Is there a schizophrenia to diagnose?
Authors: MICHAEL J. OWEN
Journal: World Psychiatry (2011)

Lawrie et al provide a useful review of the diagnostic process and the potential application of various biological parameters in different settings: diagnosis, differential diagnosis, early diagnosis and prediction of treatment response. They conclude that a number of measures have the potential to increase the rigour of clinical assessments in psychiatry and improve diagnostic precision. While I agree with much of what they write and share their concerns about the de-medicalization of psychiatry, I do have one major concern: I am not convinced that we can be certain that schizophrenia is necessarily a valid diagnostic entity. Because we are still largely ignorant of the underlying pathogenesis of schizophrenia and other severe psychiatric disorders, we are forced to rely upon a diagnostic process that is largely descriptive and syndromic, with disease categories that are highly heterogeneous and overlapping. Lawrie et al's response to this is to suggest that we need to seek biological validators of schizophrenia that can be used to distinguish it from other disorders. But this assumes that Kraepelin's original dichotomous conceptualization of the functional psychoses was correct. What if the underlying structure is different? Perhaps there are many schizophrenias or perhaps the functional psychoses are better conceived of in dimensional terms 1,2,3. In the last three years, the application of novel genomic approaches to disorders such as schizophrenia, bipolar disorder, autism and attention-deficit/hyperactivity disorder (ADHD) has yielded a number of important new insights. Highlights include increasing evidence that common risk alleles are shared by schizophrenia and bipolar disorder 4 and evidence that specific submicroscopic deletions and duplications of segments of DNA, known as copy number variants (CNVs), confer risk of schizophrenia and other neurodevelopmental disorders such as autism, ADHD, epilepsy and intellectual disability 4,5. These findings not only challenge the aetiological basis of current diagnostic categories but, together with evidence for frequent comorbidity (which is often obscured by the application of rigid diagnostic categories in research studies), suggest that we should view the functional psychoses as members of a group of related and overlapping syndromes that result in part from a combination of genetic and environmental effects on brain development and which are associated with specific and general impairments of cognitive function. These findings also suggest that many biological and psychological correlates of disease will not map neatly onto diagnostic categories and therefore will be of questionable utility to diagnosis at least where current criteria are concerned. Furthermore, they do suggest that a simple categorical approach to diagnosis might not capture the complexity that exists and that other models might be more useful for research and clinical practice 3. To my mind, the search for the mechanistic underpinning of psychiatric disorders in the immediate and near future needs to be focussed on two distinct domains. First, we should seek to refine our understanding of the major psycho- pathological syndromes/dimensions, such as psychosis, negative symptoms, mood disturbance and cognitive impairment, that occur in different combinations in our diagnostic categories 3. This should include detailed cognitive and neurocognitive studies. This will give us better and more objective measures of psychopathology, allowing us to target therapies and measure their response more effectively as well as giving us greater insights into how these syndromes might arise. Second, we need to characterize these syndromes/dimensions at the level of cellular and neuronal function by focussing on the biological systems implicated by genetic and other biological studies. This work will need to include cellular and animal models as well as the study of endophenotypes that are related to fundamental neuronal and systems function. A combination of these top-down and bottom-up approaches might ultimately allow us to trace the links between underlying biology, environmental factors and manifest psychopathology. In the meantime, I would argue that, at least as far as research is concerned, we need to worry less about how we place our patients into specific diagnostic groups and more about defining phenotypes to suit the specific hypotheses we are testing. In the clinic too, perhaps we should admit that we treat syndromes like psychosis, depression and mood instability rather than diagnoses, and focus more on improving the way we measure these than on refining the way we place patients into categories that in all likelihood do not represent real underlying disease entities.