A substantial subset of patients with major depressive disorder (MDD) experience treatment-resistant depression (TRD), typically defined as failure to respond to at least two sequential antidepressant trials at adequate dose and length.

To examine clinical and service-level associations of TRD, and the experiences of people with TRD and clinicians involved in their care within a large, diverse National Health Service trust in the UK.

This mixed-methods study integrated quantitative analysis of electronic health records with thematic analysis of semi-structured interviews. Chi-squared tests and one-way analysis of variance were used to assess associations between lines of antidepressant treatments and sociodemographic and clinical variables, and binary logistic regression was used to identify associations of TRD status.

Nearly half (48%) of MDD patients met TRD criteria, with 36.9% having trialled ≥4 antidepressant treatments. People with TRD had higher rates of recurrent depression (odds ratio = 1.24, 95% CI: 1.05–1.45, P = 0.008), comorbid anxiety disorders (odds ratio = 1.21, 95% CI: 1.03–1.41, P = 0.019), personality disorders (odds ratio=1.35, 95% CI: 1.10–1.65, P = 0.003), self-harm (odds ratio = 1.76, 95% CI: 1.06–2.93, P = 0.029) and cardiovascular diseases (odds ratio = 1.46, 95% CI: 1.02–2.07, P = 0.0374). Greater treatment resistance was linked to increased economic inactivity and functional loss. Qualitative findings revealed severe emotional distress and frustration with existing treatments, as well as organisational and illness-related barriers to effective care.

TRD is characterised by increasing mental and physical morbidity and functional decline, with individuals experiencing barriers to effective care. Improved pathways, service structures and more effective biological and psychological interventions are needed.

Despite the availability of effective therapies, many patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD).

To evaluate and compare prescribing patterns, contact with specialist services and treatment outcomes in patients with MDD and TRD.

This was a retrospective analysis of linked primary and secondary care National Health Service data in the north-west London Discover-NOW data-set. Eligible patients were adults who had diagnostic codes for depression and had been prescribed at least one antidepressant between 2015 and 2020.

A total of 110 406 patients were included, comprising 101 333 (92%) with MDD and 9073 (8%) with TRD. Patients with TRD had significantly higher risks of suicidal behaviour and comorbidities such as anxiety, asthma, and alcohol or substance misuse (all P < 0.0001). Citalopram, sertraline, fluoxetine and mirtazapine accounted for 83% of MDD and 71% of TRD prescriptions. Use of antidepressant switching (1% MDD, 7% TRD) and combination therapy (1%, 5%) was rare, whereas augmentation occurred more frequently in the TRD group (4%, 35%). Remission was recorded in 42 348 (42%) patients with MDD and 1188 (13%) with TRD (P < 0.0001), whereas relapse was seen in 20 970 (21%) and 4923 (54%), respectively (P < 0.0001). Mean times from diagnosis to first contact with mental health services were 38.9 (s.d. 33.6) months for MDD and 41.5 (s.d. 32.0) months for TRD (P < 0.0001).

There appears to be a considerable difference between treatment guidelines for depression and TRD and the reality of clinical practice. Long-term treatment with single antidepressants, poor remission, and high relapse rates among patients in primary care highlight the need to optimise treatment pathways and access to newer therapies.