor performance of the early onset patients
may simply reflect a deterioration of cognitive function
with disease progression ; the longer one remains psychotic, the more disorganized one’s semantic network
becomes. Longitudinal studies would be needed to
address this hypothesis. A second hypothesis is that
disorganization of semantic knowledge may reflect premorbid cerebral vulnerability which predisposes individuals to both disorganized thought organization and
illness manifestation at an earlier age. However, the
superior performance of late-onset patients may simply be
due to their longer previous opportunity for social
interaction. There is evidence to suggest these language
disturbances may be viewed as possible genetic vulnerability markers since communication impairment in the
relatives of schizophrenic patients appear to be heterogeneous in both form and origin (Docherty et al.,
1997). Similar to the schizophrenic patients, their parents
showed frequent instances of communication failures in
their speech characterized by structural lack of clarity,
vague references and ambiguous word meanings.
4.3. Executive function and memory
Frontal\executive impairments have been observed in
schizophrenia (Morice and Delahunty, 1996). The term
‘ executive ’ refers generally to the ability to maintain or
shift a mental set, to establish goals, and to plan –
elements that can be measured by neuropsychological
tests such as WCST and the Tower of London. Executive
function includes the capacity to both devise and carry
out solutions to problems whose solutions are not
immediately obvious (e.g. problems that may require
abstract reasoning). Of the three functions gaining greater
recognition as executive functions – cognitive shift (or
flexibility), forward planning, and working memory, much
work is being performed to better understand their
implications in schizophrenia. Working memory has been
associated with complex functions ranging from mental
arithmetic, syntactic processing, comprehension and reading to the acquisition of complex cognitive skills and
development of procedural skills (Baddeley et al., 1985 ;
Carlson et al., 1989 ; Logie et al., 1989). Although an
executive function test such as the WCST purportedly
measures reasoning ability, it also taps short- and longterm memory, distractibility, sustained attention and
learning ability (Heaton, 1981). The increased perseverative error scores by schizophrenia patients performing the WCST has been of particular interest. Poor
WCST performance has been linked both to cognitive
inflexibility and to left dorsolateral PFC dysfunction
(Weinberger et al., 1986).
A study of frontal executive impairment in schizophrenic patients indicated that 64n7 % schizophrenia
patients and no controls were impaired on WCST with
respect to perseverative errors (cognitive flexibility) and
76n5 % schizophrenia patients and no controls were
impaired on the Tower of London Test with respect to
targets achieved in minimum moves (forward planning)
(Morice and Delahunty, 1996). Further cognitive assessment by different tests indicated that the schizophrenics were significantly impaired compared to controls
on two tests of working memory, Alphabet Span and
Sentence Span. Using a cutoff derived from the mean
score for the controls, 65 % of schizophrenia patients
proved to be impaired on Sentence Span and 94 % were
impaired on one or more of the three tests of executive
functioning used. It was hypothesized that schizophrenia
represents a loss of, or a failure to acquire, the ability to
process complex information.
Memory deficits observed in schizophrenia are not
restricted to a single element of memory but strike
Dopamine receptors and schizophrenia
different systems, such as declarative memory, procedural
memory and working memory (Goldberg et al., 1993 ;
McKenna et al., 1990 ; Tamlyn et al., 1992). McKenna et
al. (1990) and Tamlyn et al. (1992) reported significant
correlations between declarative memory deficits and
both formal thought disorders and negative symptoms,
while Goldberg et al. (1993) found that negative
symptoms also correlate with procedural memory impairment. In a study investigating learning and memory
using a wide number of neuropsychological measures in
monozygotic pairs of individuals discordant for schizophrenia, compared to normal pairs of monozygotic twins,
significant correlations between many measures of memory and global level of social and vocational functioning
within the discordant group were observed (Goldberg et
al., 1993).
The assessment of a graded memory task on brain
activation of schizophrenic patients is an important subject
to study. In an experiment in which schizophrenic patients
and volunteers underwent scanning while learning and
recalling word lists of variable length, it was observed that
all patients showed perfect recall with word lists of up to
4 words (Fletcher et al., 1998). Beyond this, performance
declined, with the steepest fall in the impaired schizophrenic patients. As task demands increased and performance deteriorated, schizophrenic patients failed to
show an increasing frontal response. The more demanding
tasks may have engaged frontally mediated strategies that
the schizophrenic patients did or could not adopt.
