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Molecular Psychiatry (2006) 11, 815–836
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FEATURE REVIEW
Subtyping schizophrenia: implications for
genetic research
A Jablensky
Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western
Australia, Perth, WA, Australia
Phenotypic variability and likely extensive genetic heterogeneity have been confounding the
search for the causes of schizophrenia since the inception of the diagnostic category. The
inconsistent results of genetic linkage and association studies using the diagnostic category
as the sole schizophrenia phenotype suggest that the current broad concept of schizophrenia
does not demarcate a homogeneous disease entity. Approaches involving subtyping and
stratification by covariates to reduce heterogeneity have been successful in the genetic study
of other complex disorders, but rarely applied in schizophrenia research. This article reviews
past and present attempts at delineating schizophrenia subtypes based on clinical features,
statistically derived measures, putative genetic indicators, and intermediate phenotypes,
highlighting the potential utility of multidomain neurocognitive endophenotypes.
Molecular Psychiatry (2006) 11, 815–836. doi:10.1038/sj.mp.4001857; published online 27 June 2006
Keywords: schizophrenia; heterogeneity; pleiotropy; subtypes; genetics; endophenotypes
Introduction
More than a century since the delineation of dementia
praecox by Kraepelin,1 the aetiology, neuropathology,
and pathophysiology of schizophrenia remain elusive.
Despite the availability of criteria2,3 allowing reliable
diagnostic identification, schizophrenia essentially
represents a broad clinical entity defined by subjective
symptoms, behavioural signs, and patterns of course.
Research has marked out numerous biological indicators tentatively associated with the disorder, including
neurocognitive dysfunction, brain dysmorphology,
and neurochemical abnormalities. Yet none of these
variables has to date been definitively proven to
possess the sensitivity and specificity expected of
a diagnostic test. Genetic linkage and association
studies have targeted multiple candidate loci and
genes, but failed to demonstrate that any specific gene
variant, or a combination of genes, is either necessary
or sufficient to cause schizophrenia.4–6 Thus, the
existence of a specific brain disease underlying
schizophrenia is still a hypothesis, for which no
conclusive proof or refutation has yet been produced.
The paradox of an ever increasing volume of
research data, and the apparent stalemate of the
search for causes of the disorder, has fuelled doubts
about the validity of the schizophrenia construct,
some leading to proposals to discard the category7,8 or
Correspondence: Dr A Jablensky, Medical Research Foundation
Bldg, Level 3, The University of Western Australia, 50 Murray
Street, Perth, WA 6000, Australia.
E-mail: [email protected]
Received 8 May 2006; accepted 23 May 2006; published online
27 June 2006
to replace it with a pre-Kraepelinian notion of a
unitary ‘psychosis’.9 Given the protean nature of the
symptoms of schizophrenia and the poor coherence of
the clinical and biological findings, such doubts are
not without reason. However, simply dismantling the
concept is unlikely to beget an alternative model that
would account for the host of clinical phenomena and
research data consistent with a disease hypothesis
of schizophrenia. A well replicated epidemiological
finding is that, on average, about 1% of the population develop schizophrenic disorders in their lifetime.10,11 Further evidence that schizophrenia is
not an arbitrary construct comes from the relative
invariance of its clinical presentation and incidence
across populations and over time, established by field
research conducted by the World Health Organization
(WHO) in over 20 diverse populations and cultures.12
In this article, we survey the evidence for phenotypic
variation and likely aetiological heterogeneity as major
sources of inconsistent findings and argue that, like
other complex disorders, schizophrenia is not a
nosological monolith. We review past and present
attempts at delineating subtypes based on clinical
features, statistically derived measures, putative genetic
indicators, and endophenotypes. The end point is that
conceptual and methodological constraints, well articulated in the genetics of complex disorders, have not
been adequately considered in schizophrenia research.
Arguments for and against heterogeneity in the
aetiology of schizophrenia
The debate on heterogeneity and the likely existence
of aetiologically distinct subtypes has waxed and
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A Jablensky
816
waned in the schizophrenia literature without ever
reaching a closure. Over 10 years ago, the editors of
Schizophrenia Research invited researchers to state
reasons for and against schizophrenia being a homogeneous single disease.13 In summary, the arguments
were as follows.
A. The case for homogeneity
There are no disease entities in psychiatry, only
continua of variation.14 Even when the aetiology of
a disorder is known and is unitary, the presentation
and outcome may be remarkably varied.
Phenotypic variation in schizophrenia reflects
a continuum of severity in which patients vary
along cognitive and neurobiological dimensions.15
Phenotypic variation is compatible with aetiological homogeneity resulting from a liability-threshold
process.16
B. The case for heterogeneity
The candidate gene findings reject the parsimonious hypothesis that all schizophrenia is caused
by the same pattern of genetic mutations, birth
complications and viral infections.
There is already evidence for several subtypes of
schizophrenia associated with specific chromosome abnormalities. It may be worthwhile to
subdivide schizophrenic patients on the presence
or absence of a putative aetiological factor, as in
other complex diseases, such as diabetes.
The question ‘heterogeneity: yes or no?’ should be
reworded to ‘heterogeneity: how much?’17
In a review of the meta-analytical evidence,
Heinrichs18 reformulated the ‘continuum of severity’
argument in terms of a ‘pathological shift’, which
holds that a single aetiological factor may, in each
individual case, affect differentially various dimensions of psychopathology and biology, with a resulting net effect mimicking heterogeneity. He argued that
such a model would be difficult to refute by direct
evidence. The contrasting hypothesis of biological
subtypes offers an interpretation of the evidence that
is refutable. The demonstrated success in resolving
heterogeneity by phenotype subtyping in a number of
complex disorders, such as noninsulin-dependent
diabetes;19 asthma;20 Parkinson’s disease (PD);21
autism;22 and familial Alzheimer disease (AD)23
provides prima facie support to a ‘splitting’ approach
in schizophrenia genetics.
How heterogeneous is schizophrenia?
Genetic heterogeneity and pleiotropy
Genetic heterogeneity – ‘the existence of two or more
genetically distinct entities with essentially one and
the same phenotype’24 – is a common attribute of
human disease, characterizing not only the genetically complex disorders, but inherently present in
monogenic mendelian conditions as well. In the
latter, locus heterogeneity is usually estimated as
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the proportion of families linked to a given locus
using a Bayesian model25 or likelihood-ratio tests.26
The approaches to resolving such heterogeneity
include segregation analysis and search for subclinical markers that may index aetiological subtypes.
Retinitis pigmentosa is an apt example, where the
identification of mutations in over 30 genes has
resulted in a genetic classification of the retinal
degeneration syndromes.27 Extensive heterogeneity
is the rule in many common complex disorders,
including inflammatory bowel disease,28 rheumatoid
arthritis,29 and osteoporosis.30 The obverse phenomenon of pleiotropy, that is, multiple phenotypes
arising from one genetic factor, is equally common,
for example, in demyelinating peripheral neuropathy
or axonal neuropathy with vocal cord paresis caused
by mutations in the same GDAP1 gene.31,32 A range of
dissimilar syndromes may be varying expressions of a
single genetic defect, such as severe neonatal intestinal obstruction, bronchiectatic lung disease, idiopathic pancreatitis, and male infertility, caused by
mutations in the CFTR gene.33–35 Both heterogeneity
and pleiotropy are implicated in the phenotypic
variation of common brain disorders,36 where their
effects may be aggravated by unknown or poorly
understood environmental contributions to the
phenotype.37
Schizophrenia cannot be an exception from these
laws. Although heterogeneity is generally acknowledged and genetic linkage analysis often performed
under the assumption of heterogeneity, this is usually
performed post hoc, that is, after the data have been
collected, or by default, when difficult to interpret
results have been obtained.38 Apart from locus and
allelic heterogeneity, commonly suspected sources of
‘nuisance’ variance in schizophrenia include a poorly
understood, poly- or oligogenic transmission; incomplete penetrance; variable phenotype expression;
unknown environmental contribution; phenocopies;
misspecification of the genetic model; and measurement or classification error.39,40 Less often acknowledged, but potentially critical sources are a fallible
phenotype;41 existence of latent disease subtypes
that may be aetiologically different;42 and population admixture (of subtypes and ethnic variation)
that could seriously compromise the power of the
available analytic methods.43,44
The likely existence of aetiologically different
subtypes of the disorder (Bleuler’s notion of a ‘group
of schizophrenias’45), is rarely considered in genetic
studies, which tend to be predicated on the broad
clinical diagnosis as the phenotype, implicitly assuming a unitary view of the disorder. Phenotype
refinement through disaggregation into clinical subtypes, or extension by covariate quantitative traits,
has been a successful strategy in the genetic dissection of asthma,20 type I diabetes,19 or dementia.23 This
approach has had limited following in schizophrenia
research. The failure to address the unresolved
heterogeneity in schizophrenia continues to be a
serious obstacle to the effective harnessing of novel
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A Jablensky
technologies, such as whole-genome association
analysis, or joint association and expression studies,
into an effort to ‘deconstruct’ schizophrenia.
Symptoms and course as criteria defining the
phenotype
As its inception and to the present day, the clinical
entity of schizophrenia is diagnosed by analysis of the
subjective symptoms reported by patients, their
history and course, observation of behaviour, affect
and speech, and (to a lesser extent) by evaluation
of premorbid development, personality traits, and
family background. The diagnostic criteria of the
International Classification of Diseases ICD-102 and
Diagnostic and Statistical Manual (DSM)-IV3 were
originally conceived with a view to achieving three
fundamentally different goals: (i) to identify groups of
patients with broadly similar clinical presentation
and prognosis; (ii) to facilitate early diagnosis and
choice of treatment; and (iii) to define a homogeneous
heritable diagnostic category for genetic aetiological
research.46 Whereas the first two goals have, by and
large, been achieved as regards the clinical utility of
the criteria, attainment of the third goal remains
remote. The estimated high heritability of schizophrenia (B80%, on the basis of twin studies using
DSM-III criteria47) has not been matched by unambiguous genetic linkage findings in studies using the
diagnostic category as the phenotype. Two recent
meta-analyses48,49 suggested greater consistency of
linkage results when pooled samples from different
sources were examined, but the actual agreement
between the two studies on specific linkage findings
was disappointingly low. The inconsistency of the
results suggests extensive locus and allelic heterogeneity, as well as an admixture of phenotypically
varied clinical populations.
Notwithstanding the reasonable level of inter-rater
agreement that can be achieved on the broad
diagnosis, the symptoms of schizophrenia span a
wide range of psychopathology and display an
extraordinary amount of interindividual variability
and temporal inconstancy, calling to mind Wittgenstein’s remark that classifying subjective psychological phenomena was akin to classifying clouds by their
shape.50 As no symptom is pathognomonic or necessary, but variable subsets of symptoms can be
sufficient for the diagnosis, patients may be allocated
to the diagnostic category of schizophrenia without
having a single symptom in common. As a consequence, the phenomenological similarity of patients,
selected for genetic and other biological research by
the current criteria is modest at best, and disconcertingly low at worst. This might be part of the reason for
the limited capacity of the diagnosis to predict
accurately which biological or behavioural attributes
will be shared by the majority of individuals allocated
to the diagnostic category, or to draw ‘zones of
rarity’51 that clearly demarcate schizophrenia from
other disorders, such as bipolar affective disorder.52,53
Such flaws raise doubts about the capacity of the
broad clinical definition of schizophrenia to carve out
biologically homogeneous clinical populations for
genetic analysis.
Such concerns are not new – attempts to parse the
complexity of schizophrenia into simpler component
disorders or subtypes have been undertaken since the
earliest formulation of the diagnostic concept, using
clinical or biological criteria, as well as a variety of
statistical methods. In the overview, that follows, the
terms ‘subtype’, ‘component disorder’ or ‘variant’ are
used near-synonymously to denote sets of phenotypic
attributes defining discrete subgroups of individuals
likely to be internally more homogeneous for aetiologically relevant genes than the whole of the clinical
population meeting broad diagnostic criteria for
schizophrenia.
817
Putative schizophrenia subtypes based
on clinical features
Kraepelin’s clinical forms of dementia praecox
Acknowledging the diversity of the clinical pictures
subsumed under dementia praecox and the absence
of pathognomonic symptoms, Kraepelin1 articulated,
‘for the sake of a more lucid presentation’, nine
different ‘clinical forms’ (Table 1). However, he
emphasized that ‘we everywhere meet the same
fundamental disorders in the different forms of
dementia praecox, in very varied conjunctions, even
though the clinical picture may appear at first sight
ever so divergent’. The ‘fundamental disorders’,
holding together the disease entity, were cognitive
deficit (a ‘general decay of mental efficiency’) and
executive dysfunction (‘loss of mastery over volitional
action’), most clearly manifested in the residual,
‘terminal states’ of the illness. Kraepelin was reluctant to impute aetiological significance to the clinical
variants he described, and regarded the issue of a
unitary process versus multiple disease states within
schizophrenia ‘an open question’. The renewal of
interest in Kraepelin’s dementia praecox since the
1990’s has led researchers to attempt delineating a
‘Kraepelinian’ subtype of schizophrenia, in terms of
negative or disorganized symptoms, poor outcome,
neuropsychological deficits, and risk factors.54–56
However, as indicated in Table 1, Kraepelin’s original
typology allowed for much greater heterogeneity in
the clinical manifestations of dementia praecox than
it is currently assumed.
Bleuler’s ‘group of schizophrenias’
Having coined the term ‘schizophrenia’ to replace
dementia praecox, Bleuler45 stated that schizophrenia
‘is not a disease in the strict sense, but appears to be a
group of diseases.Therefore, we should speak of
schizophrenias in the plural’. He acknowledged that
the clinical subgroups of paranoid schizophrenia,
catatonia, hebephrenia and simple schizophrenia –
retained in the present DSM and ICD classifications –
were not ‘natural’ nosological entities. What were
then the multiple ‘schizophrenias’? Bleuler argued
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Subtyping schizophrenia
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818
Table 1
K
K
K
K
K
K
K
K
K
Emil Kraepelin’s ‘clinical forms’1
Dementia praecox simplex
(‘Impoverishment and devastation of the whole psychic life which is accomplished quite imperceptibly’)
Hebephrenia
(Insidious change of personality with shallow capricious affect, senseless, and incoherent behaviour, poverty of
thought, occasional hallucinations, and fragmentary delusions, progressing to profound dementia)
Depressive dementia praecox (simple and delusional form)
(Initial state of depression followed by slowly progressive cognitive decline and avolition, with or without
hypochondriacal or persecutory delusions)
Circular dementia praecox
(Prodromal depression followed by gradual onset of auditory hallucinations, delusions, marked fluctuations of mood,
and aimless impulsivity)
Agitated dementia praecox
(Acute onset, perplexity, or exaltation, multimodal hallucinations, fantastic delusions)
Periodic dementia praecox
(Recurrent acute, brief episodes of confused excitement with remissions)
Catatonia
(‘Conjunction of peculiar excitement with catatonic stupor dominates the clinical picture’ in this form, but catatonic
phenomena frequently occur in otherwise wholly different presentations of dementia praecox)
Paranoid dementia (mild and severe form)
(The essential symptoms are delusions and hallucinations. The severe form results in a ‘peculiar disintegration of
psychic life’, involving especially emotional and volitional disorders. The mild form is a very slowly evolving
‘paranoid or hallucinatory weak-mindedness’ which ‘makes it possible for the patient for a long time still to live as an
apparently healthy individual’)
Schizophasia (confusional speech dementia praecox)
(Cases meeting the general description of dementia praecox but resulting in an end state of ‘an unusually striking
disorder of expression in speech, with relatively little impairment of the remaining psychic activities’)
that ‘the disease schizophrenia must be a much
broader concept than the overt psychosis of the same
name’. Along with the ‘latent’ schizophrenias, which
manifested mainly aberrant personality traits, he
listed atypical depressive or manic states, Wernicke’s
motility psychoses, reactive psychoses, and other
nonorganic, nonaffective psychotic disorders as belonging to the broad group of schizophrenias, suggesting that ‘this is important for the studies of heredity’,
thus foreshadowing the notion of schizophrenia
spectrum disorders.
