Nearly Half of Adults Diagnosed with MDD May Have Treatment Resistant Depression, Many Feel Hopeless

A recent mixed-methods study that examined treatment-resistant depression (TRD), reveals important findings regarding its prevalence, clinical associations, and the patient-clinician experience.¹

Steven Marwaha, PhD

The study, in an adult population served by the National Health Service (NHS) in the UK, investigated lived experiences of individuals diagnosed with major depressive disorder (MDD), determining that nearly half (48%) met the criteria for TRD, with approximately 36.9% having attempted 4 or more antidepressant treatments without achieving satisfactory response. Results of the analysis, which integrated quantitative data derived from electronic health records (EHR) and qualitative insights garnered from semi-structured interviews with both patients and clinicians, were published in the British Journal of Psychiatry.¹

TRD represents one of the most challenging yet also neglected conditions within psychiatry, with mental, physical, and social impacts exceeding that of MDD, according to experts.² The team of British researchers stated that most research on the condition has relied solely on data from EHRs, with very few using a mixed methods approach to capture both patient and clinician experiences and perspectives, a research and information gap they set out to correct.¹

The quantitative component of the study analyzed electronic health records from 5,136 adults (mean age 49 years) diagnosed with MDD. Of these, 2,461 (47.92%) were identified as having TRD, defined as depression that has failed to respond to at least 2 sequential antidepressant trials at adequate doses. The remaining 52.8% were classified as having MDD.

Among the most prominent results from this part of the study, researchers, led by Steven Marwaha, PhD, of the Institute for Mental Health, School of Psychology, University of Birmingham, Birmingham, UK, reported significantly higher recurrence of depressive episodes among those with TRD compared to those without (31.76% vs 26.62%; P <.001) as well as significantly greater rates of mental health comorbidities including anxiety disorders (30.80% vs 18.17%; P =.015), personality disorders (16.54% vs 11.18%; P <.001), self-harm (2.70% vs 0.90%, P <.001) and psychotic illness (15.03% vs 8.30%; P <.001). Physical comorbidities were also significantly higher among adults with TRD, including cardiovascular, respiratory, and gastrointestinal diseases as well as rates of both type 1 and type 2 diabetes, according to the results.¹

Marwaha et al found that mortality rates among participants with TRD were lower than for those with MDD (5.70% vs. 7.20%, P =.026), although the average age at death was approximately 5 years younger for the former group.

Economic inactivity, a key indicator of the impact of TRD on functioning and quality of life, was higher among those with resistant disease, reported among 41.2% compared with 32.6% of those with MDD (P <.001).

Lived Experience of TRD

Qualitative interviews conducted with participants experiencing TRD and their clinicians provided deeper insights into challenges of effective treatment. Through thematic, researchers discovered frustration in both groups with existing treatment pathways. For patients, this was often linked to organizational challenges and a perceived lack of support from health care providers. For their part, clinicians voiced frustration with current treatment guidelines, noting they often did not address the complex needs of their patients, leaving them feeling ill equipped to make treatment decisions.

Participants linked severe emotional distress to ineffective treatments and many expressed feelings of hopelessness following repeated treatment failure. Clinicians acknowledged their own feelings of helplessness faced with sequential treatment failures in their patients with TRD. ¹

“There is an irony that the experience of struggling to treat depression is in itself a risk factor for a worsening sense of ‘hopelessness’ as one patient described it." Marwaha and colleagues wrote. "This should be a clarion call to recognise that treatment-resistant depression needs to be factored into clinical decision making and the ongoing support that patients are offered.”

Many patients had only limited understanding of TRD as a marker of treatment failure and clinician use of inconsistent terminology was further confusing and frustrating. Acknowledging the variable continuum of severity of TRD, both groups emphasized the need for a holistic, patient-centered treatment approach, saying that the ‘one size fits all’ approach, typically characterized by an overreliance on pharmacologic solutions, was inadequate. Post-discharge support was found inadequate by both patients with TRD and clinicians alike, exposing a gap in continuous nonurgent care outside of acute care settings.

“This study is important as the data demonstrates people with TRD are at a higher risk of a range of poorer outcomes, and that we need better defined care pathways for helping this population, and are in urgent need of developing and testing new treatments for this group,” authors concluded.¹

References
Gill K, Hett D, Carlish M, et al. Examining the needs, outcomes and current treatment pathways of 2461 people with treatment-resistant depression: mixed-methods study. Br J Psychiatry. Published online March 12, 2025:1-8. doi: 10.1192/bjp.2024.275.2025
Costa T, Menzat B, Engelthaler T, et al. The burden associated with, and management of, difficult-to-treat depression in patients under specialist psychiatric care in the United Kingdom. J Psychopharmacol. 2022;36:545–56.