Roughly half of diagnosed depression cases deemed treatment-resistant

A considerable number of individuals who have received a diagnosis of major depressive disorder (MDD) show little to no improvement despite having tried multiple antidepressant medications, according to new research.

In a cohort of 5,136 patients diagnosed with MDD in the secondary care setting, 2,461 (47.92 percent) met the criteria for treatment-resistant depression (TRD). Based on their treatment history, 946 (35.40 percent) had tried two antidepressants, 529 (19.78 percent) had tried three, and 986 (36.93 percent) had tried at least four. The total number of antidepressant prescriptions in the TRD group reached 9,478. [Br J Psychiatry 2025;doi:10.1192/bjp.2024.275]

The odds of having TRD were high among MDD patients with psychotic illness (odds ratio [OR], 1.59, 95 percent confidence interval [CI], 1.27–2.00; p<0.001), those experiencing a single depressive episode vs recurrent depression (OR, 1.24, 95 percent CI, 1.05–1.45; p=0.008), those with comorbid anxiety disorders (OR, 1.21, 95 percent CI, 1.03–1.41; p=0.019), those with comorbid personality disorders (OR, 1.35, 95 percent CI, 1.10–1.65; p=0.003), those with comorbid cardiovascular diseases (OR, 1.46, 95 percent CI, 1.02–2.07; p=0.037), and those with a history of self-harm (OR, 1.76, 95 percent CI, 1.06–2.93; p=0.029).

Consequently, greater treatment resistance was linked to increased economic inactivity and functional loss.

Patients, clinicians on TRD

In semi-structured interviews with eight clinicians (two psychiatrists, two clinical psychologists, one psychotherapist, one physiotherapist, and two nursing staff) and seven patients with TRD (aged 28–63 years), several themes emerged. These included TRD criteria, the emotional impact of TRD, current treatment pathways, barriers to and facilitators of treatment, and future treatment recommendations.

There was a disconnect in how TRD was perceived and described. Patients frequently lacked awareness of TRD as a distinct and severe condition, whereas clinicians employed varied terminology, including chronic or recurrent depression.

In terms of experience, patients expressed a sense of hopelessness after trying multiple treatment options for their condition, and many shared their frustrations with a one size fits all approach to treatment. On the other hand, clinicians often reported feeling helpless when faced with severely distressed patients with TRD and their family members.

The limitations of current TRD treatment pathways were a key concern. While some patients found success with specific antidepressants, many were hampered by side effects that outweighed the benefits. Both patients and clinicians stressed the necessity of individualised treatment, advocating for exploring psychological interventions, such as compassion-focused therapy alongside cognitive behavioural therapy (CBT), as alternatives or additions to medication.

Treatment barriers were also discussed. Patients described a discouraging ‘trial and error’ approach, often leading to them giving up on further support. Meanwhile, clinicians also reported feeling ill-equipped, noting the lack of dedicated funding and consistent care pathways for depression compared to conditions like psychosis, where ‘depression is singled out’.

The interviewees identified key facilitators that could improve treatment experience. Patients emphasized the importance of feeling genuinely heard by their healthcare team and appreciated initiatives to improve TRD awareness. However, the persistent issue of discontinuity in care remained a major issue, with one patient saying, “I’m left in limbo… I’ve been here nearly 4 years.” To address this, both patients and clinicians agreed on the benefit of indicating TRD prominently in patient records.

Finally, the interviewees gave several recommendations for establishing a dedicated TRD care pathway. Some of these were providing tailored patient information, creating standardized routes to specialist services, improving access to diverse psychological therapies like CBT, enhancing clinician training on TRD guidelines and research, introducing support such as peer groups and occupational therapy, adopting a holistic treatment approach with consistent clinician involvement, and increasing opportunities for patients to participate in clinical research.

Better treatment options needed

“This paper highlights how widespread treatment-resistant depression is among those who are diagnosed with depression,” according to first study author Dr Kiranpreet Gill from the University of Birmingham, Birmingham, UK.

Gill stressed the need for better treatment options to be able to support patients for whom first line antidepressant medications don’t make a difference.

“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. This should be a clarion call to recognize that treatment-resistant depression needs to be factored into clinical decision-making and the ongoing support that patients are offered,” Gill said.