Elsevier

Schizophrenia Research

Volume 79, Issue 1, 1 November 2005, Pages 45-57
Schizophrenia Research

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

https://doi.org/10.1016/j.schres.2005.07.004Get rights and content

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).

Section snippets

Early, or “first generation” high-risk studies

The idea of examining young relatives at risk for schizophrenia is not new, and goes back to Emil Kraepelin who said: “In children … one might think of …prophylaxis especially if the malady had been already observed in the parents or brothers or sisters. Whether it is possible … to ward off the outbreak of the threatening disease, we do not know. But in any case it will be advisable to promote to the utmost of one's power general bodily development and to avoid one-sided training in the brain

Recent, “second generation” studies: the Edinburgh HR study

It would be instructive to reexamine Garmezy's pessimistic projections as we draw close to 2006. Eventhough an inter-galactic institute is yet to be realized, recent developments in biological psychiatry have significantly advanced our understanding of schizophrenia, and have set the stage for more effective strategies to ascertain premorbid neurodevelopmental vulnerability. First, schizophrenia is now increasingly viewed as a disorder of brain development during the critical period of the 2nd

The Pittsburgh high-risk study

The goals of the Pittsburgh high-risk study were to characterize the neurobehavioral, psychopathologic and biological features of young relatives of schizophrenia patients with matched healthy comparison subjects and to identify potential predictors of emergent psychopathology during follow-up. The study is ongoing, all data are not available in every subject, and therefore the analyses presented must be viewed as preliminary.

Conclusions

In summary, the first generation HR studies were instrumental in characterizing the frequency and patterns of psychopathological outcome in young at risk relatives, and offered some broad clues to neurocognitive and behavioral predictors of later schizophrenia spectrum disorders. Nevertheless, the limited predictive data and long follow-up periods reduced the cost-effectiveness of these studies. Recent HR studies have begun to yield valuable data concerning the possible premorbid

Acknowledgement

This work was supported in part by NIMH grants MH 64023, 01180 (MSK), 68680 (VAD), 62134, 01433 and a NARSAD independent Investigator award (MSK), NARSAD Young Investigator awards (DMM, VAD) and GCRC grant M01 RR00056. We thank Diana Dworakowski MS for help supervising the recruitment and clinical assessments and Jeffrey Nutche BS and Madhuri Vemulapalli MS for image processing.

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