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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.
The Kraepelinian dichotomy – the broad division of major mood and psychotic illness of adulthood into schizophrenia and ‘manic–depressive’ (bipolar) illness – has been enshrined in Western psychiatry for over a century and continues to influence clinical practice, research and public perceptions of mental illness. Nearly 5 years ago, we published an editorial1 in which we summarised emerging evidence undermining the dichotomy, and argued that continued adherence to this approach is hampering research and clinical care. Since then, a substantial and increasingly convergent body of evidence has accrued from genetic studies that supports and refines this view. Here, we summarise these findings and their implications for clinical psychiatry and illness classification.
Several studies have been published in the past 5 years that provide compelling evidence that genetic susceptibility and, by implication, elements of the underlying pathogenetic mechanisms are shared between bipolar disorder and schizophrenia. Although most of this new evidence has come from large-scale molecular genetic analyses, the molecular findings are fully supported by a large family study of the two disorders. The recent evidence also points to the need to reconsider the relationship of mood and psychotic illness with other neuropsychiatric phenotypes such as autism. Key findings include the largest family study of the two disorders ever conducted that shows overlap in genetic susceptibility across bipolar disorder and schizophrenia. This study included over 2 million nuclear families identified from Swedish population and hospital discharge registers, and showed that there are increased risks of both schizophrenia and bipolar disorder in first-degree relatives of probands with either disorder. Moreover, there is evidence from half-siblings and adopted-away relatives that this is due substantially to genetic factors.2,3
Additionally, genome-wide association studies (GWAS) have demonstrated the existence of common DNA variants (single nucleotide polymorphisms) that influence risk of both schizophrenia and bipolar disorder. There is direct molecular genetic support for a substantial genetic overlap between schizophrenia and bipolar disorder from the recent large-scale GWAS of bipolar disorder and schizophrenia in which thousands of individuals have been studied for hundreds of thousands of common DNA variants spread across the genome. This evidence includes analyses of specific risk loci, including ZNF804A, initially identified as a risk gene for schizophrenia,4 and CACNA1C,5 which was strongly implicated initially in GWAS of bipolar disorder.6 It is of interest that there is evidence that variation at CACNA1C also influences risk of recurrent unipolar depression.5 More broadly, there is evidence for overlap in the identity of genes showing gene-wide association signals in GWAS of schizophrenia and bipolar disorder.7 Perhaps most compellingly, there is strong evidence that the aggregate polygenic contribution of many alleles of small effect to susceptibility for schizophrenia also influences susceptibility to bipolar disorder.8
Although a great deal of work remains to be undertaken in delineating the pathogenically relevant DNA variants and the biological mechanisms by which they influence disease risk, the studies described above indicate that schizophrenia and bipolar disorder (and recurrent depression) do not ‘breed true’, but have an overlap in genetic risk and are therefore likely to share some aspects of pathogenesis. This does not equate to a simple dichotomous notion of completely distinct and unrelated disease categories and allows us to reject the traditional, simplistic view of the dichotomy. We think this is unlikely to surprise clinicians, who frequently have to decide how to categorise and treat individuals with a mixture of prominent mood and psychotic symptoms.
It has recently been recognised that structural genomic variants of small or modest size (copy number variants (CNVs) of stretches of DNA of 1000 base pairs or more) are a common cause of genetic variation in humans,9 and such variants have been reported in neuropsychiatric phenotypes, including autism, ‘mental retardation’ (intellectual disability) and schizophrenia.10–15 The overall ‘load’ of CNVs has been shown to be greater in individuals with schizophrenia compared with controls, and there is convincing evidence that a number of specific rare CNVs (<1% population minor allele frequency) confer risk of schizophrenia, particularly those at 22q11 (the velocardiofacial syndrome deletion), 1q21.1, 15q13.3 and 15q11.2,12–14 as well as deletions of the gene encoding the synaptic neural adhesion molecule, neurexin 1.16 The specific CNVs associated with risk of schizophrenia also confer risk of multiple neuropsychiatric phenotypes, including autism and mental retardation.17 This indicates an overlap of genetic susceptibility and pathogenesis across the categories of schizophrenia, autism and other neurodevelopmental disorders and challenges the view that these are completely unrelated diagnostic entities.
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).
Data suggesting a degree of specificity between pathophysiology and phenotype come from work at the interface of the traditional dichotomous categories. Cases with a rich mix of clinical features of bipolar mood episodes and the psychotic symptoms typical of schizophrenia (a broadly defined schizoaffective illness) may be particularly useful for genetic studies,22 and there is evidence that variation within genes encoding gamma-aminobutyric acid (A) receptor subunit genes may predispose relatively specifically to such mixed mood–psychosis clinical pictures.23 Although continued reliance on the relatively narrow DSM–IV and ICD–10 definitions of schizoaffective disorder would appear to be untenable, particularly on the grounds of poor reliability,24,25 this clinical entity merits explicit recognition in order to explore this possibility further. We note that the abolition of a schizoaffective category from revisions to current classifications, as advocated by some (e.g. Heckers25), would risk further reinforcing a completely inappropriate dichotomous view.