Post-Kraepelinian and post-Bleulerian subtypes and
dichotomies
Further subnosological distinctions have been proposed, including schizoaffective disorder;57 schizophreniform psychoses;58 process – nonprocess;59 and
paranoid – nonparanoid schizophrenia.60 Schneider61
claimed that nine groups of psychotic symptoms,
designated as ‘first-rank symptoms’ (FRS), had a
‘decisive weight’ in the diagnosis of schizophrenia:
audible thoughts; voices arguing about, or discussing
the patient; voices commenting on the patient’s
actions; experiences of influences on the body;
thought withdrawal and other interference with
thought; thought broadcast (diffusion of thought);
delusional perception; and other experiences involving ‘made’ impulses and feelings experienced as
caused by an outside agency. Owing to the sharpness
of their definition and the hope that they could be
reliably ascertained, the FRS have been incorporated
in the Research Diagnostic Criteria, RDC;62 DSM III;63
and ICD-10.2 The Catego algorithm,64 used in the
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WHO cross-national studies, defined a ‘nuclear’
schizophrenia (S þ ) characterized by presence of at
least three out of six FRS. Familiality and modest to
substantial heritability has been reported for the
FRS,65,66 but a study comparing their occurrence in
affected subjects with and without linkage to chromosomes 5q, 6p, 8p, and 10p produced ambiguous
results.67
Leonhard’s alternative classification of the
‘endogenous’ psychoses
In a clinical tradition striving to group psychotic
illnesses on the basis of presumed localized cerebral
dysfunction, Leonhard68 developed a classification of
the ‘endogenous’ psychoses which departed substantially from the Kraepelinian nosology. Leonhard
defined sharply delineated disease entities, described
by a detailed psychopathology emphasizing objective
signs (e.g. psychomotor behaviour), course and outcome, and family history. The nonaffective psychoses
were split into two groups of schizophrenias –
‘systematic’ and ‘unsystematic’ – and a third group
of ‘cycloid’ psychoses, each containing further subtypes (Table 2), for which clinical homogeneity and
distinct disease status were claimed. The resulting
categorical taxonomy is the antithesis of the notion of
a continuum. While the ‘unsystematic’ schizophrenias are considered to be primarily genetic, hereditary
factors play a secondary role in the cycloid psychoses
and in the ‘systematic’ schizophrenias, presumed to
be exogenously determined by maternal obstetric
complications or early failure of social learning.
Notably, Leonhard’s classification neither expands,
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A Jablensky
Table 2
819
Karl Leonhard’s classification of the nonaffective endogenous psychoses68
I. Group of systematic schizophrenias
(Insidious onset, auditory and somatic hallucinations, delusions, early blunting of affect, continuous unremitting course,
personality deterioration)
Paraphrenias
(Auditory hallucinosis, audible thoughts, thought broadcast, passivity experiences, delusional misidentifications,
falsifications of memory)
Hebephrenias
(Extreme autistic withdrawal, flat affect, impoverished or disorganized speech and behaviour)
Catatonias
(Excessive parakinesias, mannerisms, verbigeration, posturing, stereotypies, mutism, auditory hallucinations)
II. Group of unsystematic (atypical) schizophrenias
(Rapid onset, relatively preserved affect, remitting course, mild personality deterioration)
Affect-laden paraphrenia
(Paranoid delusions with affective loading)
Cataphasia (schizophasia)
(Incoherent, pressured speech but well-organized behaviour)
Periodic catatonia
(Episodic hyper- or hypokinesia, mixed excitatory and hallucinatory symptoms)
III. Group of cycloid psychoses
(Sudden onset, pervasive delusional mood, multimodal hallucinations, labile affect, polarity of manifestations, typically
complete recovery from episode)
Anxiety-happiness psychosis
(Extreme shifts of affect, polarity e.g. intense fear – ecstatic elation)
Motility psychosis
(Impulsive hypermotility – psychomotor inhibition)
Confusion psychosis
(Incoherent pressure of speech – mutism)
nor constricts the outer boundaries of schizophrenia
as defined by ICD-10,2 and DSM-IIIR,69 but carves the
schizophrenia spectrum in a different way.
Leonhard’s family studies, although richly descriptive, may be methodologically outdated by presentday criteria. However, his conjectures have found
support in a twin study,70 in which the highest MZ/
DZ concordance rate differential was obtained with
‘unsystematic’ schizophrenia (88.9% MZ, 25.0% DZ)
and the lowest with cycloid psychoses (38.5% MZ,
36.4% DZ), consistent with the prediction about the
role of genetic factors in the aetiology of the different
psychoses. A genome scan of 12 German multiplex
pedigrees with periodic catatonia (one of the ‘unsystematic’ schizophrenias with a 26.9% recurrence
risk71), revealed significant linkage on chromosome
15q15, and suggestive evidence on 22q13.72,73 The
follow-up of the 15q finding has so far excluded the
nicotinic acetylcholine receptor alpha7 subunit gene,
the zinc transporter SLC30A4, and the NOTCH4
gene.74–76 The putative 22q13 locus contains the
MLC1 (WKL1) gene, coding for a cation channel
expressed exclusively in the brain and causing, in its
mutated form, a severe neurodegenerative disorder
(megaencephalic leukoencephalopathy). A rare missense mutation in this gene, cosegregating with
periodic catatonia in a single pedigree was detected,
but not confirmed in an independent sample.77,78
Although the jury is still out, the apparent clinical
homogeneity of the syndrome of periodic catatonia
may not be underpinned by genetic homogeneity.
The notion of a schizophrenia spectrum
The concept of a spectrum of schizophrenia-related
phenotypes originates in the observation that several
ostensibly different disorders tend to cluster among
biological relatives of individuals with clinical schizophrenia.45,79,80 Epidemiological and family study
data suggest that the genetic liability to schizophrenia
is shared with liability to other related syndromes.81,82
The term ‘schizotypy’, introduced by Rado83 and
Meehl,84 describes a personality characterized by
anhedonia, ambivalence, ‘interpersonal aversiveness’,
body image distortion, ‘cognitive slippage’, and
sensory, kinaesthetic or vestibular aberrations.
Chapman et al.85 designed scales to measure perceptual aberrations and ‘magical ideation’ as traits
predicting ‘psychosis proneness’. These constructs
were amalgamated with clinical descriptions from the
Danish-US adoptive study into the DSM-III diagnostic
category of schizotypal personality disorder (SPD),
which is now central to the spectrum notion.8186 The
frequent occurrence of SPD among first-degree relatives of probands with schizophrenia has been
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A Jablensky
820
replicated in the Roscommon epidemiological
study,87 which added to the schizophrenia spectrum
further disorders cosegregating within families. The
resulting ‘continuum of liability’ included: (i) ‘typical’ schizophrenia (ii) schizotypal and paranoid
personality disorders; (iii) schizoaffective disorder,
depressed type; (iv) other nonaffective psychotic
disorders (schizophreniform, atypical psychosis);
and (v) psychotic affective disorders. The correlation
of liability to the five disorders between probands
with schizophrenia and their first-degree relatives
was 0.36.87 Recent evidence from the Finnish family
adoptive study of schizophrenia suggests more
restrictive genetic boundaries of the spectrum, by
excluding paranoid personality disorder and psychotic affective disorders.88 In all its variations, however,
the spectrum concept remains critically dependent on
the validity of the SPD concept. Accumulating
evidence from family and twin data indicates that
SPD is multidimensional and may be genetically
heterogeneous.89–92 Its manifestations fall into two
genetically independent clusters: a ‘negative’ cluster
(odd speech and behaviour, inappropriate affect and
social withdrawal), more common among relatives of
schizophrenic probands, and a ‘positive’ cluster
(magical ideation, brief quasipsychotic episodes),
associated with increased incidence of affective
disorders in relatives.93 ‘Negative’ schizotypy may
indeed represent a personality-based counterpart of
schizophrenia,94 manifesting attenuated cognitive
deficits95–97 and brain structural abnormalities98
characteristic of schizophrenia.
Positive–negative schizophrenia (‘Type I’ and ‘Type II’)
A general ‘weakening’ of mental processes resulting
in a ‘defect’ was the cornerstone of Kraepelin’s
dementia praecox, who suggested that precursors of
‘defect’ could be detected early in the illness,
coexisting with ‘productive’ or ‘florid’ symptoms.
Since the 1970s, the terms ‘defect’ and ‘productive’
symptoms have been virtually replaced by ‘negative’
and ‘positive’ symptoms.99 Crow100 proposed a simple
subclassification of schizophrenia, based on the
predominance of either positive or negative symptomatology. ‘Type I’ (positive) schizophrenia was
characterized by hallucinations, delusions, and formal thought disorder, with a presumed underlying
dopaminergic dysfunction, while patients with ‘Type
II’ (negative) schizophrenia displayed social withdrawal, loss of volition, affective flattening, and
poverty of speech, presumed to be associated with
structural brain abnormalities. Criteria and rating
scales for positive (SAPS) and negative (SANS)
schizophrenia were proposed by Andreasen and
Olsen.101 The initial typology, implying pathogenetically discrete and mutually exclusive ‘types’, was
later replaced by a negative and a positive dimension,
allowing the two kinds of symptoms to co-occur in
the same individual and share a common aetiology.102
In essence, the positive–negative typology is
a descriptive device without a strong theoretical
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basis.103 Its construct validity and neurobiological
correlates remain ambiguous.104–106 As no theorybased rule exists for classifying the symptoms of
schizophrenia as negative or positive, the distinction
is supported by their differential loadings on separate
factors. The argument is somewhat circular, since
cross-sectional symptomatology is typically assessed
by rating scales designed a priori to reflect such
distinction.107
Deficit–nondeficit schizophrenia
Carpenter and co-workers108,109 proposed the delineation of a subtype of schizophrenia characterized by
enduring ‘primary’ negative symptoms that could not
be construed as sequelae of other psychopathology
(Table 3). This clinical construct, evocative of
Kraepelin’s dementia praecox, was termed ‘deficit
schizophrenia’ (DS) and hypothesized to be an
aetiologically distinct ‘disease’ within the schizophrenia spectrum.110 Studies comparing DS cases
with ‘nondeficit’ (NDS) patients and controls, estimate the prevalence of the DS subtype at 16.5% in
unselected epidemiological samples of schizophrenia
cases111 and 25–30% within samples of chronic
schizophrenia.110 Compared to NDS, DS cases exhibit
less paranoid ideation and depression, less substance
abuse, more prominent anhedonia, poor social functioning, treatment resistance and a higher schizophrenia risk in relatives.111 DS and NDS do not differ
on age at onset and length of illness, which argues
against a progression leading from NDS to DS.
Supportive evidence for the DS construct has been
Table 3 Diagnostic criteria for the deficit syndrome of
schizophrenia108,109
1. At least 2 of the following 6 negative symptoms must be
present:
Restricted affect
Diminished emotional range
Poverty of speech
Curbing of interests
Diminished sense of purpose
Diminished social drive
2. Some combination of two or more of the above negative
symptoms have been present for the preceding 12 months
and always present during periods of clinical stability.
3. The negative symptoms are primary, that is, not
secondary to factors other than the disease process, for
example
Anxiety
Drug effects
Suspiciousness or other psychotic symptoms
Mental retardation
Depression
4. The patient meets DSM-III criteria for schizophrenia
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A Jablensky
provided by neuropsychological studies, which
found those patients to be particularly impaired on
the Stroop colour-word interference test,112 the
degraded stimulus version of the continuous performance task,113 and tests of general ability.114
Oculomotor control measures indicate deficient
tracking and antisaccade performance115–117 and
neurological examination suggests deficient sensory
integration.118 The overall pattern has been interpreted as indicative of a fronto-temporo-parietal
dysfunction, against a background of a more global
impairment.119 Taxometric analysis of 238 schizophrenia patients120 suggests a discrete taxon status for
DS. The DS–NDS typology with its covariates is well
replicated, yet rarely used in genetic research121,122
despite its potential suitability as a phenotype.
Statistically derived symptom dimensions or clusters
Factor analysis has been applied to psychiatric rating
scales since the 1960s.123 Essentially, factor analysis
and related methods reduce the covariation of the
primary data matrix to covariances of small numbers
of latent factors which account for the interrelationships among the primary variables and explain a
proportion of their variance. Based on a relatively
small number of input variables (SANS/SAPS scores),
a three-factor structure was proposed by Liddle124 and
replicated by other investigators.125–127 In this model,
negative symptoms load on a single factor of ‘psychomotor poverty’, while positive symptoms split
into a delusions-and-hallucinations factor (‘reality
distortion’) and a thought-and-speech disorder factor
(‘disorganization’). The model has been shown to be
longitudinally stable128 and replicable in non-European populations.129,130 It was incorporated in DSMIV3 and tested in field trials.131
Results of factor-analysis of symptomatology depend strongly on the content of the clinical rating
scales used as input. Studies using the SANS and
SAPS result in different solutions from those produced by the PANSS,132 BPRS,133 or OPCRIT,134
including a general neurotic syndrome factor;135
excitement and depression;136,137 paranoid, first-rank
delusions and first-rank hallucinations;138 premorbid
adjustment deficits factor;139 and autistic preoccupation factor.140 In a large sample of probands with
schizophrenia, McGrath et al.141 identified five factors
(positive, negative, disorganized, affective, and early
onset/developmental), which were associated with
risks of psychoses and affective disorders in relatives.
In a series of factor analyses based on an expanded
list of 64 psychopathological symptoms, Cuesta and
Peralta142 concluded that a hierarchical 10-dimensional model provided the best fit on statistical and
clinical grounds. Factor solutions, therefore, are not
unique and the question ‘how many factors parsimoniously describe the symptomatology of schizophrenia?’ can only be answered in the context of a
particular selection of symptoms and measurement methods. Therefore, factor-analytical studies
suggesting ‘established’ dimensions or syndromes of
schizophrenia should be viewed with caution, considering the diversity of clinical populations and the
limitations of the instruments used to generate the
input data.
Whereas factor analysis groups variables, cluster
analysis groups individuals on the basis of maximum
shared characteristics. Farmer et al.143 identified
two clusters into which patients with schizophrenia
could be fitted, based on their scores on a checklist
of 20 symptom and history items: one characterized
by good premorbid adjustment, later onset, and well
organized delusions, and another including early
onset, poor premorbid functioning, incoherent
speech, bizarre behaviour, and family history of
schizophrenia. However, using the Positive and
Negative Syndrome Scale,132 Dollfus et al.144 obtained
four quite different distinct clusters, corresponding to
positive, negative, disorganized and mixed symptomatology. Thus, cluster analysis is as dependent on
the selection of input variables as factor analysis.
Latent class analysis (LCA) assumes the existence
of a finite number of mutually exclusive and jointly
exhaustive groups of individuals, within which
person characteristics, for example, responses to
symptom items, are: (a) determined by class membership and (b) locally independent.145 A latent class
typology of schizophrenia, proposed by Sham
et al.,146 using data on 447 patients with nonaffective
psychoses, suggested the existence of three subgroups: a ‘neurodevelopmental’ subtype resembling
the hebephrenic form of the disorder (poor premorbid
adjustment, early onset, prominent negative, and
disorganized features); a ‘paranoid’ subtype (less
severe, better outcome); and a ‘schizoaffective’ subtype (dysphoric symptoms). In an epidemiological
sample of 343 probands with schizophrenia and
affective disorders, Kendler et al.147 found six latent
classes, broadly corresponding to the nosological
groups of ‘Kraepelinian’ schizophrenia; major depression, schizophreniform disorder; schizoaffective disorder (manic), schizoaffective disorder (depressed),
and hebephrenia. Increased risk for schizophrenia
spectrum disorders was found among the relatives of
subjects assigned to the schizophrenia and schizophreniform classes, while increased risk for affective
disorders was only found in the relatives of patients
assigned to the major depression and schizoaffective
(depressed) classes. Similar results, using a combination of principal component (factor) analysis and
LCA in an epidemiologically ascertained sample of
387 patients with psychoses, have been reported by
Murray et al.148
In contrast to conventional LCA, a special form of
latent structure analysis, the grade of membership
(GoM) model, allows individuals to be members of
more than one class and represents the latent groups
as ‘fuzzy sets’,149,150 where individuals can be members of more than one set. The GoM model simultaneously extracts from the data matrix a number of
latent ‘pure types’ and assigns each individual a set of
numerical weights quantifying the degree to which
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822
that individual resembles each one of the identified
pure types. When applied to the symptom profiles of
1065 cases in the WHO International Pilot Study of
Schizophrenia,151 the method identified eight pure
types of which five were related to schizophrenia, two
to affective disorders and one to patients in remission,
all showing significant associations with course and
outcome variables used as external validators.