Therefore, the abnormal PFC activation under more
demanding conditions may reflect a motivation deficit
occurring as the task becomes too difficult for a patient. It
is also interesting to note the difference of performance
between STM and LTM. Verbal STM function has been
noted to be relatively preserved in schizophrenia, whereas
the deficit in LTM is significant (Goldberg et al., 1993 ;
Tamlyn et al., 1992). A striking observation in the study
performed by Fletcher et al. (1998) was that a region
showing impaired activation, the posterior parietal region
(Brodmann area 40) was specific to the impaired schizophrenic group. Posterior parietal activations are a common
finding in functional imaging studies of memory retrieval
and the significant decrease of activation in the impaired
schizophrenic group may reflect an impairment in LTM
retrieval processes in schizophrenia (Shallice et al., 1994).
Several studies have considered recall and recognition
memory impairment in schizophrenic patients. Recall
refers to the ability to actively retrieve the information
sought from memory stores, whereas recognition involves determining whether a particular stimulus has
previously been learned. Some studies have reported
impaired recall along with normal recognition in patients
relative to controls (Beatty et al., 1993 ; Koh, 1978). A
213
similar pattern of impairment has also been observed in
patients with frontal lobe lesions (Jetter et al., 1986).
However, recognition deficits in schizophrenic patients
especially when more severely disturbed patients were
assessed have been reported (Gold et al., 1992). A greater
memory deficit in schizophrenic patients than in controls
has been reported when a delay intervened between
learning and recall stages. This appeared in both verbal
and visuospatial performance (Bre! bion et al., 1997).
Regarding verbal memory, all these storage deficits were
also found in tasks with delays of at least 30 min. The
deficits in recall in schizophrenic patients may result from
an inability to encode information in an organized way
(Koh, 1978). The investigation of the mechanisms involved in verbal memory impairments in schizophrenia
suggest that a major deficit in encoding appeared in the
patient group, with a lesser use of deep encoding and a
lesser efficiency of superficial encoding (Bre! bion et al.,
1997). The early phase of storage and the retrieval
function appears not to be affected. The overall memory
performance in schizophrenics appears to be related to the
depth of encoding (Bre! bion et al., 1997).
Recently, the assessment of verbal and non-verbal
memory in schizophrenic patients has shown word and
tone working memory deficits in schizophrenia (Wexler et
al., 1998). Using word list immediate recall, tone-delayed
discrimination and word-and-tone serial position tasks, it
was observed that patients who performed normally on
the screening test of perception and attention performed
normally on both non-verbal tests but had significant
deficits on both verbal tests. On the other hand, patients
who performed poorly on the screening test had highly
significant performance deficits on all the memory tests.
This observation is interesting as it shows two subgroups
of memory deficit patients ; one subgroup of patients has
a selective deficit in auditory verbal memory despite
performing normally on an auditory non-verbal memory
test. Most importantly, these patients did not suffer from
global auditory processing problems, such as may result
from perceptual or attentional dysfunction, and their
verbal memory deficits cannot be explained by nonspecific performance factors. Furthermore, the memory
deficit itself is not global in those patients because their
performance on the tone memory tests was intact. The
second group of patients in this study showed deficits in
multiple aspects of cognitive function, indicative of failure
in early stages of information processing.
4.4. Cognitive deficits and negative symptoms
The cognitive deficits that are characteristic of schizophrenia suggest a frontal–medial–temporal dysfunction
(Goldberg and Gold, 1995). It was suggested that
214
G. Emilien et al.
‘ hypofrontality ’ characterizes schizophrenia because it
was observed that patients with prominent negative
symptoms did not mount a significant increase in
perfusion to their left meso-frontal cortex during performance in neuropsychological tests such as the Tower
of London (Andreasen et al., 1992). This was in contrast to
both normal control and schizophrenic patients with less
prominent negative symptoms who demonstrated a
regional increase in perfusion. These findings seem to
indicate that hypofrontality is related to negative
symptoms and highlight the utility of neuropsychological
assessment in the study of schizophrenia.
A certain degree of statistical correlation exists between
cognitive deficits and negative symptoms which may
reflect a common biological abnormality, such as dysfunction of the frontal cortex or a common association of
the two with a third factor such as poor cooperation
(Perlick et al., 1992). Severity of negative symptoms was
found to be strongly correlated with poor performance on
the WCST as reflected by a high proportion of perseverative errors, perseverative responses and a low
number of completed categories (Berman et al., 1997). On
the other hand, positive symptoms are more closely
associated with poor performance on the Digit Span,
particularly the Digit Span Forward (Berman et al., 1997).
In recent studies, the value of the WCST as a predictor of
rehospitalization and stability of negative symptoms in
schizophrenia has been demonstrated (Lysaker et al.,
1996, 1997).
