Pressing public health concern
Schizophrenia and depression are among the leading causes of disability in Europe, and worldwide. Schizophrenia and depression represent a tremendous health, social, and economic burden, not only for patients but also for families, other caregivers, and the wider society, making them one of the most pressing public health concerns. In the EU in 2016, the total costs of psychiatric illnesses were estimated at more than 4% of gross domestic product (GDP) – or over EUR 600 billion - with more than one in six people across the EU having a mental health issue in 2016, equivalent to about 84 million people. Schizophrenia and depression are commonly diagnosed based on patient interviews, and scientists are still trying to understand how genetic and environmental factors interact to cause them. Schizophrenia is heritable; people whose parents both have schizophrenia have a 50 % chance of developing the disease, while just 1 % of those with no family history develop the sickness. Moreover, schizophrenia is probably not just one, but several disorders that have different underlying causes, and this makes drug development difficult. Depression, like schizophrenia, is caused by genetics – close to 40 % of the risk of disease is heritable. The disorder is treatable, but about 50 % of major depression still goes untreated and long-lasting depression may become a serious health condition.
Defining and solving bottlenecks
NEWMEDS, the first consortium of its kind in psychiatry, set out to find new avenues for treatments for schizophrenia and depression. The team focused on a redefinition of the biology behind these diseases as ‘connectopathies’, disorders of key brain circuits in the brain, and identified and solved major bottlenecks hampering progress in the area. To start with, the consortium developed standardised, more accurate and predictive animal models, which use brain recording and behavioural tests. Such models produce highly reliable and reproducible results thus reducing the number of animals needed for drug discovery tests.
To tackle the lack of tools and tests that can provide early indications of the efficacy of new drugs, NEWMEDS developed positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) based tools and models to serve as early or surrogate markers to provide guidance for drug development. Thirdly, NEWMEDS examined a set of genetic risk factors - copy number variations (CNV) which are closely linked with schizophrenia - by studying them in human and animal models. This allowed them to identify which changes and mechanisms in the brain are caused by these factors, and will pave the way for the development of new treatments. Furthermore, the project examined biomarkers that can be used to stratify patients within an umbrella diagnosis, like depression, in that way allows for more targeted clinical trials and individualised treatments, matching patients to the most effective drugs.
Those comprehensive tasks would not be have been possible without a broad public-private partnership (PPP) which allowed the sharing of ideas and resources. The project brought together 7 leading academic institutions in Europe and Israel, 2 biotech companies (SMEs), and 10 pharmaceutical companies. Through NEWMEDS, they were able to share their individual approaches to psychiatric diseases, and openly discuss technical questions and work together towards standardising technology.
Focus on schizophrenia and depression
Some of the most promising methods to diagnose schizophrenia or depression are biomarker tests. NEWMEDS used these new approaches to evaluate the validity of animal models of psychiatric disorders, which were previously only characterised based on behavioural measures. A major scientific breakthrough and was the demonstration that certain variations in the human genome, CNVs, have a direct effect on the brain and that they are associated with impaired intellectual and cognitive function in people with these variations. High-risk CNV will still have an impact on cognitive skills and brain structure in people who carry the genes but do not suffer from schizophrenia.
In addition, NEWMEDS discovered that clinical trials for antipsychotic drugs (in which patients on active treatment are compared to patients taking a placebo) could still be effective if shortened by a week or two (usually they last six weeks). The team also noticed that 71 % of the participants in schizophrenia clinical trials were male, but females had significantly less placebo response and slightly more treatment response than males.
All this was possible because five large pharmaceutical companies in the project made available clinical trial data to create the largest known database of studies on schizophrenia, including information on over 23 000 patients from 67 studies in over 25 countries. The database offers the industry and the academic community a unique opportunity for the development of tools and models that will help find targeted treatments for schizophrenia.
Four pharmaceutical companies in NEWMEDS shared data from 39 placebo-controlled studies of 12 217 patients from antidepressant studies. The analysis of these studies identified aspects of trial design that can be optimised to increase their success. NEWMEDS also determined why some patients respond to one kind of antidepressants, and others do not, by studying data on the genetics and clinical response in over 1 800 patients. That became the largest existing resource of well-characterised patients with depression, treated with different antidepressants, providing information on who responds best to which drug.
Achievements of the project:
- A new approach to the biology of schizophrenia and depression and novel tools and methods to support a revamped drug discovery and development ecosystem for much needed new treatments for mental health disorders.