The main clinical aims of diagnosis include the optimisation of treatments and allowing useful prognostic statements to be made. The history of medicine suggests that therapeutic and prognostic decision-making are usually facilitated, often greatly, as classifications move closer to the underlying biological mechanisms. For this reason, it is desirable to move towards a classification that maps the expression of illness onto the underlying biological systems. It is not yet clear whether this will be most usefully achieved by using multiple overlapping ‘categorical’ domains of psychopathology or multiple dimensions.1,26,27 Clinicians benefit from the simplest, most user-friendly model that is clinically useful. Of course, the traditional dichotomy is simple and this perhaps explains its persistence despite increasingly questioned clinical usefulness.1 In our 2005 editorial we suggested that recent evidence made it necessary to consider a mood–psychosis clinical dimension with at least three possible overlapping broad domains of psychopathology (‘prototype schizophrenia’, ‘schizoaffective’ and ‘prototype bipolar’). More recent genetic data are broadly consistent with such a model. However, these newer data also point to the need to consider a broader clinical spectrum that includes also autism and mental retardation/cognitive impairment at one end and non-psychotic mood disorder at the other.
If models of illness are to map onto the underlying functional systems of the brain, it is obviously essential to take close account of normal as well as abnormal brain function. The brain is a highly complex structure in which high levels of anatomical and functional connectivity occur at many levels.28,29 Plasticity occurs at all stages of development and environmental influences cause important short- and long-term effects on brain function. Psychiatry must strive to integrate evidence from various levels of neuroscientific investigation – including molecular biology, cognitive neuroscience and affective neuroscience – to move towards a coherent understanding of psychiatric illness that can appropriately use models from each area of inquiry for the benefit of patients.
Here, we present a simple uniaxial model for the relationship between several traditional diagnostic entities that is broadly consistent with current genetic data (Fig. 1). The aim is to aid thinking, guide future work and stimulate debate. Key features of the model include:
We have entered a period of unprecedentedly rapid progress in understanding mental illness. While ensuring that the needs of our patients are at the forefront of thinking and planning, we need to prepare ourselves to move towards more complex and biologically plausible models of illness rather than clinging on to the biology-free models based on clinical empiricism that have been the tradition of psychiatry.
Although current data suggest that there is some degree of genetic specificity at the level of clinical symptoms, it is an empirical question as to what degree of specificity it will be possible to delineate and which specific domains (or dimensions or syndromes) of psychopathology will be most useful to recognise and measure.31 There is a pressing need to characterise the neurocognitive disturbances that underlie the major domains of psychopathology if we wish to develop a more refined taxonomy of mental disorders29 as well as better entities for genetic and other aetiological studies. It is to be hoped that more fundamental phenotypes might emerge from studies of the biological systems implicated by genetic and other biological findings.
A combination of these top-down and bottom-up approaches might ultimately allow us to trace the links between genotype and phenotype. These efforts will require greater integration between different research modalities, including genetics, psychopathology, and cognitive and affective neuroscience, together with insights from systems biology. This should be complemented by consideration of social and other relevant environmental variables, and include a developmental perspective. There is also a need for more longitudinal studies; it seems inconceivable that future taxonomies will not address the considerable variations in course and outcome seen in the clinic. This will require major investment in research, closer cooperation between different research paradigms and a movement away from schools of thought that are often held with ideological zeal.
At a time of transition it will be necessary to be open-minded and flexible. Care must be taken to ensure that the diagnostic entities (be they dimensions, categories or a mixture) are based on solid data, are usable and have proven clinical utility. Inevitably, research must move faster and be willing to explore a wide range of options unconstrained by current diagnostic categories. Clinical practice must expect a slower pace of change and a longer transitional period. Efforts to reformulate DSM–V and ICD–11 are currently underway. In our view, the most pragmatic solution to current needs is to encourage the careful measurement and reappraisal of psychopathology by using dimensional measures of key domains of psychopathology which can sit alongside the use of categories. The resulting detailed clinical diagnostic evaluation will allow the efficacy of current and future treatments to be monitored in individual cases and better serve research into aetiology, classification and treatment. Thus, it is likely to be a while yet before the traditional dichotomous prototypes will make an exit from official classifications, even though evidence and thinking are moving on.
At the time Emil Kraepelin introduced his dichotomy based on longitudinal course there were no effective treatments. At the end of the 19th century, it was logical to use a simple diagnostic approach that offered reasonable prognostic validity. At the beginning of the 21st century, we must set our sights higher.
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.
We are members of the MRC Centre for Neuropsychiatric Genetics and Genomics in Cardiff University. M.J.O. is a member of the DSM–V Work Group on Psychotic Disorders. The opinions expressed in this article do not necessarily reflect the consensus of the DSM–V Work Group or Task Force. We are indebted to all the participants in our studies.
Declaration of interest