4.5. Neuropsychological deficits as markers of
vulnerability
First-degree relatives of schizophrenic patients are of
special interest in the search for indicators of vulnerability
to schizophrenia, as they have a risk of developing
schizophrenia that is about 10 times that of the general
population (Kendler and Diehl, 1993). Various observations suggest that the neuropsychological variables
may be important endophenotypes for schizophrenia and
studies of schizophrenic patients and their non-affected
relatives have yielded several phenotypes (e.g. eye
tracking dysfunction and neuropsychological impairments, including attentional and working memory deficits)
that might aid the identification of genes (Cornblatt and
Keilp, 1994 ; Holzman et al., 1984 ; Levy et al., 1994 ; Park
et al., 1995). A recent study comparing neuropsychological performance of stable schizophrenics and their
biological full siblings with normal controls also suggests
that in the sibling group, the observed impaired neuropsychological deficits may represent indicators of the
genetic vulnerability to schizophrenia (d’Amato et al.,
1998). These findings further indicate that the deficiency
of the neuropsychological performance of the siblings are
related to the genetic factors.
The WCST was suggested to serve as an indicator of
vulnerability in absence of psychopathological features
(Franke et al., 1992). In a study comparing schizophrenic
patients (off medication) with their first-degree relatives
(33 siblings, 28 parents) and controls, it was noted that the
performance of schizophrenic patients was worse than the
performance of healthy controls in all variables of the
WCST, including perseverative and non-perseverative
responses. Healthy siblings of schizophrenic probands
revealed more perseverative responses than healthy
controls, but did not show any difference with respect to
the non-perseverative responses. It was hypothesized that
the difficulty to shift a cognitive set, reflected by the
frequency of perseverative responses, is in favour of the
WCST as a vulnerability marker for schizophrenia,
whereas non-perseverative response which probably
indicates a state, may not be used as a trait marker of the
disease.
Neuropsychological research using the CPT since an
early age has shown that subtle abnormalities in attention
are present among first-degree relatives of schizophrenic
patients (Rosvold et al., 1956). A deficit in discriminating
target and non-target stimuli among 7- to 12-year-old
children of schizophrenic patients, using a CPT that
demanded recognition of occasions on which two successive pictures of playing cards were identical, was
reported (Rutschmann et al., 1986). Recent studies have
also confirmed the robustness of CPT findings in new
samples of children of schizophrenic patients (Grove et al.,
1991 ; Mirsky et al., 1992 ; Steinhauer et al., 1991). A
similar deficit among first-degree relatives of schizophrenic patients has been observed by various other
researchers using tasks that demand sustained, focused
attention (Schreiber et al., 1992 ; Wood and Cook, 1979).
Thus, it is clear that some forms of deficit in rapid,
sustained discrimination of briefly presented information
is present among first-degree relatives of schizophrenic
patients. However, the nature of the information-processing deficit reflected in these findings needs clarification. It is not clear if the abnormality was a typical one
of sustained attention. In studies of schizophrenic patients
or children of schizophrenic patients, although a slight
and non-significant tendency towards differential vigilance decrement is present, much of the deficit in
discrimination of target and non-target stimuli is present
during the initial 4 min of a vigilance period of almost
12 min (Cornblatt et al., 1989 ; Nuechterlein, 1983).
Although the vulnerability-linked deficit in information
processing is revealed in a task that demands sustained
attention, the critical deficit might not be in sustained
attention per se. One possibility could be that the central
Dopamine receptors and schizophrenia
executive control of voluntary attention is malfunctioning, leading to either failure to place the appropriate stimuli in the focus of attention or a failure to
enhance the processing of the selected stimuli.
A strategy for isolating the form of informationprocessing deficit relevant to vulnerability to schizophrenia is to use paradigms other than CPT that have
special advantages for making certain distinctions. Backward masking methods offer possibilities for separating
certain sensory and early perceptual processes from
attentional shifting processes for brief visual stimuli
(Michaels and Turvey, 1979). Visual masking is a
procedure that is used to assess the earliest components of
visual processing. In backward masking, the identification
of an initial stimulus (the target) is disrupted by a later
stimulus (the mask). The masking function can be divided
into an early component (e.g. up to about 60 ms) that
reflects the involvement of sensory-perceptual processes,
and a later component that reflects susceptibility to
attentional disengagement as a mask diverts processing
away from the representation of the target. Schizophrenic
patients show anomalies on both masking components.
This vulnerability appears to be associated with early,
sensory–perceptual processes.
5. Methodological issues and testing
The interpretation of the literature is limited by a number
of methodological issues including variation of groupmatching procedures, test selection, differential test
sensitivity and psychopathological status of the patients
investigated. In order to achieve a consensus on neuropsychological assessment of the schizophrenic patients, it
is important to use tests which are well standardized and
validated. For the purposes of assessing treatment-related
change in the cognitive performance of schizophrenic
patients, the tests should assess cognitive functions that
reflect the ability to perform socially relevant day-to-day
activities, be relatively short and easy to administer and
cover a broad array of cognitive impairments. Therefore,
no single test is sufficient to characterize the impairment
and multiple measures from a valid battery of tests are
required for assessing treatment-related cognitive improvement.
