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The Kraepelinian dichotomy – going, going … but still not gone

  • Nick Craddock (a1) and Michael J. Owen (a1)
Summary

Recent genetic studies reinforce the view that current approaches to the diagnosis and classification of major psychiatric illness are inadequate. These findings challenge the distinction between schizophrenia and bipolar disorder, and suggest that more attention should be given to the relationship between the functional psychoses and neurodevelopmental disorders such as autism. We are entering a transitional period of several years during which psychiatry will need to move from using traditional descriptive diagnoses to clinical entities (categories and/or dimensions) that relate more closely to the underlying workings of the brain.

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Corresponding author
Nick Craddock, MRC Centre for Neuropsychiatric Genetics and Genomics, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Email: craddockn@cardiff.ac.uk
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The authors' work on the genetics of psychosis and mood disorders is funded through grants from the Wellcome Trust, MRC, NIH and Stanley Medical Research Institute.

Declaration of interest

None.

Footnotes
References
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1 Craddock, N, Owen, MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry 2005; 186: 364–6.
2 Lichtenstein, P, Yip, BH, Björk, C, Pawitan, Y, Cannon, TD, Sullivan, PF, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009; 373: 234–9.
3 Owen, MJ, Craddock, N. Diagnosis of functional psychoses: time to face the future. Lancet 2009; 373: 190–1.
4 O'Donovan, MC, Craddock, N, Norton, N, Williams, H, Peirce, T, Moskvina, V, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–5.
5 Green, EK, Grozeva, D, Jones, I, Jones, L, Kirov, G, Caesar, S, et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry 2009; Epub ahead of print, doi: 10.1038/mp.2009.49.
6 Ferreira, MA, O'Donovan, MC, Meng, YA, Jones, IR, Ruderfer, DM, Jones, L, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40: 1056–8.
7 Moskvina, V, Craddock, N, Holmans, P, Nikolov, I, Pahwa, JS, Green, E, et al. Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol Psychiatry 2009; 14: 252–60.
8 The International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–52.
9 McCarroll, SA, Altshuler, DM. Copy-number variation and association studies of human disease. Nat Genet 2007; 39 (suppl 7): S3742.
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11 Walsh, T, McClellan, JM, McCarthy, SE, Addington, AM, Pierce, SB, Cooper, GM, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008; 320: 539–43.
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13 The International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–41.
14 Kirov, G, Grozeva, D, Norton, N, Ivanov, D, Mantripragada, KK, Holmans, P, et al. Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet 2009; 18: 1497–503.
15 Pagnamenta, AT, Wing, K, Akha, ES, Knight, SJ, Bölte, S, Schmötzer, G, et al. A 15q13.3 microdeletion segregating with autism. Eur J Hum Genet 2008; 17: 687–92.
16 Kirov, G, Rujescu, D, Ingason, A, Collier, DA, O'Donovan, MC, Owen, MJ. Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull 2009; 35: 851–4.
17 Burbach, JP, van der Zwaag, B. Contact in the genetics of autism and schizophrenia. Trends Neurosci 2009; 32: 6972.
18 Zhang, D, Cheng, L, Qian, Y, Alliey-Rodriguez, N, Kelsoe, JR, Greenwood, T, et al. Singleton deletions throughout the genome increase risk of bipolar disorder. Mol Psychiatry 2008; 14: 376–80.
19 McCarthy, SE, Makarov, M, Kirov, G, Addington, AM, McClellan, J, Yoon, S, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009; 41: 1223–7.
20 Grozeva, D, Kirov, G, Ivanov, D. Rare copy number variants (CNVs): a point of rarity in genetic risk for bipolar disorder and schizophrenia? Arch Gen Psychiatry 2010; in press.
21 Murray, RM, Sham, P, van Os, J, Zanelli, J, Cannon, M, McDonald, C. A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophr Res 2004; 71: 405–16.
22 Hamshere, ML, Green, EK, Jones, IR, Jones, L, Moskvina, V, Kirov, G, et al. Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept. Br J Psychiatry 2009; 195: 23–9.
23 Craddock, N, Jones, L, Jones, IR, Kirov, G, Green, EK, Grozeva, D, et al. Strong genetic evidence for a selective influence of GABA(A) receptors on a component of the bipolar disorder phenotype. Mol Psychiatry 2008; Epub ahead of print, doi: 10.1038/mp.2008.66.
24 Craddock, N, O'Donovan, MC, Owen, MJ. Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or ‘schizoaffective’) psychoses. Schizophr Bull 2009; 35: 482–90.
25 Heckers, S. Is schizoaffective disorder a useful diagnosis? Curr Psychiatry Rep 2009; 11: 332–7.
26 Craddock, N, Owen, MJ. Rethinking psychosis: the disadvantages of a dichotomous classification now outweigh the advantages. World Psychiatry 2007; 6: 8491.
27 van Os, J, Kapur, S. Schizophrenia. Lancet 2009; 374: 635–45.
28 Bullmore, E, Sporns, O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci 2009; 10: 186–98.
29 Zielasek, J, Gaebel, W. Modern modularity and the road towards a modular psychiatry. Eur Arch Psychiatry Clin Neurosci 2008; 258 (suppl 5): 60–5.
30 Kendler, KS. Reflections on the relationship between psychiatric genetics and psychiatric nosology. Am J Psychiatry 2006; 163: 1138–46.
31 Cross-Disorder Phenotype Group of the Psychiatric GWAS Consortium, Craddock, N, Kendler, K, Neale, M, Nurnberger, J, Purcell, S, et al. Dissecting the phenotype in genome-wide association studies of psychiatric illness. Br J Psychiatry 2009; 195: 97–9.
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The Kraepelinian dichotomy – going, going … but still not gone