Subtypes based on putative genetic indicators
Familial–sporadic schizophrenia
Subtyping schizophrenia by the presence/absence of
a positive family history for schizophrenia spectrum
disorders was proposed in the 1980s as a strategy
expected to be more successful in resolving heterogeneity than symptom-based typologies.152 Although
inclusion/exclusion criteria varied across studies,
‘familial’ (F) cases were typically defined as having
X1 first-degree relative affected, while ‘sporadic’ (S)
cases had none among either first- or second-degree
relatives.153 The F/S dichotomy rests on the assumption that the familial aggregation of cases is primarily
of a genetic origin, while sporadic cases result from
environmental insults (e.g. maternal obstetric complications) or de novo somatic mutations. In the
majority of studies applying this classification, the
proportion of familial cases was in the range of
8–15%, that is, lower than the 19% prevalence
estimated by Gottesman et al.154 from pooled European studies between 1920 and 1978. As the F/S
subtypes were hypothesized to differ aetiologically, a
number of studies, mostly of small to moderate
sample size ( < 100), compared the phenotypic characteristics of the two groups.155,156 No consistent and
significant differences have been found in age at
onset, symptom patterns, severity, treatment response
and outcome,157–159 and the findings with regard to
obstetric complications are inconclusive.160–162 Sporadic cases are more likely to be winter-born159,163,164
and have more electroencephalographic (EEG)
abnormalities153 and enlarged ventricles on CT scan
or MRI.152,165,166 Familial cases, on the other hand,
have more neurological signs,164,167–169 poorer sustained attention performance;170 cortical abnormalities on MRI171 and reduced temporoparietal resting
regional blood flow.172
By and large, the F/S classification has not been
successful in identifying homogeneous phenotype
groups for genetic research. The dichotomy, based on
recurrence of manifest schizophrenia among biological relatives, might easily result in a misclassification
unless: (i) ascertainment of all family members is
complete; (ii) appropriate adjustments for family size,
age, and lifetimes at risk are made; and (iii) the
spectrum of disorders counted as recurrence cases is
stringently defined. However, even if such confounding factors are adequately controlled for, and ‘familiality’ is represented as a continuous trait rather than a
dichotomy,173 the method remains open to error due
to the likely presence of unexpressed genotypes in
Molecular Psychiatry
schizophrenia families.39 Moreover, simulation power
analyses174 suggest that the F/S design can be useful
only in the context of very large samples of nuclear
families.
Subtyping based on genetic linkage or association data
Several studies based on samples with well-characterized clinical phenotypes have examined associations between selected clinical features and
previously established genetic linkage regions or
putative candidate genes. Various approaches have
been employed to interrogate genome-wide linkage or
association data with a view to exploring pathways of
disease expression. Thus, a potential 6p locus,
associated with a quantitative trait assessing the
severity of psychotic symptoms, was reported by
Brzustowicz et al.175 Pulver et al.176 used diagnostic
information to stratify 54 multiplex pedigrees by
diagnostic phenotypes cosegregating in nonschizophrenic first-degree relatives of the probands and
reported genome-wide significant linkage to 8p21 and
suggestive linkage to 1p21 for schizophrenia spectrum personality disorders. Subsequent analyses of
affected siblings from these families revealed that the
linkage evidence for 8p21 was mainly contributed by
a subgroup of 30 affected siblings sharing two alleles
identity by descent in the 8p21 region and one allele
at a locus on chromosome 14, suggesting an interaction effect. Phenotypically, this subgroup was characterized by a high prevalence of bizarre delusions,
affective symptoms early in the course of illness,
history of seizures, and attendance of special
school.177
Using data from the Irish Study of High-Density
Schizophrenia Families, Kendler et al.67 reported
high levels of positive thought disorder, affective
deterioration, and worse outcome in probands from
families with evidence of linkage to 8p22–21, suggesting that a susceptibility gene in the region may be
predisposing to a Kraepelinian, dementia praecox
type of illness. Within the same cohort of families,
family-based transmission disequilibrium tests produced suggestive evidence of association between
affective symptoms and the His452Tyr polymorphism
in the serotonin 2A receptor; between negative
symptoms and the brain-derived neurotrophic factor
(BDNF); and between negative symptoms and a highrisk haplotype in the dystrobrevin-binding protein 1
(dysbindin, DTNBP1) on 6p24–22.178,179 Recently, an
association between a six-locus haplotype in DTNBP1
and psychometrically assessed generalized cognitive
deficit in schizophrenia patients was reported by
Burdick et al.180
A special focus in the search for genetic subtypes of
schizophrenia has been the B3 Mb region on chromosome 22q11, which contains at least three genes
implicated in schizophrenia (COMT, PRODH2, and
ZDHHC8) and is hemizygously deleted in the velocardiofacial syndrome (VCFS, DiGeorge syndrome, or
Shprintzen syndrome). The microdeletion has a
population frequency of B1 in 6000 births181 and is
Subtyping schizophrenia
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associated with increased risk for several neuropsychiatric syndromes, including schizophrenia,182 bipolar disorder, learning disability, and ADHD.183
Approximately, 1% of adult schizophrenia patients
are carriers of the microdeletion184 but the frequency
may be as high as 5% among individuals with
childhood onset of schizophrenia.185 No evidence
has been produced to date that such patients express
a schizophrenia phenotype that is clinically distinguishable from schizophrenia in the absence of
VCFS.186 However, schizophrenia patients with VCSF
have more severe cognitive deficits of spatial working
memory, visual recognition, and attention than VCFS
individuals without schizophrenia.187 Compared to
matched normal controls, schizophrenia patients
with VCSF have smaller total grey matter volume,
larger lateral ventricles,188 and decreased gyrification
in the frontal and parietal lobes.189 Considering the
potential to trace causal pathways linking specific
gene effects with intermediate phenotypes and clinical disease expression, studies of rare genetic defects
have a special place in schizophrenia research. The
discovery of a translocation break point cosegregating
with schizophrenia in a Scottish pedigree190 has
facilitated the recent identification of DisruptedIn-Schizophrenia 1 (DISC1) as a positional candidate
gene with likely effects on brain development and
neurocognition191,192 in schizophrenia.
Endophenotypes: signposts to a biological
subclassification of schizophrenia?
Amidst growing doubts in the capacity of the broad
diagnostic category to serve as a reliable phenotype
for gene discovery,193–196 the concept of endophenotype (intermediate, elementary, alternative, or correlated phenotype) offered a novel perspective on
subtyping schizophrenia that could be either an
alternative or a complement to symptom-based
phenotypes. The term, originating in early 20th
century plant and insect genetics, was introduced
into schizophrenia genetics by Gottesman and
Shields.197 As ‘measurable components unseen by
the unaided eye along the pathway between disease
and distal genotype’,198 endophenotypes must meet
criteria of being: (i) associated with the clinical
disorder but not necessarily part of its diagnosis; (ii)
heritable; (iii) state-independent (i.e. present before
the onset of active illness or during remissions); (iv)
cosegregating with illness in families; and (v) found
in unaffected family members at a higher rate than in
the general population.193,198 Earlier desiderata, for
example that endophenotypes have a mendelian
genetic architecture, may be unrealistic. An important
requirement, however, is that an endophenotype
should be a quantitatively measurable trait (on a rank
scale as a minimum, but preferably on an interval
scale). Examples of endophenotypes meeting the
above criteria and successfully used in gene identification include the long QT syndrome,199 familial
adenomatous intestinal polyposis,200 idiopathic
Table 4 ‘Candidate’ endophenotype markers in schizophrenia research
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Neurophysiological markers and endophenotypes
Electrodermal deviance205
Prepulse inhibition of the startle reflex206–208
Deficient gating of the auditory evoked response (P50)209–211
P300 amplitude reduction and latency delay212
N400 amplitude reduction (semantic context
underutilization)213
Mismatch negativity (MMN)214–217
Smooth pursuit eye movement dysfunction (SPEM)218–221
Antisaccade error rate (AS)222–224
Composite inhibitory phenotype (P50, AS, SPEM)225
Multivariate electrophysiological endophenotype (MMN,
P50, P300, AS)226
Neuroimaging markers and endophenotypes
Fronto-thalamic-cerebellar gray matter deficit227
Fronto-striato-thalamic gray matter deficit228
MRI-derived three-factor phenotype229
MRI whole-brain nonlinear pattern classification230
Frontal hypoactivation in response to cognitive tasks
(hypofrontality)231
Atrophic and static (neurodevelopmental) schizophrenia
endophenotypes232
Cognitive markers and endophenotypes
Continuous performance tests (CPT, signal/noise ratio)233–235
Attention and vigilance-based subtype18
Verbal dysmnesic subtype18
Verbal memory deficit, cortical or subcortical type236,237
Dysexecutive subtype18
Prefrontal executive/working memory phenotype238
Frontal/abstraction deficit profile239
Spatial working memory240
Generalized (diffuse, pervasive) cognitive deficit, CD239,241–243
Other markers and endophenotypes
Neurological soft signs244–247
Composite laterality phenotype248
Nailfold plexus visibility249
Minor physical anomalies250,251
haemochromatosis,201 and juvenile myoclonic
epilepsy.202 In schizophrenia research, an endophenotype approach, based on smooth pursuit eye movements (SPEM) was first explored by Holzman203,204
and followed by a growing number of studies utilizing
psychophysiological, brain imaging, and cognitive
measures (Table 4).
Cognitive dysfunction as an endophenotype
Cognitive deficits are widely regarded as a core
feature of schizophrenia and not an epiphenomenon
of the illness.251-253 There is remarkable agreement in
the literature that deficits in multiple cognitive
domains predate the onset of clinical symptoms;254–258
are not attributable to antipsychotic medications;259
persist over the course of the illness; are unrelated
to its duration;260–262 and behave like a stable
trait.233,263,264 Pervasive cognitive dysfunction has
been reported in > 50% of schizophrenia patients in
a community-based survey in Scotland,265 and there
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is compelling evidence that cognitive deficits are
significantly correlated with impairments in activities of daily living (ADL) in patients with schizophrenia,266–270 but only weakly associated with
psychotic symptoms.271 Patients with paranoid
schizophrenia and pronounced positive symptoms
tend to show better cognitive functioning compared
to patients with undifferentiated or disorganized
schizophrenia.272–274
Population-based,
longitudinal
cohort
studies254,275,276 have found that compromised general
cognitive ability in late adolescence is a strong
predictor of subsequent schizophrenia risk. Family
studies indicate that a proportion of the unaffected
first-degree relatives of index cases of schizophrenia
display similar patterns of deficit in an attenuated
form,234,235,277–279 and an epidemiologically-based
study of 111 DZ and MZ twin pairs discordant for
schizophrenia280 found that deficits in working
memory, attention, reaction time and word recall
intrusions were highly heritable. Thus, the balance of
the evidence suggests that cognitive dysfunction
meets most of the criteria198 of an endophenotype in
schizophrenia. This conclusion is underscored by the
meta-analysis by Heinrichs and Zakzanis281 of 204
studies published between 1980 and 1994 (a total of
7420 schizophrenia patients and 5865 controls), in
which effect sizes (Cohen’s d) and the U statistic
(degree of nonoverlap) were calculated for 22 neurocognitive test variables ranging from IQ, verbal
memory, and attention to executive function, and
language. Neurocognitive deficit was found to be a
reliable and well replicated finding in schizophrenia,
although no single test or cognitive construct was
capable of separating perfectly schizophrenia patients
from normal controls. Seven widely used measures
achieved effect sizes greater than 1.0 (60–70% nonoverlap between the cases and controls): global verbal
memory (1.41), bilateral motor skills (1.30), performance IQ (1.26), the continuous performance task
(1.16), word fluency (1.15), the Stroop task (1.11), and
WAIS-R IQ (1.10). Although a subset of B50% of
patients had nearly normal performance, significant
cognitive impairment was common in schizophrenia
and exceeded the deficits found in some neurological
disorders, justifying the view that ‘schizophrenia is a
neurological disorder that manifests itself in behaviour’.281
Subtypes of cognitive dysfunction
Cognitive deficits in schizophrenia are heterogeneous, ranging from pervasive generalized dysfunction through patchy focal disorders to mild focal
deficits or nearly normal performance.282–288 Yet
amidst seemingly extensive heterogeneity, converging
evidence points to specific deficits in verbal declarative memory and working memory (mainly in the
early encoding stage) as major sources of variance.289,290 This observation has prompted attempts
at delineating particular profiles or subtypes.
While conventional cluster analyses tend to simply
Molecular Psychiatry
distribute patients into groups of severely compromised, intermediate and mildly affected performance,291,292 ‘classical’ fine-grain neuropsychological
analyses (case studies of individual profiles rather
than group means; delineation of generalized/differential deficits; search for ‘double dissociations’) have
identified patterns of dysfunction that parallel the
amnestic syndromes in coarse brain disease, such as
Huntington’s (HD), PD, or AD.
In a series of 175 schizophrenia patients, compared
with 229 normal controls on the performance of the
California Verbal Learning Test (CVLT), Paulsen
et al.236 elicited from 50% of the patients a subcortical
(striatal, HD/PD-type) memory profile combining
prominent retrieval deficit (poor free-format recall of
word lists, improving substantially on presentation of
cues) with absence of storage deficits (lack of rapid
forgetting). Another 15% had a cortical (hippocampal-thalamic, AD-type) profile (primary encoding and
storage impairment, with an excess of irrelevant word
intrusions on free and cued recall), while the profiles
of the remaining 35% did not deviate significantly
from those of the controls. These findings were
replicated by Turetsky et al.237 and supported by
neuroimaging data suggesting ventricular enlargement with preserved temporal lobe grey matter and
no significant metabolic abnormalities in the subcortical group. In contrast, the cortical group was
characterized by a left-hemisphere temporal and
frontal volume reduction, and metabolic abnormalities in the superior temporal gyrus, hippocampus,
and thalamus. Using a different statistical approach,
Dickinson et al.241 estimated that over 30% of the
variance in cognitive test performance by schizophrenia patients could be explained by a large-effect ‘g’
factor, affecting fundamental processes that integrate
multiple intermodal brain functions into ‘core’ cognitive operations such as concept formation and
reasoning skills. Further variance, however, can be
explained by a number of independent, small-effect
variables selectively affecting specific functions, such
as processing speed and visual memory. Table 4
provides an overview of proposed cognitive subtypes
associated with schizophrenia.
Promising as they are, these approaches to ‘splitting
schizophrenia’293 are limited by sample size, as well
as by insufficient efforts to integrate multidomain
data (e.g. neuroimaging and neurophysiological measurements) that might increase their capacity to parse
the deficits characterizing schizophrenia.
Cognitive phenotypes have rarely been tested as
phenotypes in molecular genetic studies. In one such
study, Egan et al.294 used working memory/executive
function (assessed by the Wisconsin Card Sorting test,
WCST) as the phenotype in a functional investigation
of the val158/108met polymorphism in the catecholo-methyltransferase (COMT) gene. Allele dosage
effect of worsening WCST performance and reduced
fMRI activation response in the prefrontal cortex
was found for the val/met and val/val genotypes,
likely due to a more rapid inactivation of synaptic
Subtyping schizophrenia
A Jablensky
dopamine by the COMT-val variant. No effect on
sustained attention was detected.238 In another study,
using a more inclusive neurocognitive battery, Bilder
et al.295 found greater impact of the val158/108met
genotype on processing speed and attention than on
executive function, suggesting that the effect of the
COMT polymorphism on cognition may not be
exclusively mediated by prefrontal dopamine. Considering that the COMT-val allele has shown an association with schizophrenia in some reports,296–298
although not in others,299–301 the possibility that
this polymorphism might contribute to the risk of
schizophrenia requires further study.
In a study of 168 Finnish families with schizophrenia, Paunio et al.302 applied a variance component analysis (SOLAR) to genome scan data, using 11
neuropsychological test battery scores obtained from
probands and relatives as quantitative trait phenotypes before linkage analysis. Compared with diagnosis only as the phenotype, use of quantitative traits
resulted in a stronger signal and evidence of linkage
for verbal learning and memory over a 30 cM region
on 4q13–25 (Zmp = 3.84), as well as suggestive
evidence for visual working memory on 2q36
(Zmp = 2.08), visual attention on 15q22 and executive
function on 9p22. Although the advantages of using
quantitative traits are demonstrated by this study, the
interpretation of specific linkage findings for subcomponent cognitive processes will be tenuous until
replication or convergent evidence from endophenotyping studies become available.
