John L. Waddington1 and Paul J. Scully1

It is surely correct to conclude that schizophrenia, even when diagnosed according to contemporary, operationalized criteria (DSM-III-R/IV; ICD-10), is a disorder characterized by diversity in phenomenology and long-term outcome, and that no known biological or psychological index is pathognomonic of the disease. However, the affirmation that schizophrenia is therefore a heterogeneous group of disorders requires further consideration in relation to the available data and how they should be analysed to address directly this fundamental issue [1]. For example, the proposition that a certain proportion of patients with the disorder evidence a given abnormality while a lesser proportion of controls do so, is not informative. More specifically, to say that X% of patients evidence a given abnormality in comparison with only Y% of controls (X > Y) cannot be interpreted fully when the presence or absence of that abnormality is defined using some arbitrary value along the continuous or categorical scale used in the measure thereof; such an arbitrary definition of abnormality inherently dichotomizes patients (and controls) into two (or more) groups independent of whether the underlying distribution of the measured variable actually indicates the presence of such (sub)groups.

Consider the ''core'', most widely replicated and accepted biological finding in the brains of individuals with schizophrenia, namely ventricular enlargement [1]. There is now a substantial body of evidence to contradict the (widely held) assertion that such enlargement is present in some but not all patients with the disease; on the contrary, ventricular size in patients with schizophrenia is distributed unimodally in a manner similar to that of normal individuals, the difference being that in patients the mean of this distribution is shifted significantly to the right (greater ventricular size) [2,3].

Several conclusions follow from these analyses [1]: (a) ventricular enlargement appears to be a population phenomenon in essentially all patients with schizophrenia; (b) overlap between the distributions of ventricular size in patients and controls, with only a proportion of patients having ventricular size outside of the control range or 2 SDs above the control mean, affirm that this measure has limited diagnostic utility, but should not be misinterpreted as indicating any subgroup(s) or heterogeneity, for which there is no evidence; (c) for each patient, even those having ''small'' ventricles well within the control range, ventricular size appears greater than would have

1 Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, 23 St Stephen's Green, Dublin 2, Ireland been the case had schizophrenia not emerged in that person. Whether this generic increase in ventricular size does or does not progress over the course of chronic illness has been a contentious issue [1]; a recent prospective study [4] has indicated progression therein, with the distribution of enlargement not deviating from unimodality in a manner consistent with a homogeneous process. Similarly, neuronal size in layer III of the prefrontal cortex in schizophrenia evidences a unimodal distributional shift in mean to the left (reduced neuronal size) relative to controls [5]; though a large number of neurons were examined in only a limited number of cases, the data indicate a homogeneous effect.

This analytical approach has been applied to other aspects of schizophrenia in comparison with control populations, within a developmental model of the disorder [1], as follows: reduced premorbid IQ in the late teens [6], reduced educational test score in childhood [7], increased craniofacial dysmorphogenesis over the first half of pregnancy [8]. When each of these diverse experimental findings along a lifetime trajectory of disease [1] is analysed in this manner, the data appear to be characterized consistently by a unimodal distributional shift in mean value among patients, and thus a homogeneous process, at each time-point and for each level of enquiry.

In summary, while this and alternative analytical approaches need be applied to additional levels of enquiry at a wider range of time-points along this dynamic, lifetime trajectory [1], the evidence to date suggests that when schizophrenia is diagnosed in accordance with contemporary, operational-ized criteria, diversity in a range of biological and psychosocial measures may reflect normal variation within an unexpectedly homogeneous process. The extent to which these notions might generalize to other operationally-defined disorders, particularly schizophrenia spectrum conditions, other non-affective and affective psychoses and bipolar illness, is unknown.

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