Are brain structural abnormalities useful as endophenotypes in schizophrenia?

Endophenotypes, which represent intermediate phenotypes on the causal pathway from the genotype to the phenotype, can help unravel the molecular etiopathology of complex psychiatric disorders such as schizophrenia. Several candidate endophenotypic markers have been proposed in schizophrenia, including neurocognitive and neurophysiological impairments. Over the past three decades, there has been an impressive body of literature in support of brain structural alterations in schizophrenia, but few studies have critically examined whether these abnormalities can be considered useful endophenotypic markers. We critically reviewed the extant literature on the neuroanatomy of schizophrenia in this paper to evaluate their candidacy as endophenotypes. Structural brain changes are robustly associated with schizophrenia, are state independent and may cut across the diagnostic boundaries of major psychotic illnesses. Brain morphometric measures are heritable, co-segregate with the broadly defined neurocognitive and behavioural phenotypes within the first degree relatives of schizophrenia patients and are present in unaffected family members more frequently than in the general population. Taken together, brain morphometric alterations appear largely to meet the criteria for endophenotypes in psychotic disorders. Further work is needed to examine how specific genes and their interactions with the environment may produce alterations in brain structure and function that accompany psychotic disorders.