- A hunt for pharmacogenetics biomarkers to stratify response to antidepressant treatments did not find major stratifiers, but did lead to a simple tool for assessing the clinical utility of future biomarkers.
- Establishment of the DupCheck tool (www.dupcheck.org) – that allows those running a clinical trial in any area of medicine to check globally if a patient is alreadyenrolled in another trial.
Scientists are trying to understand the pathology of schizophrenia and to develop the means to control so-called positive symptoms, such as hallucinations and delusions, as well as negative ones, such as social withdrawal and apathy, and cognitive deficits. During the project, it was discovered that the negative symptoms, could respond better to existing treatments than was previously thought. NEWMEDS also showed that in the future the diagnosis of brain diseases would be defined based on biological characteristics, with a more precise biological classification of patients enabling to provide tailor-made treatment of specific patients.
Achievements & News
The ability of public-private partnerships (PPPs) to drive progress in drug development is highlighted in a comment piece in Nature Reviews Drug Discovery written by members of IMI’s NEWMEDS project. NEWMEDS was launched in 2009 with the goal of developing new tools and techniques to speed up the development of new drugs for schizophrenia and depression. ###In the paper, the authors note that pre-competitive and competitive areas were clearly defined, providing a ‘fertile environment’ for scientists to openly discuss technical questions and work together. Some of the results of this open collaboration are summarised in the paper, including work on different brain circuits, knowledge on the genetics of schizophrenia, and the validation of new technologies. According to the authors, the public-private collaboration enabled ‘major synergies’ as they could cross-validate each other’s work, thereby helping the field to move forward ‘more rapidly, while not needlessly duplicating animal work’. The authors conclude: ‘Where research is clearly precompetitive, there are immense benefits for open discussion between competitive companies, and this should be the rule rather than the exception. Furthermore, psychiatric drug discovery must make translational effects on brain circuits a priority.’
Dr Francesc Artigas is the recipient of the 2015 Neuropsychopharmacology Award by the European College of Neuropsychopharmacology (ECNP) in recognition of his pioneering work in the field of systems neuropharmacology. The award is presented annually and recognises distinguished research in neuropsychopharmacology and closely related disciplines. ###Dr Artigas is a member of the IMI NEWMEDS project, aimed at finding new methods for the development of drugs for schizophrenia and depression. He picked up his prize at the recent ECNP congress in Amsterdam, the Netherlands.
A leader in the study of the mechanism of action of antidepressant and antipsychotic drugs, Francesc Artigas is Chair of the Department of Neurochemistry and Neuropharmacology at the Instituto de Investigaciones Biomédicas de Barcelona of the Spanish Research Council (CSIC).
An international team of scientists has revealed how brains handle multitasking. The study, which included researchers from IMI’s NEWMEDS project on schizophrenia and depression, was published in the Proceedings of the National Academy of Sciences.### The findings will help us to better understand diseases where the ability to multitask is impaired, such as schizophrenia and dementia, and could ultimately aid in the development of new treatments. In the study, 344 healthy people switched between two tasks while undergoing magnetic resonance imaging (MRI) scans of the brain. The scientists assessed how the participants’ brain networks reconfigured themselves when switching between tasks. They found that the participants who were best at multitasking, flicking between the tasks with ease, showed greater rearrangement of the connections both within the frontal cortex (which is responsible for control over our thoughts and actions) and between the frontal cortex and other parts of the brain. ‘A signification motivation for our research is to understand disruptions to the dynamic of neural networks that are associated with psychiatric disorders,’ said Andreas Meyer-Lindenberg of the Central Institute for Mental Health in Mannheim, Germany. ‘This study underlines the potential of modern neuroscientific methods for basic psychiatric research.’
NEWMEDS, one of IMI’s early projects is drawing to a close and the project has published a video of its final meeting dedicated to the legacy it will leave behind.###
NEWMEDS was set up in 2009 to help find new methods for the development of drugs for schizophrenia and depression and was one of the first consortia launched under IMI. During its 5 years, NEWMEDS has shown that fierce competitors can and will work together in a pre-competitive space.
The project brought together top scientists from academic institutions with a wide range of expertise, and partnered them with nearly all major biopharmaceutical companies. It focussed on developing new animal models using brain recording and behavioural tests to identify innovative and effective drugs for schizophrenia; it developed standardised paradigms, acquisition and analysis techniques to apply brain imaging, especially fMRI and PET imaging to drug development; it examined how new genetic findings influence the response to various drugs, and whether this information can be used to choose the right drug for the right patient; and finally, it has developed new approaches for shorter and more efficient trials of new medication – trials that may require fewer patients and give faster results.
