In this issue, Papakostas and colleagues (1) report the results of an adjunctive trial of S-adenosyl methionine (SAMe) in 73 patients with major depression who had failed a prior selective serotonin reuptake inhibitor trial at an adequate dose for at least 6 weeks. Patients were randomly assigned to SAMe, with a targeted dose of 800 mg twice a day, or placebo. Both were added to the ongoing antidepressant regimen and continued for 6 weeks. Response according to the primary outcome, the Hamilton Depression Rating Scale (HDRS), was more likely with SAMe (36.1%) than with placebo (17.6%), as was remission (HDRS score ≤ 7): 25.8% versus 11.7%, respectively. Differences were statistically significant and clinically meaningful.

To put this in context, the only medications approved by the U.S. Food and Drug Administration (FDA) for adjunctive treatment in major depression are aripiprazole and quetiapine extended-release. The olanzapine/fluoxetine combination is approved in resistant depression. A recent review and meta-analysis of the 16 trials of adjunctive atypical use in major depressive disorder found that mean pooled response rates with drug and placebo respectively were 44.2% versus 29.2% (2). The risk difference for response rates by meta-analysis (the mean difference in response to drug and placebo) was 0.12 for a number needed to treat of 9. In the adjunctive SAMe trial, the drug-placebo difference in response was 18.5% for a number needed to treat of 6. The magnitude of the drug effect observed in the SAMe trial is quite respectable, although it may in part reflect the careful patient selection and more reliable ratings that can be achieved in a single-site trial compared with the large multisite trials of atypical agents that likely suffer from substantial intersite variability.

In the current trial, SAMe was well tolerated. There was no difference between SAMe and placebo in the number of patients who discontinued treatment because of adverse events (5.1% versus 8.8%, respectively). In fact, the relative lack of side effects helped to insure the double-blind conditions. The slight increase of 1.6 mmHg in supine systolic blood pressure with SAMe versus 0.3 mmHg with placebo seems of questionable importance.

The current study is the first placebo-controlled trial of SAMe for adjunctive use. There is a modest literature exploring the efficacy of SAMe as monotherapy in depression. A systematic review commissioned by the Agency for Healthcare Research and Quality found 11 placebo-controlled trials of SAMe that reported change on a standard scale (3). The trials ranged in size from 15 to 75. The effect size of the difference between SAMe and placebo in these trials was 0.65, a moderate and meaningful effect. The analysis found significant heterogeneity that might reflect differences in route of administration, dose, or other unidentified factors, and an asymmetry test for publication bias was near significant (p=0.07). Six of these trials reported response rates and were examined in another meta-analysis that found a significant advantage for SAMe with an effect size of 0.38 (4). Only four of these placebo-controlled trials employed an oral form of SAMe. Three of these trials found an advantage for SAMe relative to placebo, but two of these studies were small (i.e., less than 20 patients). The two largest oral administration trials differed. Fava et al. (5) selected 55 patients with major depression and found no difference in response to drug and placebo: 67% versus 65%. Salmaggi et al. (6) studied 60 postmenopausal women between the ages of 45 and 55 with major depression or dysthymia and a HAMD ≥17. In these selected patients, SAMe was much more effective than placebo, with CGI response rates of 67% versus 3%, respectively. I have emphasized the oral administration trials, since that route will be the preferred.

SAMe monotherapy has also been compared with other antidepressants in double-blind trials. Hardy et al. (3) found 11 studies reporting response rates and 14 studies in which effect size could be determined from change scores. Almost all studies compared SAMe with a tricyclic antidepressant, and most employed parenteral SAMe. The meta-analysis found no difference in response rates or effect sizes. These findings do not indicate efficacy (placebo effects could account for response in both groups); yet, these data suggest conventional antidepressants are no more effective than SAMe given as monotherapy.

The actions of S-adenosyl methionine in the central nervous system have been reviewed previously (3, 7, 8). SAMe acts as a major methyl donor for the synthesis of brain amines and maintenance of phospholipid cell membranes. Low levels of SAMe have been reported in the cerebrospinal fluid (CSF) of severely depressed patients. Oral and parenteral administration of SAMe result in a rise in CSF SAMe concentrations, indicating the compound crosses the blood-brain barrier. An increase in SAMe levels has been positively correlated with improvement in depression. SAMe concentrations also appear to rise in patients who respond to other antidepressants such as desipramine. SAMe is produced in the one-carbon cycle involving folate, homocysteine, and vitamin B12 and abnormalities of each of these compounds has been associated with depression. In short, the hypothesis is that abnormalities in the one-carbon cycle may result in low concentrations of SAMe that in turn may limit the 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.

Ironically, this "naturally" occurring compound has been difficult to synthesize in a stable oral form with predictable dissolution characteristics. As a result, most initial studies gave the drug parenterally. A stable oral salt formulation was developed, but after four placebo-controlled trials of oral SAMe in major depressive disorder were conducted between 1990—1993, the FDA terminated trials of SAMe in the United States because of concerns regarding the dissolution of the oral tablets. In 1999, SAMe became available again in the United States as an over-the—counter enteric coated dietary supplement. The FDA does not routinely test the constituents of dietary supplements. In 2000, testing of marketed SAMe products by an independent laboratory revealed half of the products studied included significantly less of the compound than claimed (9). In 2007, testing was repeated and 11 marketed SAMe products were found to contain the claimed weight and had recommended dissolution characteristics (9). The report noted that the milligram dose was in some cases based on the weight of the salt rather than the active SAMe moiety. For example, 200 mg of SAMe tosylate disulfate contains about 100 mg of SAMe. Apparently this is a "let the buyer beware" situation.

SAMe is relatively expensive. A local national chain sells thirty-six 400 mg SAMe tablets for $42.99. A monthly supply of 1600 mg per day would be $142.80. The lowest Internet price I found was $58 for a similar month supply but this was not one of the products tested above. Since SAMe is not covered by insurance, these prices are considerably higher than usual co-pays.

To date, SAMe appears to be well tolerated, as the current augmentation study indicates. It does carry the warning that it may induce mania in bipolar patients, but this is a characteristic of most antidepressants and in fact might indicate antidepressant activity. While SAMe has been studied for more than 30 years, most studies of major depressive disorder have focused on acute treatment. Long-term safety data in major depressive disorder are limited. It is not well established what effects long-term SAMe has on the one carbon cycle. On the other side of the risk/benefit question, SAMe may have beneficial effects on pain associated with osteoarthritis and on some liver conditions.

Usual oral doses of SAMe in major depressive disorder have been between 800 and 1600 mg per day. Optimal oral doses in major depressive disorder and a safe upper limit for dosing have not been determined. An early study suggested sex differences in time to peak plasma concentrations and higher peak concentrations in women (10). To my knowledge potential sex differences in bioavailability have not been examined with currently marketed SAMe products in major depressive disorder.

Having said all that, 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.