Diagnosing Schizophrenia A Personal View

Assen Jablensky1

In reviewing the ''state-of-the-art'' of diagnosing schizophrenia, one hundred years after the concept of dementia praecox became established, we cannot escape addressing the question what is the entity that we wish to diagnose? Is schizophrenia a disease, a syndrome arising as a ''final common pathway'' for a variety of pathological processes, or a loose collection of poorly interrelated symptoms and syndromes of multiple underlying causes, held together by nosographic convention or lack of a better alternative?

By lumping together hebephrenia, catatonic insanity and dementia paranoides into ''one illness process'', Kraepelin initiated a project for world psychiatry that remains unfinished: to validate schizophrenia as a disease entity by emulating the great nineteenth-century medical and neuropatholog-ical precedents, best illustrated by general paresis. The process of discovery was to proceed in stages: clinical (grouping the variable symptoms on the basis of a common outcome and thus describing a provisional disease entity that could be delineated from other entities); epidemiological (mapping its incidence and distribution across populations and cultures); and laboratory (describing its neuropathology, pathophysiology and neuropsychology, ultimately narrowing down the search for causes). As it were by default, this design is still providing a conceptual framework for schizophrenia research, in spite of recurring doubts on the validity of its assumptions. Kraepelin was among the first to realize the flaws, and to anticipate the critique, of the disease entity theory, when he wrote, late in his life, that ''our formulation of the problem may be incorrect ... the affective and schizophrenic forms of mental disorder do not represent the expression of particular pathological processes, but rather indicate the areas of our personality in which these processes unfold''[1]. Yet we continue to rely almost exclusively on

1 Department of Psychiatry, University of Western Australia, 50 Murray Street, Perth, WA 6000, Australia symptoms and history in diagnosing schizophrenia, thereby inferring an underlying pathological process.

What is the value of symptoms in defining schizophrenia and in leading us to where its causes might be? Much of the current research into the causes of schizophrenia is predicated on a genetic paradigm, while the clinical diagnosis is predicated on its symptoms. However, neither the symptoms, nor the course of schizophrenia (including age at onset) appear to be under tight genetic control. A telling example is provided by the Genain monozygotic quadruplets, concordant for schizophrenia [2]. Although sharing a virtually identical genome, the four sisters display very different clinical types of illnesses and outcomes. The high heritability of the phenotype of schizophrenia (defined by symptoms) does not necessarily imply a simple direct pathway from genes to symptoms and behaviour. Complex intermediary mechanisms and feedback loops are likely to be involved, and the search for endophenotypes is a strategy of rising importance [3]. Promising leads include abnormalities in the P50 event-related potential, the control of antisaccadic eye movements and sustained attention, all present in the majority of patients, in a high proportion of their asymptomatic relatives, and in a low proportion of controls drawn from the general population. While the functional relationship of such endophenotypes to the clinical symptoms remains yet to be understood, their genetic basis may be simpler to dissect than that of schizophrenia. Other, novel candidate markers and phenotypes are likely to emerge from functional brain imaging and neurochemistry. It is this kind of empirical systematic research, abreast with advances in basic neuroscience, that will eventually bring us to a state of knowledge from which attempts to define the nature of schizophrenia will be more than speculation. Until then, efforts to reduce schizophrenia to linear causal models are likely to be defeated by the complexity of the disorder and the persisting gaps in fundamental knowledge about the organization of brain functioning.

This suggests a medium-term research agenda that involves a two-track approach. On one track, clinical description should be further refined using comprehensive, semi-standardized phenomenological interviewing schedules such as the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) [4] rather than rating scales as short cuts. Alternative typologies, like Leonhard's system of subtyping the disorder [5] are probably worth exploring more systematically. On the other track, the search and testing of endophenotypes and the exploration of their associations with segments of the schizophrenic syndrome, as well as with candidate genes and regions, must transcend the conventional diagnostic boundaries and extend into neighbouring territories (affective and personality disorders) and general population samples.

Up to this point I deliberately avoided any mention of the current diagnostic criteria of ICD-10 and DSM-IV. They are, beyond doubt, extremely useful for several different purposes, but research into the aetiology of schizophrenia need not be subordinated to their dictate. Their role has been aptly described as "gatekeeping" [6]. It is important to reiterate that such criteria do not define schizophrenia but rather provide a common frame of reference enabling clinicians and researchers to index their diagnostic formulations for retrieval and comparisons.

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