Rising to the challenge of delivering therapeutic discovery for mental disorders

Professor Matthew Hotopf, Director of NIHR Maudsley Biomedical Research Centre, and Professor John R Geddes, Director of NIHR Oxford Health Biomedical Research Centre, discuss the impact of the NIHR Translational Research Collaboration for Mental Health, and how it can fight back against dwindling investment in the discovery and development of mental health interventions

Drug discovery and development for mental disorders has stalled over the past two decades due to the lack of clear biological targets and the related absence of the reliable biomarkers required for efficient drug development programmes. Together, this has led to few genuinely innovative new drugs being developed with high failure rates in costly later phase trials. As identified by Kola and Landis in their important article in 2004, this situation was widespread across several therapeutic areas. Kola and Landis proposed several approaches to reducing the failure rate – the most important of which was to use experimental medicine and early phase trials to ensure that if failure (which is inevitable) does occur, it happens earlier, before expensive late phase drug development programmes. This is understandably considered to be more feasible in disease areas where more is known about basic disease mechanisms, and where better targets and biomarkers exist than in mental disorders. This has been a major reason for the large scale withdrawal of pharmaceutical companies from drug development in mental disorders.

It is perhaps worth noting that the situation in psychological treatment development is similar, although it has never stalled to such a dramatic extent as in drug therapy. The history of psychological treatment development can be seen as an initial phase of innovation (e.g. cognitive behaviour therapy) and research into effectiveness, followed by modest further innovation and extension (repurposing) into other disorders. Psychological treatments urgently need to be made both more precise and targeted on understanding of disease mechanism, and more efficient, for example by using new technology to enhance scalability to meet the population need.  

There are now grounds for considerable optimism. As Directors of the UK’s two mental health-focussed NIHR Biomedical Research Centres at Kings/Maudsley and Oxford, we are in the highly privileged position of witnessing first-hand the emergence of new avenues for drug discovery-based on a combination of advances in basic biology and better technology.  In drug therapy, we now have targets from genome-wide association studies (GWAS), from advances of knowledge into biological systems such as immunology, from deeper understanding of mechanisms of action of existing psychoactive drugs (cannabinoids, psychedelics, ketamine etc). Induced pluripotential stem cells are promising human cellular models – critically important given the known inadequacy of animal models – and advances in neuroimaging and digital phenotyping are leading to the development of efficient experimental medicine models and early phase clinical trials. In psychological therapies, we now have growing understanding into the cognitive mechanisms underlying disorder, with better information technology for delivering treatments at scale combined in the UK with the highly innovative Improving Access to Psychological Treatments service which includes routine outcome assessment.

Our optimism is shared by others. Husseini Manji, Head of Neuroscience at Janssen – one of the few large pharmaceutical companies with current large scale psychiatric development programmes – is reported as being optimistic.  Manji believes that one or two successes would lead to widespread re-entry into the field.

UK National Institute for Health Research – infrastructure 

The UK Life Sciences Industrial Strategy makes a number of recommendations to increase the potential for growing life sciences industry which is one of the UK’s dominant economic sectors. Several of these focus on how to build the UK’s health and academic environment to facilitate partnership with the life sciences industry in the broadest sense. The National Institute for Health Research (NIHR) was created in 2006 with the purpose of funding health and care research providing the infrastructure to translate scientific discovery into practical health benefits. A key goal of NIHR is to support research funded by others, including industry and charities, to encourage investment in, and economic growth from, health research.

The NIHR Biomedical Research Centres (BRCs) are a central component of NIHR translational infrastructure. BRCs are partnerships between England’s leading research universities and NHS organisations, with funded infrastructure to enable the translation of advances in basic science into new treatments, diagnostics and procedures for patients. The NIHR BRCs were first created in 2007 with £450 million of government funding awarded competitively to NHS/University partnerships. NHS organisations delivering mental health care are separate from those delivering acute care and initially there was only one BRC focused on mental health, based in the Maudsley Hospital and its partnering institute of Psychiatry at Kings College. In the third BRC competition (total £816 million) in 2016, a second mental health BRC was funded to a partnership between Oxford Health NHS Foundation Trust and the University of Oxford. A further four acute hospital BRCs (Bristol, Cambridge, Nottingham and UCL) include mental health themes. This increased NIHR investment means that mental health is now the second highest funded illness area across the BRCs after cancer. This increased investment reflects the increasing awareness of the health burden of mental illness, as well as the emerging science and enhanced coordination and cooperation within and between centres of excellence. It also provides an unprecedented opportunity to deliver innovative therapies for patients.  The BRCs include prominent involvement of patients and public in strategic and operational matters – as is particularly important in mental health. 

As well as the BRCs, the NIHR funds infrastructure which creates a full translational pipeline from discovery to implementation. The dedicated Clinical Research Facilities (CRFs) in several centres linked to the BRCs which provide the specialist staffing, environment and equipment required for externally-funded high intensity early phase clinical studies. Recruitment of patients into clinical studies is facilitated by the NIHR Clinical Research Networks which provide support for the delivery of studies to time and target.

The UK NIHR Translational Research Collaboration for Mental Health

The substantial increase in NIHR-funded infrastructure in Mental Health across multiple sites in England, along with similar developments in the Scotland and Wales, also provides an obvious opportunity to create an integrated national framework for taking novel therapies and procedures from early phase work all the way through to implementation in the NHS. The NIHR Mental Health Translational Research Collaboration (TRC-MH) was launched in September 2018, following a similar operating model to that already established through the NIHR’s collaborations in joint and related inflammatory diseases, respiratory disease and dementia. The TRC-MH includes the BRCs (London, Oxford, Cambridge, Bristol, Nottingham, University College London) plus the CRF hosting sites in Manchester, Newcastle and Exeter and the comparable developments in Cardiff and Edinburgh.  

TRC-MH is therefore underpinned by world class clinical research facilities provided by the NIHR’s Biomedical Research Centres and Clinical Research Facilities, and the NIHR Mental Health MedTech Co-operative, and acts as a single partnership. This ensures that research opportunities can be explored more quickly and efficiently. The TRC-MH provides a single point of contact for partners such as industry and medical research charities to work with the 11 participating centres of excellence. The TRC-MH will also speed up the negotiation of agreements and contracts and coordinates all steps from first contact through to delivery of the agreed project and ultimately the development of new interventions, technologies and diagnostics.  Following consultation, the initial focus of the TRC-MH will be on developing better approaches to treatment-resistant depression and in improving the characterisation of people ‘at risk’ of developing mental illness to help develop preventive strategies. The TRC-MH will also develop well-defined cohorts of patients who have consented to be re-contacted to participate in research studies.  This should increase the numbers of people with mental disorders who can take part in experimental medicine studies and trials – the aim is to facilitate access from across the UK.

We believe the formation of the TRC-MH is a "quick win" following the increased BRC funding in the 2016 competition. It reflects the enormous collaborative intent and enthusiasm across the leading UK centres of research and service excellence. We are determined to make the UK the world’s leading location for innovation in mental health care.  We are looking forward to working with global partners to transform the care provided to people with mental disorders, and to find better ways of preventing mental disorders. 

-----------------------------------------------------------------------
Editor's Note:

To apply for becoming a contributor of En-CPhI.cn,

welcome to send your CV and sample works to us,

Email: Julia.Zhang@ubmsinoexpo.com.