BRITISH JOURNAL OF PSYCHIATRY (2005), 186, 364^366 EDITORIAL

The beginning of the end for the Kraepelinian and bipolar illness and between schizo- affective disorders and both and (reviewed dichotomy by Craddock et aletal, 2005).,2005).

NICK CRADDOCK and MICHAEL J. OWEN (b)(b)AA recent twin study – the only one that has used an analysis unconstrained by the diagnostic hierarchy inherent in current classification systems – demon- strated an overlap in the genetic susceptibility to mania and schizo- phrenia (Cardno et aletal, 2002) and provided evidence that there are genes For the past hundred years most clinical increased risk of schizophrenia but not bi- that confer susceptibility across the work and research in psychiatry has pro- polar disorder in the relatives of probands Kraepelinian divide, to schizoaffective ceeded under the assumption that schizo- with schizophrenia, and vice versa in corre- disorder and to some cases of schizo- phrenia and bipolar affective disorder (or sponding studies of bipolar disorder. It is phrenia and bipolar disorder. This the corresponding earlier terms, such as also true that groups of individuals classi- study also confirmed the traditional notion that there are genes specific to and manic–depressive ill- fied as having typical schizophrenia can be the two prototypical disorders. ness) are distinct entities with separate discriminated from sets of individuals underlying disease processes and treatments. classified as having typical bipolar disorder (c)(c)Systematic,Systematic, whole-genome linkage This so-called ‘Kraepelinian dichotomy’ has on the basis of clinical features and out- studies of schizophrenia and bipolar pervaded Western psychiatry since Emil come.come. disorder have implicated some chromo- Kraepelin (1919) ‘crystallised dementia As well as having apparent empirical somal regions in common; this is praecox and manic–depressive illness from support, the Kraepelinian view holds consistent with the presence of shared an amorphous mass of madness’ (Brocking- attractions for clinicians; it is conceptually susceptibility genes (Berrettini, 2003; ton & Leff, 1979), and remains enshrined simple and allows psychiatrists to demon- CraddockCraddock et aletal, 2005).,2005). in current classifications. However, many strate diagnostic expertise by exercising (d)(d)MostMost recently, and most convincingly, individuals with severe psychiatric illness judgement over an often complex clinical genes have been identified in which have both prominent mood and psychotic picture and to reach a clear diagnosis. variation appears to confer risk to symptoms – raising the possibility, indeed However, most psychiatrists, although will- both schizophrenia and bipolar the likelihood, that there is not a neat bio- ing to make use of the advantages of the disorder. One example is the gene logical distinction between schizophrenia dichotomy, are fully aware of its limita- encodingencoding DD-amino acid oxidase acti- and bipolar affective disorder. Genetic epi- tions, and this is mirrored in the failure of vator (formerly known as the G72/G72/ demiology has always been influential in nosologists to identify any ‘point of rarity’ G30G30 locus) on chromosome 13q, one shaping and validating psychiatric nosology between the two disorders (Kendell, of the regions implicated in genome scans of both disorders (Craddock etet (Robins & Guze, 1970). Now molecular 1987). Cogent arguments for abandoning alal, 2005). This locus was originally genetic studies are beginning to challenge a categorical approach in favour of a di- reported as showing association in and will soon, we predict, overturn the mensional or continuous formulation have schizophrenia in two independent traditional dichotomous view. been advanced (e.g. Crow, 1990). How- samples. Subsequently association has ever, these failed to gain widespread sup- been reported in bipolar disorder in port, in part because of a lack of robust three independent samples. Another WHY HAS scientific data, and possibly also because example is the gene Disrupted in THE KRAEPELINIAN of the practical complexity of applying Schizophrenia 1 (DISC1DISC1). The gene, as DICHOTOMY SURVIVED dimensional classifications in clinical the name implies, is disrupted in a FOR SOLONG? practice and research settings. family in which both schizophrenia and bipolar disorder co-segregate with In the absence of ‘laboratory’ tests based on WHY IS THIS DICHOTOMY a chromosomal translocation. Recent a solid understanding of pathogenesis, the NOW BEING CHALLENGED? findings suggest that schizophrenia, criteria available to psychiatry for validat- and bipolar ing nosological categories have been re- Evidence from genetic epidemiology has disorder might be associated with poly- stricted to clinical features, outcome and been gradually accumulating over the past morphisms in this gene (Craddock et aletal,, family history (Robins & Guze, 1970). two decades that is inconsistent with the 2005).2005). These were the tools used by Kraepelin in dichotomous view, and recent molecular formulating his ideas and have been applied genetic findings seem set finally to overturn WHAT ARE to research data in shaping the modern it. Key pieces of evidence include the THE IMPLICATIONS operational classifications. One of the key following.following. FOR PSYCHIATRIC scientific observations supporting the RESEARCH? Kraepelinian dichotomy was that the proto- (a)(a)FamilyFamily studies point to the existence of typical disorders tend to ‘breed true’. Thus, a non-trivial degree of familial co- The Kraepelinian dichotomy has served a consistent finding has been a substantially aggregation between schizophrenia academic psychiatry well. Indeed,