5.1. Computerized neuropsychological test battery
Recently a simple computerized neuropsychological assessment of schizophrenic patients was proposed (Cutler
et al., 1996). The use of a computerized neuropsychological test battery (CNTB) was found to provide
215
interesting cognitive information in schizophrenic
patients who showed significant impairment as compared
to a control group. In addition to displaying sensitivity to
mild impairment in schizophrenics, the CNTB was shown
to have high test–retest reliability. It was suggested that
the CNTB may be useful for evaluating cognitive
impairment in clinical trials of prospective pharmacological treatments in schizophrenia.
5.2. Mini-mental state examination
Neuropsychological tests such as the Mini-Mental Examination (MMSE) may be used to assess the longitudinal
stability of cognitive impairment in schizophrenia because
the test-retest reliability of this scale is extremely good at
different retest intervals (Folstein et al., 1975 ; Harvey et
al., 1995). Although it is acknowledged that schizophrenic
patients as a group demonstrate a variety of cognitive
deficits that can be observed at the onset of the illness, it
is still unclear how these cognitive deficits progress with
ageing (Heaton and Drexler, 1987). The assessment of
cognitive functions by neuropsychological tests such as
MMSE suggests that intellectual functions in cohorts of
schizophrenic patients did not markedly decline (Hyde
et al., 1994). Recent studies suggest that there is a stability
or an amelioration of symptoms in chronic schizophrenic
patients with advancing age (Harding et al., 1987,
Lindenmayer et al., 1997). These findings support the
notion of schizophrenia as a disorder with a relatively
stable psychopathological course, once established, and
one that is only minimally affected by age and length of
illness. Apart from the confirmation that there is no
progression of impairments in cognitive functioning in
older schizophrenic patients, these observations also
suggest that the hypothesis of a dementia-like course of
the cognitive functions in schizophrenia should be
excluded. MMSE has become a frequently used test in
longitudinal studies of schizophrenia and therefore, it may
be useful in the long-term assessment of treatment effects
of patients with schizophrenia.
6. Effects of neuroleptics on cognitive deficits
The five cloned dopamine receptors are now facilitating
the discovery of selective antipsychotic drugs. The notion
of atypicality among antipsychotic neuroleptics has rested
on the idea that typical or classic neuroleptics produce
extrapyramidal symptoms (EPS), whereas atypical neuroleptics produce antipsychotic effects without EPS. Tardive
dyskinesia complicates treatment with neuroleptics and is
characterized by abnormal involuntary movements often
216
G. Emilien et al.
involving the orofacial musculature. Tardive dyskinesia
occurs in 20 % of patients on chronic neuroleptic therapy
(Saltz et al., 1991). Up-regulation of D receptors
#
secondary to chemical denervation remains one of the
most popular hypotheses of tardive dyskinesia, despite
contradictions to this hypothesis and no direct evidence
supporting such a mechanism (Jenner and Marsden, 1986).
Although some neuroleptics such as thioridazine and
molindone produce fewer EPS, the prototype atypical
neuroleptic is clozapine. The introduction of risperidone
into clinical practice in 1993, together with prospects for
other new antipsychotics sharing pharmacological properties with both of these agents have created great
therapeutic optimism. The new typical agents (so called
because they lack effects in animals that are typical of
older agents, e.g. catalepsy) are as effective as the old
drugs, showing comparable efficacy against the positive
symptoms of schizophrenia. But they are also effective
against negative symptoms such as apathy and withdrawal, and they have a much better side-effect profile,
with little or no EPS and prolactin-linked sexual effects.
These improvements stem from an additional pharmacological action (combined dopamine\serotonin antagonists).
However, there is no conclusive evidence of the use of
conventional neuroleptics in improving cognitive function (King, 1994). Conventional neuroleptic drugs in the
majority of studies do not ameliorate impairments in
short-term working memory or long-term recall memory
(Cassens et al., 1990 ; Hagger et al., 1993 ; Medallia et al.,
1988). Performance on tests of executive function, such as
the WCST, Digit Symbol Test, and Stroop Test remains
unaltered by conventional neuroleptic treatment (Berman
et al., 1986 ; Classen and Laux, 1988 ; Medallia et al.,
1988).
