Immune-mediated disease and risk of depression across the life-course: results from the ALSPAC and UK Biobank cohorts

Background

Immune mediated inflammatory and atopic diseases (IMIDs) are associated with depression, but evidence on directionality, timing, and heterogeneity across disease subtypes and multimorbidity patterns remains limited.

Aims

We examined life-course associations between IMIDs and depression, quantified bidirectional risks, and characterised IMID multimorbidity phenotypes linked to depression.

Methods

We analysed data from two population-based cohorts: ALSPAC (n=4,019; at age 22 and age 24) and UK Biobank (UKB; ages 40–69 years; n=501,936). In ALSPAC, depression was assessed using the Short Mood and Feelings Questionnaire (SMFQ≥12) at age 22 and the Clinical Interview Schedule–Revised (CIS-R) at age 24. In UKB, depression was assessed using recorded diagnoses of depression (ICD-10 F32) from electronic health records, including hospital, primary care and self-report data. Cross-sectional associations at baseline were estimated using Poisson-modified generalised linear models (GLM). Bidirectional longitudinal associations were examined using time-varying Cox proportional hazards models within a baseline healthy cohort. Restricted mean survival time (RMST) was used to quantify absolute differences in depression-free survival (τ=10 years). Latent class analysis (LCA) identified IMID multimorbidity clusters, and their associations with depression were assessed using GLM and Cox models. Sensitivity analyses using negative controls (e.g., cataract and inguinal hernia) assessed residual confounding and detection bias. Models were adjusted for sociodemographic confounders (e.g., age, sex, education, etc.).

Results

In ALSPAC, the presence of any IMID was associated with depression at age 22 (adjusted prevalence ratio [aPR]: 1.23, 95% CI 1.01-1.50) and at age 24 (adjusted risk ratio [aRR] 1.38, 95% CI 1.07-1.79), with stronger effects observed for co-occurring inflammatory and atopic diseases (aPR 2.01, 1.20-3.39).

In UKB, IMIDs were associated with increased risk of depression. Individuals with IMIDs had a twofold higher risk (aHR 2.04, 1.92-2.18), corresponding to shorter depression-free survival (−51 days over 10 years). Elevated risks were observed across inflammatory (aHR 1.94; 1.77-2.12) and atopic (aHR 2.11, 1.95-2.30) conditions, with the largest effects for systemic diseases, including ankylosing spondylitis (AS) (aHR 3.18, 2.02-4.99), systemic lupus erythematosus (SLE) (aHR 2.68, 1.43-5.02), Sjögren syndrome (aHR 2.45, 1.57-3.82) as well as multiple sclerosis (MS) (aHR 2.54, 1.61-4.01). Individuals with SLE, Sjögren and MS had lowest depression-free days (116-152 days lost). Similarly, prior depression also increased risk of subsequent IMIDs (aHR 1.78, 1.65-1.91, −63 days lost) across most of the disease, except for Sjögren and Graves’, with consistent but lower effect size.

LCA identified five distinct IMID multimorbidity clusters. The multi-system inflammatory cluster showed the highest risk of depression (aHR 2.93, 2.66-3.22), followed by psorio-arthritic (aHR 2.79, 2.32-3.35) and inflammatory bowel disease (aHR 2.14, 1.80-2.54) clusters, compared with healthy reference. Negative control analyses using non-inflammatory condition i.e., cataract, inguinal hernia showed weaker associations with depression, supporting specificity of the IMID-depression relationship.

Conclusions

IMIDs are associated with an increased risk and earlier onset of depression, with consistent evidence of bidirectionality. Multimorbidity and systemic inflammatory phenotypes further increases this risk. As these findings are observational, they highlight the need for further studies to examine shared biological mechanisms and support integrated approaches to mental and physical healthcare in individuals with IMIDs.

References

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