Heterogeneity of brain structural variation and the structural imaging endophenotypes in schizophrenia

Schizophrenia is often assumed to comprise a group of biologically distinct disorders, yet it has been difficult to dissect subgroups using biological markers. We review recent brain imaging morphometry studies addressing the issue of heterogeneity within the diagnostic category of schizophrenia. Studies of subgroups of schizophrenia patients have mostly used either symptom structure or clinical course for the delineation of potentially meaningful subgroups. Studies defining subgroups according to outcome, i.e. good versus poor outcome (or 'non-Kraepelinian' vs. 'Kraepelinian', respectively) have shown that while these two subgroups might overlap in the extent (and possibly also strength) of prefrontal deficits, they differ in temporal and occipital areas, where poor-outcome patients show stronger deficits. More recent studies have investigated subgroups of schizophrenia based on factor analysis of psychopathology. They have demonstrated a complex pattern of regional changes, where the typical three subgroups might overlap in prefrontal changes, but show divergence in structural deficits in other areas such as the thalamus, hippocampus, or cerebellum. Altogether, these studies demonstrate that brain structure per se is not a uniform endophenotype, but rather a combination of regional deficits highly heterogeneous in both meeting endophenotype criteria as well as in their distribution within the disease category.