Mental disorders represent one of the largest burdens for the European Health Care system, due to large number of patients and a lack of efficient treatment options. Today, drug treatment of mental disorders is characterized by severe adverse effects and suboptimal response in more than a third of the patients. Optimizing treatment is based on a trial-and-error approach, which combined with frequent multi-morbidities, often leads to polypharmacy and poor outcome. Due to limited understanding of the disease mechanisms that underlie mental disorders, new drugs with novel therapeutic targets are lacking, and existing treatments are ineffective for many people. It is therefore urgent that cutting-edge research approaches are deployed to develop innovative tools to individualize treatments using available psychiatric medication, and thus improve clinical outcomes and reduce costs for health care systems. The main goal of the multidisciplinary REALMENT project is to optimize treatment of mental disorders through novel precision medicine strategies based on current pharmaceutical options. REALMENT includes world leading research institutes and pharmaceutical industry at the very forefront of mental disorder research. REALMENT will achieve its objectives by exploiting population-scale Real-World Data (RWD) in combination with Randomized Clinical Trial (RCT) data available to the partners. Big data from populations (Nordic registries), cohorts (European biobanks), and eHealth samples (medical records), including whole genome genotypes (n=1.9 million), will be analysed in an EU-wide sustainable infrastructure using artificial intelligence and machine learning to develop prediction and stratification tools (precision psychiatry). These algorithms will be validated in large RCT data (n=10k) and re-phenotyping projects, and implemented in a clinical management platform (4MENT), which will be made available to provide decision support to clinicians to optimize therapeutic effects.

The current nosology of neuropsychiatric disorders provides a pragmatic approach to diagnosis and treatment choice but lacks reference to quantitative biological underpinnings of disease. This weakness impedes innovative drug development. To test whether a quantitative biological approach to the understanding and classification of neuropsychiatric disorders is both feasible and useful the PRISM 1 consortium was formed by academics, SMEs, patient organizations, regulators, ECNP, and EFPIA partners. PRISM 1 has now successfully identified quantitative biological parameters related to diagnosis (Schizophrenia (SZ) and Alzheimer Disease (AD)) as well as to social functioning irrespective of diagnosis. From the relationships between social function, neuroimaging, and cognitive endpoints a new neurobiological framework has emerged now needing further validation. Genetic studies of social functioning outcomes revealed known and novel loci for this phenotype. In addition, a preclinical test battery was developed, based on homologs of the clinical paradigms, to allow effective back-translation and a deepening of our neurobiological knowledge. Finally, a novel digital tool for assessing social function provided a novel, objective characterization that transcended the initial diagnostic classification and the digital readouts were associated with other study parameters. To build on outcomes of PRISM 1, PRISM 2 has three objectives. First, to determine the reproducibility of the transdiagnostic and pathophysiological relationship between DMN integrity and social dysfunction in SZ and AD that emerged from PRISM 1 and determine its potential to generalise to Major Depressive Disorders. Second, to test the causality between the quantitative variation in DMN integrity and social dysfunction. Third, to translate and communicate project results to the benefit of stakeholders, such as regulators, patients and their families, and health care providers.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition affecting over five million people in the European Union. The combination of core symptoms (deficits in social-communication and repetitive and restricted behaviours and interests) and common comorbidities (e.g. epilepsy and depression) significantly reduces the quality of life and life-span of affected individuals. Currently there are no effective drug treatments for the core symptoms. Key factors that have hampered progress include; 1) limited understanding of the underlying pathophysiolog(ies); 2) lack of successful translation from animal models to humans; 3) testing of drugs with specific actions in biologically heterogeneous populations; 4) limited expertise of many European ASD centres in running large-scale clinical trials; and 5) trial designs (e.g. placebo effects). Our vision, therefore, is to apply a precision medicine approach to ASD and improve patient outcomes by tailoring treatments to a patient’s biological profile. Our efforts will build on the achievements of 5 other IMI initiatives, 4 Horizon 2020 networks, and 6 SMEs for the first time to; 1) align global resources to validate and qualify stratification biomarkers from infancy to adulthood; 2) develop objective outcome measures that can be used in trials; 3) create a European-wide clinical trials network that reliably carries out studies able to support filings to the EMA/FDA; 4) carry out better targeted clinical trials linked to other international efforts – including quick wins or “fast fails” of ineffective agents; 5) translate molecular mechanisms and drug effects between preclinical models and particular subtypes of ASD. Together we will bring Europe to the forefront of clinical research in ASD. Also we will provide a sustainable legacy that is accessible by others across the world, attracts industry into ASD, and helps transform healthcare.

