The underlying biological causes of neuropsychiatric disorders like schizophrenia, Alzheimer’s disease and major depressive disorder are very poorly understood. The majority of people with these mental health conditions are still diagnosed based on symptoms alone because there is a lack of objective and easy-to-measure biological signs of the illness. A good point of comparison is diabetes: the symptoms are caused by high levels of sugar in the blood. Measuring this parameter, therefore, gives doctors a solid clue to help them make a diagnosis.
Many neuropsychiatric diseases share the same outward symptoms, but the difficulty in finding a medicine that works leads to the conclusion that the biological causes could be very different. The big question is: are different processes being affected but producing the same symptoms? Or is it that the exact same processes are being disturbed in some way, but for whatever reason, they are presenting in different patients completely differently? This lack of clarity has caused a dramatic slowdown in new drugs being brought to the market. Mental illnesses like those mentioned have for decades been treated with the same list of 100 or so compounds in an empirical manner i.e. keep going until you find something that works.
The symptom in question – social dysfunction
The project partners in PRISM made progress in untangling the ways in which these diseases overlap, by trying to understand and classify them in a quantitative, biological way. They chose to focus on the symptom of social dysfunction, one of the earliest outward signs that can be observed in Alzheimer’s, schizophrenia and major depression. It is also considered an early indicator of cognitive deficits. PRISM probed the biological brain systems of traditionally-diagnosed schizophrenic and dementia patients using a wide range of state-of-the-art technologies and then analysed the data blind i.e. without information on the diagnosis, to see if the patients can be clustered into groups based on the underlying impaired brain biology.
Clustering into new groups
165 individuals with schizophrenia or Alzheimer’s disease, as well as a group of healthy controls, underwent a battery of tests. Of 4,330 biological markers picked up from functional magnetic resonance imaging (fMRI) scans (which register blood flow to functioning areas of the brain) and EEG tests (electroencephalograms, which show abnormalities in brain wave activity) along with observations of the participants’ behaviour, 139 markers showed a significant relationship with one of the two diseases, or with the control. More endpoints - 183 in total - showed a significant relationship with measures of social functioning. These new clusters were shown not to equate to existing diagnostic-based categorisation of patients.
The project also carried out genetic testing that revealed 604 genome-wide variants in 19 different places in the chromosome that have an association with social functioning. Further tests using preclinical models, by mirroring the tests carried out on human subjects, now allows the consortium to effectively back-translate the human clinical findings thereby expanding their neurobiological knowledge. This will be done as part of the PRISM 2 project.
Real-world social functioning measurement tools
New technologies played a major role in the PRISM project. Innovative statistical techniques derived insights from the data generated by genetic testing and neuroimaging, which was then consolidated with a wealth of existing clinical data from major European and global disease cohorts. PRISM also created new digital tools that can be used to measure social functioning linked to the neurobiological parameters, going further than the traditional diagnostic classification.
By passively measuring the number of phone calls and chats, location data from GPS signals (indicating outside visits and the length of time spent at home) generated by the participants’ smartphones, they were able to produce new and objective insights into the real-world environment and of a person’s individual social communication and exploration behaviour. This real-world analysis revealed three clusters that did not completely match the initial diagnostic groups, demonstrating the potential for further new classifications.
The smartphone-based behavioural endpoints developed by the project for measuring social functioning were shown to have potentially wide application in future research. PRISM initiated a dialogue with the Innovation Task Force of the European Medicines Agency with respect to the qualification of potential digital biomarkers for social functioning. The EMA Innovation Task Force provided encouraging feedback and progress is being made toward establishing the app outcomes as qualified biomarkers.
PRISM was able to accelerate the discovery and development of new treatments for neuropsychiatric conditions like schizophrenia and Alzheimer’s disease by differentiating these diseases based on the underlying impaired brain biology and showing where they overlap. They have bridged and important translation gap between discovery and validation of biomarkers and the technology that can measure them. They established a network of pre-clinical research sites that can perform high-quality studies, helping pave the way for recognition of social dysfunction as a registrable symptom across disorders. They also offered a new framework to help physicians better inform their patients of the complexity of their illness, leading to better understanding and disease management.
Their work continues to encourage the clinical community to consider neuropsychiatric disorders through a more quantitative lens, influencing patients, carers and the public, and adding to the growing evidence that neuropsychiatric disorders are ‘real’ and that there is demonstrable biomedical proof of their existence, just like physical illnesses. This is helping to reduce the stigma associated with mental disorders. The outline of the work carried out by PRISM was published in a special issue of Neuroscience & Biobehavioral Reviews on the PRISM project.
Funding for the follow-on phase of the PRISM project was granted in 2021. This new funding will allow the project to build on the work of PRISM by replicating their initial clinical findings on new patient cohorts and investigating the neurobiological mechanisms underlying these patient clusters. Major Depressive Disorders will be included as a third indication in the PRISM 2 project.
Achievements & News
PRISM is in talks with the EMA on the use of data from smartphones and wearables as biomarkers of social functioning in neuropsychiatric disorders.###
Measuring human social behaviour i.e. interactions with others, or activities outside the home, is usually done via a variety of methods that, despite being used widely in biomedical research, are plagued with problems: interviews, questionnaires and self-rating (or rating by a carer or family member) are subjective, qualitative and usually after-the-fact.
