Autoimmune Disorders in Treatment-Resistant Depression

We conducted a population-based study using both cohort design and nested case-control design in parallel, with the intention to preserve the advantages and complement the limitations of the other as we consider that cohort studies conventionally have a higher level of evidence, whereas case-control analysis was more appropriate for evaluating rare outcomes. The study period started in January 2014 and ended in December 2020. The cohort consisted of all incident patients aged above 10 years with diagnosis codes for depression (ICD-9-CM codes: 296.2, 296.3, 300.4, 311) between January 2014 and December 2016 without history of diagnosis for depression since 1993, when the database first became available. Patients were excluded if they had history of studied autoimmune diseases before onset of depression, or if they died immediately after cohort entry.
Throughout the study, patients were defined as treatment-resistant (exposed) if they had taken at least two antidepressant regimens of adequate duration (same antidepressant or combined therapy of at least 28 days with gaps of no longer than 14 days within regimens, whilst the 28-day duration was the minimum recommended duration to assess treatment responsiveness [26 ]) and had a third antidepressant regimen to confirm failure of the previous two trials. Patients who did not fulfil the criteria for TRD were considered as non-TRD (unexposed). Onset of outcome was confirmed on the date of the first autoimmune diagnosis in (1) organ-specific diseases including inflammatory bowel diseases, spondyloarthritis, psoriasis, insulin-dependent diabetes mellitus, Hashimoto’s thyroiditis, Graves’ disease, coeliac disease, vitiligo, alopecia areata, pemphigus vulgaris, dermatitis herpetiformis, pernicious anaemia, immune thrombocytopenic purpura, iridocyclitis and pemphigoid, and (2) systemic diseases including systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s disease, systemic sclerosis, polymyositis/dermatomyositis, multiple sclerosis and juvenile arthritis, captured across all settings including outpatient, inpatient and emergency services. List of ICD-9-CM codes to identify the cohort and outcomes is presented in Supplementary Table 1. Using the comorbidity rates reported from a previously similar population-based study, the sample sizes required for data collection were 5403 and 12545 for the analyses in systemic and organ-specific autoimmune diseases, respectively, to achieve an 80% statistical power in the cohort study [17 (link), 27 ].