Clinical and genetic high-risk strategies in understanding vulnerability to psychosis

Neurodevelopmental processes active during the adolescent period have been hypothesized to participate in the deterioration in functioning associated with the onset of schizophrenia. A number of studies are now underway evaluating individuals in an ultra high-risk clinical state with neuroimaging assessments repeatedly over time, to determine whether particular neural changes predict an imminent onset of psychosis. However, the results of such studies will be difficult to interpret without reference to studies examining the distribution of these neural indicators in the non-clinically-affected first-degree relatives of patients with schizophrenia. Recent work deriving primarily from twin and family studies (i.e., genetic high-risk designs) indicates that some of the alterations in brain function and structure in schizophrenia are primarily genetically mediated and also appear in some of their unaffected first-degree relatives, while other alterations are present in individuals who manifest the illness phenotype but not in relatives at genetic risk. Whereas the primarily genetically mediated deficits shared by at-risk but non-symptomatic relatives are not likely to show differential change in the premorbid period, and may be necessary but clearly not sufficient for the development of psychotic symptoms, the deficits specific to patients who manifest the illness phenotype are good candidates for marking the neurobiological processes associated with the emergence of psychotic symptoms at the time of schizophrenia onset. Preliminary results from longitudinal studies of individuals ascertained initially in a prodromal (i.e., “clinical high-risk”) state appear to be interpretable within this framework.