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BEDREHELSE-Bedre helse og livskvalitet

Longitudinal Brain Imaging and Investigation of Etiological and Outcome Factors in Early Onset Psychosis.

Awarded: NOK 7.6 mill.

Project Manager:

Project Number:

213700

Application Type:

Project Period:

2012 - 2020

We have established a comprehensive database of systematically collected research information on adolescent schizophrenia and affective spectrum psychosis disorders (early-onset psychosis disorders; EOP) for current and future scientific investigations. The database contains detailed data on clinical symptoms, demographics, family history, physical and mental health, brain structure and function, cognitive test results, global functioning, immune and lipid parameters, and gene variants from DNA, and a biobank. We follow the participants who are aged between 12 and 18 years over time, initially over three years. This database connects with a similar database of adult-onset schizophrenia and bipolar spectrum disorders enabling comparison across all ages and disease onsets. We have simultaneously collected a similar clinical cohort of patients with EOP and healthy controls for comparison at the Karolinska Institutet to use in conjunction with our Norwegian sample. The database will also serve for comparison with adolescents at high risk for developing psychosis disorder, a project that we plan to start and for which we have laid the foundation. We have developed a collaborative international network with regard to brain neuroimaging and an international network of cognition researchers and have demonstrated new scientific findings (cognitive markers, brain structure profile). Using MRI, we have identified a neurodevelopmental marker in EOP patients with small intracranial volumes that we do not find in adult patients with schizophrenia or bipolar disorder who had their disease onset after age 19 years. We believe this is a very important finding and will continue to investigate early adverse biological or sociodemographic environment and genetics as antecedents to intracranial and brain development in childhood that might lead up to early psychosis development. We have obtained normalized cognitive test results in healthy adolescents using the MATRICS Consensus Cognitive Battery (MCCB), which will enable standardized comparison of cognitive performance across different clinical populations and ages. This is important since we have demonstrated lower performance in adolescents with psychosis. We have also shown the negative and disorganized psychosis symptoms mediate the relationship between verbal learning and global functioning, which are compromised at group level in adolescents with EOP. Antipsychotic medication given during adolescence has effects on brain structure as well as on lipid profiles, as we have shown, but some of the changes that we detect are not due to the medication given. Antipsychotic medication however, seemed to have an unexpected trophic effect on white matter connective tracts in the brain and our in vitro findings suggest that the antipsychotic agent clozapine may have a protective/anti-apoptotic effect on neural stem cells. Stress has been implicated as contributory to lipid or immune abnormalities but there may also be other factors that contribute in ways that are not yet understood. The IL-18 immune system has shown increased activity in adolescents with EOP and cortisol and depressive symptoms both contributed to this effect. Our findings support activation of inflammatory pathways in adolescent psychosis and suggest interactions between stress, inflammation and depressive symptoms in EOP. Having antibodies against the NMDA-receptor could point to a propensity toward a disrupted glutamate system leading to early psychosis development, but presence of NMDAR antibodies in EOP patients or healthy controls was not associated with any distinctive clinical or radiological features and had no diagnostic implication. We therefore concluded that a positive NMDAR antibody test in youth should be interpreted with care and reviewed within the individual clinical context. Auditory verbal hallucinations (AVH) present in 80% of EOP. Our pilot mobile phone application (app) study for real-time experience sampling and monitoring of AVH demonstrated validity but emphasizes the value of including patients' experiences in the development and pilot testing of new technology. Based on the small sample size, the use of mobile phones with experience sampling and monitoring seems feasible for patients with EOP, but the acceptability of using apps needs consideration. The project has educated and developed young investigators, from clinical and technical research assistants to the postdoc and researcher level. It connects with child and adolescent psychiatric clinics for recruitment, and has used operational and standardized diagnostic instruments for the clinical investigation, which is useful also for the clinic, to which we communicate relevant results, as well as to the patients and their parents or care takers. With continued studies, we expect to contribute more knowledge on psychosis disorders that develop already in adolescence.

We established a database and biobank of adolescent early-onset psychosis disorders; EOP, for scientific research. Connection with adult psychosis and Swedish EOP-cohorts enables comparison across age and clinical high-risk samples. We developed international neuroimaging and cognition networks and demonstrate new scientific findings. We enabled standardized comparison of cognitive performance across populations. We identified a neurodevelopmental brain marker in EOP, a key to finding the antecedents of psychosis development. Antipsychotic medication use effects adolescent brain structure and lipids. Activated inflammatory pathways suggest interactions between stress, inflammation and depression. Our app-study demonstrates value of including patients experiences in developing and testing new technology. The project educated young investigators, from assistant to researcher level. Results are shared with clinics, patients and their guardians.

Early-onset psychosis and particularly early-onset schizophrenia (EOS) are long term devastating mental diseases with unknown cause and suboptimal treatment. EOS is considered to involve more premorbid neurodevelopmental abnormalities, worse anatomic brai n abnormalities, and higher rate of cytogenetic abnormalities, more rare copy number variants and worse long-term outcome than what is found in adult-onset disease. It is important to use the improved methodologies of today to acquire new knowledge abo ut the etiology and to find better treatments and prevention. We will base the study on adolescent patients (ages 12-18 years) with schizophrenia or bipolar spectrum early-onset psychosis and healthy control subjects of the same ages and gender. The cohor t will be characterized with clinical, neurocognitive, and genetic methods (whole genome scanning and deep sequencing of selected gene regions), longitudinal magnetic resonance imaging (MRI) of structural brain anatomy using vertex-based morphometry and d iffusion tensor imaging, and brain intrinsic function dynamics using resting-state functional MRI. We obtain information on family history and early environmental risk factors; e.g. obstetric complications from medical records and birth registry, and mark ers for cardiovascular disease risk, and inflammation, as independent or related factors to brain abnormalities and connectivity. The project is part of a long-term research project agenda (the TOP Study) and has as the ultimate goal to establish a long itudinal prospectively followed adolescent cohort for study of etiology (genetic effects and environmental hazards) and other factors that may be predictive of outcome. The present proposal limits focus to baseline characterization and one-year follow-up.

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Funding scheme:

BEDREHELSE-Bedre helse og livskvalitet