New report with the collaboration of Vall d’Hebron calls for clearer definition of treatment-resistant depression

This work is the base to develop an integrate research platform focus on this pathology.


A group of mental health experts from research, industry, regulatory bodies and with lived experience, with Dr. Josep Antoni Ramos Quiroga, head of the Mental Health Service at Vall d’Hebron Hospital and the Psychiatry, Mental Health and Addictions at Vall d’Hebron Research and researcher at CIBERSAM, 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.

The study, published in Molecular Psychiatry, is part of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) coordinate by Vall Hebron Research Institute (VHIR), 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 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.  

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. First author Dr Luca Sforzini from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London said: “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.”

Many antidepressants are available but there are still patients who are responding only partially or are resistant to treatments. 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. To J. Antoni Ramos-Quiroga, “this work is the base to develop an integrate research platform focus on TRD. The plan is to carry out for the first time on TRD adaptative clinical trials with the new molecules under investigation”.

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.

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.

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