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

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 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.

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.

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.