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The Kraepelinian dichotomy - going, going... but still not gone.

Craddock N, Owen MJ - Br J Psychiatry (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. craddockn@cardiff.ac.uk

ABSTRACT
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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Related in: MedlinePlus

Hypothesised model of the complex relationship between biological variation and some major forms of psychopathology.This is a simplified model of a highly complex set of relationships between genotype and clinical phenotype. Starting at the level of genetic variation (lowest tier in figure), we have represented DNA structural variation (in purple) as contributing particularly to neurodevelopmental disorders and associated particularly with enduring cognitive and functional impairment. Single gene variants, of which there are many, are shown as asterisks. In general, even single base-pair changes in a gene may influence multiple biological systems because genes typically have multiple functions and produce proteins that interact with multiple other proteins. For simplicity, we have shown only an example of a variant that influences three biological systems (blue asterisk and arrows) and another that influences only one system (black asterisk and arrow). Variation in the relevant biological systems is influenced by genotype at many genetic loci and by environmental exposures/experiences both historically during development and currently to influence the dynamic state of the systems. The relevant biological systems influence the neural modules that comprise the key relevant functional elements of the brain (shown as solid turquoise circles). Typically, multiple biological systems influence each neural module. The (abnormal) functioning of the neural modules together influences the domains of psychopathology experienced and ultimately the clinical syndromes. We have ordered some important clinical syndromes along a single major axis with a gradient of decreasing proportional neurodevelopmental contribution to causation and reciprocal increasing gradient of proportion of episodic affective disturbance (we use the term ‘mental retardation’ in the diagram because it is understood internationally, but recognise that the terms intellectual disability and learning disability are commonly used in the UK). The single axis is a simplifying device – there is substantial individual variation and it is recognised that, for example, it is not uncommon for individuals diagnosed with autism to experience substantial mood pathology. Key features of the model are described within the text.
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fig1: Hypothesised model of the complex relationship between biological variation and some major forms of psychopathology.This is a simplified model of a highly complex set of relationships between genotype and clinical phenotype. Starting at the level of genetic variation (lowest tier in figure), we have represented DNA structural variation (in purple) as contributing particularly to neurodevelopmental disorders and associated particularly with enduring cognitive and functional impairment. Single gene variants, of which there are many, are shown as asterisks. In general, even single base-pair changes in a gene may influence multiple biological systems because genes typically have multiple functions and produce proteins that interact with multiple other proteins. For simplicity, we have shown only an example of a variant that influences three biological systems (blue asterisk and arrows) and another that influences only one system (black asterisk and arrow). Variation in the relevant biological systems is influenced by genotype at many genetic loci and by environmental exposures/experiences both historically during development and currently to influence the dynamic state of the systems. The relevant biological systems influence the neural modules that comprise the key relevant functional elements of the brain (shown as solid turquoise circles). Typically, multiple biological systems influence each neural module. The (abnormal) functioning of the neural modules together influences the domains of psychopathology experienced and ultimately the clinical syndromes. We have ordered some important clinical syndromes along a single major axis with a gradient of decreasing proportional neurodevelopmental contribution to causation and reciprocal increasing gradient of proportion of episodic affective disturbance (we use the term ‘mental retardation’ in the diagram because it is understood internationally, but recognise that the terms intellectual disability and learning disability are commonly used in the UK). The single axis is a simplifying device – there is substantial individual variation and it is recognised that, for example, it is not uncommon for individuals diagnosed with autism to experience substantial mood pathology. Key features of the model are described within the text.

Mentions: Although we can reject a simple model of separate, unrelated disease categories, the data do not support a model of a single-disease category that is undifferentiated with respect to the relationship between clinical expression and genetic susceptibility, and, hence, underlying biological mechanisms. For example, the same large family study2 that demonstrated a substantial overlap in genetic susceptibility to bipolar disorder and schizophrenia also provided clear evidence for the existence of non-shared genetic risk factors. These findings are fully consistent with earlier genetic data suggesting that there are relatively specific as well as shared susceptibility genes.1 Recent studies suggest that some of this specificity might be due to structural genomic variation (CNVs). Although there is emerging evidence that CNVs have some influence on the risk of bipolar disorder,18,19 they appear to contribute less to the susceptibility to bipolar disorder than to schizophrenia (to date, variants influencing bipolar disorder seem to be smaller, less likely to be deletions, and have smaller effect sizes).19,20 Under the assumption that bigger structural genomic variants, particularly involving DNA loss, are more likely to affect brain development, we note that these findings are consistent with the view that schizophrenia has a stronger neurodevelopmental component than bipolar disorder21 and suggest that it lies on a gradient of decreasing neurodevelopmental impairment between syndromes such as mental retardation and autism on one hand, and bipolar disorder on the other (Fig. 1).