  • Nick Craddock (a1) and Michael J. Owen (a1)
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eLetters

Predictions can be quantified

Saad F Ghalib, Consultant in Old Age Psychiatry
31 August 2011

A closer analysis of the apparent irreconcilability of dimensional and categorical models of psychiatric disorders, may reveal hidden insights that certainly require some consideration. It is well known that,and from its early inception that, a categorical approach(signs and symptoms) is non-etiological.However,further scrutiny will also show that discrete variables in the same model are also non-causally linked. For example,the probability of identifying depressed mood is not causally connected to the identification of loss of interest and vice versa.That's said, it is still safe to assume that at a phenomenological level(the basis of categories) both symptoms are expected to correlate despite the fact that they are not causally related. From a probability point of view, phenomenologically correlated symptoms can also be considered ''non-local'',i,e,the probability value of depressed mood will inadvertently fix the probability value of loss of interest.Incidentally, non-local correlations is actually what characterises phenomenology at the quantum level(1). By contrast, a dimensional approach, which underpins most biological and genetic studies, is typically causal,in the sense that oncedepressed mood is identified, it is somehow assumed this to be related to 5-HT abnormalities,and this in turn is causally connected to genes,but most notably, even yet to be discovered variables(hidden-variables) will be taken into account as ''locally''causal.A way out, is Bayes statistics. A sort of conditional probability; the probability of [A] given only initial information [I], P(A/I) is known as the prior probability(what betting odds the scientist would take or decline, on whether their beliefs are correct).The updated conditional probability of [A], given [I] and the outcome of the event [B] ,is known as the posterior probability, P(A/B,I).Bayes' theory can play a significant role in reducing type I errors when analysing the results of drug trials. Curiously, a Bayesian model is non-local in the sense that itmeasures correlation and not causation(2). Recent reports do already indicate that a Bayesian approach of prior and posterior probability in MRbrain imaging is more efficient in comparison with other methods(3). Besides, the application of a Bayesian approach in this endeavour fits inso naturally, considering that the human brain is one big Bayesian machine.It is via evolution that many ''prior hypotheses'' are hard wired in our brains, and on the basis of its belief about the world, the brain can ''predict'' the pattern of activity that should be detected by the senses.The brain imposes its opinion on what the world should be like by assigning probabilities to potential models of the world and using evidence/errors to update those models(4).Therefore, by virtue of its lackof one way causality and its non-local distribution of probability variables, Bayes' methodology may herald the way to the future integrationof dimensions and categories.References;1.Bell,J S. Speakable and Unspeakable in Quantum Mechanics.Cambridge Univ.Press,2004 edition.2.Fuchs,C A. Quantum Bayesianism at the Perimeter. arXiv; 1003.5182.3.Peng,Z; Wee,W; Jing-Huei Lee. MR brain imaging segmentation based on spatial Gaussian mixture model and Markov random field. Image Processing. ICIP 2005.4.Frith,C. Making Up the Mind. Blackwell Publishing.2007.