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Kraepeliniandiagnoses formed the basis of This research agenda will best be served schizophrenia might in part be mediated recent successes in genetics, probably be- by adopting broader inclusion criteria for by neurodevelopmental abnormalities with cause their net effect is to simplify the the functional psychoses and by a combina- associated structural brain changes and genetic architecture of the groups defined, tion of inductive and hypothesis-driven cognitive impairments (Murray et aletal,, albeit at the expense of excluding many approaches aimed at relating biological 2004). Risk of developing positive psy- cases. The dichotomy also formed the basis processes to symptoms and syndromes de- chotic symptoms might be conferred by of the operational diagnostic criteria that fined at both clinical and endophenotypic genetically influenced abnormalities in brought a degree of rigour and reproduci- levels. This will require more detailed clin- dopamine and glutamate neurotransmis- bility to psychiatric research. However, ical analysis and the integration of data sion, with abnormalities of synaptic func- there is a danger that it will now impede across multiple domains such as genetics, tion leading to abnormal connectivity rather than aid progress. The recent find- environmental measures, brain imaging (Owen(Owen et aletal, 2005). These suggestions are ings are compatible with a model of func- and cognitive neurosciences. In order to illustrative, to indicate the directions that tional in which susceptibility to achieve this, academic psychiatry will need research is likely to take in the coming dec- a spectrum of clinical phenotypes is under to scale up its ambitions and plan detailed ade and the power of genetics to shape this the influence of overlapping sets of genes multidisciplinary, multicentre studies of agenda. Epidemiology, too, will benefit which, together with environmental fac- large numbers of individuals with psycho- from integration of the analysis of genetic tors, determine an individual’s expression sis. The creation of the Mental Health Re- and environmental risk factors and ex- of illness (Fig. 1). Such a model, although search Network under the auspices of the ploration of the interplay between these a better approximation than the dichoto- UK Clinical Research Collaboration offers two classes of aetiological agent. mous view, is itself only crude. A more ac- a possible route towards such studies in curate model would probably be based in the UK.theUK. multidimensional space because, in addi- Genetics will have an increasingly im- WHAT ARE tion to the interface between bipolar disor- portant role in all research aimed at under- THE IMPLICATIONS der and schizophrenia, there is genetic standing the aetiology and pathogenesis of FOR CLINICAL PRACTICE? overlap between the functional psychoses psychosis. As risk genes are identified, so and major depressive disorder – and, in- it will become possible to determine how In the coming years psychiatrists are likely deed, other disorders – with extension into genetic variation relates to clinical variation to have at their disposal simple and inex- subclinical (or normal) variation. It seems across and outwith current diagnostic cate- pensive tests to help identify the pathways likely that sets of overlapping genes will gories, and to explore the relationship be- involved in an individual’s illness and there- be identified that confer risks along differ- tween variation in specific susceptibility by inform treatment decisions. Such tests ent domains of psychopathology, corre- genes and the disruption of functional sys- will not replace the clinical skills now used sponding to the disruption of different tems using techniques such as imaging, psy- in diagnosis and management but will be brain systems. Unravelling the biology un- chological testing and neuropathological tools to aid these processes, much as lipid derlying these overlaps will shed light on studies. Thus it will become increasingly levels and blood enzyme measurements the bewildering degree of ‘comorbidity’ ob- possible to seek correlations between psy- aid cardiologists in management of cardio- served across disorders and the widespread chopathology and biological dysfunction. vascular disease. non-specificity of treatments. For example, genetic risk for prototypical Changes in classification will accom- pany the improvements in understanding of pathogenesis. These will require clini- cians to embrace classifications that are both more complex (more categories or, perhaps, dimensions) and also simpler (be- cause they map on to the biology of the ill- ness more closely). These developments have much to offer patients and the profes- sional standing of psychiatry. Most patients want to be given an unambiguous and accu- rate diagnosis, but psychiatrists are under- standably reluctant to be too dogmatic in the early stages of psychotic illness, recog- nising that the cross-sectional picture may change longitudinally – often frustrating patients, leading to diagnostic revisions Fig.1Fig.1 Possible relationship between susceptibility genes and the clinical picture for disorders in the psychosis^ between categories and creating an impres- bipolar spectrum. Recent genetic studies suggest that there are genes specific to schizophrenia (S), genes sion that psychiatrists are indecisive or in- specific to bipolar disorder (B) and genes that confer risk to schizoaffective disorder, schizophrenia and bipolar competent. Moving to a spectrum concept disorder (M). The combination of susceptibility genes inherited by an individual, together with the environ- (be it with categories or dimensions) with mental exposures, determine the key clinical features of the illness, positioned on a spectrum from prototypical recognition of overlapping pathogenetic schizophrenia at one end to prototypical bipolar disorder at the other.Mostother. Most cases lie somewhere in the central factors and varying expression (dependent part of the spectrum. upon both genetic risk and environmental