NEWMEDS will leave a legacy of over 300 published papers, posters and talks as well as a number of web-based tools for use in drug discovery. The scientific relationships among the project participants will also build the next generation of collaborations and, hopefully, the next generation of compounds to help schizophrenia and depression patients.
- Watch NEWMEDS video and try the tools here
IMI’s NEWMEDS project on schizophrenia and depression has developed a number of new features for its DupCheck tool, which allows those running a clinical trial in any area of medicine to check if a patient is already enrolled in another trial elsewhere. ###DupCheck works globally. The issue of duplicate enrolment in trials is important for patients and trial organisers alike. For patients, interactions between experimental drugs could be harmful and even fatal. For those running the clinical trial, avoiding multiple trial enrolments also helps to ensure the validity of the trial results – a patient could be given the placebo in one trial and an active ingredient for the same condition in another. Alternatively, if a patient is taking active treatments in two trials, both trials will attribute any improvements (or adverse reactions) to their own trial drug. In DupCheck, all patient data is encrypted and access to the site is restricted to those working on clinical trials.
DupCheck’s features now include:
- DupCheck provides real time information on attempted duplicate enrolment at time of screening.
- Users can screen for previous participation in a trial of investigational drug.
- DupCheck can be linked to existing electronic data capture systems—eliminating additional data entry—and run in the background.
- DupCheck provides sponsors with one-click, real-time data on screening by site.
Trial sponsors can enrol at www.dupcheck.org.
IMI project NEWMEDS has launched an online tool that alerts those running a clinical trial if a patient is already enrolled in another trial elsewhere. Dubbed DupCheck, the tool is set to both improve patient safety during clinical trials and enhance the validity of trial results.### Clinical trials do not accept patients who are already involved in another trial. This is partly to protect the patient - interactions between experimental drugs can be harmful and even fatal. Avoiding multiple trial enrolments also helps to ensure the validity of the trial results – a patient could be given the placebo in one trial and an active ingredient for the same condition in another. Alternatively, if a patient is taking active treatments in two trials, both trials will attribute any improvements (or adverse reactions) to their own trial drug. The scale of the multiple enrolment problem is not well understood, although some studies suggest that around 5% of patients taking part in large trials may be enrolled in the same trial twice, but at different locations. There is no systematic data yet on enrolment across studies. DupCheck was created to tackle the issue. Those running trials can input or upload data collected into DupCheck, and the system alerts users of any potential duplicates. All patient data is encrypted and access to the site is restricted to those working on clinical trials. According to NEWMEDS scientist Jonathan Rabinowitz of Bar Ilan University in Israel, DupCheck is ‘the only solution to this problem that has been qualified by a regulatory agency’. The tool is currently in free beta and is being systematically incorporated by companies participating in NEWMEDS and other companies globally across therapeutic areas. Trial sponsors can enrol at www.dupcheck.org. ‘The benefits of DupCheck for the advancement of medical research are commensurate with the growing number of studies using it,’ says Professor Rabinowitz. ‘It is precompetitive collaboration taken to a new level. Every sponsor wants others to use it.’
Early clinical trials of schizophrenia drugs could be made shorter and more efficient if more women and more people with certain types of symptoms and/or younger patients were recruited, according to research from the NEWMEDS project published recently in the Journal of Clinical Psychiatry.### This would dramatically reduce patients’ exposure to the trial drug or placebo. Conventional trials of schizophrenia drugs typically last between six and eight weeks, and many have questioned their usefulness as nearly half of the patients drop out before the end of the trial. The NEWMEDS team pooled study data from 29 trials of antipsychotics run by 5 different pharmaceutical companies. This revealed that trials could be cut to as little as 4 weeks while the number of patients could be cut to 49 per trial arm if more women, more people with both positive and negative symptoms, and more young non-first episode patients were included, as these groups respond more strongly to the medicine compared to the placebo. (Positive symptoms are those which are not normally found in healthy people, such as hallucinations, while negative symptoms are those where patients lack behaviours found in healthy people like the ability to feel pleasure or act spontaneously.) A 6-week trial with 79 patients per arm would result in 474 weeks of patient exposure to the placebo and drug; cutting the trial to 4 weeks and 49 patients per arm would cut this figure to just 196 weeks of patient exposure.
