Post-mortem structural analyses of schizophrenic brain: study designs and the interpretation of data.

This paper discusses various factors that must be considered in designing histological studies of schizophrenic brain. An examination of the literature prior to 1952 reveals that much of the controversy arising during the first half of this century can be understood within the context of methodological flaws that included the use of inappropriate controls, the lack of systematic diagnosis of schizophrenia, an absence of blind quantitation and finally, a failure to control for the effects of several potential confounding variables. In addition to these latter concerns, the design of post-mortem structural analyses of schizophrenic brain must also consider what brain areas are reasonable to examine, what morphometric parameters should be evaluated to test a hypothesis in question and whether any differences noted represent primary, secondary or perhaps even epiphenomenal changes in the brain. The life cycle of schizophrenic patients should be considered in these designs so that factors intrinsic to the disorder, such as a genetic trait marker or the effects of perinatal insult, can be distinguished from changes that may arise later, perhaps in relation to the acquisition of the defect state. The basic principles of neurobiology and clinical psychiatry should be applied in developing a design and in interpreting data that emerges. Taking all of these issues into account, complex strategies will be required in order to obtain reliable, valid and clinically relevant information that can contribute to our understanding of the pathophysiology of schizophrenia.