In this paper, 25 studies of first-degree relatives of schizophrenia patients were found in the recent literature, and volumes of brain structures examined by at least three studies were included in meta-analyses. The first-degree relatives included siblings, monozygotic twins, dizygotic twins, parents, and offspring. The brain structures analyzed were total brain, intracranial, lateral ventricle, third ventricle, gray matter, white matter, amygdala-hippocampal, hippocampal, and cerebrospinal fluid volume. The authors computed the effect sizes between volumes of the relatives of schizophrenia patients and controls and reported whether the effect sizes were significantly different from zero. Also reported was a “fail-safe” number in order to account for potential unpublished studies of no effect.
Significant effects were found in three structures: total hippocampal and cerebral gray matter volume (both with relatives’ volume being smaller than the controls’), and the third ventricle volume (with relatives’ volume being larger than the controls’).
The meta-analysis brings into focus significant differences in brain structure volumes between first-degree relatives of schizophrenia subjects and controls, whereas individual studies may be underpowered and therefore could not reach statistical significance. However, not all of the structures of interest, notably, thalamus, cingulate gyrus, and prefrontal cortex, were included because there were not enough studies of these structures in first-degree relatives of schizophrenia patients, but these structures could be affected in these relatives. Further, better specificity of those at risk for schizophrenia based on structural findings may also be attained by studying shape, which has been shown to increase statistical power in the absence of significant volume differences, and by combining measures from multiple structures. Such approaches may have important clinical relevance in early identification of those at risk for developing schizophrenia.
The emerging evidence from this meta-analysis could suggest genetic vulnerabilities to developing the illness and the identification of endophenotypes for schizophrenia. The authors cautioned that abnormal findings in relatives may not necessarily mean genetic vulnerability to schizophrenia, but could represent shared environmental effects. Genetic studies of homogenous schizophrenia pedigree relationships to structural abnormalities would shed light on gene effects. Toward this end, studies of the relationship between particular environmental insults that could be prevalent in schizophrenia families and brain structure could be beneficial.
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Modern research has undoubtedly shown significant relationships between at-risk relatives of patients of schizophrenia and the development of disease. This paper simplifies a lot of information about brain structure abnormalities in at-risk individuals. At this point of research there is no doubt that these changes exist. There is also no doubt that these changes are significantly more pronounced in relatives of schizophrenia patients that what is seen in general population or non-patient relatives. This information however does not translate into addressing major questions.
Regrettably not many studies take into account the various environmental and developmental factors that might directly or indirectly affect the brain volumes. The same has been a problem with this meta-analysis. The studies selected are not uniform in design except that they all have the same objectives. While brain abnormality has been observed, its causes and origins are not explained. It is extrapolated that the changes are possibly a reflection of genetic vulnerability, while more careful study might well find that the same may be due to environmental brain insults. It therefore does not in anyway establishes a causal link. It merely stops at a possible association between brain changes in at-risk relatives of schizophrenia patients and possible development of psychopathology. It would be interesting to follow up the candidates and observe keenly different changes at different ages and development of prodrome or psychosis. The analysis is interesting from a research review point of view, however.
View all comments by Amresh Shrivastava