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Conflict of interest: None declared

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A delusion referred to as schizophrenia?

Hirofumi Morioka, Professor
23 September 2010

Here we challenge the dogma that schizophrenia is a distinct clinicalentity, which is widely accepted in every psychiatric journal. Growing genetic evidence including results of genome-wide association studies is still perplexing scientists in the fields of human complex traits (1) and compelling them to reconsider the relationship between autism and schizophrenia (2,3). Although many etiological possibilities, including susceptibility overlapping between these traits (2), have been proposed toexplain the genetic puzzle, the last alternative model in which schizophrenia is mere one of the secondary derivative states in autistic individuals is strangely left untouched. Because the entity of schizophrenia had been established more than thirty years prior to the descriptions of autism by Kanner and Asperger, the distinction between autism and the preceding clinical entity had been well attempted. The conviction that the age of onset and schizophrenic symptoms of the first rank (Schneider) can distinguish the early onset schizophrenia variant from autism only implies that autism is not a subset of schizophrenia. Theupside-down relationship in which schizophrenia is a subset of autism had,so far, never attracted researcher's attention. Our clinical experiences at university campus are evidently compatible with this historically neglected possibility.

The autistic characteristics are sometimes not noticed even by families until social environmental demands exceed the limited capacities in autistic individuals, as described in the draft version of DSM-5 (http://www.dsm5.org/Pages/Default.aspx). Misdiagnosis of psychosis in masked autistic individuals is never exceptional (4) and adolescent cases of autism in isolative, stressful, or traumatic circumstances are often diagnosed as psychoses including schizophrenia. In such cases, the manifested features that are evaluated as psychotic symptoms can be explained in the context of developmental maladaptation (social dropout) and/or cessation of familial/non-familial support. As known well, both developmental cognitive deviation and social (occupational) functioning deficits are common phenotypes between autism and schizophrenia (2,4). In DSM, the only distinctive symptom for the additional diagnosis of schizophrenia in autistic individuals is apparent emergence of reality distortion (delusions or hallucinations). Because the psychotic delusions and hallucinations are usually associated with relationships between 'self' and others, it could be recognized that misattribution of negative events5 (one of the inclinations of autistic adolescents) and the perceptual thinking style (one of the autistic characteristics) constitutes the underpinning of the so-called reality withdrawal in barelyexperienced autistic individuals who obtained insufficient "theory of mind".

References

1. Maher B. Personal genomes: The case of the missing heritability. Nature 2008; 456: 18-21.

2. Craddock N, Owen MJ. The Kraepelinian dichotomy - going, going... but still not gone. Br J Psychiatry 2010; 196: 92-5.

3. Crespi B, Stead P, Elliot M. Evolution in health and medicine: Comparative genomics of autism and schizophrenia. Proc Natl Acad Sci USA 2010; 107 Suppl 1: 1736-41.