Genetic variants associated with schizophrenia and autism still have an impact on cognitive skills and brain structure in people who carry the genes but do not suffer from these conditions, according to new research published in Nature by scientists from the NEWMEDS project.### The findings add to our understanding of the risk factors that contribute to these conditions and could make it easier to study the neural and biochemical foundations of cognitive abilities. The team studied 27 genetic variants known to be associated with an increased risk of schizophrenia and/or autism. The results revealed that the cognitive abilities of healthy carriers of risk-associated genetic variants lie between those of schizophrenia patients and people without the risk variants. In addition, the brain scans showed that healthy carriers of the risk variants had brain abnormalities linked to schizophrenia and cognitive processes. The findings suggest that the cognitive abnormalities seen in people with schizophrenia are not necessarily a consequence of the disease; rather, having these cognitive problems may be a risk factor for the disease.
- Read the IMI press release on the study
NEWMEDS researchers were out in force at the recent congress of the European College of Neuropsychopharmacology (ECNP) in Barcelona.### Francesc Artigas of the Spanish National Research Council gave one of the event’s plenary lectures, where he presented NEWMEDS findings on the effects on brain activity of drugs used as models of schizophrenia, as well as mechanisms used by antipsychotic drugs to reverse these effects. Elsewhere, NEWMEDS researchers explained how they have identified the brain networks involved in schizophrenia, and uncovered new targets for antipsychotic drug development – both major goals for NEWMEDS. Finally, Jonathan Rabinowitz of Bar Ilan University in Israel led a brainstorming session on placebo controlled trials which featured a discussion on new approaches to reducing the placebo response in double blind trials.
Machine learning for neuroimaging was the focus of a successful workshop run by the NEWMEDS project in London. The goal of the workshop was to demonstrate the NEWMEDS machine learning toolbox which is designed for the analysis of clinical and pharmacological data.### Participants also had the opportunity to try out the tool on their own data. According to workshop organiser Mick Brammer of King’s College London, machine learning is only starting to be used in imaging.
What sets NEWMEDS apart from other groups working on machine learning for imaging is the wide range of methods used. ‘Our main distinguishing feature has been to work closely with our neuroscience and pharma colleagues to introduce methods that are best suited to the problems that interest us,’ he explained. ‘Most imagers are not doing this but using the most common “off the shelf” method regardless of the problem.’ Feedback from the workshop was extremely positive, and the participants left feeling excited about using the toolbox in the future.
- The presentations from the workshop can be downloaded from the NEWMEDS website.
IMI’s NEWMEDS project presented some of its findings at a symposium held during the 20th World Congress of Psychiatric Genetics (WCPG) in Hamburg, Germany in October.### The symposium, entitled Identification and functional consequence of genetic variants conferring risk of psychiatric disease – outcome of NEWMEDS collaboration, featured presentations of NEWMEDS work on how Copy Number Variations (CNVs, in which sections of DNA are present in more or fewer copies than usual) affect intellectual disability, autism, and schizophrenia. The presentations also discussed how NEWMEDS is attempting to model these conditions in mice. The hope is that these studies will shed light on the link between CNVs and the brain and deliver novel and more relevant animal models for research into psychiatric disorders.
Andreas Meyer-Lindenberg of the Central Institute of Mental Health in Mannheim, Germany and a participant in IMI’s NEWMEDS and EU-AIMS projects has been awarded the prestigious ECNP Neuropsychopharmacology Award 2012### for his groundbreaking work linking genetic variation associated with risk of mental illness to brain structure and function. The award, handed out at the annual congress of the ECNP (European College of Neuropsychopharmacology), recognises innovative and distinguished research achievements in neuropsychopharmacology and related fields. Dr Meyer-Lindenberg’s work focuses on the genetic and environmental risk factors associated with psychiatric diseases such as schizophrenia. ‘Especially our recent work on rare, high-risk genetic variants associated with schizophrenia and autism would not have been possible without the cooperative science funded in IMI,’ Dr Meyer-Lindenberg said.
