Disclosed herein are novel assays, systems and kits for selecting a treatment regimen for a subject with depression by identifying at least one nucleic acid polymorphism, e.g., but not limited to, at the MTHFR, MTR, or MTRR locus, and/or determining expression levels of peripheral biomarkers (e.g., SAM, SAH, and 4-HNE) in a test sample from a human subject. These biomarkers can be used to determine the effectiveness of treating a depressed subject with a folate-containing compound (alone or as an adjunct to an antidepressant). Additionally, these biomarkers can be used to select an appropriate treatment regimen for subjects with treatment-resistant depression (e.g., resistant to at least one selective serotonin reuptake inhibitor). Methods and compositions for treating a subject with depression and/or determining or improving the effectiveness of an antidepressant drug taken by a subject are also provided herein.