What is treatment-resistant depression? New report calls for clearer definition to inform research and improve treatment.

What is treatment-resistant depression? New report calls for clearer definition to inform research and improve treatment.

A group of mental health experts from research, industry, regulatory bodies and with lived experience have proposed new agreed criteria to define the type of depression that current medications and therapies cannot treat effectively. The report aims to provide consistent definitions for future research, and especially for designing clinical trials for new medications, with the aim of helping to develop more tailored and effective treatments for people experiencing this difficult condition.

Published in Molecular Psychiatry, the report used a well-known method to gain consensus, the Delphi Method, which collected and summarised the views of over 60 experts in the field of depression. The report was led by researchers from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) King’s College London and National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre.

Treatment-resistant depression (TRD) affects up to 30 per cent of adults with major depressive disorder, which is a clinical condition characterised by persistent feelings of sadness and loss of interest experienced by around 230 million people worldwide.

The term TRD is used to describe those people who have not responded to ‘adequate’ antidepressant treatments, but there is a lack of consensus around the concept and what is understood by ‘adequate’ treatments.

The authors found that there is variation around how TRD is defined, and that only about a third of studies in TRD enrol participants who met the most common definition of having experienced at least two failures with antidepressant approaches. In addition, only one in five studies enrol participants who met the additional criteria of adequate dose and duration of medications, according to the report. This questions the applicability of the results from research to the real-world and potentially hinders progress in the development of novel treatments.  

First author Dr Luca Sforzini from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London said: “So far there has been confusion about what is meant by treatment-resistant depression in research, practice and regulation, and the lack of a shared understanding is creating a barrier to effectively assessing current and future treatments. To address this, the report convened a range of experts to provide an agreed definition that we hope can support and accelerate much-needed progress in this field and enable the development of effective new approaches to treatment, eventually helping people with depression.”

The report brought together a group of international experts including those with lived experience, clinicians, academics, researchers, employees of pharmaceutical companies and regulatory bodies representatives. Using a Delphi-method-based consensus approach, the report formulated agreed definitions of TRD and a set of recommendations on researching unmet needs and designing clinical trials.

Co-authors from the European Medicines Agency, Florence Butlen-Ducuing and Andrew Thomson, said: “Many antidepressants are available but there are still patients who are responding only partially or are resistant to treatments. As Scientific Officers of the European Medicines Agency, we welcome work that can improve our understanding of treatment-resistant depression and partially responsive depression and guide better clinical trials to try and address this unmet medical need.”

The report strongly recommended that a clearer definition of TRD should be adopted: this would classify people as having TRD when they experience a minimal reduction in symptoms (by 25% or less) after the use of at least two antidepressants. They also suggested making a distinction between TRD and partially responsive depression (PRD), where people with PRD show a reduction of between 25 to 50% in symptoms to at least one antidepressant. This differentiation between these levels of treatment resistance will be useful to identify who will be appropriate for certain trials and eventually for treatments, according to the authors.

Co-author Fanni-Laura Mäntylä who has experience of living with depression said: “Personally, as a patient with a very difficult and lengthy path with the recovery from major depressive disorder, I feel a clearer definition between partially responsive depression and treatment-resistant depression would be very beneficial; as well as a more patient-centric and personalised approach to the treatment.”

In the case of TRD, the study also called for greater clarity around timing, so that only those with a lack of treatment response falling within the current episode of depression are diagnosed with TRD.  Alongside this, the authors agreed that the TRD definition should be as inclusive as possible in terms of other types of treatments, so that it does not exclude people who have failed psychotherapy or some brain stimulation techniques.

Lead author, Professor Carmine Pariante from the IoPPN and theme lead for affective disorders at the NIHR Maudsley Biomedical Research Centre said: “This is a very exciting time for research and practice around treatment-resistant depression, with a number of innovative new approaches on the horizon such as psychedelics, anti-inflammatory medications and brain stimulation techniques. We hope our report will pave the way for the acceptance and implementation of a standard definition to ensure these new therapies work effectively in patients who are not currently helped by available antidepressants.”

The authors also discussed the assessment of depression and called for more standardisation and shared practice in this area in terms of which instruments are used to provide a diagnosis or assess change in depressive symptoms. They agreed that the collection of biological data, such as blood samples and brain scans, should be done consistently with the aim of identifying possible markers or measures that could identify people with different forms of depression that may respond to different types of treatment.

The study is part of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI), a public-private strategic partnership funded by the Innovative Medicines Initiative (IMI)-2 Joint Undertaking (grant agreement No 853966) to lead the design of master protocols for future platform trials in different diseases, including MDD.

The paper ‘A Delphi-method-based consensus guideline for definition of Treatment-Resistant Depression for clinical trials’ was published in Molecular Psychiatry. DOI: 10.1038/s41380-021-01381-x

After the embargo has lifted it will be available here: https://www.nature.com/articles/s41380-021-01381-x

For more information please contact

• Franca Davenport, Communications and Engagement Manager, NIHR Maudsley Biomedical Research Centre, franca.davenport@kcl.ac.uk  (Monday)
• Patrick O’Brien, Senior Press Officer, Institute of Psychiatry, Psychology & Neuroscience, patrick.1.obrien@kcl.ac.uk (Monday)
• Ryan Jewell, communications and Engagement Officer, NIHR Maudsley Biomedical Research Centre, ryan.jewell@kcl.ac.uk (Tuesday)

For more information about EU-PEARL, please visit https://eu-pearl.eu/, or contact info@eu-pearl.eu (for general enquiries) or press@eu-pearl.eu (for media enquiries).

Notes to editors

The paper is under strict embargo until Wednesday 15 December 2021 13:00 UK time

The labels have been added to this press release as part of a project run by the Academy of Medical Sciences seeking to improve the communication of evidence. For more information, please see: http://www.sciencemediacentre.org/wp-content/uploads/2018/01/AMS-press-release-labelling-system-GUIDANCE.pdf

About King’s College London and the Institute of Psychiatry, Psychology & Neuroscience

King's College London is one of the top 35 UK universities in the world and one of the top 10 in Europe (QS World University Rankings, 2020/21) and among the oldest in England. King's has more than 31,000 students (including more than 12,800 postgraduates) from some 150 countries worldwide, and 8,500 staff. King's has an outstanding reputation for world-class teaching and cutting-edge research. The Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s is the premier centre for mental health and related neurosciences research in Europe. It produces more highly cited outputs (top 1% citations) on mental health than any other centre (SciVal 2019) and on this metric we have risen from 16th (2014) to 4th (2019) in the world for highly cited neuroscience outputs. World-leading research from the IoPPN has made, and continues to make, an impact on how we understand, prevent and treat mental illness and other conditions that affect the brain.

www.kcl.ac.uk/ioppn @KingsIoPPN

The National Institute for Health Research (NIHR)

The mission of the National Institute for Health Research (NIHR) is to improve the health and wealth of the nation through research. We do this by:

• Funding high quality, timely research that benefits the NHS, public health and social care;
• Investing in world-class expertise, facilities and a skilled delivery workforce to translate discoveries into improved treatments and services;
• Partnering with patients, service users, carers and communities, improving the relevance, quality and impact of our research;
• Attracting, training and supporting the best researchers to tackle complex health and social care challenges;
• Collaborating with other public funders, charities and industry to help shape a cohesive and globally competitive research system;
• Funding applied global health research and training to meet the needs of the poorest people in low and middle income countries.

NIHR is funded by the Department of Health and Social Care. Its work in low and middle income countries is principally funded through UK Aid from the UK government.