Major depressive disorder (MDD) and insulin resistance-related conditions are major contributors to global disability. Their co-occurrence complicates clinical outcomes, increasing mortality and symptom severity.

In this study, we investigated the association of insulin resistance-related conditions and related polygenic scores (PGSs) with MDD clinical profile and treatment outcomes, using primary care records from UK Biobank.

We identified MDD cases and insulin resistance-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 insulin resistance-related PGSs were calculated using PRS-CS. Univariable analyses were conducted to compare sociodemographic and clinical variables of MDD cases with (IR+) and without (IR−) lifetime insulin resistance-related conditions. Multiple regressions were performed to identify factors, including insulin resistance-related PGSs, potentially associated with treatment outcomes, adjusting for confounders.

Among 30 919 MDD cases, 51.95% were IR+. These had more antidepressant prescriptions and classes utilisation and longer treatment duration than patients without insulin resistance-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 insulin resistance-related conditions. After adjusting for confounders, insulin resistance-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 insulin resistance-related conditions. No significant PGS associations were found with antidepressant treatment outcomes.

Our findings support an integrated treatment approach, prioritising both psychiatric and metabolic health, and public health strategies aimed at early intervention and prevention of insulin resistance in MDD.