Link Between Treatment Resistant Depression And Onset Of Autoimmune Disease

A study published by Translational Psychiatry tested for the association between treatment resistant depression (TRD)  with the onset of autoimmune diseases. The authors discuss important implications and steps to be taken that may prevent and protect those living with treatment resistant depression. They also emphasise the differences between men and women in developing autoimmune conditions. Follow the details of the study below: 

Approximately 280 million people worldwide live with depression, which is ranked a leading cause of disability and a major contributor to the global disease burden. Antidepressants are important treatment modalities with significantly increasing consumption between 2008 and 2019. However, more than half of patients fail to respond to their first trial of antidepressant, and a significant proportion still do not reach remission following subsequent therapies as a result, these patients are known to have treatment-resistant depression (TRD).

Compared with responders, patients with TRD often further present a significant fatal and non-fatal burden on society and the healthcare system in the form of excessive premature deaths and utilisation of various types of healthcare resources. 

The multifactorial nature of depression also stimulates a growing interest in its impact on physical health. Due to the bidirectional crosstalk between the endocrine and immune systems, depression and inflammation often influence each other via the balance of cytokine messengers. Recent literature increasingly indicates the role of depression in predicting subsequent autoimmune diseases owing to the increased immune activation and levels of pro-inflammatory cytokines among depressed individuals.

Study design: 

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 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 erythema- tosus, 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.


Study results: 

Using two study designs based on a territory-wide longitudinal EMR database, the study presents an attempt to delineate the association between antidepressant resistance and develop- ment of autoimmune diseases with consideration of temporal causality. Our findings provide support to the hypothesis that TRD status could be a risk predictor of developing autoimmune diseases. We also identified that the increased risk more likely stemmed from organ-specific autoimmune diseases than systemic autoimmune diseases. The magnitude of risk among men appeared to be generally higher than in women in the studied associations from both study designs and consistent across subtypes of autoimmune diseases

As the patients with depression and autoimmune diseases in our study are predominantly women, it is reasonable that a significant association was observed only among women. How- ever, the risk magnitudes of association appeared to be higher among men instead across study designs and outcome types. Despite non-significance, the observed trend was consistent with previous studies which found that the increased CRP was stronger in male patients with depression compared with female patients. In addition, a previous Danish retrospective cohort study which similarly explored sex-specific differences with temporality consideration also identified an increased risk of multiple sclerosis associated with TRD only in male patients. A possible hypothesis was given by the link between inflammation and the dysregulation of hormonal systems, in which estrogen may exert a protective effect given its anti-inflammatory properties. Over the years, there has been rising awareness of sex-specific disparities in medical research, with the aim to identify health modifiers and vulnerabilities to inform intervention efforts. Although it was not possible to explain the mechanism based on our study, further laboratory-based studies capable of elucidating the potential sex-specific mechanism is important in the identification of vulnerabilities.


Our findings reported herein underpin several implications with regards to understanding and managing hard-to-treat depression. In the TRD population, clinical awareness should be raised to manage treatment refractoriness early and detect subsequent development of autoimmune diseases, followed by timely intervention to prevent disease progression, such that potential excessive burdens in healthcare resources jointly arising from multifaceted mental and somatic consequences can be avoided. We found increased risk of autoimmune diseases in patients with TRD compared with patients who responded to antidepressants. Inflammation control in hard-to-treat depression might play an important role in the prevention of subsequent autoimmune conditions. Association of sex-specific disparities deserves further mechanistic investigation.

Materials provided by Translational Psychiatry and Nature Journal 

Note: Content may be edited for style and length.


Chan, V.K.Y., Luo, H., Chan, S.S.M. et al. Treatment-resistant depression and risk of autoimmune diseases: evidence from a population-based cohort and nested case-control study. Transl Psychiatry 13, 76 (2023).


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