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When the name does matter

When the name does matter

The importance of definitions in treatment-resistant depression and a new published guideline for clinical studies

Most, if not all, of us in our lives have experienced occasional sadness and low mood, or a lack of interests and motivation in daily activities. This is not necessarily depression. Short-lived mood fluctuations, mostly if clearly linked with a different range of challenging situations, can (and should) be considered as a normal and physiological component of an individual’s life experience.

I am a Psychiatrist and a PhD Student in the Stress, Psychiatry and Immunology (SPI)-Lab at King’s College London, and my research focus is on major depression and specifically on treatment-resistant depression (TRD) and its biological correlates. I have written previous blogs for InSPIre the Mind, on the comorbidity between depression and cancer and on seasonal depression.

In the present blog , I will discuss the importance of definitions in TRD-related research. I will start with an overview on TRD and core gaps in knowledge and I will then summarise the main recommendations of a newly published guideline for TRD clinical studies, which has been led by our research group.

Depression, or more precisely ‘major depression’, is different from normal sadness.

Major depression is, indeed, a complex and serious clinical condition in which a person experiences a depressed mood or a loss of pleasure in things and activities for most of the day, nearly every day, for at least two weeks, in addition to other specific physical, cognitive, and psychological symptoms.

Photo by Alex Ivashenko on Unsplash

Currently, according to the World Health Organization, approximately 280 million people worldwide are living with depression. Notably, most people with depression have a chronic course of illness and recurrent episodes.

Complicating matters, although a wide range of treatments are currently available and effective in a lot of people, they are not effective in all people.

In fact, about one third of individuals with depression do not show any significant response after one or several antidepressant treatments.

That means that almost 100 million people are suffering from a ‘not-effectively-treated’ depression all around the world.

Given these premises, it is not surprising that depression is nowadays recognized as a leading contributor to the global burden of disease and as a major cause of disability worldwide. An important and fundamental step to tackle this dramatic evidence is to understand why the same treatments have different outcomes in different people.

By focussing research on these individuals who ‘do not adequately respond’ to conventional treatments we may understand the reasons behind this non-response and how they could eventually respond or to which treatment, maybe targeting something different from standard antidepressants, as we have also previously discussed on InSPIre the Mind.

When a treatment fails to eradicate or effectively improve depressive symptoms, we are conventionally referring to a condition named treatment-resistant depression, or TRD.

Quite surprisingly considering this evidence, there is still uncertainty around concepts such as response, non-response, and partial response to treatments, and a clear and unequivocal definition of TRD is still missing. Correctly differentiating between different clinical phenotypes may lead to more tailored research, eventually allowing the discovery of novel treatments for selected group of individuals.

Therefore, the name matters. A clear consensus on disease definitions is the necessary foundation to build reliable future research in psychiatry.

Photo by Thom Milkovic on Unsplash

Which are the main uncertainties and core gaps in knowledge?

As discussed, there is still no clear consensus on what we mean by TRD.

When we try, for example, to test the efficacy of a new treatment in individuals in whom conventional treatments failed to improve symptoms, a discordance in definitions may be reflected in a discrepancy in clinical populations between different studies, with potentially different results, generating confusion in TRD-related research.

Now, let’s suppose we carry out five different clinical trials on people with TRD to test the efficacy of a new medication. Having ambiguous definitions for inclusion of participants in these trials may imply that different studies potentially analyse five different conditions — each of them equally defined as TRD.

This is what has been happening. Only one in five TRD studies utilise the most consistently accepted definition of TRD in literature that is, a non-response to at least two previous antidepressant treatments, administered at an adequate dosage and for an adequate duration.

If these definitions differ between the different theoretical and operational approaches, an unfortunate consequence may be to compare the same interventions — and to standardise outcomes — in clinically different populations, therefore raising the famous problem of ‘comparing oranges and apples’.

Here, the issue may be even more complicated. In fact, the different TRD definitions usually only differ slightly between one another.

This may imply we are not necessarily comparing oranges and apples, but we are probably not noticing important nuances, for example the difference that lies within different types of apples.

Photo by James Yarema on Unsplash

Here lies the importance of the consensus guideline recently published on Molecular Psychiatry and coordinated by our research group.

The original paper has been produced as part of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) project. The aim of the project is to design a protocol for platform trials in different diseases, including major depression.

To develop the guideline, we followed an iterative consensus process involving over 60 experts in the treatment of depression, including clinicians, academicians, members of industry and regulatory agencies, and people with lived experience of depression.

We aimed to gain consensus on the main uncertainties and gaps in knowledge in order to produce clear definitions of TRD for inclusion of participants in clinical studies and clinical trials.

Future directions towards no more uncertainties

Co-author on the report Fanni-Laura Mäntylä, who has experience of living with depression and has written a fascinating blog article about her own personal experience, said: “Personally, as a patient with a very difficult and lengthy path with the recovery from major depressive disorder, I feel a clearer definition would be very beneficial; as well as a more patient-centric and personalised approach to the treatment.”

It was almost unanimous opinion that a better definition of TRD for clinical trials conducted for regulatory purposes is necessary.

A definition of partially responsive depression (PRD), distinguished from TRD, has been also recommended.

In more detail, we propose that to define TRD (and PRD) it is necessary to confirm a diagnosis of major depression and to document a non-response (or a partial response) to an antidepressant treatment. Non-response or partial response should be carefully assessed by examining number, type, dosage, and duration of current and past treatments.

TRD should be defined after a minimum of two failed treatments (defined as an improvement less than 25% in clinical scores before and after treatment), with adequate dosing and duration (the minimal licensed dosage administered for at least four weeks) and different mechanisms of action. PRD can be defined even after a single treatment (improvement between 25 and 50%) with adequate dosing and duration.

The improvement in depressive symptoms is usually measured prospectively, using the percentage reduction in clinical scales (pre- and post- treatment). However, it can also be evaluated retrospectively (only in the past two years), based on medical records.


Participants’ inclusion algorithm for TRD/PRD clinical studies (from Sforzini et al., Molecular Psychiatry, 2021)

Still a lot must be discovered to correctly understand depression and treatment resistance. There are many different clinical phenotypes of depression and, probably, these are related to different biological and molecular profiles. Inflammation is certainly important in TRD, for example.

Therefore, a depression that ‘does not respond’ (or ‘respond partially’) to treatments may have some intrinsic differences compared with ‘responsive’ depression, with peculiar clinical, biological, and molecular features. Understanding these features may allow a better characterization of TRD/PRD, ultimately leading to novel discoveries for diagnosis, prevention, and treatment.

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