Premorbid indicators and risk for schizophrenia: A selective review and update

Abstract

Prospective studies of young relatives at risk for schizophrenia (high-risk studies, HR) can shed light on premorbid precursors of schizophrenia. Early HR studies pointed to a wide prevalence of schizophrenia spectrum psychopathology among young relatives at increased genetic risk. Recent studies suggest that young HR relatives have neurobehavioral deficits and structural, physiological, and neurochemical brain abnormalities that may date back to childhood or earlier. In this paper, we provide a selected overview of the lessons and limitations of early “first generation” studies and the beginning insights from recent “second generation” studies. We also provide an interim summary of data from the ongoing studies of young relatives at risk for schizophrenia in Pittsburgh. Collectively, such data may help us to predict the eventual emergence of schizophrenia, and schizophrenia spectrum or non-spectrum psychopathology.

Introduction

The view that schizophrenia is a neurodevelopmental disorder suggests that pathogenetic biological events may be detectable in individuals at risk before the typical onset of features of the illness (e.g., psychosis) during childhood, adolescence or early adulthood (Chua and Murray, 1996, Murray and Lewis, 1987, Weinberger, 1987). Genetic factors are among the best-established etiological risk factors in schizophrenia. The heritability of schizophrenia is estimated to be 60–90% (Gottesman, 1991, McGuffin et al., 1984, Kendler, 2002). The risk of schizophrenia increases in proportion to the familial proximity and the number of affected relatives. Offspring of schizophrenic parents have about a 13% risk of developing schizophrenia, and having two schizophrenic parents increases the risk to about 40% (Gottesman and Shields, 1982). Having a schizophrenic first-degree relative increases the risk by 5 times in parents, and 8 times in siblings. The challenge for learning how genetic risk impacts brain and behavioral functions is addressed by assessing specific premorbid alterations in the appropriate group of subjects. Prospectively studying relatives of schizophrenia patients with high genetic risk (the high-risk, or HR approach) will continue to be instructive in our search of markers that predict the onset of the illness. In this report, we provide a limited review of the HR studies and an interim summary of methods and findings from the Pittsburgh HR studies in the context of this literature. This paper is not intended as a comprehensive or detailed review of the vast literature on high-risk research; the reader is referred to other works (Niemi et al., 2003, Cornblatt et al., 1999, Sarfati and Hardy-Bayle, 2002).