Periodic Reporting for period 3 - PRISM 2 (Psychiatric Ratings using Intermediate Stratified Markers 2)
Reporting period: 2023-06-01 to 2024-11-30
The current neuropsychiatric disorder classification focuses on diagnosis and treatment but lacks quantitative biological insights, hindering drug development. To explore a quantitative biological approach, the PRISM consortium was formed, bringing together academics, SMEs, patient organizations, regulators, ECNP, and EFPIA. PRISM1 identified key quantitative biological parameters related to diagnoses (Schizophrenia and Alzheimer’s) and social functioning (https://doi.org/10.1080/15622975.2021.1966714(opens in new window)) regardless of diagnosis. A new neurobiological framework has emerged, requiring further validation. Genetic studies revealed loci associated with social functioning (https://doi.org/10.1038/s41386-021-01044-z(opens in new window)) and a preclinical test battery deepened our neurobiological understanding (https://doi.org/10.1016/j.jneumeth.2019.108323(opens in new window)). Additionally, a novel digital tool objectively assessed social function, moving beyond initial diagnostic classifications (https://doi.org/10.1016/j.euroneuro.2023.09.010(opens in new window)).
Building on the PRISM1 findings, the objectives of the PRISM2 consortium were:
1. Determine the reproducibility of the transdiagnostic and pathophysiological relationship between Default Mode Network (DMN) integrity and social dysfunction in Schizophrenia (SZ) and Alzheimer’s disease (AD) and its potential to generalise to Major Depressive Disorders (MDD).
2. To test the causality between the quantitative variation in DMN integrity and social dysfunction.
3. Translate and communicate the project results for the benefit of stakeholders including patients and their families, regulators, health care providers, the general public, learned societies, and the pharmaceutical industry, amongst others
Building on the PRISM1 findings, the objectives of the PRISM2 consortium were:
1. Determine the reproducibility of the transdiagnostic and pathophysiological relationship between Default Mode Network (DMN) integrity and social dysfunction in Schizophrenia (SZ) and Alzheimer’s disease (AD) and its potential to generalise to Major Depressive Disorders (MDD).
2. To test the causality between the quantitative variation in DMN integrity and social dysfunction.
3. Translate and communicate the project results for the benefit of stakeholders including patients and their families, regulators, health care providers, the general public, learned societies, and the pharmaceutical industry, amongst others
Clinical study - results
• As main finding, the PRISM2 clinical study showed reproducibility and generalizability of the identified quantitative biological biomarkers of social dysfunction and Default Mode Network (DMN) integrity (https://doi.org/10.1101/2025.01.09.631642(opens in new window)) that accounted for patient stratification in PRISM1. Based on the identified quantitative biological parameters in PRISM1, a refined and optimized test battery was implemented as part of the PRISM2 clinical study.
• Following the execution of the PRISM2 clinical study, subsequent data pre-processing and data analyses according to the developed statistical analysis plan, the consortium has reproduced the transdiagnostic and pathophysiological relationship between DMN integrity and social dysfunction in SZ and AD that was identified in the PRISM1 project.
• In addition, in PRISM2 this neurobiological finding was generalised to Major Depressive Disorders (MDD).
Animal study - results
• PRISM2 also tested for the causality between DMN integrity and social dysfunction. Therefore, rodent studies were implemented that allow for specific interventions to manipulate DMN integrity, namely through demyelination and chemo-genetic technologies in specific brain regions. Using a variety of animal studies, PRISM2 showed causality between DMN integrity and social dysfunction. For example, rodent studies in the social arena task indicated a decrease in social activity in animals with sub-chronically activated DREADDs in Orbitofrontal Cortex (OFC) neurons.
• Furthermore, a complementary approach of forceps minor demyelination also affected social behaviors in the social arena task (doi:10.1038/s41598-024-81930-w). The chemogenetic manipulations as well as the forceps minor demyelination led to impairment of DMN integrity as shown by functional ultrasound measurements and EEG assessments.
