Gene expression in cells changes as diseases progress, even in psychiatric disorders such as depression. For example, compared with healthy people, some patients with depression have altered patterns of DNA methylation, a chemical modification that typically reduces gene expression. Now researchers report one way in which antidepressants can manipulate these epigenetic pathways. Their findings suggest a possible blood test to determine whether a certain antidepressant will be effective for a given patient. Based on tests conducted on mice and cultured cells, Theo Rein of the Max Planck Institute of Psychiatry and colleagues studied how the antidepressant paroxetine reduces the activity of an enzyme that adds methyl groups to DNA. They found that the drug works though a chaperone protein that prevents the enzyme from becoming phosphorylated, a key step in the enzyme’s activation. When the researchers added paroxetine to blood cells from patients with depression, they found that the decrease in enzyme phosphorylation inversely correlated with how well the patient responded to antidepressant treatment: Larger drops in phosphorylation on average led to a greater improvement in depression symptoms (Sci. Signaling 2015, DOI: 10.1126/scisignal.aac7695).