Smartphones and wearables are already collecting reams of data on our physical movements and social activities. The IMI PRISM project looked at which kinds of data from these devices could be considered reliable biomarkers of social functioning. The PRISM team found promising data that measures such as the number of phone calls made, chats, and number of places visited, can be used to better stratify participants. If this can be confirmed, it offers a way of significantly improving clinical trial outcomes, ultimately resulting in better treatments.
The PRISM team is currently in talks with the European Medicines Agency (EMA) to establish how they can successfully make this kind of digital phenotyping part of future clinical trials, alongside traditional data-gathering methods and assessments.
Find out more
- Read the article in full
IMI projects are among those featured in a new brochure on how the digital revolution is transforming EU-funded brain research. The brochure, produced by CORDIS, was published to coincide with IMI’s Stakeholder Forum on the same subject. The IMI projects featured are AETIONOMY, EU-AIMS and PRISM. AETIONOMY systematically captures and represents knowledge on neurodegenerative diseases in a computable format that represents causes and effects and that can be analysed using algorithms. EU-AIMS has developed a large autism database, one of the richest of its kind in the world, which has the potential to drastically change the knowledge base for autism. Finally, PRISM has developed a new framework that would help researchers better understand the complexity of neuropsychiatric illness, moving away from current reductive disease classifications, to pave the way for new treatments.
- Read the brochure
The PRISM project’s clinical study on the biological underpinnings of social withdrawal in Alzheimer’s disease and schizophrenia is now officially underway, as the first patients have had their first clinical visits.### Social withdrawal is a common early symptom of both Alzheimer’s disease and schizophrenia. However, we do not know if the underlying causes of social withdrawal in the two diseases are the same or different. In this study, PRISM scientists will study over 200 people, including people with suspected Alzheimer’s disease, people with schizophrenia, and healthy people (the control group). Participants with the diseases under study will include people who show signs of social withdrawal as well as people who do not. Participants will undergo a range of tests, including brain scans, blood tests and questionnaires. They will also be offered the opportunity to use a smartphone app called BeHapp that measures people’s sociability and social exploration in their daily lives. ‘The ability to precisely link symptoms to underlying neurobiology would not only facilitate the development of better treatments, it would also allow physicians to provide patients and relatives with a better understanding of the complexities and management of their illness,’ said the project. ‘Moreover, there is a growing realisation that psychiatric and neurodegenerative disorders overlap by much more than previously thought, and that they may better be described as domains of trans-diagnostic traits rather than separable categories.’
ParticipantsShow participants on map
- Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- Janssen Pharmaceutica Nv, Beerse, Belgium
- Novartis Pharma AG, Basel, Switzerland
- Takeda Development Centre Europe LTD, London, United Kingdom
Universities, research organisations, public bodies, non-profit groups
- Academisch Ziekenhuis Leiden, Leiden, Netherlands
- Alma Mater Studiorum - Universita Di Bologna, Bologna, Italy
- Consorcio Centro De Investigacion Biomedica En Red M.P., Madrid, Spain
- Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, Netherlands
- Rijksuniversiteit Groningen, Groningen, Netherlands
- Stichting Buro Ecnp, Utrecht, Netherlands
- Stichting Radboud Universiteit, Nijmegen, Netherlands
- Stichting Vumc, Amsterdam, Netherlands
- The University Of Exeter, Exeter, United Kingdom
- Universitair Medisch Centrum Utrecht, Utrecht, Netherlands
Small and medium-sized enterprises (SMEs) and mid-sized companies (<€500 m turnover)
- Biotrial, Rennes, France
- Concentris Research Management GMBH, Fürstenfeldbruck, Germany
- Drug Target Id BV, Nijmegen, Netherlands
- P1vital Limited, Wallingford, United Kingdom
- Sbgneuro LTD, Thame, United Kingdom
- Europese Federatie Van Familieverenigingen Van Psychiatrisch Zieke Personen Ivzw, Leuven, Belgium
- P1vital Products Limited, Wallingford, United Kingdom
|Name||IHI funding in €|
|Academisch Ziekenhuis Leiden||334 775|
|Alma Mater Studiorum - Universita Di Bologna||100 000|
|Concentris Research Management GMBH||315 000|
|Consorcio Centro De Investigacion Biomedica En Red M.P.||678 450|
|Drug Target Id BV||200 250|
|Erasmus Universitair Medisch Centrum Rotterdam||100 000|
|Europese Federatie Van Familieverenigingen Van Psychiatrisch Zieke Personen Ivzw||18 563|
|P1vital Limited||766 171|
|Rijksuniversiteit Groningen||2 105 481|
|Sbgneuro LTD||490 500|
|Stichting Buro Ecnp||168 500|
|Stichting Radboud Universiteit||840 250|
|Stichting Vumc||775 000|
|The University Of Exeter||90 000|
|Universitair Medisch Centrum Utrecht||286 645|
|Name||Funding in €|
|P1vital Products Limited||460 416|
|Total Cost||8 080 001|