‘Negative’ symptoms of schizophrenia could respond better to existing treatments than was previously thought, according to new research from IMI’s NEWMEDS project.### Schizophrenia patients are said to have negative symptoms when they lack behaviours that are found in healthy people. For example, people with schizophrena may appear to lack emotion or the ability to feel pleasure or act spontaneously. (For comparison, symptoms such as hallucinations which are not normally experienced by healthy people are called ‘positive’ symptoms). NEWMEDS’ Jonathan Rabinowitz of Bar Ilan University in Israel and his colleagues studied data from large numbers of clinical trials studying various second generation antipsychotics in schizophrenia amassed by the NEWMEDS project. Their analyses revealed that the overall response to treatment was similar in patients with only prominent negative symptoms to patients who had either only prominent positive symptoms or both prominent negative and positive symptoms before treatment. Moreover, around two thirds of all patients who complete six weeks of treatment with second generation antipsychotic drugs have no residual negative symptoms of moderate or higher severity. Only a minority of patients were still suffering from prominent negative symptoms that would make such patients suitable to be studied in adjunctive treatment with new compounds particularly developed for the treatment of negative symptoms. ‘It has generally been maintained that negative symptoms do not respond to currently-used second generation antipsychotic medications,’ commented Professor Rabinowitz. ‘Our results suggest that they do respond.’ The findings suggest that it will be harder than expected for new medicines to prove themselves against existing medicines. ‘The findings were shared with drug developers and regulators who expressed interest in this work,’ said Professor Rabinowitz.
The length of clinical trials in which patients on active treatment are compared to patients taking a placebo could be shortened by one or two weeks, according to research from the IMI project NEWMEDS.### Speaking at the recent European College of Neuropsychopharmacology (ENCP) congress, Professor Jonathan Rabinowitz of Israel’s Bar Ilan University explained how the team studied 29 trials of schizophrenia drugs sponsored by 5 pharmaceutical companies. The research revealed that in many trials lasting 6 weeks or longer, significant results can be observed in weeks 4 and 5, suggesting that such trials could be shortened. In addition, the researchers highlight the importance of including far more women in trials, as women appear to respond less to placebos than men, yet less than a third of the participants in the trials studied were female. The findings contribute to NEWMEDS’ goal of improving the design of clinical trials of schizophrenia treatments.
In a remarkable and unprecedented collaboration in schizophrenia research, the companies involved in the NEWMEDS project have pooled their data to create a large collaborative dataset that brings together the data of 23 401 anonymized patients from 67 trials on 11 compounds in over 25 countries.### This makes it by far the single largest database of clinical trial data ever amassed in psychiatric research. The academic community will greatly benefit from the partnership, as the exceptionally large and valuable database on schizophrenia will be made available to all participants in the project.
Read the full press release.
ParticipantsShow participants on map
- Abbvie Deutschland GMBH & Co Kg, Wiesbaden, Germany
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- H. Lundbeck As, Valby, Denmark
- Institut De Recherches Servier, Suresnes, France
- Islensk Erfdagreining Ehf, Reykjavik, Iceland
- Janssen Pharmaceutica Nv, Beerse, Belgium
- Novartis Pharma AG, Basel, Switzerland
- Orion Oyj, Espoo, Finland
- Pfizer Limited, Sandwich, Kent , United Kingdom
Universities, research organisations, public bodies, non-profit groups
- Agencia Estatal Consejo Superior De Investigaciones Cientificas, Madrid, Spain
- Bar Ilan University, Ramat Gan, Israel
- Karolinska Institutet, Stockholm, Sweden
- King'S College London, London, United Kingdom
- The University Of Manchester, Manchester, United Kingdom
- University of Cambridge, Cambridge, United Kingdom
- Zentralinstitut Fuer Seelische Gesundheit, Mannheim, Germany
Small and medium-sized enterprises (SMEs)
- Gabo:Mi Gesellschaft Fur Ablauforganisation:Milliarium mbH & Co. KG, Munich, Germany
- Psynova Neurotech LTD, Cambridge, United Kingdom
|Name||IHI funding in €|
|Agencia Estatal Consejo Superior De Investigaciones Cientificas||682 467|
|Bar Ilan University||355 999|
|Gabo:Mi Gesellschaft Fur Ablauforganisation:Milliarium mbH & Co. KG||564 810|
|Islensk Erfdagreining Ehf (left the project)||869 378|
|Karolinska Institutet||792 550|
|King'S College London||2 592 966|
|Psynova Neurotech LTD||40 226|
|The University Of Manchester||604 471|
|University of Cambridge||1 333 476|
|Zentralinstitut Fuer Seelische Gesundheit||1 149 873|
|Total Cost||8 986 216|