• In addition, resting state EEG measurements in the socially deficient DRD2 autoreceptor genetic mouse line have been performed and showed, comparable to the human findings, altered connectivity between nodes of the DMN.
• PRISM2 investigated the global and local-regional shared genetics between sociability and default mode network activity/connectivity, using global genetic correlation, local genetic correlation and colocalization in the UK biobank data. Final results support specific genetic correlations with default mode network (doi: 10.1101/2024.05.24.24307883).
Communication, dissemination and data management - results
• A communication and dissemination plan has been generated and measures were evaluated regularly. Successful dissemination and communication of the PRISM 2 activities was facilitated and achieved by the European College of Neuropsychopharmacology’s (ECNP) through their extensive network of stakeholders (https://www.ecnp.eu/?sc_itemid=%7BF2028432-FAD1-42E7-ADE4-28565A7EC9D1%7D(opens in new window)).
• We have finalized a formal EMA qualification procedure for a novel digital endpoint for social dysfunction.
• Patient events were organized, such as the presentation of the PRISM2 study at the EUFAMI bi-annual congress.
• Scientific publications have been generated and submitted to international peer-reviewed journals, with the particular highlights of, a podcast (https://www.buzzsprout.com/1734430/episodes/14644454(opens in new window)) and a video that have been produced to inform the general scientific community about the PRISM2 findings and its impact.
• Finally, for data sharing beyond the duration of the project, data management, data sustainability and exploitation plans were delivered. In line with these plans, the EPND platform (https://epnd.org/resources/announcing-the-enhanced-epnd-catalogue(opens in new window)) will be used for PRISM data accessibility for the general scientific community.
• As main finding, the PRISM2 clinical study showed reproducibility and generalizability of the identified quantitative biological biomarkers of social dysfunction and Default Mode Network (DMN) integrity (https://doi.org/10.1101/2025.01.09.631642(opens in new window)) that accounted for patient stratification in PRISM1. Based on the identified quantitative biological parameters in PRISM1, a refined and optimized test battery was implemented as part of the PRISM2 clinical study.
• Following the execution of the PRISM2 clinical study, subsequent data pre-processing and data analyses according to the developed statistical analysis plan, the consortium has reproduced the transdiagnostic and pathophysiological relationship between DMN integrity and social dysfunction in SZ and AD that was identified in the PRISM1 project.
• In addition, in PRISM2 this neurobiological finding was generalised to Major Depressive Disorders (MDD).
Animal study - results
• PRISM2 also tested for the causality between DMN integrity and social dysfunction. Therefore, rodent studies were implemented that allow for specific interventions to manipulate DMN integrity, namely through demyelination and chemo-genetic technologies in specific brain regions. Using a variety of animal studies, PRISM2 showed causality between DMN integrity and social dysfunction. For example, rodent studies in the social arena task indicated a decrease in social activity in animals with sub-chronically activated DREADDs in Orbitofrontal Cortex (OFC) neurons.
• Furthermore, a complementary approach of forceps minor demyelination also affected social behaviors in the social arena task (doi:10.1038/s41598-024-81930-w). The chemogenetic manipulations as well as the forceps minor demyelination led to impairment of DMN integrity as shown by functional ultrasound measurements and EEG assessments.
• In addition, resting state EEG measurements in the socially deficient DRD2 autoreceptor genetic mouse line have been performed and showed, comparable to the human findings, altered connectivity between nodes of the DMN.
• PRISM2 investigated the global and local-regional shared genetics between sociability and default mode network activity/connectivity, using global genetic correlation, local genetic correlation and colocalization in the UK biobank data. Final results support specific genetic correlations with default mode network (doi: 10.1101/2024.05.24.24307883).
Communication, dissemination and data management - results
• A communication and dissemination plan has been generated and measures were evaluated regularly. Successful dissemination and communication of the PRISM 2 activities was facilitated and achieved by the European College of Neuropsychopharmacology’s (ECNP) through their extensive network of stakeholders (https://www.ecnp.eu/?sc_itemid=%7BF2028432-FAD1-42E7-ADE4-28565A7EC9D1%7D(opens in new window)).
