Insulin resistance and poorer treatment outcomes in depression: evidence from UK Biobank primary care data

Abstract Background: Major depressive disorder (MDD) and insulin resistance (IR)-related conditions are major contributors to global disability. Their co-occurrence complicates clinical outcomes, increasing mortality and symptom severity. Aim: In this study, we investigated the association of IR-related conditions and related polygenic scores (PGSs) with MDD clinical profile and treatment outcomes, using primary care records from UK Biobank. Methods: We identified MDD cases and IR-related conditions, as well as measures of depression treatment outcomes (e.g., resistance) from the records. Clinical-demographic variables were derived from self-reports, and IR-related PGSs were calculated using PRS-CS. Univariable analyses were conducted to compare socio-demographic and clinical variables of MDD cases with and without lifetime IR-related conditions (IR+). Multiple regressions were performed to identify factors, including IR-related PGSs, potentially associated with treatment outcomes, adjusting for confounders. Results: Among 30,919 MDD cases, 51.95% were IR+. These had more antidepressant prescriptions and classes utilisation and longer treatment duration than patients without IR-related conditions (p<0.001). IR+ participants showed distinctive depressive profiles, characterised by concentration issues, loneliness and inadequacy feelings, which varied according to the timing of MDD diagnosis relative to IR-related conditions. After adjusting for confounders, IR-related conditions (i.e., cardiovascular diseases, hypertension, non-alcoholic fatty liver disease, obesity/overweight, prediabetes, and type 2 diabetes mellitus) were associated with antidepressant non- response/resistance and longer treatment duration, particularly when MDD preceded IR-related conditions. No significant PGS associations were found with antidepressant treatment outcomes. Conclusions: Our findings support an integrated treatment approach, prioritising both psychiatric and metabolic health, and public health strategies aimed at early intervention and prevention of IR in MDD.