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.