The Western Australian family study of schizophrenia
The Western Australian family study of schizophrenia (WAFSS) was designed as a testbed for exploring
heterogeneity in schizophrenia, delineating genetic
variants, or subtypes, and putting them to the test of
genetic linkage analysis. Our group adopted from the
outset the conjecture that: (a) the broad syndrome of
schizophrenia is a conflation of several underlying
disorders that may be aetiologically distinct; and (b)
endophenotypes anchored in objective measures of
brain dysfunction might separate out such disorders
more clearly than clinical symptoms alone. The
available evidence was pointing to cognitive and
neurobehavioural measures as being particularly
sensitive to dysfunction associated with schizophrenia, as well as being longitudinally stable, stateindependent, and heritable. As most neurocognitive
tasks typically engage several component processes,
we reasoned that a linear composite of such variables
would be an appropriate endophenotype for genetic
studies and developed a design allowing simultaneous analysis of performance in the various cognitive domains for shared patterns of dysfunction,
rather than for isolated deficits.
In this study, involving 112 families (388 members,
of which 138 affected with schizophrenia or schizophrenia spectrum disorders) and 143 population
controls, we employed a comprehensive clinical and
cognitive assessment protocol243 to evaluate patients,
first-degree relatives, and controls. The test results
were analysed for complex patterns of dysfunction
using a GoM model, a form of latent structure analysis
which defines a parsimonious number of latent
groups or patterns of responses (‘pure types’), allowing individuals to resemble each group to varying
degrees, rather than allocating them to mutually
exclusive clusters as performed in standard
LCA.149,150 GoM resolves sample heterogeneity by
assigning to each individual GoM scores of affinity
to each one of several pure types. The resulting
classification identified two distinct pure types of
multivariate neurocognitive profiles (Figure 1), which
comprised over 90% of the schizophrenia patients in
the sample, as well as 23% of their clinically
unaffected first-degree relatives: a cognitive deficit
(CD) subtype and a cognitively spared (CS) subtype.
In the CD subtype verbal memory impairment was the
most consistently observed cognitive deficit. Multiple
(3 þ ) cognitive deficits were exhibited by all CD
cases, and estimated current IQ was low in the
majority of these patients. Consequently, generalized
cognitive deficiency was the most salient characteristic of this subtype, in contrast to mild or patchy
deficits in the CS subtype.
To test the hypothesis that the two subtypes are
genetically distinct, a 10 cM whole genome scan was
performed using 380 microsatellite markers in 93
schizophrenia families (34 of which had been assigned the CD subtype). Linkage analysis revealed
evidence for linkage on several chromosomes, with
the most significant finding at 6p25–24.243 The data
were then assessed by ordered subsets analyses
(OSA), where the families were rank-ordered by their
CD and CS quantitative trait scores (highest to lowest)
and compared for changes in the logarithm of odds
(LOD) scores between the subset and the overall
sample. The greatest increase in the LOD score, at
6p24, was accounted for by the families ranked from
1st to 47th by the proband’s CD score. Fifteen
additional microsatellite markers genotyped in this
region (6p25–22) increased the maximal LOD score in
the CD families to 3.32. Linkage was excluded in the
non-CD families for the entire chromosome 6. The
6p25–24 locus coincides almost exactly with the
linkage findings in 270 Irish schizophrenia families,
previously reported by Straub et al.303 The coincident
linkage region and the common ancestry (Anglo-Irish)
of our families lead us to believe that they share the
same susceptibility allele(s). Important independent
support for these findings was recently provided by a
study of general cognitive abilities in 634 healthy sib
pairs,304 which reported quantitative trait loci evidence of linkage of full-scale IQ and verbal IQ to the
same 6p region. A notable aspect of the linkage results
is that they were predicted with considerable accuracy by the composite endophenotypes defined prior
to genetic analysis (Figure 2), and that the distributions of several of the cognitive measures differentiating the two subtypes suggest bimodality, supporting
their relative independence.
825
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826
2.0
cognitive deficit (CD)
1.5
cognitively spared (CS)
1.0
z-scores
0.5
0.0
-0.5
-1.0
Baseline: standardised performance of controls
-1.5
-2.0
1
2
3
4
5
6
7
8
neurocognitive measures
1 - Premorbid IQ
2 - Current IQ
3 - Verbal memory (immediate recall)
4 - Verbal memory (delayed recall)
5 - Verbal fluency
6 - Sustained attention CPT-IP
7 - Sustained attention CPT-DS
8 - Speed of information processing (inspection time)
9
10
11
12
13
14
neurobehavioural measures
9 - Schizotypal symptoms
10 - Neurological soft signs
11 - Handedness lateralisation quotient
personality factors (TCI)
12 - Harm-avoidance
13 - Self-transcendence
14 - Self-directedness
Figure 1 Profiles of the two cognitive subtypes (CD and CS), identified in the Western Australian Family Study of
Schizophrenia.243
Clinically, the CD subtype exhibits some affinity
with the deficit syndrome described by Carpenter
et al.108 and Kirkpatrick et al.109 with predominance of
negative symptoms, relative paucity of complex
delusions, and poor social functioning. Subsequent
statistical analyses by our group indicate that a fair
approximation to the CD/CS typology can be achieved
with an abridged, cost-efficient neurocognitive battery, which should facilitate the replication of this
approach to subtyping schizophrenia and its genetic
underpinnings.
Deconstructing a complex disease?
The overview of the evidence suggests that phenotypic variability has been confounding the search for
the causes of schizophrenia since the inception of the
diagnostic category. Attempts at redefining its boundaries by either ‘lumping’ or ‘splitting’ strategies24 have
been undertaken over decades, with limited success.
Most such attempts, based on various rearrangements
of clinical symptoms and syndromes have ended in a
failure to find natural boundaries between proposed
clinical subtypes, either by locating a ‘zone of rarity’
between them, or by demonstrating a nonlinear
Molecular Psychiatry
relationship between the symptom profiles and a
validating variable, such as outcome or heritability.51
The inconsistent and poorly replicated results of
genetic linkage and association studies using the
diagnostic category as the sole schizophrenia phenotype are kindling discontent with the current nosology of schizophrenia, based on the recognition that
‘current nosology, now embedded in DSM-IV,
although useful for other purposes, does not define
phenotypes for genetic study’.194 It is now almost
certain that the current broad diagnostic concept
of schizophrenia does not demarcate a specific
genetic entity.
Schizophrenia geneticists are facing a particularly
difficult situation, seeking to discover specific genes
contributing to an overinclusive diagnostic category
for which no specific biological substrate has yet been
identified – most likely due to extensive genetic
heterogeneity and an admixture of different underlying disease subtypes. Many ‘top-down’ attempts
have been made to define an overarching disturbance
in schizophrenia, sought in ‘a weakening of the
mainsprings of volition’ and ‘loss of inner unity of
mental activities’;1 ‘structural loosening of associations’;45,305 ‘intrapsychic ataxia’;306 ‘neurointegrative
Subtyping schizophrenia
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a 0.9
0.8
0.7
-1 SD
MEAN
+ 1SD
CD giks
0.6
0.5
0.4
0.3
0.2
-1SD
MEAN
0.1
+ 1SD
0.0
CD
CS
b 1.0
0.8
-1SD
MEAN
+ 1SD
CS giks
0.6
0.4
-1SD
MEAN
+ 1SD
0.2
0.0
CD
CS
Figure 2 Genetic findings (linkage to chromosome 6p25–
22) in the Western Australian Family Study of Schizophrenia243 for 93 fully characterized families phenotypically
classified into a CD and a CS subtype, based on the
probands’ GoM (gik) scores on composite quantitative traits
CD and CS. ’ = linked family; J = nonlinked family. (a)
Distribution of the families on trait CD. (b) Distribution of
the families on trait CS.
defect’;307 ‘cognitive dysmetria’;308 and ‘dysconnection disorder’.309,310 Although intuitively appealing,
such formulations achieve little more than highlighting one or another of the many facets of a
complex syndrome. It is doubtful that a specific
genetic basis for a causa prima explaining the
phenomenology of schizophrenia will ever be found.
In contrast, it appears almost certain that the genetic
polymorphisms and neurobiological deficits underlying schizophrenia are multiple, varied, and partly
shared with predisposition to other disorders,
although they primarily express a ‘common final
pathway’ within the schizophrenia spectrum. Such
polymorphisms and deficits need not be intrinsically
pathological and may represent extreme variants of
normal structure and function. Above a certain
density threshold, their additive or nonlinear interaction could give rise to the diagnostic symptoms in
probands, but subclinical manifestations as endophenotype traits will be detectable in otherwise healthy
people, with a higher relative risk in biological
relatives of probands.
While reasoning along such lines is increasingly
common among researchers, the approaches proposed
to deal with the phenotype bottleneck in schizophrenia research differ substantially. On one hand, there
are proposals to abandon the ‘Kraepelinian dichotomy’ of schizophrenic and affective disorders in
favour of a ‘psychosis-spectrum illness’9,311 or a ‘shift
from narrow phenotypes to broad endophenotypes’,
associated with an even broader spectrum of abnormal behaviours and emotions.312 On the other hand,
there is an emerging ‘splitting’ agenda seeking and
testing narrowly constrained phenotypes that may tag
distinct variants or subtypes of schizophrenia,313
resolving at least part of its aetiological heterogeneity.
‘Candidate’ endophenotypes or markers of pathogenetic processes affecting cognition, brain morphology
and neurophysiology constitute the mainstay of this
approach. Several genetic linkage and association
studies employing such endophenotypes have produced promising results175,176,179,180,191,192,243,302,314 that
set a high priority for replication.
In the absence of direct evidence that schizophrenia
is either a homogeneous multifactorial disease or an
amalgamation of aetiologically distinct component
disorders, both ‘lumping’ and ‘splitting’ strategies are
legitimate and should be put to the test. The question
is, which approach holds at present greater promise
for advancing schizophrenia genetics? Two arguments
reinforce doubts that greater power for genetic studies
would be achieved by redefining the clinical boundaries of the phenotype. First, lumping different
disorders into an expanding phenotype of ‘psychosis’
runs against the grain of a large body of clinical
research indicating that psychotic symptoms in the
context of schizophrenia, other nonaffective psychotic illnesses, and affective disorders are phenomenologically different315 and may be influenced by
different genetic mechanisms, notwithstanding partial overlap in their effects. This would increase,
rather than decrease, heterogeneity. Secondly, despite
the availability of diagnostic criteria for research and
structured diagnostic instruments, misclassification
error in the fine-grain assessment of symptoms is
likely to remain a factor compounding further the
heterogeneity of family or case–control samples
collected at different sites and at different times.
Such heterogeneity is likely to be a serious problem in
whole-genome association studies, which require
very large case-control samples, feasible only by
827
Molecular Psychiatry
Subtyping schizophrenia
A Jablensky
828
pooling data collections from multiple sites. In
contrast, subtyping strategies are supported by
mounting evidence that sample stratification, particularly using quantitative traits as covariates, can
reduce heterogeneity and substantially increase
power.316–321 This approach has scored successes in
the genetics of other complex diseases and its
application to schizophrenia genetics will bring the
disorder into the mainstream of current research into
the common genetic diseases.
What kind of data would constitute supportive
evidence for distinct component disorders or subtypes within schizophrenia? Converging evidence
from endophenotype-based studies suggests that
measures of neurocognitive dysfunction arguably
provide the largest effect sizes and increases in
relative risk to relatives among a host of ‘candidate’
endophenotypes,236,237,241,281,294,295 being also cost efficient for phenotyping large samples. In particular,
several characteristic patterns of short-term and
working memory impairment against a background
of generalized cognitive deficit have been replicated
across studies and are present in a substantial
proportion (B50%) of schizophrenia patients. As
many of neurocognitive tests tap into several component processes, composite endophenotypes, integrating multiple neurocognitive measures, are more likely
to capture variation that is genetically influenced
than single-feature endophenotypes. The subtypes
generated by such approaches should be capable of
classifying individuals, rather than variables, and the
resulting classification is likely to be polythetic (based
on subsets of correlated features, rather than on the
presence of all defining attributes). Whether subtypes
are discrete taxa, that is, identifiable by marked areas
of discontinuity with other subtypes; dimensional,
representing continua with fuzzy boundaries; or
hybrid (class-quantitative, with dimensions superimposed on discrete categories), is testable with
taxometric methods common in biological classifications.323,324 In the context of genetic research, the most
significant criterion of their validity will be the gain
in predictive power and ‘process understanding’325 in
the sense of mechanistic explanation of disease
phenomena.
To sum up, we do not know whether schizophrenia
is a single process with pleiotropic manifestations at
the level of cerebral organization, or a collection of
aetiologically unrelated but dynamically interacting
processes. Although there are good grounds for the
suspicion that schizophrenia is not a homogeneous
entity, this has never been directly demonstrated,
mainly because few studies of the appropriate kind
have ever been undertaken. Its manifestations in toto
do not fit neatly into the proposed disease models,
although reasoning by analogy suggests an affinity to
other complex multifactorial diseases, such as cancer,
ischemic heart disease, or diabetes. For the time
being, the clinical concept of schizophrenia is
supported by empirical evidence that its multiple
facets form a broad syndrome with some internal
Molecular Psychiatry
cohesion and a characteristic evolution over time.
The dissection of the syndrome into modular endophenotypes with specific neurocognitive or neurophysiological underpinnings is beginning to be
perceived as a promising approach in schizophrenia
genetics. The current evidence is neither final nor
static, and needs to be re-examined as new concepts
and technologies coming from molecular genetics,
cognitive science, or brain imaging bring forth new
perspectives on disease causation and brain function.
This must be complemented by a refined, reliable,
and valid phenotyping not only at the level of
symptoms, but involving correlated neurobiological
features. The study of endophenotypes cutting across
the conventional diagnostic boundaries may reveal
unexpected patterns of associations with symptoms,
personality traits, or behaviour. The mapping of
clinical phenomenology on specific brain dysfunction
(and vice versa) is becoming feasible and the resulting
functional psychopathology322,326 may in the future
substantially recast the present nosology.
Acknowledgments
Work on the Western Australian Family Study of
Schizophrenia has been supported by grants (to AJ)
from the National Health and Medical Research
Council, Australia, and the North Metropolitan
Health Services, Perth, Western Australia. Invaluable
assistance with the bibliography and illustrations for
this review was provided by Lyn Kløve, Milan
Dragović and Vera Morgan.
References
1 Kraepelin E. Psychiatrie. 8 Auflage. Barth: Leipzig, 1909.
[Reprinted English translation: Dementia Praecox and Paraphrenia. Krieger Publishing: Huntington, New York, 1971].
2 World Health Organization. The ICD-10 Classification of Mental
and Behavioural Disorders. Diagnostic Criteria for Research.
WHO: Geneva, 1993.
3 American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, 4th edn. American Psychiatric
Association: Washington, DC, 1994.
4 Harrison PJ, Owen MJ. Genes for schizophrenia? Recent findings
and their pathophysiological implications. Lancet 2003; 361:
417–419.
5 Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol
Psychiatry 2004; 10: 40–68.
6 Norton N, Williams HJ, Owen MJ. An update on the genetics of
schizophrenia. Curr Opin Psychiatry 2006; 19: 158–164.
7 Bentall RP, Jackson HF, Pilgrim D. Abandoning the concept of
‘schizophrenia’: some implications of validity arguments for
psychological research into psychotic phenomena. Br J Clin
Psychol 1988; 27: 303–324.
8 Boyle M. Schizophrenia. A Scientific Delusion?. Routledge:
London and New York, 1990.
9 Craddock N, Owen MJ. The beginning of the end for the
Kraepelinian dichotomy. Br J Psychiatry 2005; 186: 364–366.
10 Jablensky A. Epidemiology of schizophrenia: the global burden of
disease and disability. Eur Arch Psychiatry Clin Neurosci 2000;
250: 274–285.
11 Jablensky A. The epidemiological horizon. In: Hirsch SR,
Weinberger DR (eds). Schizophrenia, 2nd edn. Blackwell
Publishing: Massachusetts, USA, 2003, pp. 203–231.
Subtyping schizophrenia
A Jablensky
12 Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper
JE et al. Schizophrenia: manifestations, incidence and course in
different cultures. A World Health Organization ten-country
study. Psychol Med Nonogr Suppl 1992; 20: 1–97.
13 DeLisi LE, Nasrallah HA. Current controversies in schizophrenia
research. I. Is schizophrenia a heterogeneous disorder? Schizophr
Res 1995; 17: 133.
14 Crow TJ. A continuum of psychosis, one human gene, and not
much else – the case for homogeneity. Schizophr Res 1995; 17:
135–145.
15 Goldberg TE, Weinberger DR. A case against subtyping in
schizophrenia. Schizophr Res 1995; 17: 147–152.
16 Cardno AG, Farmer AE. The case for or against heterogeneity in
the etiology of schizophrenia. The genetic evidence. Schizophr
Res 1995; 17: 153–159.
