What is it about?
Depression that does not improve with standard treatment is often labelled "treatment-resistant". This article argues that this label is too narrow and frequently misused. It distinguishes treatment-resistant depression (TRD), defined simply by the failure of two or more medications, from a broader and more useful concept: difficult-to-treat depression (DTD). DTD shifts the focus away from medication alone and towards the whole person, taking into account psychological, social, family, and biological factors that shape how someone responds to care. Rather than aiming only at a cure, this approach aims to manage the illness over time, improving daily functioning and quality of life. The article explains why recognising this distinction matters: it can reduce the stigma attached to depression, encourage a team-based approach involving psychotherapy, brain stimulation, and social support alongside medication, and ultimately improve care for patients whose depression has been hard to treat.
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Why is it important?
Millions of people live with depression that does not respond fully to standard treatment, and the way clinicians label their condition directly shapes the care they receive. When such depression is framed only as "treatment-resistant", the response tends to stop at trying more medications. Reframing it as "difficult-to-treat" opens the door to a wider set of options and a more realistic goal: helping people live better even when full remission is not achievable. This matters for three reasons. For patients and families, it can reduce the sense of failure and stigma that comes with being called "resistant", and it brings their own experience and involvement into the care process. For clinicians, it offers a clearer framework for combining medication with psychotherapy, brain stimulation, and social support rather than relying on drugs alone. For researchers and health systems, it highlights an urgent gap: there is still no agreed definition or set of criteria for difficult-to-treat depression, which limits both research and the fair allocation of care. Clarifying the concept is a first step towards better tools, better treatments, and better outcomes for a group of patients who are too often left without effective help.
Perspectives
This Viewpoint marks the starting point of a longer line of work on difficult-to-treat depression. Building on it, I first set out the conceptual case for the construct in a scoping review distinguishing it from treatment-resistant depression (Paganin, Signorini & Sciarretta, 2023, Clinical Neuropsychiatry), and then developed both its clinical and its biological dimensions: a proposal for multifamily therapy as an integrated treatment strategy (Paganin, Signorini & Sciarretta, 2024, Frontiers in Psychiatry), a scoping review linking early-life trauma to difficult-to-treat depression (Paganin, Signorini & Sciarretta, 2024, BJPsych Bulletin), and an opinion piece proposing a biologically distinct inflammatory endotype within DTD, marked by low-grade systemic inflammation, as a route towards precision immunopsychiatry (Paganin, 2025, Clinical Neuropsychiatry). My hope is that clarifying the concept helps move the field away from a narrow, medication-centred notion of "resistance" and towards a model that recognises the biological, psychological, and relational complexity of these patients, and that treats improved functioning and quality of life as legitimate goals in their own right.
PhD in Neuroscience Walter Paganin
StudioPsicologiaSignorini
Read the Original
This page is a summary of: Viewpoint: Difficult-to-treat depression versus treatment-resistant depression: A new integrative perspective for managing depression, European Psychiatry, January 2023, Royal College of Psychiatrists,
DOI: 10.1192/j.eurpsy.2023.2448.
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