6.1. Clozapine
The dibenzodiazepine, clozapine, antagonizes D more
"
than D receptors, while it is also a potent antagonist of
#
D receptors (Coward, 1992). Further, many other
%
neurotransmitter systems (adrenergic, serotoninergic,
cholinergic, histaminergic) are also influenced by clozapine
(Coward, 1992). Clinical studies suggest that it has
enhanced therapeutic effects in patients who are otherwise
poorly responsive to traditional neuroleptic treatment
(Kane et al., 1988 ; Pickar et al., 1986). While a good
response with clozapine was observed in patients with
treatment refractory first-episode of schizophreniform
disorders, its early use in individuals at high risk of suicide
was recommended (Meltzer and Okayli, 1995 ; Szymanski
et al., 1994). A current hypothesis to account for the
atypical neuroleptics such as clozapine is that they may
block D and D receptors (Seeman et al., 1998). A
#
%
favourable response to clozapine has been achieved when
D receptor occupancies were between 20 and 90 %
#
(Heinz et al., 1996). However, a significant association
between the degree of D receptor blockade and EPS has
#
been reported with D receptor blockade above 70 %
#
being associated with a high incidence of EPS (Broich et
al., 1998 ; Scherer et al., 1994). The fact that the therapeutic
effects of clozapine may be observed at low D occu#
pancies permit to avoid EPS which occur at high D
#
occupancy. However, recent evidence has implicated
cortical D receptors as important sites of action of
#
antipsychotics, and clinical doses of clozapine produce
high levels of D receptor occupancy in the cerebral
#
cortex, thus resembling other antipsychotics (Lidow et al.,
1998 ; Pilowsky et al., 1997). Regarding D receptors,
%
with the use of D -selective $H ligands, little or no
%
detectable amounts of D receptors in human control or
%
schizophrenic striata were noted. However, it is suggested
that the increased D -like sites in schizophrenia which
%
may not be genuine D receptors, could represent
%
modified features of D or D -like receptors.
#
#
Few studies have addressed the effects of clozapine on
cognitive deficits in schizophrenic patients. In an openlabel study, 36 treatment-resistant schizophrenic patients
received clozapine (Hagger et al., 1993). At baseline and
after 6 and 24 wk treatment, patients were evaluated with
the Brief Psychiatric Rating Scale (BPRS) and a cognitive
performance battery. At both follow-up points, BPRS
scores were indicated significant improvement in psychopathology. Relative to cognitive performance, at 6 wk
significant improvement was observed in retrieval from
reference memory. After 24 wk, significant improvement
was also observed in short-term recall memory, attention
and executive function.
In a double-blind, randomized trial, 41 schizophrenic
patients received either clozapine or haloperidol for 10 wk
(Buchanan et al., 1994). Subsequently, all patients entered
an open-label study in which they received clozapine for
1 yr. A neuropsychological test battery was given at
baseline and again after 10 wk of the double-blind study
and after 1 yr of open-label clozapine treatment. At 10 wk
there were significant group-by-time interactions on the
categorical fluency and Wechsler Adult Intelligence ScaleRevised (WAIS-R) block design measures. After 1 yr,
significant improvements were observed in verbal fluency
of WAIS-R block design performance. These clozapinerelated changes in cognitive function were unrelated to
other symptomatic changes.
The results of the study of the effects of clozapine on
cognitive function suggest, in general, that long-term
clozapine treatment may have a beneficial effect on a
broad range of areas of cognitive function. Clozapine
Dopamine receptors and schizophrenia
generally improves cognitive performance on measures of
verbal fluency, reaction time and attention. It produces
fewer EPS than do conventional neuroleptics (Farde et al.,
1992 ; Lieberman et al., 1991). The ability of clozapine to
spare dopaminergic neurons in the striatum and to
enhance dopaminergic output in the cortex may account
for its ability to improve cognitive function compared to
conventional neuroleptics (Meltzer, 1991).
217
relatively dependent on the negative symptoms of this
disorder. However, it may be argued that the beneficial
effect of risperidone on cognitive deficits may be due to
the direct effect of the drug, possibly through antagonism
of the 5-HT A receptor rather than mainly through D
#
#
receptors.
6.3. New generation of antipsychotic drugs
6.2. Risperidone
Risperidone (a benzisoxazole derivative), like clozapine,
has affinities for dopaminergic and serotonergic systems
(Janssen et al., 1988 ; Leysen et al., 1992). In contrast to
clozapine, risperidone is a relatively potent D antagonist
#
and is a highly potent 5-HT antagonist. In addition to
#
these effects on dopaminergic and serotonergic systems,
risperidone also has affinity for the α receptor in the
#
nanomolar range. Clinical data suggest that risperidone is
an appropriate first-line antipsychotic agent for use in
both positive and negative symptoms (Keshavan et al.,
1998). During treatment with risperidone, schizophrenic
patients display improved performance on attentional
components, specifically selective attention and alertness
(Stip and Lussier, 1996). There was a positive correlation
between improvement in psychopathology and improvement in cognitive tests of explicit memory and alertness.