17 Tsuang MT, Faraone SV. The case for heterogeneity in the etiology
of schizophrenia. Schizophr Res 1995; 17: 161–175.
18 Heinrichs RW. Meta-analysis and the science of schizophrenia:
variant evidence or evidence of variants? Neurosci Biobehav Rev
2004; 28: 379–394.
19 Ghosh S, Watanabe RM, Valle TT, Hauser ER, Magnuson VL,
Langefeld CD et al. The Finland-United States Investigation of
Non-Insulin-Dependent Diabetes Mellitus Genetics (FUSION)
Study. I. An autosomal genome scan for genes that predispose
to Type 2 diabetes. Am J Hum Genet 2000; 67: 1174–1185.
20 Laitinen T, Daly MJ, Rioux JD, Kauppi P, Laprise C, Petäys T et al.
A susceptibility locus for asthma-related traits on chromosome 7
revealed by genome-wide scan in a founder population. Nat
Genet 2001; 28: 87–91 (letter).
21 Dekker MCJ, Bonifati V, van Duijn CM. Parkinson’s disease:
piecing together a genetic jigsaw. Brain 2003; 126: 1722–1733.
22 Shao Y, Cuccaro ML, Hauser ER, Raiford KL, Menold MM,
Wolpert CM et al. Fine mapping of autistic disorder to
chromosome 15q11–q13 by use of phenotypic subtypes. Am J
Hum Genet 2003; 72: 539–548.
23 Scott WK, Hauser ER, Schmechel DE, Welsh-Bohmer KA, Small
GW, Roses AD et al. Ordered-subsets linkage analysis detects
novel Alzheimer disease loci on chromosomes 2q34 and 15q22.
Am J Hum Genet 2003; 73: 1041–1051.
24 McKusick VA. On lumpers and splitters, or the nosology of
genetic disease. Perspect Biol Med 1969; Winter: 298–312.
25 Smith CAB. Testing for heterogeneity of recombinant values in
human genetics. Ann Hum Genet 1963; 27: 175–182.
26 Risch N. A new statistical test for linkage heterogeneity. Am J
Hum Genet 1988; 42: 353–364.
27 Rivolta C, Sharon D, De Angelis MM, Dryja TP. Retinitis
pigmentosa and allied diseases: numerous diseases, genes, and
inheritance patterns. Hum Mol Genet 2002; 11: 1219–1227.
28 Duerr RH. The genetics of inflammatory bowel disease.
Gastroenterol Clin North Am 2002; 31: 63–76.
29 Miterski B, Drynda S, Boschow G, Klein W, Oppermann J, Kekow
J et al. Complex genetic predisposition in adult and juvenile
rheumatoid arthritis. BMC Genet 2004; 5: 2.
30 Shen H, Liu Y, Liu P, Recker RR, Deng HW. Nonreplication in
genetic studies of complex diseases – lessons learned from
studies of osteoporosis and tentative remedies. J Bone Miner Res
2005; 20: 365–376.
31 Ammar N, Nelis E, Merlini L, Barisic N, Amouri R, Ceuterick C
et al. Identification of novel GDAP1 mutations causing autosomal
recessive Charcot-Marie-Tooth disease. Neuromuscul Disord
2003; 13: 720–728.
32 Stojkovic T, Latour P, Viet G, de Seze J, Hurtevent JF,
Vandenberghe A et al. Vocal cord and diaphragm paralysis, as
clinical features of a French family with autosomal recessive
Charcot-Marie-Tooth disease, associated with a new mutation in
the GDAP1 gene. Neuromuscul Disord 2004; 14: 261–264.
33 Cutting GR. Modifier genetics: cystic fibrosis. Annu Rev
Genomics Hum Genet 2005; 6: 237–260.
34 Cohn JA, Neoptolemos JP, Feng J, Yan J, Jiang Z, Greenhalf W et
al. Increased risk of idiopathic chronic pancreatitis in cystic
fibrosis carriers. Hum Mutat 2005; 26: 303–307.
35 Larriba S, Bonache S, Sarquella J, Ramos MD, Gimenez J, Bassas L
et al. Molecular evaluation of CFTR sequence variants in male
infertility of testicular origin. Int J Androl 2005; 28: 284–290.
36 Chesler EJ, Lu L, Shou S, Qu Y, Gu J, Wang J et al. Complex trait
analysis of gene expression uncovers polygenic and pleiotropic
networks that modulate nervous system function. Nat Genet
2005; 37: 233–242.
37 Zubenko GS. Do susceptibility loci contribute to the expression
of more than one mental disorder? A view from the genetics of
Alzheimer’s disease. Mol Psychiatry 2000; 5: 131–136.
38 Holliday E, Mowry B, Chant D, Nyholt D. The importance of
modelling heterogeneity in complex disease: application to
NIMH schizophrenia genetics initiative data. Hum Genet 2005;
117: 160–167.
39 Gottesman II, Bertelsen A. Confirming unexpressed genotypes for
schizophrenia. Risks in the offspring of Fischer’s Danish
identical and fraternal discordant twins. Arch Gen Psychiatry
1989; 46: 867–872.
40 Moffitt TE, Caspi A, Rutter M. Strategy for investigating
interactions between measured genes and measured environments. Arch Gen Psychiatry 2005; 62: 473–481.
41 Bearden CE, Reus VI, Freimer NB. Why genetic investigation of
psychiatric disorders is so difficult. Curr Opin Genet Dev 2004;
14: 280–286.
42 Tsuang MT, Lyons MJ, Faraone SV. Heterogeneity of schizophrenia. Conceptual models and analytic strategies. Br J
Psychiatry 1990; 156: 17–26.
43 Gibbons RD, Dorus E, Ostrow DG, Pandey GN, Davis JM, Levy DL.
Mixture distributions in psychiatric research. Biol Psychiatry
1984; 19: 935–961.
44 Moldin SO, Rice JP, Gottesman II, Erlenmeyer-Kimling L.
Psychometric deviance in offspring at risk for schizophrenia: II.
Resolving heterogeneity through admixture analysis. Psychiatry
Res 1990; 32: 311–322.
45 Bleuler E. Lehrbuch der Psychiatrie. Springer Verlag: Berlin, 1920
[Reprinted English translation: Textbook of Psychiatry. Arno
Press: New York, 1976.].
46 Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz
R. Diagnostic criteria for use in psychiatric research. Arch Gen
Psychiatry 1972; 26: 57–63.
47 Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex
trait. Evidence from a meta-analysis of twin studies. Arch Gen
Psychiatry 2003; 60: 1187–1192.
48 Badner JA, Gershon ES. Meta-analysis of whole-genome linkage
scans of bipolar disorder and schizophrenia. Mol Psychiatry
2002; 7: 405–411.
49 Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I
et al. Genome scan meta-analysis of schizophrenia and
bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003;
73: 34–48.
50 Wittgenstein L. Philosophische Bemerkunen II Band. Springer
Verlag: Vienna, 1964.
51 Kendell R, Jablensky A. Distinguishing between the validity
and utility of psychiatric diagnoses. Am J Psychiatry 2003; 160:
4–12.
52 Stassen HH, Scharfetter C, Winokur G, Angst J. Familial
syndrome patterns in schizophrenia, schizoaffective disorder,
mania, and depression. Eur Arch Psychiatry Clin Neurosci 1988;
237: 115–123.
53 Bebbington P. Recent findings in bipolar affective disorder.
Psychol Med 2004; 34: 767–776.
54 Keefe RSE, Frescka E, Apter SH, Davidson M, Macaluso JM,
Hirschowitz J et al. Clinical characteristics of Kraepelinian
schizophrenia: replication and extension of previous findings.
Am J Psychiatry 1996; 153: 806–811.
55 Bralet M-C, Loas G, Yon V, Maréchal V. Clinical characteristics
and risk factors for Kraepelinian subtype of schizophrenia:
replication of previous findings and relation to summer birth.
Psychiatry Res 2002; 111: 147–154.
56 Roy M-A, Lehoux C, Émond C, Laplante L, Bouchard R-H, Everett
J et al. A pilot neuropsychological study of Kraepelinian and nonKraepelinian schizophrenia. Schizophr Res 2003; 62: 155–163.
57 Kasanin J. The acute schizoaffective psychosis. Am J Psychiatry
1933; 90: 97–126.
58 Langfeld G. The prognosis of schizophrenia. Acta Psychiatria
Neurologica Scandinavica (Suppl 110). Munksgaard: Copenhagen, 1956.
829
Molecular Psychiatry
Subtyping schizophrenia
A Jablensky
830
59 Stephens JH, Astrup C. Prognosis in ‘process’ and ‘non-process’
schizophrenia. Am J Psychiatry 1963; 119: 945–953.
60 Tsuang MT, Winokur G. Criteria for subtyping schizophrenia.
Arch Gen Psychiatry 1974; 31: 43–47.
61 Schneider K. Klinische Psychopathologie, 8th edn. Thieme:
Stuttgart, 1950 [English translation Hamilton MW, Anderson
EW: Clinical Psychopathology. Grune and Stratton: New York,
1959.].
62 Spitzer RL, Endicott J, Robins E. Research diagnostic criteria.
Rationale and reliability. Arch Gen Psychiatry 1978; 35: 773–782.
63 American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, 3rd edn. American Psychiatric
Association: Washington, DC, 1980.
64 Wing JK, Cooper JE, Sartorius N. Measurement and Classification
of Psychiatric Symptoms. An Instruction Manual for the PSE and
CATEGO Program. Cambridge University Press: London,
England, 1974.
65 Loftus J, DeLisi LE, Crow TJ. Factor structure and familiality of
first-rank symptoms in sibling pairs with schizophrenia and
schizoaffective disorder. Br J Psychiatry 2000; 177: 15–19.
66 Cardno AG, Sham PC, Farmer AE, Murray RM, McGuffin P.
Heritability of Schneider’s first-rank symptoms. Br J Psychiatry
2002; 180: 35–38.
67 Kendler KS, Myers JM, O’Neill FA, Martin R, Murphy B,
MacLean CJ, et al. Clinical features of schizophrenia and linkage
to chromosomes 5q, 6p, 8p, and 10p in the Irish Study of
High-Density Schizophrenia Families. Am J Psychiatry 2000; 157:
402–408.
68 Leonhard K. Classification of Endogenous Psychoses and their
Differentiated Etiology, 2nd edn. Springer Verlag: Vienna, New
York, 1999.
69 American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, 3rd edn, Revised. American
Psychiatric Association: Washington, DC, 1987.
70 Franzek E, Beckmann H. Different genetic background of
schizophrenia spectrum psychoses: a twin study. Am J Psychiatry
1998; 155: 76–83.
71 Beckmann H, Franzek E, Stöber G. Genetic heterogeneity in
catatonic schizophrenia: a family study. Am J Med Genet
Neuropsychiatry Genet 1996; 67: 289–300.
72 Stöber G, Saar K, Rüschendorf F, Meyer J, Nürnberg G, Jatzke S et
al. Splitting schizophrenia: periodic catatonia-susceptibility
locus on chromosome 15q15. Am J Hum Genet 2000; 67:
1201–1207.
73 Stöber G, Seelow D, Rüschendorf F, Ekici A, Beckmann H, Reis A.
Periodic catatonia: confirmation of linkage to chromosome 15
and further evidence for genetic heterogeneity. Hum Genet 2002;
111: 323–330.
74 Meyer J, Ortega G, Schraut K, Nürnberg G, Rüschendorf F, Saar K
et al. Exclusion of the neuronal nicotinic acetylcholine receptor
alpha7 subunit gene as a candidate for catatonic schizophrenia in
a large family supporting the chromosome 15q13–22 locus.
Mol Psychiatry 2002; 7: 220–223.
75 Kury S, Rubie C, Moisan JP, Stöber G. Mutation analysis of the
zinc transporter gene SLC30A4 reveals no association with
periodic catatonia on chromosome 15q15. J Neural Transm
2003; 110: 1329–1332.
76 McKeane DP, Meyer J, Dobrin SE, Melmed KM, Ekawardhani S,
Tracy NA et al. No causative DLL4 mutations in periodic
catatonia patients from 15q15 linked families. Schizophr Res
2005; 75: 1–3.
77 Meyer J, Huberth A, Ortega G, Syagailo YV, Jatzke S, Mössner R
et al. A missense mutation in a novel gene encoding a putative
cation channel is associated with catatonic schizophrenia in a
large pedigree. Mol Psychiatry 2001; 6: 302–306.
78 Devaney JM, Donarum EA, Brown KM, Meyer J, Stöber G, Lesch
KP et al. No missense mutation of WKL1 in a subgroup of
probands with schizophrenia. Mol Psychiatry 2002; 7: 419–423.
79 Rüdin E. Studien über Vererbung und Enstehung geistiger
Störungen, I: Zur Vererbung und Neuenstehung der Dementia
praecox (Studies on the inheritance and origin of mental Illness,
I: The problem of the inheritance and primary origin of Dementia
praecox). Monographien aus dem Gesamtgebeit der Neurologie
und Psychiatrie, No. 12. Springer Verlag: Berlin, 1916.
Molecular Psychiatry
80 Kallman FJ. The Genetics of Schizophrenia. Augustin: New York,
1938.
81 Kendler KS, Gruenberg AM. An independent analysis of the
Danish Adoption Study of Schizophrenia. VI. The relationship
between psychiatric disorders as defined by DSM-III in the
relatives and adoptees. Arch Gen Psychiatry 1984; 41: 555–564.
82 Baron M, Risch N. The spectrum concept of schizophrenia:
evidence for a genetic-environmental continuum. J Psychiatry
Res 1987; 21: 257–267.
83 Rado S. Theory and therapy: the theory of schizotypal organization and its application to the treatment of decompensated
schizotypal behaviour. In: Scher SC, Davis HR (eds) The
Outpatient Treatment of Schizophrenia. Grune and Stratton:
New York, 1960.
84 Meehl PE. Schizotaxia, schizotypy, schizophrenia. American
Psychologist 1962; 17: 827–838 [Reprinted in Meehl PE. Psychodiagnosis: selected papers. University of Minnesota Press:
Minneapolis, 1973, pp 135–155.].
85 Chapman LJ, Chapman JP. Scales for rating psychotic and
psychotic-like experiences as continua. Schizophr Bull 1980; 6:
476–489.
86 Kety SS, Wender PH, Jacobsen B, Ingraham LJ, Jansson L, Faber B.
Mental illness in the biological and adoptive relatives of
schizophrenic adoptees. Arch Gen Psychiatry 1994; 51: 442–455.
87 Kendler KS, Neale MC, Walsh D. Evaluating the spectrum
concept of schizophrenia in the Roscommon Family Study.
Am J Psychiatry 1995; 152: 749–754.
88 Tienari P, Wynne LC, Läksy K, Moring J, Nieminen P, Sorri A et al.
Genetic boundaries of the schizophrenia spectrum: evidence
from the Finnish Adoptive Family Study of Schizophrenia. Am J
Psychiatry 2003; 160: 1587–1594.
89 Fogelson DL, Nuechterlein KH, Asarnow RF, Payne DL, Subotnik
KL, Giannini CA. The factor structure of schizophrenia spectrum
personality disorders: signs and symptoms in relatives of
psychotic patients from the UCLA family members study.
Psychiatry Res 1999; 87: 137–146.
90 Fosatti A, Maffei C, Battaglia M, Bagnato M, Donati D, Donini M
et al. Latent class analysis of DSM-IV schizotypal personality
disorder criteria in psychiatric patients. Schizophr Bull 2001; 27:
59–71.
91 Suhr JA, Spitznagel MB. Factor versus cluster models of
schizotypal traits. I. A comparison of unselected and highly
schizotypal samples. Schizophr Res 2001; 52: 231–239.
92 Kendler KS, McGuire M, Gruenberg AM, Walsh D. Schizotypal
symptoms and signs in the Roscommon Family Study. Arch Gen
Psychiatry 1995; 52: 296–303.
93 Torgersen S, Onstad S, Skre I, Edvardsen J, Kringlen E. ‘True’
schizotypal personality disorder: a study of co-twins and
relatives of schizophrenic probands. Am J Psychiatry 1993; 150:
1661–1667.
94 Fanous A, Gardner C, Walsh D, Kendler KS. Relationship
between positive and negative symptoms of schizophrenia and
schizotypal symptoms in nonpsychotic relatives. Arch Gen
Psychiatry 2001; 58: 669–673.
95 Cadenhead KS, Perry W, Shafer K, Braff DL. Cognitive functions
in schizotypal personality disorder. Schizophr Res 1999; 37:
123–132.