PRIME introduces the novel concept of insulin signalling as a key mechanism underlying the multimorbidity of major mental and somatic illnesses. It is well known that aberrant insulin signalling causes high health and socioeconomic burden through its role in diabetes, metabolic syndrome, and obesity. We posit that the impact of ‘insulinopathies’ is still largely underestimated, since insulin multimorbidity also extends to the brain, where altered insulin signalling appears to be implicated in dementias such as Alzheimer disease and – based on our pilot work - in mental illnesses characterized by compulsivity, especially obsessive compulsive disorder and autism. We therefore further posit that insulin multimorbidity evolves throughout life, necessitating a lifespan approach. PRIME brings together a multidisciplinary team to (1) extend our understanding of insulin multimorbidity across the lifespan, (2) understand the causal mechanisms linking somatic and mental insulin-related illnesses, (3) develop tools for early diagnosis, improved clinical care, and prevention of insulin-related lifespan multimorbidity. We will leverage the world’s largest registry, clinical cohort, and population data sets to identify and validate new insulinopathies. Through an interdisciplinary battery of innovative approaches, we will clarify the causal mechanisms linking peripheral and central insulin signalling to body-brain comorbidity, integrating across animal models and studies in humans from molecule to cell, brain, cognition, and behaviour. Our prior evidence enables PRIME to bring the new knowledge to society, based on e.g. repurposing medication and lifestyle interventions (diet/exercise monitored by mHealth assessment), identifying and validating novel drug targets, developing and testing candidate biomarkers, and by improving existing medical guidelines and policy. Furthermore, educational approaches to inform clinicians, patients, and general public will be developed.

Maladaptive impulsivity and compulsivity predispose to antisocial and addictive behaviours. Factors influencing those traits are not well understood, but diet, lifestyle, socio-economic status (SES), sex, and heritability play pivotal roles. Here, we aim (1) to identify nutrition and lifestyle drivers that can be employed to prevent detrimental impulsivity/compulsivity in males and females across the lifespan, (2) to characterize the etiologic paths leading to extreme behaviour, and (3) to promote policy changes to counteract maladaptive impulsivity/compulsivity by disseminating evidence-based information about health-related behaviours to families, clinicians, policy makers, and general public. We use epidemiologic approaches in the world-wide largest existing samples to investigate association of nutrition components & lifestyle with impulsivity/ compulsivity, and how such associations are moderated by age, culture, sex, SES, and genetics. We assess beneficial effects of key nutritional interventions through RCTs in highly impulsive males/females, going beyond state-of-the-art by directly comparing personalized, high-intensity approaches with one-size-fits-all and microbiome-dependent supplementations. We study the protective potential of acute exercise and habitual physical activity. We monitor intervention-induced changes in real time through objective mHealth-based experience sampling. Uniquely, we study effects of the gut-microbiome and its metabolites, as well as brain connectivity and epigenetic patterns as mediators and predictors of behavioural change. We initiate and support societal change by media-based information and education. We innovate the field by measuring behavioural change using social media downstream of educational campaigns and by translation of our findings into tangible healthy food solutions with a celebrity chef. Our group, in which experts from multiple disciplines join forces, is in a unique position to carry out the proposed project.