4. Starling J, Dossetor D. Pervasive developmental disorders and psychosis. Curr Psychiatry Rep 2009; 11: 190-6.

5. Langdon R, Corner T, McLaren J, Ward PB, Coltheart M. Externalizing and personalizing biases in persecutory delusions: the relationship with poor insight and theory-of-mind. Behav Res Ther 2006; 44: 699-713.
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Conflict of interest: None Declared

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Some reasons why the Kraepelinian dichotomy is still not gone and will (or should) not go

Victor Peralta, Head of the Psychiatry Section B
03 August 2010

In their essay, Craddock and Owen (1) summarize evidence supporting amovement for abandoning the Kraepelinian dichotomy between schizophrenia and bipolar disorder. Whereas we would agree with most of their statements, we believe that there are powerful reasons, both conceptual and practical, that will impede abandoning this dichotomy. The main conceptual issue regarding Kraepelin’s dichotomy is that his constructs ofdementia praecox and manic-depressive illness represent ideal types or prototypes of mental illnesses (2). These ideal types have proven to be among the most powerful heuristic constructs in the field of psychiatry, which explains their persistence over a century across national diagnosticmodes, consensus nosological systems and empirical tests. This is so because the categorical/prototypical approach has and continues to function reasonably well for classifying diseases, case ascertainment, organizing and communicating information, clinical decision making and predicting outcome.

The claim made here is not that schizophrenia and bipolar disorder are natural entities with clear zones of rarity, but that, according to current evidence, these diagnoses are better understood as the extreme ends on a continuum of risk factors, neurobiological mechanisms, psychopathology and outcome (3). As prototype diagnoses, schizophrenia andbipolar disorder are the reference disorders on which other disorders, both psychotic and non-psychotic, can be ordered according to their grade of membership or resemblance. In this sense, schizophrenia and bipolar disorder are the pillars of their respective spectrum disorders.

One of the main arguments advocated for Craddock and Owen for abandoning the dichotomy is the substantial overlap between schizophrenia and bipolar disorder. However, this overlap only partially concerns Kraepelin’s dichotomy, since his dementia praecox concept does not closelycorrespond with the current concept of schizophrenia. It should be realized that a DSM-IV schizophrenia diagnosis does not represent an idealtype of the disease, since its polythetic character conveys substantial clinical (and possibly neurobiological) heterogeneity that undermines the concept of dementia praecox as a more severe and homogeneous disorder. Thus, if we strictly adhere to Kraepelin’s dementia praecox concept, the similarities between schizophrenia and bipolar disorder may have been overstated. Historically, there have been several prototypical definitionsof schizophrenia, namely the Kraepelinian, Schneiderian and Bleulerian ones, to cite the most relevant. The DSM-IV schizophrenia diagnosis represents a mixture of these constructs and thus fails to grasp their underlying nature as disease paradigms (4).

Psychiatric classification systems must be evaluated in the light of their success in serving the basic underlying goals of psychiatry, namely clinical utility and neurobiological validity. This can be only accomplished by empirically testing the predictive value of alternative representations of mental disorders. Given the lack of a unitary paradigm for schizophrenia, this approach needs to be supplemented by a polydiagnostic approach to the diagnosis (5). Before abandoning the Kraepelinian dichotomy, in the terms mentioned above such a dichotomy means, we need to have a better nosological model for psychotic disorders.We are far from having it, thus the Kraepelinian dichotomy is still alive and likely will long survive.

Declaration of interest: none

1. Craddock N, Owen MJ. The Kraepelinian dichotomy- going, going…but still not gone. Br J Psychiatry 210; 196: 92-95.

2. Schwarzt MA, Wiggins OP. Diagnosis and ideal types: a contributionto psychiatric classification. Compr Psychiatry 1987; 28: 277-291.