96 Nuechterlein KH, Asarnow RF, Subotnik KL, Fogelson DL, Payne
DL, Kendler KS et al. The structure of schizotypy: relationships
between neurocognitive and personality disorder features in
relatives of schizophrenic patients in the UCLA Family Study.
Schizophr Res 2002; 54: 121–130.
97 Asarnow RF, Nuechterlein KH, Asamen J, Fogelson D, Subotnik
KL, Zaucha K et al. Neurocognitive functioning and schizophrenia spectrum disorders can be independent expressions of
familial liability for schizophrenia in community control children: the UCLA Family Study. Schizophr Res 2002; 54: 111–120.
98 Dickey CD, McCarley RW, Shenton ME. The brain in schizotypal
personality disorder: a review of structural MRI and CT findings.
Harv Rev Psychiatry 2002; 10: 1–15.
99 Strauss JS, Carpenter Jr WT, Bartko JJ. The diagnosis and
understanding of schizophrenia. Part III. Speculations on the
processes that underlie schizophrenic symptoms and signs.
Schizophr Bull 1974; Winter: 61–69.
Subtyping schizophrenia
A Jablensky
100 Crow TJ. Molecular pathology of schizophrenia: more than one
disease process? BMJ 1980; 280: 66–68.
101 Andreasen NC, Olsen S. Negative v positive schizophrenia.
Definition and validation. Arch Gen Psychiatry 1982; 39:
789–794.
102 Crow TJ. The two-syndrome concept: origins and current status.
Schizophr Bull 1985; 11: 471–486.
103 Berrios GE. Positive and negative symptoms and Jackson. A
conceptual history. Arch Gen Psychiatry 1985; 42: 95–97.
104 Sommers AA. ‘Negative symptoms’: conceptual and methodological problems. Schizophr Bull 1985; 11: 364–379.
105 Tandon R, Greden JF. Negative symptoms of schizophrenia: the
need for conceptual clarity. Biol Psychiatry 1991; 30: 321–325.
106 Peralta V, Cuesta MJ, De Leon J. Positive and negative symptoms/
syndromes in schizophrenia: reliability and validity of different
diagnostic systems. Psychol Med 1995; 25: 43–50.
107 Jablensky A. Symptoms of schizophrenia. In: Henn F, Sartorius
N, Helmchen H, Lauter H (eds). Contemporary Psychiatry. Vol 3.
Specific Psychiatric Disorders. Springer Verlag: Berlin, 2001,
pp. 3–36.
108 Carpenter Jr WT, Heinrichs DW, Wagman AMI. Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry
1988; 145: 578–583.
109 Kirkpatrick B, Buchanan RW, Breier A, Carpenter Jr WT. Case
identification and stability of the deficit syndrome of schizophrenia. Psychiatry Res 1993; 47: 47–56.
110 Kirkpatrick B, Buchanan RW, Ross DE, Carpenter Jr WT. A
separate disease within the syndrome of schizophrenia.
Arch Gen Psychiatry 2001; 58: 165–171.
111 Kirkpatrick B, Ross DE, Walsh D, Karkowski L, Kendler KS.
Family characteristics of deficit and nondeficit schizophrenia in
the Roscommon family study. Schizophr Res 2000; 45: 57–64.
112 Buchanan RW, Strauss ME, Kirkpatrick B, Holstein C, Breier A,
Carpenter Jr WT. Neuropsychological impairments in deficit vs
nondeficit forms of schizophrenia. Arch Gen Psychiatry 1994; 51:
804–811.
113 Buchanan RW, Strauss ME, Breier A, Kirkpatrick B, Carpenter Jr
WT. Attentional impairments in deficit and nondeficit forms of
schizophrenia. Am J Psychiatry 1997; 154: 363–370.
114 Addington J, Addington D, Maticka-Tyndale E. Cognitive
functioning and positive and negative symptoms in schizophrenia. Schizophr Res 1991; 5: 123–134.
115 Ross DE. The deficit syndrome and eye tracking disorder may
reflect a distinct subtype within the syndrome of schizophrenia.
Schizophr Bull 2000; 26: 855–866.
116 Nkam I, Thibaut F, Denise P, Van Der Elst A, Ségard L, Brazo P
et al. Saccadic and smooth-pursuit eye movements in deficit and
non-deficit schizophrenia. Schizophr Res 2001; 48: 145–153.
117 Hong LE, Avila MT, Adami H, Elliot A, Thaker GK. Components
of the smooth pursuit function in deficit and nondeficit
schizophrenia. Schizophr Res 2003; 63: 39–48.
118 Arango C, Kirkpatrick B, Buchanan RW. Neurological signs and
the heterogeneity of schizophrenia. Am J Psychiatry 2000; 157:
560–565.
119 Galderisi S, Maj M, Mucci A, Cassano GB, Invernizzi G, Rossi A
et al. Historical, psychopathological, neurological, and neuropsychological aspects of deficit schizophrenia: a multicenter
study. Am J Psychiatry 2002; 159: 983–990.
120 Blanchard JJ, Horan WP, Collins LM. Examining the latent
structure of negative symptoms: is there a distinct subtype
of negative symptom schizophrenia? Schizophr Res 2005; 77:
151–165.
121 Bakker SC, Hoogendoorn MLC, Selten J-P, Verduijn W, Pearson
PL, Sinke RJ et al. Neuregulin 1: genetic support for schizophrenia subtypes. Mol Psychiatry 2004; 9: 1061–1063 (letter).
122 Hong LE, Wonodi I, Avila MT, Buchanan RW, McMahon RP,
Mitchell BD et al. Dihydropyrimidinase-related protein 2 (DRP-2)
gene and association to deficit and nondeficit schizophrenia. Am
J Med Genet B Neuropsychiatry Genet 2005; 136B: 8–11.
123 Lorr M, Klett CJ, McNair DM. Syndromes of Psychosis. Pergamon:
New York, 1963.
124 Liddle PF. The symptoms of chronic schizophrenia. A
re-examination of the positive-negative dichotomy. Br J
Psychiatry 1987; 151: 145–151.
125 Johnstone EC, Frith CD. Validation of three dimensions of
schizophrenic symptoms in a large unselected sample of
patients. Psychol Med 1996; 26: 669–679.
126 Grube BS, Bilder RM, Goldman RS. Meta-analysis of symptom
factors in schizophrenia. Schizophr Res 1998; 31: 113–120.
127 Smith DA, Mar CM, Turoff BK. The structure of schizophrenic
symptoms: a meta-analytic confirmatory factor analysis. Schizophr Res 1998; 31: 57–70.
128 Arndt S, Andreasen NC, Flaum M, Miller D, Nopoulos P. A
longitudinal study of symptom dimensions in schizophrenia.
Prediction and patterns of change. Arch Gen Psychiatry 1995; 52:
352–360.
129 Gureje O, Aderibigbe YA, Obikoya O. Three syndromes in
schizophrenia: validity in young patients with recent onset of
illness. Psychol Med 1995; 25: 715–725.
130 Emsley RA, Niehaus DJH, Mbanga NI, Oosthuizen PP, Stein DJ,
Maritz JS et al. The factor structure for positive and negative
symptoms in South African Xhosa patients with schizophrenia.
Schizophr Res 2001; 47: 149–157.
131 Ratakonda S, Gorman JM, Yale SA, Amador XF. Characterization
of psychotic conditions. Use of the domains of psychopathology
model. Arch Gen Psychiatry 1998; 55: 75–81.
132 Kay SR, Fizbein A, Opler LA. The Positive and Negative
Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull
1987; 13: 261–276.
133 Overall JE, Gorham DR. The Brief Psychiatric Rating Scale
(BPRS): recent developments in ascertainment and scaling.
Psychopharmacol Bull 1988; 24: 97–99.
134 McGuffin P, Farmer AE, Harvey IH. A polydiagnostic application
of operational criteria in studies of psychotic illness: development and reliability of the OPCRIT system. Arch Gen Psychiatry
1991a; 48: 764–770.
135 Rey E-R, Bailer J, Bräuer W, Händel M, Laubenstein D, Stein A.
Stability trends and longitudinal correlations of negative and
positive syndromes within a three-year follow-up of initially
hospitalized schizophrenics. Acta Psychiatry Scand 1994; 90:
405–412.
136 Lindenmayer J-P, Grochowski S, Hyman RB. Five factor model of
schizophrenia: replication across samples. Schizophr Res 1995;
14: 229–234.
137 Serretti A, Rietschel M, Lattauda E, Krauss H, Schulze TG, Müller
DJ et al. Major psychoses symptomatology: factor analysis of 2241
psychotic subjects. Eur Arch Psychiatry Clin Neurosci 2001; 251:
193–198.
138 Cardno AG, Jones LA, Murphy KC, Asherson P, Scott LC,
Williams J et al. Factor analysis of schizophrenic symptoms
using the OPCRIT checklist. Schizophr Res 1996; 22: 233–239.
139 Lenzenweger MF, Dworkin RH. The dimensions of schizophrenia
phenomenology. Not one or two, at least three, perhaps four. Br J
Psychiatry 1996; 168: 432–440.
140 White L, Harvey PD, Opler L, Lindenmayer JP, The PANSS Study
Group. Empirical assessment of the factorial structure of clinical
symptoms in schizophrenia. Psychopathology 1997; 30: 263–274.
141 McGrath JA, Nestadt G, Liang KY, Lasseter VK, Wolyniec PS,
Fallin MD et al. Five latent factors underlying schizophrenia:
analysis and relationship to illnesses in relatives. Schizophr Bull
2004; 30: 855–873.
142 Cuesta MJ, Peralta V. Integrating psychopathological dimensions
in functional psychoses: a hierarchical approach. Schizophr Res
2001; 52: 215–229.
143 Farmer AE, McGuffin P, Spitznagel EL. Heterogeneity in
schizophrenia: a cluster-analytic approach. Psychiatry Res
1983; 8: 1–12.
144 Dollfus S, Everitt B, Ribeyre JM, Assouly-Besse F, Sharp C, Petit
M. Identifying subtypes of schizophrenia by cluster analyses.
Schizophr Bull 1996; 22: 545–555.
145 McCutcheon AL. Latent Class Analysis. Sage Publications:
Beverly Hills, California, 1987.
146 Sham PC, Castle DJ, Wessely S, Farmer AE, Murray RM. Further
exploration of a latent class typology of schizophrenia. Schizophr
Res 1996; 20: 105–115.
147 Kendler KS, Karkowski LM, Walsh D. The structure of psychosis.
Latent class analysis of probands from the Roscommon Family
Study. Arch Gen Psychiatry 1998; 55: 492–499.
831
Molecular Psychiatry
Subtyping schizophrenia
A Jablensky
832
148 Murray V, McKee I, Miller PM, Young D, Muir WJ, Pelosi AJ et al.
Dimensions and classes of psychosis in a population cohort: a
four-class, four-dimension model of schizophrenia and affective
psychoses. Psychol Med 2005; 35: 499–510.
149 Woodbury MA, Clive J, Garson A. Mathematical typology: a grade
of membership technique for obtaining disease definition.
Comput Biomed Res 1978; 11: 277–298.
150 Manton KG, Woodbury MA, Tolley DH. Statistical Applications
Using Fuzzy Sets. John Wiley: New York, 1994.
151 Manton KG, Korten A, Woodbury MA, Anker M, Jablensky A.
Symptom profiles of psychiatric disorders based on graded
disease classes: an illustration using data from the WHO
International Pilot Study of Schizophrenia. Psychol Med 1994;
24: 133–144.
152 Lewis SW, Reveley AM, Reveley MA, Chitkara B, Murray RM.
The familial/sporadic distinction as a strategy in schizophrenia
research. Br J Psychiatry 1987; 151: 306–313.
153 Kendler KS, Hayes P. Familial and sporadic schizophrenia: a
symptomatic, prognostic, and EEG comparison. Am J Psychiatry
1982; 139: 1557–1562.
154 Gottesman II, McGuffin P, Farmer AE. Clinical genetics as clues
to the ‘real’ genetics of schizophrenia (A decade of modest gains
while playing for time). Schizophr Bull 1987; 13: 23–47.
155 Lyons MJ, Kremen WS, Tsuang MT, Faraone SV. Investigating
putative genetic and environmental forms of schizophrenia:
methods and findings. Int Rev Psychiatr 1989; 1: 259–276.
156 Roy M-A, Crowe RR. Validity of the familial and sporadic
subtypes of schizophrenia. Am J Psychiatry 1994; 151: 805–814.
157 Gorwood P, Leboyer M, Jay M, Payan C, Feingold J. Gender and
age at onset in schizophrenia: impact of family history. Am J
Psychiatry 1995; 152: 208–212.
158 Alda M, Ahrens B, Lit W, Dvorakova M, Labelle A, Zvolsky P
et al. Age at onset in familial and sporadic schizophrenia. Acta
Psychiatry Scand 1996; 93: 447–450.
159 Roy M-A, Flaum MA, Gupta S, Jaramillo L, Andreasen NC.
Epidemiological and clinical correlates of familial and sporadic
schizophrenia. Acta Psychiatry Scand 1994; 89: 324–328.
160 Lewis SW, Murray RM. Obstetric complications, neurodevelopmental deviance, and risk of schizophrenia. J Psychiatry Res
1987; 21: 413–421.
161 Schwarzkopf SB, Nasrallah HA, Olson SC. Perinatal complications and genetic loading in schizophrenia: preliminary findings.
Psychiatry Res 1989; 27: 233–239.
162 O’Callaghan E, Larkin C, Kinsella A, Waddington JL. Obstetric
complications, the putative familial-sporadic distinction, and
tardive dyskinesia in schizophrenia. Br J Psychiatry 1990; 157:
578–584.
163 Shur E. Season of birth in high and low genetic risk schizophrenics. Br J Psychiatry 1982; 140: 410–415.
164 O’Callaghan E, Gibson T, Colohan HA, Walshe D, Buckley P,
Larkin C et al. Season of birth in schizophrenia: evidence for
confinement of an excess of winter births to patients without
a family history of mental disorder. Br J Psychiatry 1991; 158:
764–769.
165 Reveley AM, Reveley MA, Murray RM. Cerebral ventricular
enlargement in non-genetic schizophrenia: a controlled twin
study. Br J Psychiatry 1984; 144: 89–93.
166 Schwarzkopf SB, Nasrallah HA, Olson SC, Bogerts B, McLaughlin JA, Mitra T. Family history and brain morphology in
schizophrenia: an MRI study. Psychiatry Res 1991; 40: 49–60.
167 Bartels M, Mann K, Friedrich W. Tardive dyskinesia: marked
predominance of nongenetic schizophrenia. Biol Psychiatry
1985; 20: 94–119.
168 McCreadie RG, Hall DJ, Berry IJ, Robertson LJ, Ewing JI, Geals
MF. The Nithdale schizophrenia surveys: X. Obstetrical complications, family history and abnormal movements. Br J Psychiatry
1992; 161: 799–805.
169 Griffiths TD, Sigmundsson T, Takei N, Frangou S, Birkett PB,
Sharma T et al. Minor physical anomalies in familial and
sporadic schizophrenia: the Maudsley family study. J Neurol
Neurosurg Psychiatry 1998; 64: 56–60.
170 Walker E, Shaye J. Familial schizophrenia. A predictor of
neuromotor and attentional abnormalities in schizophrenia. Arch
Gen Psychiatry 1982; 39: 1153–1156.
Molecular Psychiatry
171 Jones PB, Owen MJ, Lewis SW, Murray RM. A case-control study
of family history and cerebral cortical abnormalities in
schizophrenia. Acta Psychiatry Scand 1993; 87: 6–12.
172 Malaspina D, Harkavy-Friedman J, Corcoran C, Mujica-Parodi L,
Printz D, Gorman JM et al. Resting neural activity distinguishes
subgroups of schizophrenic patients. Biol Psychiatry 2004; 56:
931–937.
173 Weiss KM, Chakraborty R, Majumder PP. Problems in the
assessment of relative risk of chronic disease among biological
relatives of affected individuals. J Chron Dis 1982; 35: 539–551.
174 Eaves LJ, Kendler KS, Schulz SC. The familial sporadic
classification: its power for the resolution of genetic
and environmental etiologic factors. J Psychiatry Res 1986; 20:
115–130.
175 Brzustowicz LM, Honer WG, Chow EWC, Hogan J, Hodgkinson K,
Bassett AS. Use of a quantitative trait to map a locus associated
with severity of positive symptoms in familial schizophrenia to
chromosome 6p. Am J Hum Genet 1997; 61: 1388–1396.
