It is reported that MTHFR testing is among the most ordered genetic testing (fourth in Italy), with hyperhomocysteinemia, venous thrombotic event, cerebrovascular accident, family history, intrauterine fetal demise, recurrent miscarriage, lupus, vasculitis, transplant evaluation, immune thrombocytopenic purpura, migraines, and depression reported as indications for testing, with lack of uniformity and low evidence-based recommendations [30,31]. This evidence concerns the gene MTHFR and major depressive disorder.