Early Brain Functional Connectivity Changes Induced by Antidepressants and Placebo

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder associated with significant morbidity and mortality. Despite its prevalence, the neural mechanisms underlying MDD and its treatment remain insufficiently understood, contributing to limited treatment efficacy and trial-and-error clinical practice. Although pre-treatment brain biomarkers have been associated with MDD diagnosis and antidepressant response, the precise neural circuits underlying these associations remain elusive. Antidepressant and placebo induce widespread cortical metabolic changes after six weeks of treatment6 and increase endogenous opioid release within one week, yet these findings offer limited insight into how interregional brain communication is altered by antidepressants or placebo. Using two independent cohorts of medicated MDD patients, we systematically characterize early treatment-induced changes in functional connectivity (FC) following one or two weeks of antidepressant or placebo administration. We identify a visual-precuneus-thalamus system exhibiting increased FC across patients, regardless of treatment or clinical outcome, and implicate striatal and attention networks in mediating placebo-related symptom improvement. Drug-specific effects center on the amygdala, mid-cingulate, orbitofrontal cortex, and cerebellum but are present only in a subset of patients treated with antidepressants; notably, the responses of those without such changes can be predicted with a placebo response prediction model. These findings reveal generalizable antidepressant-induced early FC changes, parse these changes into constituent placebo and drug-specific effects, and offer mechanistic insights into antidepressant action, supporting the development of interactive treatment optimization for MDD.