The Kraepelinian dichotomy - going, going... but still not gone.

Craddock N, Owen MJ - Br J Psychiatry (2010)

Hypothesised model of the complex relationship between biological variation and some major forms of psychopathology.This is a simplified model of a highly complex set of relationships between genotype and clinical phenotype. Starting at the level of genetic variation (lowest tier in figure), we have represented DNA structural variation (in purple) as contributing particularly to neurodevelopmental disorders and associated particularly with enduring cognitive and functional impairment. Single gene variants, of which there are many, are shown as asterisks. In general, even single base-pair changes in a gene may influence multiple biological systems because genes typically have multiple functions and produce proteins that interact with multiple other proteins. For simplicity, we have shown only an example of a variant that influences three biological systems (blue asterisk and arrows) and another that influences only one system (black asterisk and arrow). Variation in the relevant biological systems is influenced by genotype at many genetic loci and by environmental exposures/experiences both historically during development and currently to influence the dynamic state of the systems. The relevant biological systems influence the neural modules that comprise the key relevant functional elements of the brain (shown as solid turquoise circles). Typically, multiple biological systems influence each neural module. The (abnormal) functioning of the neural modules together influences the domains of psychopathology experienced and ultimately the clinical syndromes. We have ordered some important clinical syndromes along a single major axis with a gradient of decreasing proportional neurodevelopmental contribution to causation and reciprocal increasing gradient of proportion of episodic affective disturbance (we use the term ‘mental retardation’ in the diagram because it is understood internationally, but recognise that the terms intellectual disability and learning disability are commonly used in the UK). The single axis is a simplifying device – there is substantial individual variation and it is recognised that, for example, it is not uncommon for individuals diagnosed with autism to experience substantial mood pathology. Key features of the model are described within the text.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2815936&req=5

fig1: Hypothesised model of the complex relationship between biological variation and some major forms of psychopathology.This is a simplified model of a highly complex set of relationships between genotype and clinical phenotype. Starting at the level of genetic variation (lowest tier in figure), we have represented DNA structural variation (in purple) as contributing particularly to neurodevelopmental disorders and associated particularly with enduring cognitive and functional impairment. Single gene variants, of which there are many, are shown as asterisks. In general, even single base-pair changes in a gene may influence multiple biological systems because genes typically have multiple functions and produce proteins that interact with multiple other proteins. For simplicity, we have shown only an example of a variant that influences three biological systems (blue asterisk and arrows) and another that influences only one system (black asterisk and arrow). Variation in the relevant biological systems is influenced by genotype at many genetic loci and by environmental exposures/experiences both historically during development and currently to influence the dynamic state of the systems. The relevant biological systems influence the neural modules that comprise the key relevant functional elements of the brain (shown as solid turquoise circles). Typically, multiple biological systems influence each neural module. The (abnormal) functioning of the neural modules together influences the domains of psychopathology experienced and ultimately the clinical syndromes. We have ordered some important clinical syndromes along a single major axis with a gradient of decreasing proportional neurodevelopmental contribution to causation and reciprocal increasing gradient of proportion of episodic affective disturbance (we use the term ‘mental retardation’ in the diagram because it is understood internationally, but recognise that the terms intellectual disability and learning disability are commonly used in the UK). The single axis is a simplifying device – there is substantial individual variation and it is recognised that, for example, it is not uncommon for individuals diagnosed with autism to experience substantial mood pathology. Key features of the model are described within the text.
Mentions: Although we can reject a simple model of separate, unrelated disease categories, the data do not support a model of a single-disease category that is undifferentiated with respect to the relationship between clinical expression and genetic susceptibility, and, hence, underlying biological mechanisms. For example, the same large family study2 that demonstrated a substantial overlap in genetic susceptibility to bipolar disorder and schizophrenia also provided clear evidence for the existence of non-shared genetic risk factors. These findings are fully consistent with earlier genetic data suggesting that there are relatively specific as well as shared susceptibility genes.1 Recent studies suggest that some of this specificity might be due to structural genomic variation (CNVs). Although there is emerging evidence that CNVs have some influence on the risk of bipolar disorder,18,19 they appear to contribute less to the susceptibility to bipolar disorder than to schizophrenia (to date, variants influencing bipolar disorder seem to be smaller, less likely to be deletions, and have smaller effect sizes).19,20 Under the assumption that bigger structural genomic variants, particularly involving DNA loss, are more likely to affect brain development, we note that these findings are consistent with the view that schizophrenia has a stronger neurodevelopmental component than bipolar disorder21 and suggest that it lies on a gradient of decreasing neurodevelopmental impairment between syndromes such as mental retardation and autism on one hand, and bipolar disorder on the other (Fig. 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. craddockn@cardiff.ac.uk

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus