Uncovering novel clinical characteristics, risk factors and brain phenotypes across the spectrum of adolescent psychosis.

The reasons why some people develop psychotic disorders are unknown, and identifying possible biological disease mechanisms is an important step towards developing new and better treatments. One perspective that is central for this is the interaction between genes and the environment. In 2023, we published a study using data from the Medical Birth Registry (MFR) and 1,300 patients with schizophrenia (SZ) and healthy individuals. We found an interaction between genetic risk score (GRS) for SZ and birth asphyxia - a serious obstetric complication that leads to insufficient oxygen availability to the brain. In particular, the findings showed that the GRS was better able to distinguish patients with SZ from healthy participants when birth asphyxia had occurred. Furthermore, we examined the proportion of genetic variants in GRS for SZ that can be related to placental function (PlacGRS), and that this was associated with lower head circumference at birth in newborns with birth asphyxia. These findings suggest that the combination of genetic risk for SZ and birth complications may lead to a lasting effect on brain development. In another study published in 2024, we found an altered pattern of up- and down-regulation of gene expression (epigenetic modifications) across four DNA regions that play an important role in brain development and function. These changes were associated with birth asphyxia, suggesting that birth asphyxia affects epigenetic processes. As we discuss in a recent book chapter (Witzany, G. (eds) Epigenetics in Biological Communication. Springer, Cham), our own and previous findings suggest that birth complications and genetic risk affect brain development and together increase the risk of developing SZ. To further develop research in this field, in May 2024 we organized the Oslo Placenta-Brain Seminar at Diakonhjemmet Hospital. This seminar brought together international and national researchers from several academic disciplines to discuss how genetic factors and placental function can alter early developmental trajectories often seen in mental disorders. The seminar presented findings that will promote further innovative research on gene-environment interactions in SZ. Another important perspective for furthering our understanding of biological disease mechanisms in psychosis is in vivo brain imaging. In 2024, we published an article on brain structure in EOP through the Early-Onset Psychosis (EOP) Working Group, organized in the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium. In this study, we found that patients with EOP had lower regional gray matter volume in large parts of the cerebral cortex and cerebellum, while there were minimal differences in white matter volume. We also found that volumetric changes were associated with the use of antipsychotics, and that those who were diagnosed with EOP later had lower volumes in restricted areas compared to those diagnosed earlier. In this study, we used voxel-based morphometry (VBM), a method in which differences between individual brains and a “standard brain” form the basis of the volumetric calculations. We are now following up on the findings from the VBM study with a study using surface-based morphometry to calculate four different measures of cerebral cortex morphology. These include cortex thickness and volume, as well as surface area and folding. In preliminary analyses, we see the largest differences in surface area, volume and folding, with more focal changes for cortex thickness. The findings suggesting reduced folding in EOP compared to healthy adolescents are particularly interesting, as folding is mostly a result of early brain development, and the folding differences may therefore point to changes in early development. In late 2023 and 2024, we performed data collection for healthy participants, in addition to our ongoing data collection of cohorts of adolescents with psychotic disorders, early bipolar disorder and at clinical risk for psychosis development. These data will be used in a planned study on myelination of the cerebral cortex. We have also initiated a study on hippocampal volume in adolescents with EOP. Reduced hippocampal volume and volume reduction in the hippocampal subnuclei is a frequent finding in adults, but so far there have been few studies on this in adolescents. The plan is therefore to compare volumetric changes in the hippocampus in adolescents with those seen in adults, as well as trying to replicate previously reported biological sex differences, where several subnuclei were more affected in men than in women with SZ. Using cross-sectional and longitudinal data we expect to further investigate the importance of biological sex in brain development in early psychotic disease in adolescents using our in-house cohorts (Youth TOP study) and national and international collaborating cohorts.

Early-onset psychosis disorders (EOP) are mental diseases in youth with unknown cause and poor differentiation. The topic is important given the poor treatment response and clinical outcome, the stronger genetic load and brain abnormalities, a life-long need for pharmacological treatment, and possibility for new discoveries. In EOP, we find smaller intracranial volumes and large basal brain nuclei, which we cannot reproduce in adult-onset samples. The small brain and yet undiscovered brain features can be unique signatures for EOP, particularly schizophrenia, and keys to understanding disease development. Birth asphyxia is related with smaller brain volume, lower IQ and white matter microstructure disarrays. We characterize adolescent patients aged 12-18 years with schizophrenia or bipolar spectrum disorders, youth at clinical high risk for psychosis development, and healthy controls, both genders, initially over 3 years. Large samples are needed and we expand to include neurodevelopmental disorders and birth cohorts. We coordinate international EOP samples. By combining methods from computational psychiatry, registry data and advanced neuroimaging, gene and biomarkers, the project will yield novel knowledge about clinical characteristics, risk factors and brain phenotypes across the spectrum of adolescent psychosis. From MRI, we quantitate brain phenotypes: Cortical structures, white matter, network connectivity and myelin mapping. We study how risk factors; prenatal adversities, infections exposures, immunity and genetic risk, converge upon the EOP phenotype. We use in-depth phenotypic characterization and whole genome sequencing in large-scale collaborations. We expect to find predictive markers for youth at high risk for psychosis and to unravel aspects of the patophysiology of psychosis. Translational and interdisciplinary approaches make for diagnostic distinction and stratification, for better treatments and prevention.