It was also shown that treatment with risperidone
improved verbal working memory in treatment-resistant
schizophrenia (Green et al., 1997). The beneficial effects of
risperidone seem to be confirmed in another recent study
(Rossi et al., 1997). In this investigation, after a 1-wk
placebo wash-in phase, schizophrenic patients were
treated with risperidone for 4 wk and followed up for a 6month period. The initial daily dose of risperidone
administered was 2 mg, which was gradually adjusted to
a maximum dose of 6 mg (range 2–6 mg). Neuropsychological tests (executive function, WCST ; attention,
WAIS Digit Symbol Substitution Test and WAIS Digits
Forward ; working memory, WAIS Digits Backward) were
administered to each patient close to the time of PANSS
evaluation and then after 4 wk and 6 months of
risperidone treatment. After the study period, both
negative and positive symptoms and also measures of
cognitive performance improved significantly. The WCST
results correlated with negative symptom scores before
and after each treatment. It was hypothesized that
negative symptoms and cognitive deficit have a common
underlying substrate which is the target of the risperidone
treatment. It was suggested that risperidone may have a
substantial effect on complex cognitive functions in
schizophrenia and that certain cognitive deficits are
Several of the more recently available products such as
olanzapine (zyprexa), sertindole (serlect), quetiapine
(seroquel), ziprasidone, iloperidone and others (e.g.
pramipexole and mazapertine) targeted as antipsychotic
drugs in various stages of development may satisfy
criteria for newer or ‘ atypical ’ antipsychotic treatments.
Quetiapine is a novel antipsychotic agent that exhibits
high affinity for serotonin 5-HT receptors and markedly
#
low affinity to D and D receptors compared with
#
"
standard neuroleptics. Using PET scan technology in
patients with schizophrenia, it was observed that
quetiapine has a relatively low affinity for dopamine D
#
receptors with an occupancy half-life (10 h) which was
about twice as long as that for plasma (Gefvert et al.,
1998). A more prolonged blockade of serotonin 5-HT
#
receptors was noted in the frontal cortex, with receptor
occupancy half-life of 27 h. Quetiapine improves STM
which returns to the mean average value of normal
control subjects. Implicit and explicit memory showed
dramatic improvement (Stip et al., 1996). In general,
significant improvement in cognitive performance was
noted. It may be possible that the benefits of these newer
atypical antipsychotics are due to their non-D actions (5#
HT , α , etc.) or just a function of more appropriate dosing
# "
of their D blockade. Results of future clinical trials will
#
need to further clarify the mechanisms of action of these
new antipsychotic drugs and their effects on neuropsychological and cognitive impairment.
Evidence has accumulated to suggest that enhancing
dopaminergic activity might improve cognitive performance in schizophrenic patients. The dopaminergic innervation of the PFC and cingulate cortices has been
suggested to be deficient in schizophrenia and to play a
role in cognitive functions (Weinberger, 1987). Therefore,
it is possible that dopamine agonists may benefit cognitive
performance in schizophrenia. Interestingly, clozapine
which may improve cognitive performance in schizophrenia has been shown to release dopamine during in
vivo microdialysis studies (Chai and Meltzer, 1992). The
observation that the cerebral cortex may harbour common
sites of action of antipsychotics and that chronic treatment
with these drugs differentially regulates both families of
dopamine receptors in this structure may indicate a
218
G. Emilien et al.
reconsideration of our pharmacological therapeutic strategy. Since up-regulation of the cortical dopamine D
#
receptors is accompanied by a downregulation of the D
"
sites, the balancing of the opposing actions of D and D
"
#
receptor regulation may be an appropriate effective drugtreatment approach and to understand the pathophysiology of schizophrenia (Lidow et al., 1998). It is
possible that the adjustment of D receptor levels in the
"
cortex may become an important goal of future antipsychotic drug regimes.
7. Discussion and conclusion
Controlling dopamine and dopamine receptors is essential
for the treatment of schizophrenia and because schizophrenia is hereditary, it is important to realize significant
progress in the understanding of dopamine receptors and
the molecular genetics of schizophrenia. Although some
investigations in schizophrenia have indicated aberrations
in dopamine receptors and possible linkage on some
chromosomes, genetic-linkage experiments have, in general, excluded the dopamine receptor genes as loci of
major effect in schizophrenia (Moises et al., 1991).
