Development of Major Depressive Disorder—Does Insulin Resistance Play a Role?—Reply

We thank van Bruggen and McIntyre for their thoughtful and constructive comment on our article1 in JAMA Psychiatry. The proposed link between insulin resistance and the soft drink-microbiome-depression pathway is compelling and well supported by accumulating evidence on metabolic contributions to major depressive disorder (MDD). Unfortunately, our dataset did not include validated metabolic markers of insulin-glucose homeostasis, such as fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), oral glucose tolerance tests, or the triglyceride to high-density lipoprotein cholesterol ratio. This limitation is common in large-scale cohorts that prioritize either psychiatric or metabolic characterization. We adjusted all analyses for body mass index (BMI) to account for potential confounding by body weight; the results remained unchanged. However, BMI is a crude marker that does not capture metabolic dysregulation; therefore, we cannot exclude the possibility that insulin resistance contributed to the observed associations.