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exposure) would allow a confident and NICKCRADDOCK,NICKCRADDOCK,PhD,MRCPsych,MICHAELJ.OWEN,PhD,FRCPsych,DepartmentofPsychological PhD, MRCPsych, MICHAEL J.OWEN, PhD, FRCPsych, Department of Psychological clear diagnosis to be offered (perhaps Medicine,Wales College of Medicine,Cardiff University,Cardiff,UK ‘psychosis-spectrum illness’ or ‘mood– reality disorder’), with a clear explanation CorrespCorrespondence:ondence: Professor Nick Craddock,DepartmentCraddock, Department of Psychological Medicine,HenryMedicine, Henry Wellcome that some specific tests and a period of Building,HeathBuilding, Heath Park,Cardiff CF14 4XN,UK.Tel: +44 (0)29 2074 4663; fax: +44 (0) 29 2074 6058; observation will help to clarify the likely e-mail: craddockn@@cardiff.ac.uk course of illness and response to treatment. (First received 31 October 2004, final revision 11November 2004, accepted 11November 2004) This would be greatly preferable to the current situation and the inevitable con- sequences of damage to the therapeutic alliance caused by diagnostic revisions. The Kraepelinian dichotomy has been useful for a hundred years. Now it is time Brockington, I. F. & Leff, J. P.(19 (1979) 79) Schizo-affective Kraepelin, E.(1919) Manic-Depressive Insanity and psychosis: definitions and incidence. Psychological ParanoiaParanoia (trans. R. M. Barclay). Edinburgh: Livingstone. to move on. MedicineMedicine,, 99, 91^99.,91^99.

Cardno, A. G., Rijsdijk, F.V., Sham, P.C., et aletal (2002)(2002) DECLARATIONOF INTEREST Murray, R. M., Sham, P., van Os, J., et aletal (2004)(2004) AA A twin study of genetic relationships between psychotic developmental model for similarities and dissimilarities symptoms. American Journal of Psychiatry,, 159159, 539^545.,539^545. between schizophrenia and bipolar disorder. The authors are consultants to Glaxo- Schizophrenia Research,, 7171,405^416., 405^416. Craddock, N., O’Donovan, M. C. & Owen, M. J. SmithKline and have received honoraria (2005) Genetics of schizophrenia and bipolar disorder: dissecting of psychosis. Journal of Medical Genetics,, 4242,, for academic talks from Eli Lilly, Astra- Owen, M. J., O’Donovan, M. C. & Harrison, P.P.J. J. 193^204. Zeneca and GlaxoSmithKline. (2005) Schizophrenia: a genetic disorder of the synapse. Crow, T. J.J.Crow, (19 (1990) 9 0) The continuum of psychosis and its BMJBMJ,, 330,158^159.,158^159. genetic origins. The sixty-fifth Maudsley lecture. British REFERENCES Journal of Psychiatry,, 156, 788^797. Robins,Robins,E.&Guze,S.B. E. & Guze, S. B. (1970)(1970) Establishment of Berrettini,W. (2003)(2003) Evidence for shared susceptibility Kendell, R. E.(19 (1987) 87) Diagnosis and classification of diagnostic validity in psychiatric illness: its application to in bipolar disorder and schizophrenia. American Journal functional psychoses. British Medical Bulletin,, 43,, schizophrenia. American Journal of Psychiatry,, 126,, of Medical Genetics,, 123123,,59^64. 59^64. 499^513.499^513. 983^987.

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