Schizophrenia as a progressive developmental disorder: the evidence and its implications

Abstract

I would like to propose that there are certain limiting characteristics of the in vivo structural brain changes observed in schizophrenia that must be explained by any postulated pathogenetic hypothesis. These characteristics are not so specific as to be diagnostically useful in individuals in the absence of behavioral data, but they are useful in the search for the genetic defect(s) that most observers now agree are the necessary if not sufficient cause(s) of the illness. This potential utility comes about at two stages in this genetic search; first, because brain volume loss is a quantitative trait, it is possible to use it to separate out a sub-set of schizophrenic patients who are more likely to share a common genetic defect, even if the illness is heterogeneic in an unselected patient group. Second, even if a gene region is shown to be associated with schizophrenia with high probability, it will still be necessary to screen as many as a hundred or more genes in the region to find the specific cause. In this search a genetic defect that measurably affects brain growth and development is much more amenable to isolation in an animal model than one that affects only behavior; it’s hard to be sure what a schizophrenic mouse would look like.