In his early writings, Kraepelin  had presumed that the ''florid bouts of illness'' - psychotic episodes - lead to a certain amount of irreversible consequences he called ''defects''. This model, implying that schizophrenia shows a deteriorating course in the form of steps, as depicted in the trajectory proposed by Breier et al. , has been revived by Wyatt [76,77], Loebel et al.  and Lieberman et al. [78,79]: ''The illness gets gradually worse during that period indicating that untreated psychosis may constitute an active morbid process, 'toxic' to the brain. If this disease process is not treated and suppressed early enough, it may become chronic'' [14,76,79]. McGlashan and Johannessen  presume that the plasticity of the brain can be preserved and prevented from deteriorating if the persons affected receive both antipsychotic medication and simultaneously social stimulation at a sensitive stage of the illness.
The neurodegenerative effect of the first psychotic episode - if it really exists - should become visible as pronounced deterioration following the psychotic ''bout'' in first-episode cohorts. But this does not seem to be the case when judged by mean symptom scores and measures of social impairment in methodologically sound, prospective first-episode studies.
Nor can the effect be demonstrated on mean scores from neuropsychological tests in the majority of studies . In fact, global impairment and its social consequences emerge as early as the prodromal stage without clear signs of gaining momentum in the psychotic episode.
If the duration or severity of psychotic episodes were causally associated with indicators of a poor further illness course, evidence for such an association would be provided by findings that psychotic symptoms predict subsequent negative symptoms. For this purpose we operationalized the symptom dimensions of schizophrenia on the basis of Liddle's three-factor model [82-84] to obtain comparable measurements . We prospectively assessed the representative ABC follow-up sample of 115 first-illness episodes at six cross-sections over five years after first admission. The negative factor remained independent of the two other factors, throughout the cross-sections, but highly significantly correlated with itself from cross-section to cross-section. In conformity with results from numerous follow-up studies, the negative factor turned out to be the most stable component independent of the course of the psychotic symptom dimensions in schizophrenia. The two other factors (reality distortion and disintegration) showed a few autocorrelations and significant intercorrelations at several cross-sections as well as courses independent of the negative factor. Similar results have been reported by Arndt et al. , who showed that Liddle's three factors varied independently over two years, and Salokangas , who showed the same over five years.
The analysis discussed above of how DUP and DUI influence five-year outcome can also be regarded as a test of the hypothesis about the neurotoxicity of psychosis. The result that significant effects could be shown to exist only at the level of the quantitatively predominant symptoms corresponds to the results on the stability of the factors.
To test the neurotoxicity hypothesis, Ho et al.  recently conducted a cross-sectional study of 156 first episodes of schizophrenia at the levels of symptoms, neuropsychological test results and brain morphology. The authors were unable to find significant correlations of DUP either with changes in grey matter volumes, symptoms or neuropsychological test results.
The reasons for the inconclusiveness of the findings concerning the effects of DUP and DUI probably lie in the great methodological differences of these studies (Table 1.2). Exact comparisons of the two periods concerned, DUP and DUI, are hardly possible due to differences in the definitions used and/or non-use of appropriate assessment instruments. With a few exceptions, the samples studied were not representative. Because of the extremely heterogeneous course of schizophrenia, the proportions of unfavourable courses in the study samples probably varied a great deal. The difficulties encountered in studying associations between
DUP and illness course are by no means minor in studies based on magnetic resonance imaging (MRI) and computed tomography (CT) scans. Some studies have shown that morphological brain changes occur early in the illness, before the psychotic stage. Other studies have demonstrated that compared with age-matched controls brain volume reduction increases over time (five years) in some cases . However, it is not yet possible to tell the exact proportion of these cases in the total of people with schizophrenia (Table 1.3).
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