176 Pulver AE, Mulle J, Nestadt G, Swartz KL, Blouin J-L, Dombroski
B et al. Genetic heterogeneity in schizophrenia: stratification of
genome scan data using co-segregating related phenotypes. Mol
Psychiatry 2000; 5: 650–653.
177 Chiu YF, McGrath JA, Thornquist MH, Wolyniec PS, Nestadt G,
Swartz KL et al. Genetic heterogeneity in schizophrenia II:
conditional analyses of affected schizophrenia sibling pairs
provide evidence for an interaction between markers on
chromosome 8p and 14q. Mol Psychiatry 2002; 7: 658–664.
178 Fanous AH, Neale MC, Straub RE, Webb BT, O’Neill AF, Walsh D
et al. Clinical features of psychotic disorders and polymorphisms
in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family
based association study. Am J Med Genet B Neuropsychiatry
Genet 2004; 125B: 69–78.
179 Fanous A, van den Oord E, Riley B, Aggen SH, Neale MC, O’Neill
FA et al. Relationship between a high-risk haplotype in the
dystrobrevin-binding protein 1 (DTNBP1) gene and clinical
features of schizophrenia. Am J Psychiatry 2005; 162: 1–9.
180 Burdick KE, Lencz T, Funke B, Finn CT, Szeszko PR, Kane JM
et al. Genetic variation in DTNBP1 influences general cognitive
ability. Hum Mol Genet 2006; 15: 1563–1568.
181 Murphy KC. The behavioural phenotype in velo-cardio-facial
syndrome. J Intellect Disabil Res 2004; 48: 524–530.
182 Liu H, Abecasis GR, Heath SC, Knowles A, Demars S, Chen YJ
et al. Genetic variation in the 22q11 locus and susceptibility to
schizophrenia. Proc Natl Acad Sci USA 2002; 99: 16859–16864.
183 Swillen A, Vogels A, Devriendt K, Fryns JP. Chromosome 22q11
deletion syndrome: update and review of the clinical features,
cognitive-behavioral spectrum, and psychiatric complications.
Am J Med Genet C Semin Med Genet 2000; 97: 128–135.
184 Horowitz A, Shifman S, Rivlin N, Pisanté A, Darvasi A. A survey
of the 22q11 microdeletion in a large cohort of schizophrenia
patients. Schizophr Res 2005; 73: 263–267.
185 Sporn A, Addington A, Reiss AL, Dean M, Gogtay N, Potocnik U
et al. 22q11 deletion syndrome in childhood onset schizophrenia: an update. Mol Psychiatry 2004; 9: 225–226 (letter).
186 Bassett AS, Chow EWC, Abdel Malik P, Gheorghiu M, Husted J,
Weksberg R. The schizophrenia phenotype in 22q11 deletion
syndrome. Am J Psychiatry 2003; 160: 1580–1586.
187 van Amelsvoort T, Henry J, Morris R, Owen M, Linszen D,
Murphy K et al. Cognitive deficits associated with schizophrenia
in velo-cardio-facial syndrome. Schizophr Res 2004; 70: 223–232.
188 Chow EWC, Zipursky RB, Mikulis DJ, Bassett AS. Structural
brain abnormalities in patients with schizophrenia and 22q11
deletion syndrome. Biol Psychiatry 2002; 51: 208–215.
189 Schaer M, Schmitt JE, Glaser B, Lazeyras F, Delavelle J, Eliez S.
Abnormal patterns of cortical gyrification in velo-cardio-facial
syndrome (deletion 22q11.2): an MRI study. Psychiatry Res
Neuroim 2006; 146: 1–11.
190 Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS,
Semple CAM et al. Disruption of two novel genes by a
translocation co-segregating with schizophrenia. Hum Mol Genet
2000; 9: 1415–1423.
191 Cannon TD, Hennah W, van Erp TGM, Thompson PM, Lönnqvist
J, Huttunen M et al. Association of DISC1/TRAX haplotypes with
schizophrenia, reduced prefrontal gray matter, and impaired
Subtyping schizophrenia
A Jablensky
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
short-and long-term memory. Arch Gen Psychiatry 2005; 62:
1205–1213.
Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM,
Kane JM et al. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16: 1399–1402.
Cromwell RL, Elkins IJ, McCarthy ME, O’Neil TS. Searching for
the phenotypes of schizophrenia. Acta Psychiatry Scand 1994;
90 (Suppl 384): 34–39.
Ginsburg BE, Werick TM, Escobar JI, Kugelmass S, Treanor JJ,
Wendtland L. Molecular genetics of psychopathologies: a search
for simple answers to complex problems. Behav Genet 1996; 26:
325–333.
Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D,
Mallet J. Psychiatric genetics: search for phenotypes. Trends
Neurosci 1998; 21: 102–105.
Almasy L, Blangero J. Endophenotypes as quantitative risk
factors for psychiatric disease: rationale and study design. Am J
Med Genet Neuropsychiatry Genet 2001; 105: 42–44.
Gottesman II, Shields J. Genetic theorizing and schizophrenia. Br
J Psychiatry 1973; 122: 15–30.
Gottesman II, Gould TD. The endophenotype concept in
psychiatry: etymology and strategic intentions. Am J Psychiatry
2003; 160: 636–645.
Keating M, Dunn C, Atkinson D, Timothy K, Vincent GM, Leppert
M. Consistent linkage of the long-QT syndrome to the Harvey
ras-1 locus on chromosome 11. Am J Hum Genet 1991; 49:
1335–1339.
Leppert M, Burt R, Hughes JP, Samowitz W, Nakamura Y,
Woodward S et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of
adenomatous polyps. New Engl J Med 1990; 322: 904–908.
Lalouel JM, Le Mignon L, Simon M, Fauchet R, Bourel M, Rao DC
et al. Genetic analysis of idiopathic hemochromatosis using
both qualitative (disease status) and quantitative (serum iron)
information. Am J Hum Genet 1985; 37: 700–718.
Greenberg DA, Delgado-Escueta AV, Widelitz H, Sparkes RS,
Treiman L, Maldonado HM et al. Juvenile myoclonic epilepsy
(JME) may be linked to the BF and HLA loci on human
chromosome 6. Am J Med Genet 1988; 31: 185–192.
Holzman PS, Solomon CM, Levin S, Waternaux CS. Pursuit eye
movement dysfunctions in schizophrenia. Family evidence for
specificity. Arch Gen Psychiatry 1984; 41: 136–139.
Holzman PS. Behavioral markers of schizophrenia useful for
genetic studies. J Psychiatry Res 1992; 26: 427–445.
Sponheim SR, Iacono WG, Thuras PD, Beiser M. Using biological
indices to classify schizophrenia and other psychotic patients.
Schizophr Res 2001; 50: 139–150.
Braff DL, Geyer MA, Light GA, Sprock J, Perry W, Cadenhead KS
et al. Impact of prepulse characteristics on the detection of
sensorimotor gating deficits in schizophrenia. Schizophr Res
2001; 49: 171–178.
Joober R, Zarate J-M, Rouleau G-A, Skamene E, Boksa P.
Provisional mapping of quantitative trait loci modulating the
acoustic startle response and prepulse inhibition of acoustic
startle. Neuropsychopharmacology 2002; 27: 765–781.
Kumari V, Das M, Zachariah E, Ettinger U, Sharma T. Reduced
prepulse inhibition in unaffected siblings of schizophrenia
patients. Psychophysiology 2005; 42: 588–594.
Adler LE, Freedman R, Ross RG, Olincy A, Waldo MC.
Elementary phenotypes in the neurobiological and genetic study
of schizophrenia. Biol Psychiatry 1999; 46: 8–18.
Myles-Worsley M, Coon H, McDowell J, Brenner C, Hoff M, Lind
B et al. Linkage of a composite inhibitory phenotype to a
chromosome 22q locus in eight Utah families. Am J Med Genet
Neuropsychiatry Genet 1999; 88: 544–550.
Freedman R, Adams CE, Adler LE, Bickford PC, Gault J, Harris JG
et al. Inhibitory neurophysiological deficit as a phenotype for
genetic investigation of schizophrenia. Am J Med Genet C Semin
Med Genet 2000; 97: 58–64.
Bramon E, McDonald C, Croft RJ, Landau S, Filbey F, Gruzelier JH
et al. Is the P300 wave an endophenotype for schizophrenia? A
meta-analysis and a family study. NeuroImage 2005; 27: 960–968.
McCarley RW, Niznikiewicz MA, Salisbury DF, Nestor PG,
O’Donnell BF, Hirayasu Y et al. Cognitive dysfunction in
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
schizophrenia: unifying basic research and clinical aspects. Eur
Arch Psychiatry Clin Neurosci 1999; 249(Suppl 4): IV/69–IV/82.
Michie PT, Innes-Brown H, Todd J, Jablensky AV. Duration
mismatch negativity in biological relatives of patients with
schizophrenia spectrum disorders. Biol Psychiatry 2002; 52:
749–758.
Baldeweg T, Klugman A, Gruzelier J, Hirsch SR. Mismatch
negativity potentials and cognitive impairment in schizophrenia.
Schizophr Res 2004; 69: 203–217.
Butler PD, Zemon V, Schechter I, Saperstein AM, Hoptman MJ,
Lim KO et al. Early-stage visual processing and cortical
amplification deficits in schizophrenia. Arch Gen Psychiatry
2005; 62: 495–504.
Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a
meta-analysis. Schizophr Res 2005; 76: 1–23.
Holzman PS, Kringlen E, Matthysse S, Flanagan SD, Lipton RB,
Cramer G et al. A single dominant gene can account for eye
tracking dysfunctions and schizophrenia in offspring of discordant twins. Arch Gen Psychiatry 1988; 45: 641–647.
Levy DL, Lajonchere CM, Dorogusker B, Min DK, Lee S,
Tartaglini A et al. Quantitative characterization of eye tracking
dysfunction in schizophrenia. Schizophr Res 2000; 42: 171–185.
Tregellas JR, Tanabe JI, Miller DE, Ross RG, Olincy A, Freedman
R. Neurobiology of smooth pursuit eye movement deficits
in schizophrenia: an fMRI study. Am J Psychiatry 2004; 161:
315–321.
Matthysse S, Holzman PS, Gusella JF, Levy DL, Harte CB,
Jørgensen Å et al. Linkage of eye movement dysfunction to
chromosome 6p in schizophrenia: Additional evidence. Am J
Med Genet B Psychiatry Genet 2004; 128B: 30–36.
Clementz BA, McDowell JE, Zisook S. Saccadic system functioning among schizophrenia patients and their first-degree relatives.
J Abnorm Psychol 1994; 103: 277–287.
Malone SM, Iacono WG. Error rate on the antisaccade task:
heritability and developmental change in performance among
preadolescent and late-adolescent female twin youth. Psychophysiology 2002; 39: 664–673.
Levy DL, O’Driscoll G, Matthysse S, Cook SR, Holzman PS,
Mendell NR. Antisaccade performance in biological relatives of
schizophrenia patients: a meta-analysis. Schizophr Res 2004; 71:
113–125.
Louchart-de la Chapelle S, Nkam I, Houy E, Belmont A, Ménard
J-F, Roussignol A-C et al. A concordance study of three
electrophysiological measures in schizophrenia. Am J Psychiatry
2005; 162: 466–474.
Price GW, Michie PT, Johnston J, Innes-Brown H, Kent A, Clissa P
et al. A multivariate electrophysiological endophenotype, from a
unitary cohort, shows greater research utility than any single
feature in the Western Australian Family Study of Schizophrenia.
Biol Psychiatry, Pre-publication version available online 20
December 2005, http:///www.sciencedirect.com/science/article/
B6T4S-4HVDJK7-3/2/da823e5eacd44ad891541fe0c0c3acfe.
Marcelis M, Suckling J, Woodruff P, Hofman P, Bullmore E, van
Os J. Searching for a structural endophenotype in psychosis
using computational morphometry. Psychiatry Res Neuroim
2003; 122: 153–167.
McDonald C, Bullmore ET, Sham PC, Chitnis X, Wickham H,
Bramon E et al. Association of genetic risks for schizophrenia and
bipolar disorder with specific and generic brain structural
endophenotypes. Arch Gen Psychiatry 2004; 61: 974–984.
Faraone SV, Seidman LJ, Kremen WS, Kennedy D, Makris N,
Caviness VS et al. Structural brain abnormalities among relatives
of patients with schizophrenia: implications for linkage studies.
Schizophr Res 2003; 60: 125–140.
Davatzikos C, Shen D, Gur RC, Wu X, Liu D, Fan Y et al. Wholebrain morphometric study of schizophrenia revealing a spatially
complex set of focal abnormalities. Arch Gen Psychiatry 2005; 62:
1218–1227.
Davidson LL, Heinrichs RW. Quantification of frontal and
temporal lobe brain-imaging findings in schizophrenia: a metaanalysis. Psychiatry Res Neuroim 2003; 122: 69–87.
Garver DL, Nair TR, Christensen JD, Holcomb J, Ramberg J,
Kingsbury S. Atrophic and static (neurodevelopmental)
schizophrenic psychoses: premorbid functioning, symptoms
833
Molecular Psychiatry
Subtyping schizophrenia
A Jablensky
834
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
and neuroleptic response. Neuropsychopharmacology 1999; 21:
82–92.
Nuechterlein KH, Asarnow RF, Subotnik KL, Fogelson DL,
Ventura J, Torquato RD et al. Neurocognitive vulnerability factors
for schizophrenia: convergence across genetic risk studies and
longitudinal trait-state studies. In: Lenzenweger MF and Dworkin
RH (eds). Origins and Development of Schizophrenia: Advances
in Experimental Psychopathology. American Psychological
Association: Washington, DC, 1998, pp 299–327.
Egan MF, Goldberg TE, Gscheidle T, Weirich M, Bigelow LB,
Weinberger DR. Relative risk of attention deficits in siblings
of patients with schizophrenia. Am J Psychiatry 2000; 157:
1309–1316.
Chen WJ, Chang C-H, Liu SK, Hwang TJ, Hwu H-G. Sustained
attention deficits in nonpsychotic relatives of schizophrenic
patients: a recurrence risk ratio analysis. Biol Psychiatry 2004; 55:
995–1000.
Paulsen JS, Heaton RK, Sadek JR, Perry W, Delis DC, Braff D
et al. The nature of learning and memory impairments in
schizophrenia. J Int Neuropsychol Soc 1995; 1: 88–99.
Turetsky BI, Moberg PJ, Mozley LH, Moelter ST, Agrin RN, Gur
RC et al. Memory-delineated subtypes of schizophrenia: relationship to clinical, neuroanatonical, and neurophysiological
measures. Neuropsychology 2002; 16: 481–490.
Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T,
Kolachana BS et al. Executive subprocesses in working memory.
Relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 2003; 60: 889–896.
Kremen WS, Seidman LJ, Faraone SV, Toomey R, Tsuang MT.
Heterogeneity of schizophrenia: a study of individual neuropsychological profiles. Schizophr Res 2004; 71: 307–321.
Glahn DC, Therman S, Manninen M, Huttunen M, Kaprio J,
Lönnqvist J et al. Spatial working memory as an endophenotype
for schizophrenia. Biol Psychiatry 2003; 53: 624–626.
Dickinson D, Iannone VN, Wilk CM, Gold JM. General and
specific cognitive deficits in schizophrenia. Biol Psychiatry 2004;
55: 826–833.
Bruder GE, Wexler BE, Sage MM, Gil RB, Gorman JM. Verbal
memory in schizophrenia: additional evidence of subtypes
having different cognitive deficits. Schizophr Res 2004; 68:
137–147.
Hallmayer JF, Kalaydjieva L, Badcock J, Dragovic M, Howell S,
Michie PT et al. Genetic evidence for a distinct subtype of
schizophrenia characterized by pervasive cognitive deficit. Am J
Hum Genet 2005; 77: 468–476.
Griffiths TD, Sigmundsson T, Takei N, Rowe D, Murray RM.
Neurological abnormalities in familial and sporadic schizophrenia. Brain 1998; 121: 191–203.
Kinney DK, Yurgelun-Todd DA, Woods BT. Neurologic signs of
cerebellar and cortical sensory dysfunction in schizophrenics
and their relatives. Schizophr Res 1999; 35: 99–104.
Gourion D, Goldberger C, Bourdel M-C, Bayle FJ, Millet B,
Olie J-P et al. Neurological soft-signs and minor physical
anomalies in schizophrenia: differential transmission within
families. Schizophr Res 2003; 63: 181–187.
