Symptoms and course as criteria defining the phenotype

As its inception and to the present day, the clinical entity of schizophrenia is diagnosed by analysis of the subjective symptoms reported by patients, their history and course, observation of behaviour, affect and speech, and (to a lesser extent) by evaluation of premorbid development, personality traits, and family background. The diagnostic criteria of the International Classification of Diseases ICD-10² and Diagnostic and Statistical Manual (DSM)-IV³ were originally conceived with a view to achieving three fundamentally different goals: (i) to identify groups of patients with broadly similar clinical presentation and prognosis; (ii) to facilitate early diagnosis and choice of treatment; and (iii) to define a homogeneous heritable diagnostic category for genetic aetiological research.⁴⁶ Whereas the first two goals have, by and large, been achieved as regards the clinical utility of the criteria, attainment of the third goal remains remote. The estimated high heritability of schizophrenia ( 80%, on the basis of twin studies using DSM-III criteria⁴⁷) has not been matched by unambiguous genetic linkage findings in studies using the diagnostic category as the phenotype. Two recent meta-analyses^{48, 49} suggested greater consistency of linkage results when pooled samples from different sources were examined, but the actual agreement between the two studies on specific linkage findings was disappointingly low. The inconsistency of the results suggests extensive locus and allelic heterogeneity, as well as an admixture of phenotypically varied clinical populations.

Notwithstanding the reasonable level of inter-rater agreement that can be achieved on the broad diagnosis, the symptoms of schizophrenia span a wide range of psychopathology and display an extraordinary amount of interindividual variability and temporal inconstancy, calling to mind Wittgenstein's remark that classifying subjective psychological phenomena was akin to classifying clouds by their shape.⁵⁰ As no symptom is pathognomonic or necessary, but variable subsets of symptoms can be sufficient for the diagnosis, patients may be allocated to the diagnostic category of schizophrenia without having a single symptom in common. As a consequence, the phenomenological similarity of patients, selected for genetic and other biological research by the current criteria is modest at best, and disconcertingly low at worst. This might be part of the reason for the limited capacity of the diagnosis to predict accurately which biological or behavioural attributes will be shared by the majority of individuals allocated to the diagnostic category, or to draw 'zones of rarity'⁵¹ that clearly demarcate schizophrenia from other disorders, such as bipolar affective disorder.^{52, 53} Such flaws raise doubts about the capacity of the broad clinical definition of schizophrenia to carve out biologically homogeneous clinical populations for genetic analysis.

Such concerns are not new – attempts to parse the complexity of schizophrenia into simpler component disorders or subtypes have been undertaken since the earliest formulation of the diagnostic concept, using clinical or biological criteria, as well as a variety of statistical methods. In the overview, that follows, the terms 'subtype', 'component disorder' or 'variant' are used near-synonymously to denote sets of phenotypic attributes defining discrete subgroups of individuals likely to be internally more homogeneous for aetiologically relevant genes than the whole of the clinical population meeting broad diagnostic criteria for schizophrenia.

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Date: 2016-04-22; view: 811