3. Crow TJ. The continuum of psychosis and its genetic origins. The sixty-fifth Maudsley lecture. Br J Psychiatry1990; 156: 788-797

4. Maj M. Critique of the DSM-IV operational diagnostic criteria for schizophrenia. Br J Psychiatry 1998;172: 458-460.

5. Cuesta MJ, Peralta V. Current psychopathological issues to the psychoses: A phenome-wide approach. Schizophr Bull 2008; 34: 587-590.
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Conflict of interest: None Declared

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Genetic overlap of schizophrenia and autism

Nick Craddock, Professor of Psychiatry
22 March 2010

Dr Crespi’s hypothesized model of autism and schizophrenia as “diametric opposites” is interesting, and it was only space limitations that prevented us discussing it in our article. We favour an “overlapping”model of the relationship between the two disorders as being both simpler and more consistent with the totality of current data According to our view the two disorders share overlapping pathogenic mechanisms arising from disturbances in neurodevelopment, with autism occupying a more severeposition on a continuum of neurodevelopmental impairment (1). This is supported by a number of clinical similarities. Both disorders are more common in males and associated with cognitive impairment, and both are characterised by defects of social cognition. As Crespi mentions in his letter, clinicians used similar terminology in earlier times to refer to both diagnostic concepts (the term “autistic” was introduced originally todescribe clinical features of adults with schizophrenia; for a time the term “childhood schizophrenia” was used to refer to children with autism).Within individuals, diagnoses of autism and schizophrenia have been reported to be positively associated in a large hospital case diagnosis study (3). Finally, we note that Swedish family register data show that autism diagnosis is substantially increased by a parental family history of schizophrenia and related diagnoses (4), consistent with some sharing of genetic susceptibility. These various observations seem to us to be more indicative of similarities than of opposites.

Crepsi’s recent analysis of data from studies of rare copy number (structural genomic) variants in the two disorders has provided some support for the hypothesis that autism and schizophrenia are mediated by reciprocal variants, such that at four distinct loci, deletions predisposeto one disorder while duplications predispose to the other. However observations at other loci, such as NRXN1 (4) where deletions are associated with both schizophrenia and autism, do not support the diametric model. Moreover our overlapping model can predict reciprocity by invoking the not unreasonable notion that, at some loci it is likely that duplication (ie. extra genetic material) would have more severe effects on neurodevelopment than deletion (ie. loss of genetic material), whereas, at other loci the opposite may be the case.

Notwithstanding our differences, we share with Dr Crepsi a desire to develop new theoretical frameworks within which to view the increasing volume of novel genetic insights coming from genetics (5). This will allowus to test specific biological hypotheses that can advance understanding of psychiatric illness in general and the relationship between schizophrenia and autism in particular. This will help move psychiatric classification from descriptive traditions based upon expert opinion towards robust empirical evidence that more closely relates to the workings of the brain.

Nick Craddock* PhD, FRCPsych, Michael J. Owen PhD, FRCPsych

MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom

*Correspondence: Nick Craddock, MRC Centre for Neuropsychiatric Genetics and Genomics, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom. (Email:craddockn@cardiff.ac.uk)

Declaration of interest: The authors declare no competing interests.

References(1)Craddock N, Owen MJ. The Kraepelinian dichotomy - going, going... but still not gone. Br J Psychiatry. 2010 Feb;196(2):92-5.

(2)Rzhetsky A, Wajngurt D, Park N, Zheng T. Probing genetic overlap among complex human phenotypes. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11694-9.

(3)Larsson HJ, Eaton WW, Madsen KM, Vestergaard M, Olesen AV, AgerboE, Schendel D, Thorsen P, Mortensen PB. Risk factors for autism: perinatalfactors, parental psychiatric history, and socioeconomic status. Am J Epidemiol. 2005 May15;161(10):916-25.

(4)Kirov G, Rujescu D, Ingason A, Collier DA, O'Donovan MC, Owen MJ.Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull. 2009;35:851-4.

