OBJECTIVES: A subset of patients with Major Depressive Disorder (MDD) who are treated with, but do not respond to antidepressant and/or antipsychotic (ADAP) drugs/ mood stabilizers are characterized as progressing to treatment resistant depression (TRD). This study characterized TRD and non-TRD episodes among MDD patients in the UK Clinical Practice Research Datalink (CPRD) during 2000-2012. METHODS: Business rules centered on diagnosis and use of antidepressants were used to identify new MDD episodes. Treatment regimens were defined as mono- or combination therapy with concurrently administered ADAP drugs. TRD was defined as ≥2 distinct failed regimens in an episode. Adults 18 to 65 years of age were included. RESULTS: Of the 427,467 MDD patients, 291,388 (68.2%) were excluded because they lacked an index diagnosis date, met an exclusion diagnosis criterion, did not meet the age criteria, or had missing age or gender; 136,079 patients (31.8%) were retained. A total of 6,311 (5.1%) distinct episodes with ≥1 ADAP prescription were treatment-resistant, with 6,221 (5.9%) of all patients experiencing ≥1 TRD episode. Median time to developing TRD was <11 months (307 days). Mean duration of a TRD episode was 1,239 days versus only 305 days for non-TRD episodes. Nearly half (46%) of all TRD episodes had up to 4 lines of treatment (LOTs); in contrast, only 19% of non-TRD episodes with ≥1 ADAP prescription had >1 LOT. Use of combination drug regimens was seen in 46.6% of TRD episodes compared with 12.8% of drug-treated non-TRD episodes. TRD episodes were associated with higher electroconvulsive therapy exposure, more psychiatrist visits and behavioral therapy sessions versus non-TRD episodes. More TRD patients suffered from co-morbidities such as anxiety and panic disorder. CONCLUSIONS: This analysis of data from the largest provider of health care in the UK highlights the significant burden of TRD on patients and providers.