Periodic Reporting for period 1 - PRISM 2 (Psychiatric Ratings using Intermediate Stratified Markers 2)
Reporting period: 2021-06-01 to 2022-05-31
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 consortium was formed by academics, SMEs, patient organizations, regulators, ECNP, and EFPIA partners. PRISM1 has now successfully identified quantitative biological parameters related to diagnosis (Schizophrenia (SZ) and Alzheimer Disease (AD)) and 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. To build on outcomes of PRISM1, PRISM2 has three objectives. First, to determine the reproducibility of the transdiagnostic and pathophysiological relationship between Default Mode Network (DMN) integrity and social dysfunction in SZ and AD that emerged from PRISM 1 and determine its potential to generalise to Major Depressive Disorders (MDD). 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.
The PRISM2 clinical study will seek to determine the reproducibility and generalizability of the identified quantitative biological biomarkers of social dysfunction and Default Mode Network (DMN) integrity that accounted for patient stratification in PRISM1. Based on the identified quantitative biological parameters, a refined and optimized test battery has been implemented. In this first period the protocol for the PRISM2 clinical study and patient information sheets have been generated and approved. To implement the clinical study, hardware and software for MRI, EEG and behavioural paradigms has been installed, tested, calibrated, standardized and optimized at the clinical sites involved. Further, training of the clinical sites with respect to operational execution of the trial has been completed with the first patient visit taking place in a timely manner exactly on schedule.
PRISM2 will test the causality between DMN integrity and social dysfunction. Therefore, rodent studies will be implemented that allow for specific interventions to manipulate DMN integrity, namely through chemo-genetic technologies in specific brain regions. As a first step, an inventory of possible preclinical tools for DMN circuit manipulation has been generated. These will allow to local activation or inhibition of the neurons from the social brain network that are specifically innervated by neural structures from the DMN. The first pilot experiments have been performed to test the involvement of these specific networks in the expression of mouse social behaviour.
Finally, several measures have been initiated by the PRISM consortium to translate and communicate the PRISM 2 project results to the benefit of stakeholders. This is guided by a communication and dissemination plan that has been generated, and by the formation of the Impact and Innovation Board. Successful dissemination and communication of the PRISM 2 activities is facilitated and achieved by the European College of Neuropsychopharmacology’s (ECNP) through their extensive network of stakeholders. In addition, we have initiated a dialogue amongst all the relevant stakeholders to support and guide the application process for qualification of a novel digital endpoint for social dysfunction. Finally, to prepare for the upcoming data analysis and data sharing beyond the duration of the project, a data management, data sustainability and exploitation plans have been developed and put in place.
PRISM2 will test the causality between DMN integrity and social dysfunction. Therefore, rodent studies will be implemented that allow for specific interventions to manipulate DMN integrity, namely through chemo-genetic technologies in specific brain regions. As a first step, an inventory of possible preclinical tools for DMN circuit manipulation has been generated. These will allow to local activation or inhibition of the neurons from the social brain network that are specifically innervated by neural structures from the DMN. The first pilot experiments have been performed to test the involvement of these specific networks in the expression of mouse social behaviour.
Finally, several measures have been initiated by the PRISM consortium to translate and communicate the PRISM 2 project results to the benefit of stakeholders. This is guided by a communication and dissemination plan that has been generated, and by the formation of the Impact and Innovation Board. Successful dissemination and communication of the PRISM 2 activities is facilitated and achieved by the European College of Neuropsychopharmacology’s (ECNP) through their extensive network of stakeholders. In addition, we have initiated a dialogue amongst all the relevant stakeholders to support and guide the application process for qualification of a novel digital endpoint for social dysfunction. Finally, to prepare for the upcoming data analysis and data sharing beyond the duration of the project, a data management, data sustainability and exploitation plans have been developed and put in place.
By means of its’ innovative and multidisciplinary approach, PRISM aims to add an alternative biology-based, and potentially transdiagnostic framework to the current array of qualitative diagnostic criteria and treatment strategies for brain disorders. Scientific, clinical concepts of diagnosis and treatment, and applied technologies have and will continue to go beyond the state-of-the-art to reach these goals. We have entered conceptually uncharted territory, but are now validating the clinical and pre-clinical harmonization of study designs, methods and instruments that focus on quantitative measures that are common across brain disorders and species. Our approach to implement translational and transdiagnostic paradigms provides a paradigm for the identification of these biological substrates and parameters. In doing so we will provide new predictive model systems to identify targets for drug discovery. By focusing on social dysfunction and DMN integrity, we do move the focus beyond disease symptoms and focus on aspects that strongly impact on patients’ quality of life, functioning and disease burden. PRISM has provided the first steps in a personalized medicine approach for patients with a complex array of differing symptoms by targeting quantitative phenotypes across brain disorders rather than relying on a conventional list of qualitative symptoms. Moreover, our early-stage engagement with patients, their care givers, patient organizations and regulators facilitate the acceptability, adoption and implementation of these novel cross-disorder classification tools and instruments.
PRISM directly addresses the treatment and management of the most relevant and burdensome brain disorders in Europe. To ensure the right treatment for each patient, PRISM2 will deliver a validated innovative medicine classification facilitated by novel digital and neurobiological biomarkers. Further, PRISM2, via its new transdiagnostic framework, will drive the adoption of innovative clinical trial design and provide a novel basis for personalized treatments for brain disorders. In addition, PRISM2 will continue to deliver a sustainable European network of three preclinical and four clinical centres working cooperatively to deliver state of the art (imaging, digital and neuropsychological) techniques to specifically assess the efficacy of new interventions in SZ, AD and MDD. Finally, many patients with mental illness suffer from stigma as their symptoms are not described as having a clear cause other than individual weaknesses. Patients with SZ, MDD, or AD who experience social dysfunction are often blamed for their behaviour. Understanding the pathological neurobiological functions that underlie these symptom domains is very important for reducing such stigma. In PRISM2, we will continue to work with patient representative organisations in the most efficient way to reduce stigma associated with these conditions and symptoms.
PRISM directly addresses the treatment and management of the most relevant and burdensome brain disorders in Europe. To ensure the right treatment for each patient, PRISM2 will deliver a validated innovative medicine classification facilitated by novel digital and neurobiological biomarkers. Further, PRISM2, via its new transdiagnostic framework, will drive the adoption of innovative clinical trial design and provide a novel basis for personalized treatments for brain disorders. In addition, PRISM2 will continue to deliver a sustainable European network of three preclinical and four clinical centres working cooperatively to deliver state of the art (imaging, digital and neuropsychological) techniques to specifically assess the efficacy of new interventions in SZ, AD and MDD. Finally, many patients with mental illness suffer from stigma as their symptoms are not described as having a clear cause other than individual weaknesses. Patients with SZ, MDD, or AD who experience social dysfunction are often blamed for their behaviour. Understanding the pathological neurobiological functions that underlie these symptom domains is very important for reducing such stigma. In PRISM2, we will continue to work with patient representative organisations in the most efficient way to reduce stigma associated with these conditions and symptoms.