Francesco Di Pierro,1 Roberto Settembre2 1Scientific Department, Velleja Research, Milan, Italy; 2Neurosurgery Department, Di Venere Hospital, Bari, Italy Background: S-adenosyl-L-methionine (SAMe), a safe, endogenous, pleiotropic methyl donor well known for its antidepressant role, has been assumed to have a possible role in increasing plasma levels of compounds known to be able to raise cardiovascular risk. Although the issue is still being debated, betaine (trimethylglycine), a specific methyl donor involved in the homocysteine circuit, may be able to reduce such a risk and/or, by determining a sparing effect on endogenous SAMe, may be able to improve the clinical efficiency of SAMe itself. Indeed, preliminary results have shown clinical improvement determined by an add-on therapy with betaine administered along with SAMe, versus SAMe alone, to patients affected by mild/moderate depression. Aim: To evaluate the safety and antidepressant role played by the association of SAMe plus betaine versus amitriptyline administered in untreated individuals with a recent diagnosis of mild depression. Methods: This small, open-label, randomized, observational study enrolled 64 individuals with a diagnosis of mild depression according to the Zung Self-Rating Depression Scale. After randomization, they were treated with either Laroxyl® (amitriptyline, 75 mg/day) or DDM Metile® (enteric-coated SAMe, 500 mg/day, plus betaine, 250 mg/day) for 12 months. Assessment of clinical scores and tolerability was performed at T=0 and after 3, 6, and 12 months. Results: After 3 months, both treatments showed a small and not statistically significant improvement. After 6 and 12 months, both treated groups demonstrated a more noticeable improved response, although the group treated with SAMe plus betaine showed better results in terms of score, number of individuals in remission, and side effects. Compliance was overlapping in both treatments. Conclusion: The association of SAMe plus betaine seems to be a safe and effective tool to counteract mild depression and also when used as monotherapy in subjects with a recent diagnosis. Keywords: amitriptyline, betaine, SAMe, moderate depression, methyl donor