Wang Y, et al. - In order to assess the pathways through which antidepressant medications exert their effects and to advance the pharmacology of depression, researchers investigated how antidepressant treatment influence whole-brain functional connectivity, examined correlations between change in functional connectivity and improvement in symptoms of depression and inquired if these effects were reproducible across two studies. They conducted two double-blind, placebo-controlled trials including adults with persistent depressive disorder; of these, one was a 10-week trial of duloxetine (30–120 mg daily; mean 92·1 mg/day) and the other was a 12-week trial of desvenlafaxine (50–100 mg daily; 93·6 mg/day). MRI scans were obtained before and after treatment in the two trials. On receiving antidepressants vs placebo, participants in both studies displayed lowered functional connectivity within a thalamo-cortico-periaqueductal network that has previously been associated with the experience of pain. Within the active drug groups, they observed correlations of reductions in functional connectivity within this network with improvements in depressive symptom severity in both studies and pain symptoms in the desvenlafaxine study. The findings imply that for novel antidepressant therapeutics, the thalamo-cortico-periaqueductal network is a new and potentially important target.