August 18, 2010 — Patients with major depressive disorder who fail to respond to treatment with serotonin reuptake inhibitors (SRIs) may benefit from the addition of the nutritional supplement S-adenosyl methionine (SAMe), according to results of the first placebo-controlled trial of the supplement in refractory depression.

"The results of this study provide preliminary evidence suggesting that SAMe can be an effective, relatively well-tolerated, and safe adjunctive treatment strategy for SRI nonresponders with major depressive disorder and our findings warrant replication," the study authors conclude in the August issue of the American Journal of Psychiatry.

Included in the single-center, 6-week study were 73 adults with major depressive disorder in whom a prior selective SRI trial had failed at an adequate dose for at least 6 weeks. Thirty-nine were randomly assigned to SAMe (at a target dose of 800 mg twice a day) and 34 to matching placebo, added to their ongoing antidepressant regimen. Fifty-five patients (75.3%) completed the 6-week study: 31 (79.4%) in the SAMe arm and 24 (70.5%) in the placebo arm.

According to the investigators, led by George I. Papakostas, MD, of the Center for Treatment-Resistant Depression at Massachusetts General Hospital and Harvard Medical School in Boston, during the study, significantly more SAMe-treated than placebo-treated patients (36.1% vs 17.6%) experienced a clinical response on the 17-item Hamilton Depression Rating Scale (HAM-D), which was the primary study outcome. Remission rates (ie, HAM-D score of ≤7) were also higher with SAMe than with placebo (25.8% vs 11.7%).

The between-group differences in response and remission rates were "statistically significant and clinically meaningful," Craig T. Nelson, MD, of the University of California, San Francisco, notes in an accompanying editorial.

The number needed to treat was about 1 in 6 for response and about 1 in 7 for remission.

"The positive finding, although preliminary, is of considerable clinical importance given the high rate of non- or limited response to initial trials of antidepressants," Matthew V. Rudorfer, MD, director of treatment research at the National Institute of Mental Health in Bethesda, Maryland, who was not involved in the study, noted in an email to Medscape Medical News.

There was no significant difference in the proportion of SAMe-treated and placebo-treated patients who discontinued the trial because of adverse events (5.1% vs 8.8%).

Dr. Papakostas and colleagues report that they noted a greater increase in supine systolic blood pressure (P = .04) among SAMe-treated patients relative to placebo-treated patients, which, they say, may be of clinical relevance if noted in future studies. However, in his editorial, Dr. Nelson says the "slight increase of 1.6 mm Hg in supine systolic blood pressure with SAMe versus 0.3 mm Hg with placebo seems of questionable importance."

Potential Mechanism

SAMe is a naturally occurring compound available in Europe since the late 1970s as a treatment for depression and other conditions and in the United States since 1999 as an over-the-counter enteric coated dietary supplement. SAMe is found throughout the body and in particularly high concentrations in the liver, adrenal glands, and pineal gland. It also appears to be uniformly distributed in the brain, where it acts as a major methyl donor for the synthesis of neuronal messengers and phospholipid cell membranes.

In his editorial, Dr. Nelson points out that low levels of SAMe in cerebrospinal fluid have been reported in severely depressed individuals. Oral and parenteral administration fuel a rise in cerebrospinal fluid SAMe concentrations, indicating that the compound crosses the blood-brain barrier. An increase in SAMe concentrations has been linked to improvement in depressive symptoms.

"In short," Dr. Nelson writes, low SAMe levels "may limit synthesis of brain neurotransmitters such as serotonin, norepinephrine, and dopamine. This may directly contribute to depressive symptoms or interfere with or limit the action of other antidepressants. Administration of SAMe may ameliorate these deficiencies or augment antidepressants and facilitate neurotransmission.

"Further research," Dr. Rudorfer said, "should help identify the mediators and moderators of response to SAMe augmentation, including underlying biological markers or ‘biosignatures’ and genetic factors, with the hope of identifying individuals (and perhaps the initial prescription antidepressant) best suited for this augmentation intervention."

"Persuasive" Results

All in all, the results reported by Dr. Papakostas and colleagues are "persuasive," Dr. Nelson writes, adding "SAMe offers a novel mechanism of treatment action and opens up a new era for future exploration."

Still, he emphasizes that the clinical trial results need to be replicated and numerous other questions answered. For example, studies examining the long-term safety and efficacy of add-on SAMe, comparisons with other adjunctive agents, and selection of appropriate patients need to be conducted.

In their report, Dr. Papakostas and colleagues emphasize that their study "aimed to provide preliminary evidence on the efficacy, safety, and tolerability of adjunct oral SAMe in major depressive disorder and, as a result, was probably underpowered to consistently detect moderate effect sizes.

The results, they add, "both those that do and do not reach statistical thresholds, suggest that this adjunctive intervention shows significant promise to justify larger-scale, adequately powered tests."

The lack of a differential dose treatment arm, which could have generated important information on the effect of higher and lower target doses, is another limitation of the study. An active treatment comparator arm could also have yielded "interesting information."

Placebo Effect "Striking"

Dr. Rudofer points out that although active SAMe was clearly superior to placebo as an adjunctive intervention in this study, "the clear downward trend in depression ratings during the 6-week add-on study even in the placebo group is striking.



http://www.medscape.com/viewarticle/727089