(5)Cross-Disorder Phenotype Group of the Psychiatric GWAS Consortium, Craddock N, Kendler K, Neale M, Nurnberger J, Purcell S, Rietschel M, Perlis R, Santangelo SL, Schulze TG, Smoller JW, Thapar A. Dissecting the phenotype in genome-wide association studies of psychiatricillness. Br J Psychiatry. 2009 Aug;195(2):97-9. Erratum in: Br J Psychiatry. 2009 Oct;195(4):371.
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Revisiting Bleuler: The Relation of Autism with Schizophrenia

Bernard J Crespi, Professor
26 February 2010

The great Swiss psychiatrist Eugen Bleuler coined the terms ‘schizophrenia’, as the splitting of psychic functions in Kraepelin’s dementia praecox, and ‘autism’, as withdrawal from reality in schizophrenics, almost exactly a century ago. The term ‘autism’ was, of course, later redefined by Leo Kanner (1) for a childhood psychiatric condition first considered as a subset of schizophrenia, then regarded as separate and distinct by both himself and Michael Rutter (2). Most recently, an article by Craddock and Owen (3) not only formally challenges the distinction between schizophrenia and bipolar disorder that followed from Kraepelin’s work, but also returns ‘autism’ to the scene of its Bleulerian birth, in proposing a new model for the relationships between major mental illnesses as a continuum from intellectual disability, through autism, to schizophrenia and schizoaffective disorder, through to bipolar and unipolar mood disorder. By their model, autism is juxtaposed with schizophrenia based on overlapping neurodevelopmentally-based phenotypes of cognitive impairment and negative symptoms, and recent genetic data that show overlap in the genetic risk loci associated with both conditions, including a set of copynumber variant loci and specific genes such as CNTNAP2 and NRXN1.

Does such molecular-genetic data, dovetailed with data on select phenotypes, imply that Blueler was indeed correct, if not prescient, that autism and schizophrenia are manifestations of similar disease processes? In contrast to Craddock and Owen’s (3) proposition, a recent alternativehypothesis posits that not only are autism and schizophrenia not juxtaposed or overlapping, but they are actually diametric, psychiatric opposites characterized by under-development versus dysregulated over-development of human social-brain phenotypes (4). These alternative hypothesis for the relation of autism with schizophrenia have recently been tested using data from the seven copy number variant loci that have been linked statistically with both conditions (5). The data provide statistical support for the hypothesis that autism and schizophrenia are mediated by reciprocal variants, such that at four distinct loci, deletions predispose to one disorder while duplications predispose to the other – clear support for the diametric model.

Near the end of his life, Kraepelin made clear that schizophrenia could not be satisfactorily distinguished from bipolar disorder; his supposed dichotomy was indeed false from near the start, and recent genetic data strongly support a dimensional model for the phenotypes that make up these two conditions (3). But neither Bleuler nor Kanner should sleep soundly, nor should practitioners of psychiatric genetics or therapy, until the relation of schizophrenia with autism becomes much better understood – the implications for diagnostics, pharmacology, and psychiatry in general reach too far. Further targetted tests, based on clear alternative hypotheses with differentiating preditions, will be required - and as Craddock and Owen (3) suggest, such investigations must ultimately focus on reconciling clinical categories and dimensions with normal and abnormal neurological and psychological architecture – to dissect and define psychiatric conditions for the next hundred years.

References

(1) Kanner L. Autistic disturbances of affective contact. Nervous Child 1943 2:217-250.

(2) Rutter M. 1972 Childhood schizophrenia reconsidered. Journal of Autism and Childhood Schizophrenia 2:315-337.

(3) Craddock N, Owen, MJ. 2010 The Kraepelinian dichotomy - going, going... but still not gone. British Journal of Psychiatry 196: 92-95.

(4) Crespi B, Badcock C. 2008 Psychosis and autism as diametrical disorders of the social brain. Behavioral and Brain Sciences 31:241-261; discussion 261-320.

(5) Crespi B, Stead P, Elliot M. 2010 Comparative genomics of autism and schizophrenia. Proc Natl Acad Sci U S A. 107:1736-1741.
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