Association studies on the other hand, suggest that
variation in the D gene may confer a small relative risk to
$
the disorder. Several regions of the dopaminergic gene
from schizophrenic tissue have been isolated and sequenced and revealed only minor, non-detrimental
alterations. No specific hereditary mechanism has yet
been identified. It is important to note that in schizophrenia aberrations such as the elevated D receptor
#
densities may be caused by factors other than the
dopamine receptor gene itself. Genetic linkage to disease
may not directly involve the dopamine receptor genes but
may involve genetic defects of other proteins or cofactors responsible for the appropriate regulation of the
dopamine receptor genes. Since methodological problems
may complicate interpretation of linkage studies, the
failure to detect linkage in a single study does not
disprove the major gene hypothesis. No report has yet
identified a statistically significant finding after correction
for multiple testing.
It is possible that current psychiatric diagnostic criteria
obscure major gene effects by classifying genetically
diverse patients together. Genetic analysis of schizophrenia might be improved by the identification of basic
phenotypes for which a more homogeneous aetiology
might be expected. The possibility that genetic factors are
responsible for the cognitive impairment in schizophrenia
has been considered. Cognitive markers appear as longstanding deficits that remain constant across development
of schizophrenia and appear to be reliably measured
across the premorbid prodromal and morbid stages of
illness (Cornblatt and Kelip, 1994). However, few investigators fail to support such an hypothesis and a direct
connection of a defect in cognitive processes and the
genetics of schizophrenia is debatable. It may be pointed
out that these cognitive abnormalities may be a manifestation of, rather than a vulnerability to the illness.
Nevertheless, the expectation that molecular genetics
alone will help our understanding of inherited schizophrenia phenotypes might be short sighted. It is becoming
clear that understanding the genetics of schizophrenia
requires correct identification of the inherited phenotypes
and, therefore, assessment of clinical neuropsychology
variables in the vulnerable population will certainly
increase our understanding of the genetics of schizophrenia. Future research into the molecular genetic
aspects of schizophrenia will be required for clarification ;
such research will need to use a more adequate definition
of the phenotype, probably using all the genetic information in a family. Better nosology and more accurate
diagnosis will help to identify an aetiologically homogeneous subtype of schizophrenia for genetic studies.
Since all linkage methods used to date have focused on a
single locus, two-locus linkage analyses will need to be
performed, considering segregation at all possible pairs of
genome regions and thus require complete coverage of
the genome with highly informative markers. Indeed,
such an approach should involve loci in the regions of 6p
and 8p that have such tantalizing hints of involvement in
liability to schizophrenia. Consideration of such epistatic
models on more homogeneous data sets with more
sophisticated and powerful analyses should eventually
clarify and disentangle the complex genetics of schizophrenia.
An important issue in the study of the mechanism of
action of the neuroleptics is that there are no truly
selective drugs for any one of the three receptors in the D
#
family (Malmberg et al., 1993). Accordingly, there is
currently no single selective D receptor antagonist
#
available for clinical trials. Such antagonists will be
required to examine the D receptor hypothesis for
#
antipsychotic action. Antipsychotic phenothiazines and
butyrophenones have high affinities for D , D and D
# $
%
receptors and should give a significant occupancy of all
these receptors when given in clinical doses (Schwartz et
al., 1992). Substituted benzamides like sulpiride have high
affinities for D and D receptors but very low affinities
#
$
for D receptors. This finding seems to suggest that
%
potent antipsychotic action may be achieved in the
absence of D receptor blockade. The D receptor with its
%
$
predominant limbic localization is an interesting candidate
for antipsychotic action (Schwarz et al., 1992). D receptor
$
mRNA is exclusively expressed in brain limbic areas that
Dopamine receptors and schizophrenia
are associated with cognitive, emotional, and endocrine
functions. Thus, it is pertinent to develop a selective
D receptor drug to dissociate D receptor action from the
$
$
potent D receptor effect inherent in most of the currently
#
used antipsychotic drugs. Due to the significant implications of D receptors in cognition, the role of the
"
modulation of D receptors in the pharmacological
"
treatment of schizophrenia need to assessed. The fact that
effective atypical neuroleptics (e.g. clozapine) work on
both D receptors and 5-HT may also suggest that
#
#
specific mechanisms of action which modulate both of
these receptors may be the optimal approach to achieve
significant clinical beneficial effects on positive and
negative symptoms, as well as cognitive dysfunctions, in
the treatment of schizophrenia (Luciana et al., 1998).