• We have finalized a formal EMA qualification procedure for a novel digital endpoint for social dysfunction.
• Patient events were organized, such as the presentation of the PRISM2 study at the EUFAMI bi-annual congress.
• Scientific publications have been generated and submitted to international peer-reviewed journals, with the particular highlights of, a podcast (https://www.buzzsprout.com/1734430/episodes/14644454(opens in new window)) and a video that have been produced to inform the general scientific community about the PRISM2 findings and its impact.
• Finally, for data sharing beyond the duration of the project, data management, data sustainability and exploitation plans were delivered. In line with these plans, the EPND platform (https://epnd.org/resources/announcing-the-enhanced-epnd-catalogue(opens in new window)) will be used for PRISM data accessibility for the general scientific community.
Progress Beyond the State of the Art:
• PRISM introduced a biology-based, potentially transdiagnostic framework for diagnosing and treating brain disorders, moving beyond traditional symptom-based diagnoses.
• It advanced scientific and clinical methods by harmonizing study designs and instruments, focusing on common quantitative measures across various brain disorders and species.
• The approach enabled identification of biological substrates and predictive models for drug discovery, particularly targeting social dysfunction and Default Mode Network (DMN) integrity.
• A focus on quantitative phenotypes instead of symptoms paves the way for personalized medicine, improving treatments for patients with diverse symptoms.
• Early engagement with patients, caregivers, and regulators ensures the adoption of new classification tools once validated.
Potential Impact:
• PRISM addresses the treatment and management of major brain disorders in Europe, aiming for more accurate and personalized treatments.
• It delivered potential novel digital and neurobiological biomarkers, which could support innovative medicine classification and clinical trial design: https://doi.org/10.1080/15622975.2021.1966714(opens in new window); https://doi.org/10.1016/j.euroneuro.2023.09.010(opens in new window)
• PRISM’s new transdiagnostic framework will help guide personalized treatments for brain disorders and drive innovative clinical trial designs.
• It established a sustainable, highly collaborative European network of preclinical and clinical centers, enabling advanced techniques to assess, in newly funded projects, interventions in disorders like Schizophrenia (SZ), Alzheimer’s Disease (AD), and Major Depressive Disorder (MDD).
• By identifying the neurobiological causes of social dysfunction, PRISM helps reduce the stigma associated with mental illness, collaborating with patient organizations, such as GAMIAN Europe and EUFAMI, to support this effort.
• PRISM introduced a biology-based, potentially transdiagnostic framework for diagnosing and treating brain disorders, moving beyond traditional symptom-based diagnoses.
• It advanced scientific and clinical methods by harmonizing study designs and instruments, focusing on common quantitative measures across various brain disorders and species.
• The approach enabled identification of biological substrates and predictive models for drug discovery, particularly targeting social dysfunction and Default Mode Network (DMN) integrity.
• A focus on quantitative phenotypes instead of symptoms paves the way for personalized medicine, improving treatments for patients with diverse symptoms.
• Early engagement with patients, caregivers, and regulators ensures the adoption of new classification tools once validated.
Potential Impact:
• PRISM addresses the treatment and management of major brain disorders in Europe, aiming for more accurate and personalized treatments.
• It delivered potential novel digital and neurobiological biomarkers, which could support innovative medicine classification and clinical trial design: https://doi.org/10.1080/15622975.2021.1966714(opens in new window); https://doi.org/10.1016/j.euroneuro.2023.09.010(opens in new window)
• PRISM’s new transdiagnostic framework will help guide personalized treatments for brain disorders and drive innovative clinical trial designs.
• It established a sustainable, highly collaborative European network of preclinical and clinical centers, enabling advanced techniques to assess, in newly funded projects, interventions in disorders like Schizophrenia (SZ), Alzheimer’s Disease (AD), and Major Depressive Disorder (MDD).
• By identifying the neurobiological causes of social dysfunction, PRISM helps reduce the stigma associated with mental illness, collaborating with patient organizations, such as GAMIAN Europe and EUFAMI, to support this effort.