Cognitive underperformance, progressive changes in brain structure, and high rates of pre-psychotic mental health conditions are found among adolescents with a family history that puts them at high risk of developing schizophrenia. A wealth of such findings is exciting those keen to identify early opportunities for intervention to preserve long-term function in people at high-risk, as well as in those with first-episode psychosis (FEP).
The Pittsburgh study of high-risk children and adolescents showed the expected increase in frequency of FEP. Also of importance was the finding that subjects who do not develop psychosis have a high risk of other adverse outcomes including affective disorders, substance abuse, opposition defiant disorder, ADHD and anxiety.
Almost 90% of variation in brain volume is due to heredity
New work from the Pittsburgh and Boston collaboration, recently published in Schizophrenia Research1, brings support for the view that inflammatory and anti-angiogenic factors may be involved in the neurodevelopmental trajectory of people who will develop schizophrenia.
Researchers identified abnormally increased expression of an anti-angiogenic tyrosine kinase that binds vascular endothelial growth factor, and a reduction in interferon gamma, with the latter suggesting immunological dysfunction early in the natural history of the disease.
Also this year, René Kahn and colleagues from the University Medical Centre, Utrecht, The Netherlands, published work2 suggesting that the global reductions in white matter integrity seen in people with schizophrenia are largely accounted for by genetic risk and may represent a new marker of vulnerability to the disease.
In their recent editorial in the Schizophrenia Bulletin dedicated to neuroimaging, René Kahn and Iris Sommer emphasise that the study of brain development – structural, functional and molecular – is crucial to a better understanding of schizophrenia.
Among the advances, they highlight the following findings:
- Almost 90% of variation in brain volume is due to heredity
- Changes in volume relate especially to the progression of schizophrenia BUT
- Changes in the white matter and their connections precede FEP
- There is progressive thinning of the cortex (particularly in frontal and temporal areas) as illness worsens.
The imperative now is to establish how such insights can contribute to predicting risk, preventive intervention, establishing the diagnosis and enhancing response to treatment. Sommers and Kahn identify cognitive decline, which occurs as early as puberty in high-risk individuals, as a particularly important target for intervention.
Data from the cohort of children born in Dunedin, New Zealand, between 1972 and 1973 show that intellectual underperformance predicts the development of schizophrenia over forty years of follow-up3. From the age of eleven, people who will go on to develop psychosis have lower IQs than controls. In this prospective study, those who develop schizophrenia lose on average six IQ points between childhood and adulthood, and this decline is not accounted for by substance abuse or psychotropic medication.
Tsutomo Takahashi, from the University of Toyama, Japan, and colleagues have been investigating changes in brain morphology4. Differences in cortical folding are evident early in the course of schizophrenia and may predate disease onset.
Compared with healthy controls, the olfactory sulcus is shallower in high-risk subjects, and shallower still in patients with FEP and in those with chronic schizophrenia. Altered depth of the olfactory sulcus could therefore represent another marker of psychosis risk.
Enlargement of the pituitary, which could be stress-related, may also be a marker of vulnerability.
Early brain changes seen in high-risk subjects can aid understanding of psychosis risk. But the hope is that they may also aid understanding of resilience.