Cognitive impairment has been shown to exert a
considerable effect on a patient’s psychosocial status
(Goldberg and Gold, 1995). Confronted with such cases,
the challenge for the neuropsychologist is to provide data
from observations and a battery of sensitive validated
cognitive tests which give clues to the nature of the brain
dysfunctions which underlie the signs and symptoms
associated with schizophrenia. The use of these powerful
neuropsychological techniques may greatly further enhance our assessment of schizophrenia and more accurately monitor pharmacological treatment outcome in
schizophrenic patients. Research into subtype-specific
cognitive dysfunction in schizophrenics suggests that
whereas all schizophrenics showed significant deficits in
verbal learning (Rey Auditory Verbal Learning Test)
possibly indicating a temporal–hippocampal system dysfunction as a common denominator in both schizophrenic
subtypes, patients with paranoid schizophrenia demonstrate more intact intellectual abilities. Future research
might use neuropsychological profiles to assess the
organization of thought and behaviour to subtype the
schizophrenia spectrum. This approach may help with
treatment planning, as well as understanding the aetiology
of the illness. Cognitive impairment in schizophrenia
greatly impedes psychosocial performance and eventual
re-integration into society. Thus, the cognitive features of
schizophrenia are especially relevant based on their
resulting social and vocational disability and should, in
turn, become key targets in the development of new
therapeutic modalities.
Currently, there are limited data on the cognitive
effects of atypical antipsychotic treatment. It should soon
be possible to broaden the notion of efficacy to include
amelioration of cognitive deficits. Evidence is accumulating showing that cognitive processes are more closely
associated with functional outcome (Green, 1996). Verbal
memory was often associated with all types of functional
outcome and vigilance was related to social problem
219
solving and skill acquisition. WCST predicted community
functioning and negative symptoms were associated with
social problem solving. Notably, psychotic symptoms
were not significantly associated with outcome to be
necessary for adequate functional outcome. It was concluded that verbal memory and vigilance appear to be
necessary for adequate functional outcome and that
deficiencies in these areas may prevent schizophrenic
patients from attaining optimal adaptation and hence act
as ‘ neurocognitive rate-limiting factors ’. Therefore, in the
design of clinical trials of antipsychotic medications,
neuropsychological assessment (e.g. measures of memory,
vigilance, attention, executive function, language and
information processing) should be included in both the
screening of patients and the monitoring of drug effects.
It is not sufficient to monitor clinical psychiatric symptoms
as a measure of drug efficacy. Empirical measures of
cognitive function are important parts of evaluating new
products. With rigorous clinical trials and prudent pharmacological intervention, stabilization of the dysfunctional cognitive processes in schizophrenia may
become a realizable goal. In clinical practice, utilization of
sensitive and specific-assessment neuropsychological
methods could help guide specific psychopharmacological
treatment decisions involving dosage and type of treatment. The use of validated neurocognitive markers for
specific drug action may offer a convenient, clinically
practical index of the degree to which drugs are exerting
desired effective effects on the schizophrenic patients.
Further research is needed to understand the relationship
between distortion of the cognitive system, clinical
features of schizophrenia, and structural\functional disturbance in brain dopamine systems. Large well-controlled
studies of lengthy duration, investigating outcomes of
importance to patients and clinicians such as cognitive
improvement are greatly required. Appropriate sample
size and specific, valid, sensitive neuropsychological
measures should be employed in such a rigorous scientific
enterprise. Following such controlled clinical studies for
the treatment of schizophrenia, it appears very likely that
there will be more selective innovative drugs that will not
merely suppress symptoms, but also allow for normal
cognitive functions.
It is possible that the abnormalities of dopamine alone
will not explain the cognitive impairment in schizophrenia, or that enhancing its activity alone will not
produce a large improvement in cognitive performance,
particularly if the latter is the result of an early, persistent
abnormality which has in turn led to many adaptive and
maladaptive changes. However, even small cognitive
improvement may have significant clinically relevant
beneficial effects in schizophrenia. For example, in young
patients, improvements in executive functions and plan-
220
G. Emilien et al.
ning equivalent to a change of one or more category on
the WCST may enable a patient to organize himself
enough to live independently outside of the psychiatric
institution. Similarly, for elderly patients, a small change
on the MMSE score might affect the capacity for activities
of daily living and therefore delay the need for nursinghome care.
Clinical research over the past few years provides hints
that the very early application of existing treatments for
schizophrenia can improve prognosis or natural course of
disorder. The development of preventive interventions
appears to be more feasible today with the rapid
accumulation of markers of vulnerability to psychosis.
They offer the theoretical possibility of identifying
individuals at risk from developing schizophrenia well
before onset. Possible signs of high risk include genetic
and psychometric markers which consist of abnormalities
of neuromotor control, perception, ideation, social reinforcement, attention, and neuropsychological performance, especially memory. The assessment of neurocognitive dysfunctions may provide the potential to
establish large-scale, cost-effective screening programmes
in schizophrenia (Cornblatt et al., 1998).
8. Acknowledgements
The authors thank Professor Philip Seeman (University of
Toronto) for reviewing and providing comments on the
manuscript.
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