Keshavan MS, Sanders RD, Sweeney JA, Diwadkar VA, Goldstein
G, Pettegrew JW et al. Diagnostic specificity and neuroanatomical
validity of neurological abnormalities in first-episode psychoses.
Am J Psychiatry 2003; 160: 1298–1304.
Dragovic M, Hammond G, Badcock JC, Jablensky A. Laterality
phenotypes in patients with schizophrenia, their siblings and
controls: associations with clinical and cognitive variables.
Br J Psychiatry 2005; 187: 221–228.
Clementz BA, Iacono WG, Ficken J, Beiser M. A family study of
nailfold plexus visibility in psychotic disorders. Biol Psychiatry
1992b; 31: 378–390.
McGrath J, El-Saadi O, Grim V, Cardy S, Chapple B, Chant D et al.
Minor physical anomalies and quantitative measures of the head
and face in patients with psychosis. Arch Gen Psychiatry 2002;
59: 458–464.
Goldberg TE, David A, Gold JM. Neurocognitive deficits in
schizophrenia. In: Hirsch SR and Weinberger DR (eds)
Schizophrenia, 2nd edn. Blackwell Publishing: Cambridge,
Massachusetts, 2003, pp. 168–184.
Molecular Psychiatry
252 Phillips WA, Silverstein SM. Convergence of biological and
psychological perspectives on cognitive coordination in schizophrenia. Behav Brain Sci 2003; 26: 65–138.
253 Heinrichs RW. The primacy of cognition in schizophrenia. Am
Psychol 2005; 60: 229–242.
254 Kremen WS, Buka SL, Seidman LJ, Goldstein JM, Koren D,
Tsuang MT. IQ decline during childhood and adult psychotic
symptoms in a community sample: a 19-year longitudinal study.
Am J Psychiatry 1998; 155: 672–677.
255 Mohamed S, Paulsen JS, O’Leary D, Arndt S, Andreasen N.
Generalized cognitive deficits in schizophrenia. A study of firstepisode patients. Arch Gen Psychiatry 1999; 56: 749–754.
256 Bilder RM, Goldman RS, Robinson D, Reiter G, Bell L, Bates JA
et al. Neuropsychology of first-episode schizophrenia: initial
characterization and clinical correlates. Am J Psychiatry 2000;
157: 549–559.
257 Johnstone EC, Ebmeier KP, Miller P, Owens DGC, Lawrie SM.
Predicting schizophrenia: findings from the Edinburgh High-Risk
Study. Br J Psychiatry 2005; 186: 18–25.
258 Brewer WJ, Francey SM, Wood SJ, Jackson HJ, Pantelis C, Phillips
LJ et al. Memory impairments identified in people at ultra-high
risk for psychosis who later develop first-episode psychosis. Am
J Psychiatry 2005; 162: 71–78.
259 Torrey EF. Studies of individuals never treated with antipsychotic medications: a review. Schizophr Res 2002; 58: 101–115.
260 Hoff AL, Sakuma M, Wieneke M, Horon R, Kushner M, DeLisi LE.
Longitudinal neuropsychological follow-up study of patients
with first-episode schizophrenia. Am J Psychiatry 1999; 156:
1336–1341.
261 Heaton RK, Gladsjo JA, Palmer BW, Kuck J, Marcotte TD, Jeste
DV. Stability and course of neuropsychological deficits in
schizophrenia. Arch Gen Psychiatry 2001; 58: 24–32.
262 Kurtz MM. Neurocognitive impairment across the lifespan in
schizophrenia: an update. Schizophr Res 2005; 74: 15–26.
263 Heinrichs RW, Ruttan L, Zakzanis KK, Case D. Parsing schizophrenia with neurocognitive tests: evidence of stability and
validity. Brain Cogn 1997; 35: 207–224.
264 Caspi A, Reichenberg A, Weiser M, Rabinowitz J, Kaplan Z,
Knobler H et al. Cognitive performance in schizophrenia patients
assessed before and following the first psychotic episode.
Schizophr Res 2003; 65: 87–94.
265 Kelly C, Sharkey V, Morrison G, Allardyce J, McCreadie RG.
Nithsdale Schizophrenia Surveys 20. Cognitive function in a
catchment-area-based population of patients with schizophrenia.
Br J Psychiatry 2000; 177: 348–353.
266 Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996; 153:
321–330.
267 Gold JM, Goldberg RW, McNary SW, Dixon LB, Lehman AF.
Cognitive correlates of job tenure among patients with severe
mental illness. Am J Psychiatry 2002; 159: 1395–1402.
268 Racenstein JM, Harrow M, Reed R, Martin E, Herbener E, Penn
DL. The relationship between positive symptoms and instrumental work functioning in schizophrenia: a 10 year follow-up
study. Schizophr Res 2002; 56: 95–103.
269 Rempfer MV, Hamera EK, Brown CE, Cromwell RL. The relations
between cognition and the independent living skill of shopping
in people with schizophrenia. Psychiatry Res 2003; 117: 103–112.
270 Revheim N, Schecter I, Kim D, Silipo G, Allingham B, Butler P
et al. Neurocognitive and symptom correlates of daily problemsolving skills in schizophrenia. Schizophr Res 2006; 83: 237–245.
271 O’Leary DS, Flaum M, Kesler ML, Flashman LA, Arndt S,
Andreasen NC. Cognitive correlates of the negative, disorganized,
and psychotic symptom dimensions of schizophrenia. J Neuropsychiatry Clin Neurosci 2000; 12: 4–15.
272 Hill SK, Ragland JD, Gur RC, Gur RE. Neuropsychological
differences among empirically derived clinical subtypes of
schizophrenia. Neuropsychology 2001; 15: 492–501.
273 Brazo P, Marié RM, Halbecq I, Benali K, Segard L, Delamillieure P
et al. Cognitive patterns in subtypes of schizophrenia.
Eur Psychiatry 2002; 17: 155–162.
274 Goldstein G, Shemansky WJ, Allen DN. Cognitive function in
schizoaffective disorder and clinical subtypes of schizophrenia.
Arch Clin Neuropsychol 2005; 20: 153–159.
Subtyping schizophrenia
A Jablensky
275 David AS, Malmberg A, Brandt L, Allebeck P, Lewis G. IQ and
risk for schizophrenia: a population-based cohort study. Psychol
Med 1997; 27: 1311–1323.
276 Reichenberg A, Weiser M, Rapp MA, Rabinowitz J, Caspi A,
Schmeidler J et al. Elaboration on premorbid intellectual
performance in schizophrenia. Arch Gen Psychiatry 2005; 62:
1297–1304.
277 Sitskoorn MM, Aleman A, Ebisch SJH, Appels MCM, Kahn RS.
Cognitive deficits in relatives of patients with schizophrenia: a
meta-analysis. Schizophr Res 2004; 71: 285–295.
278 Szöke A, Schürhoff F, Mathieu F, Meary A, Ionescu S, Leboyer M.
Tests of executive functions in first-degree relatives of
schizophrenic patients: a meta-analysis. Psychol Med 2005; 35:
771–782.
279 Thompson JL, Watson JR, Steinhauer SR, Goldstein G, PogueGeile MF. Indicators of genetic liability to schizophrenia: a
sibling study of neuropsychological performance. Schizophr Bull
2005; 31: 85–96.
280 Cannon TD, Huttunen MO, Lönnqvist J, Tuullo-Henriksson A,
Pirkola T, Glahn D et al. The inheritance of neuropsychological
dysfunction in twins discordant for schizophrenia. Am J Hum
Genet 2000; 67: 369–382.
281 Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology
1998; 12: 426–445.
282 Chapman LJ, Chapman JP. Strategies for resolving the heretogeneity of schizophrenics and their relatives using cognitive
measures. J Abnorm Psychol 1989; 98: 357–366.
283 Goldstein G. Neuropsychological heterogeneity in schizophrenia:
a consideration of abstraction and problem-solving abilities. Arch
Clin Neuropsychol 1990; 5: 251–264.
284 Elliott R, Sahakian BJ. The neuropsychology of schizophrenia:
relations with clinical and neurobiological dimensions. Psychol
Med 1995; 25: 581–594.
285 Jæger J, Czobor P, Berns SM. Basic neuropsychological
dimensions in schizophrenia. Schizophr Res 2003; 65: 105–116.
286 Badcock JC, Dragovic M, Waters FA, Jablensky A. Dimensions of
intelligence in schizophrenia: evidence from patients with
preserved, deteriorated and compromised intellect. J Psychiatry
Res 2005; 39: 11–19.
287 Nuechterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF,
Heaton RK. Identification of separable cognitive factors in
schizophrenia. Schizophr Res 2004; 72: 29–39.
288 Wilk CM, Gold JM, McMahon RP, Humber K, Iannone VN,
Buchanan RW. No, it is not possible to be schizophrenic
yet neuropsychologically normal. Neuropsychology 2005; 19:
778–786.
289 Cirillo MA, Seidman LJ. Verbal declarative memory dysfunction
in schizophrenia: from clinical assessment to genetics and brain
mechanisms. Neuropsychol Rev 2003; 13: 43–77.
290 Lee J, Park S. Working memory impairments in schizophrenia: a
meta-analysis. J Abnorm Psychol 2005; 114: 599–611.
291 Seaton BE, Goldstein G, Allen DN. Sources of heterogeneity in
schizophrenia: the role of neuropsychological functioning.
Neuropsychol Rev 2001; 11: 45–67.
292 Hoti F, Tuulio-Henriksson A, Haukka J, Partonen T, Holmström L,
Lönnqvist J. Family-based clusters of cognitive test performance
in familial schizophrenia. BMC Psychiatry 2004; 4: 20 (doi:
10.1186/1471-244X-4-20).
293 Lander ES. Splitting schizophrenia. Nature 1988; 336: 105–106.
294 Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM,
Straub RE et al. Effect of COMT Val108/158 Met genotype on frontal
lobe function and risk for schizophrenia. Proc Natl Acad Sci USA
2001; 98: 6917–6922.
295 Bilder RM, Volavka J, Czobor P, Malhotra AK, Kennedy JL, Ni X
et al. Neurocognitive correlates of the COMT Val158 Met
polymorphism in chronic schizophrenia. Biol Psychiatry 2002;
52: 701–707.
296 Shifman S, Bronstein M, Sternfeld M, Pisanté-Shalom A,
Lev-Lehman E, Weizman A et al. A highly significant association
between a COMT haplotype and schizophrenia. Am J Hum Genet
2002; 71: 1296–1302.
297 Glatt SJ, Faraone SV, Tsuang MT. Association between a
functional catechol O-methyltransferase gene polymorphism
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
and schizophrenia: meta-analysis of case-control and familybased studies. Am J Psychiatry 2003; 160: 469–476.
Bray NJ, Buckland PR, Williams NM, Williams HJ, Norton N,
Owen MJ et al. A haplotype implicated in schizophrenia
susceptibility is associated with reduced COMT expression in
human brain. Am J Hum Genet 2003; 73: 152–161.
Galderisi S, Maj M, Kirkpatrick B, Piccardi P, Mucci A, Invernizzi
G et al. COMT Val158 Met and BDNF C270T polymorphisms
in schizophrenia: a case-control study. Schizophr Res 2005; 73:
27–30.
Munafo MR, Bowes L, Clark TG, Flint J. Lack of association of the
COMT (Val 158/108Met) gene and schizophrenia: a meta-analysis of
case-control studies. Mol Psychiatry 2005; 10: 765–770.
Fan J-B, Zhang C-S, Gu N-F, Li X-W, Sun W-W, Wang H-Y et al.
Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association
study plus meta-analysis. Biol Psychiatry 2005; 57: 139–144.
Paunio T, Tuulio-Henriksson A, Hiekkalinna T, Perola M, Varilo
T, Partonen T et al. Search for cognitive trait components of
schizophrenia reveals a locus for verbal learning and memory on
4q and for visual working memory on 2q. Hum Mol Genet 2004;
13: 1693–1702.
Straub RE, MacLean CJ, O’Neill FA, Burke J, Murphy B, Duke F
et al. A potential vulnerability locus for schizophrenia on
chromosome 6p24–22: evidence for genetic heterogeneity.
Nat Genet 1995; 11: 287–293.
Posthuma D, Luciano M, de Geus EJC, Wright MJ, Slagboom PE,
Montgomery GW et al. A genomewide scan for intelligence
identifies quantitative trait loci on 2q and 6p. Am J Hum Genet
2005; 77: 318–326.
Wernicke C. Grundriss der Psychiatrie in klinischen Vorlesungen.
Thieme: Leipzig, 1900.
Stransky E. Auffassung gewisser Symptome der Dementia
praecox. Neurol Centralblatt 1904; 23: 1137–1143 [English
translation In: Cutting J, Shepherd M (eds). The Clinical Roots
of the Schizophrenia Concept. Cambridge University Press:
Cambridge, 1985, pp 37–41.].
Meehl PE. Toward an integrated theory of schizotaxia, schizotypy, and schizophrenia. J Personal Disord 1990; 4: 1–99.
Andreasen NC, Paradiso S, O’Leary DS. ‘Cognitive dysmetria’ as
an integrated theory of schizophrenia: a dysfunction in corticalsubcortical-cerebellar circuitry? Schizophr Bull 1988; 24: 203–218.
Catani M, ffytche DH. The rises and falls of disconnection
syndromes. Brain 2005; 128: 2224–2239.
Stephan KE, Baldeweg T, Friston KJ. Synaptic plasticity
and dysconnection in schizophrenia. Biol Psychiatry 2006; 59:
929–939.
Craddock N, O’Donovan MC, Owen MJ. Genes for schizophrenia
and bipolar disorder? Implications for psychiatric nosology.
Schizophr Bull 2006; 32: 9–16.
Weiser M, van Os J, Davidson M. Time for a shift in focus in
schizophrenia: from narrow phenotypes to broad endophenotypes. Br J Psychiatry 2005; 187: 203–205.
Heinrichs RW. In Search of Madness. Schizophrenia and
Neuroscience. Oxford University Press: Oxford, England, 2001.
Wilcox MA, Faraone SV, Su J, Van Eedewegh P, Tsuang MT.
Genome scan of three quantitative traits in schizophrenia
pedigrees. Biol Psychiatry 2002; 52: 847–854.
Jaspers K. General Psychopathology. Manchester University
Press: Manchester, 1963.
Moldin SO. Indicators of liability to schizophrenia: perspectives
from genetic epidemiology. Schizophr Bull 1994; 20: 169–184.
Allison DB, Thiel B, St. Jean P, Elston RC, Infante MC, Schork NJ.
Multiple phenotype modeling in gene-mapping studies of
quantitative traits: power advantages. Am J Hum Genet 1998;
63: 1190–1201.
Boomsma DI, Dolan CV. A comparison of power to detect a QTL
in sib-pair data using multivariate phenotypes, mean
phenotypes, and factor scores. Behav Genet 1998; 28: 329–340.
Kovac I, Rouillard E, Mérette C, Palmour R. Exploring the impact
of extended phenotype in stratified samples. Genet Epidemiol
1999; 17(Suppl 1): S211–S216.
Marlow AJ, Fisher SE, Francks C, MacPhie IL, Cherny SS,
Richardson AJ et al. Use of multivariate linkage analysis for
835
Molecular Psychiatry
Subtyping schizophrenia
A Jablensky
836
dissection of a complex cognitive trait. Am J Hum Genet 2003; 72:
561–570.
321 Thornton-Wells TA, Moore JH, Haines JL. Genetics, statistics and
human disease: analytical retooling for complexity. Trends Genet
2004; 20: 640–647.
322 Zandi PP, DePaulo JR. Resolving the heterogeneity of psychiatric
disorders: clinical and statistical approaches. Clin Neurosci Res
2005; 5: 45–51.
323 Blashfield RK. Structural approaches to classification. In: Millon
T, Klerman GL (eds). Contemporary Directions in Psychopathology.
Molecular Psychiatry
Toward the DSM-IV. The Guilford Press: New York, London,
1986, pp 363–400.
324 Skinner HA. Construct validation approach to psychiatric
classification. In: Millon T, Klerman GL (eds). Contemporary
Directions in Psychopathology. Toward the DSM-IV. The Guilford
Press: New York, London, 1986, pp 307–330.
325 Corning WC, Steffy RA. Taximetric strategies applied to psychiatric classification. Schizophr Bull 1979; 5: 294–305.
326 Tamminga CA, Holcomb HH. Phenotype of schizophrenia: a
review and formulation. Mol Psychiatry 2004; 10: 27–39.