S-adenosyl methionine (SAM-e), an over-the-counter dietary supplement, can be an effective, relatively well-tolerated, adjunctive treatment for adults with major depression who do not respond initially to their treatment with antidepressant medication, according to a new study conducted by investigators at Harvard Medical School and Massachusetts General Hospital. SAM-e is a naturally occurring, sulfur-containing amino acid derivative that functions as a methyl donor in the brain and body (other methyl donors include vitamin B12, folate, and trimethylglycine [TMG]). SAM-e is thought to be better absorbed when taken on an empty stomach.

The study, “S-Adenosyl Methionine (SAMe) Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders With Major Depressive Disorder: A Double-Blind, Randomized Clinical Trial,” is the first randomized, placebo-controlled clinical trial conducted on SAMe in a population of patients with major depressive disorders. A total of 73 adults were enrolled in this six week study and randomly assigned to the placebo control group or the SAMe treatment group (target dose: 800 mg/twice daily). SAMe, in combination with standard depression treatment, was more effective than antidepressant treatment alone in improving measures of depression and remission rates of patients with significant clinical depression. SAMe-treated subjects had a greater response rate (36.1 percent vs 17.6 percent for placebo) and remission rate (25.8 percent vs 11.7) than the placebo-treated group.  SAMe was well-tolerated with no reported adverse reactions.

“With each study we continue to gain a better understanding of SAMe’s role in treating depression.  This new finding, albeit preliminary and in urgent need of replication, suggests significant, clinically meaningful differences in outcome among patients who had SAMe added to their antidepressant medication treatment compared to those taking a placebo with their medication,” said George Papakostas, M.D., associate professor of psychiatry at Harvard Medical School, director of treatment-resistant depression studies in the Department of Psychiatry at MGH, lead author of the current study.  “These findings provide preliminary support for the efficacy, safety, and tolerability of SAMe as an additive therapy for patients with major depressive disorders who do not respond to antidepressant treatment alone.  Continued research, however, is urgently needed to more definitively further our understanding of the role of SAMe in the treatment of adults diagnosed with depression. Adjunctive SAMe therapy is promising, but cannot yet be recommended for wide-spread clinical use,” said Papakostas.

The National Institute of Mental Health (NIMH) funded the study.  Pharmavite LLC, the manufacturer of Nature Made SAM-e Complete and the leading distributor of SAMe supplements in the United States, provided the SAM-e supplements and placebo pills used in the study. The primary outcome measure for the study was the response rates according to the 17-item Hamilton Depression Rating Scale (HAM–D).

To date, at least 40 clinical trials have been conducted on SAMe directly and in combination with traditional antidepressant medications. Studies have evaluated SAM-e’s use in naturally restoring a healthy mood to the most recent research for treating major depressive disorders. This current study follows a pilot study published in 2004 in the Journal of Clinical Psychopharmacology, which concluded that antidepressants used in combination with SAMe were significantly more effective in relieving depression than medication alone.

In an accompanying editorial, J. Craig Nelson, M.D., professor of psychiatry at the University California, San Francisco, wrote, “The study of Papakostas, et al. is persuasive. It is the first adjunctive treatment trial of SAMe and the first placebo-controlled trial of oral SAMe since 1993. The era of development for new amine reuptake inhibitors appears to be coming to a close. Some novel approaches appear to be dead ends. SAMe offers a novel mechanism of treatment action and opens up a new area for future exploration. Of course this clinical trial requires replication. And there are numerous other questions about long-term safety and efficacy, comparisons with other adjunctive agents, and selection of appropriate patients. But demonstration of a new treatment for depression with a novel mechanism is exciting news.”

Reference: George I. Papakostas, M.D., et al. S-Adenosyl Methionine (SAMe) Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders With Major Depressive Disorder: A Double-Blind, Randomized Clinical Trial. Published online July 1, 2010 and in print in the August issue of Am J Psychiatry 2010; 167:942-948.