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Molecular Psychiatry (2006) 11, 815–836 & 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00 www.nature.com/mp 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 Subtyping schizophrenia 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 Molecular Psychiatry 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 Subtyping schizophrenia 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 Molecular Psychiatry Subtyping schizophrenia A Jablensky 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 Molecular Psychiatry 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, Subtyping schizophrenia 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 Molecular Psychiatry Subtyping schizophrenia 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 Molecular Psychiatry 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 Subtyping schizophrenia 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 821 Molecular Psychiatry Subtyping schizophrenia A Jablensky 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 A Jablensky 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 823 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 Molecular Psychiatry Subtyping schizophrenia A Jablensky 824 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 Molecular Psychiatry Subtyping schizophrenia A Jablensky 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 A Jablensky 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. 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