Posted by jrbecker on November 13, 2004, at 19:22:06 [reposted on November 14, 2004, at 14:06:26 | original URL]
the response rates from this study on adjunctive SAMe are fairly good, too bad it's so expensive...
Volume 24(6) December 2004 pp 661-664
S-Adenosyl-L-Methionine (SAMe) as an Adjunct for Resistant Major Depressive Disorder: An Open Trial Following Partial or Nonresponse to Selective Serotonin Reuptake Inhibitors or VenlafaxineAlpert, Jonathan E. MD, PhD*; Papakostas, George MD*; Mischoulon, David MD, PhD*; Worthington, John J. III MD*; Petersen, Timothy PhD*; Mahal, Yasmin BA*; Burns, Alana BA*; Bottiglieri, Teodoro PhD†; Nierenberg, Andrew A MD*; Fava, Maurizio MD*
*Depression Clinical and Research Program, Massachusetts General Hospital, Department of Psychiatry, Harvard Medical School, Boston, MA and †Baylor Institute of Metabolic Disease, Dallas, TX.
Received December 11, 2003; accepted after revision June 28, 2004.
Address correspondence and reprint requests to Jonathan E. Alpert, MD, PhD, Massachusetts General Hospital, Depression Clinical and Research Program, 50 Staniford Street, 4th floor, Boston, MA 02114. E-mail: jalpert@partners.org.
--------------------------------------------------------------------------------Abstract
Background: The purpose of this open trial was to evaluate the safety, tolerability, and efficacy of oral S-adenosyl-l-methionine as an antidepressant adjunct among partial and nonresponders to serotonin reuptake inhibitors or venlafaxine.Method: Thirty antidepressant-treated adult outpatients with persisting major depressive disorder received 800 to 1600 mg of S-adenosyl-l-methionine tosylate over a 6-week trial.
Results: Intent-to-treat analyses based on the Hamilton Depression Rating Scale revealed a response rate of 50% and a remission rate of 43% following augmentation with S-adenosyl-l-methionine. Gastrointestinal symptoms and headaches were the most common side effects.
Conclusion: Augmentation of selective serotonin reuptake inhibitors or venlafaxine with S-adenosyl-l-methionine warrants a placebo-controlled trial in resistant depression.
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Acommon clinical strategy when first-line antidepressants fail is to add a second agent with established or putative antidepressant properties, including bupropion, dopamine agonists (eg, pramipexole), psychostimulants (eg, methylphenidate), lithium, thyroid, buspirone, or pindolol.1,2 Dietary supplements, widely used among patients with mood and anxiety disorders,3 have also been studied for their possible role in enhancing or speeding response to antidepressants. These supplements include the omega-3 fatty acids,4,5 inositol,6 and folate.7,8 Anecdotal experience suggests a potential role for S-adenosyl-l-methionine (SAMe) in antidepressant augmentation.9 The purpose of this study was to evaluate the safety, tolerability, and efficacy of SAMe when added to selective serotonin reuptake inhibitor (SSRI) antidepressants or venlafaxine among adults with unremitted depression.Although first marketed in the United States in 1999, SAMe has been available in parenteral and oral forms for treatment of depression in Europe since the 1970s. Enteric-coated oral preparations of SAMe (SAMe tosylate or SAMe butanedisulphonate [SD4]) have helped address problems of stability that plagued previous formulations.10,11 The recent metaanalysis of placebo-controlled SAMe trials for depression (n = 422; 7 parenteral, 4 oral) commissioned by the Agency for Healthcare Research and Quality 12 showed an overall reduction of approximately 6 points over placebo in the Hamilton Depression Rating Scale (HAM-D) score (17- or 21-item) at 3 weeks, suggesting a clinically significant albeit partial response. Similarly, metaanalysis of double-blind trials involving an active comparator (n = 1,015; 10 parenteral, 4 oral) showed that SAMe was associated with no statistically significant difference in outcomes compared to treatment with tricyclic antidepressants,12 reinforcing similar conclusions from an earlier metaanalysis by Bressa.13 However, not all of these trials were adequately powered to discern a difference between SAMe and the tricyclics, some used only low to moderate doses of the tricyclics, and a majority involved parenteral formulations of SAMe.
To our knowledge, the only published report of combining SAMe with an SSRI in a controlled trial is that by Chinchilla and colleagues 14 whose study suggested that supplementation with SAMe (100 mg im vs. placebo) shortened the latency of response to fluoxetine (20 mg). A similar claim was made for the combination of SAMe (200 mg im vs. placebo) with imipramine (150 mg po).15 A case report, however, describes altered mentation, fever, hyperreflexia, and elevated creatinine phosphokinase when SAMe (100 mg im) was combined with the tricyclic antidepressant, clomipramine (75 mg), in a 71-year-old woman.16 Although similar symptoms suggesting serotonin syndrome have not been described in previous controlled studies on the efficacy and safety of SAMe administered in conjunction with older antidepressant agents including maprotiline,17 or mianserin 18 and a case report involving addition of SAMe to phenelzine,9 further information is clearly needed regarding the safety and tolerability, as well as efficacy, for the rational use of oral SAMe for antidepressant augmentation.
MATERIALS AND METHODS
Sample
Forty-five consecutive study volunteers (ages 18 to 75) drawn from an outpatient sample of antidepressant-treated adults with persisting depressive symptoms were enrolled for screening at 1 of 3 primary care sites and at the Depression Clinical and Research Program. Subjects at the 3 primary care sites were generally outpatients already receiving medical treatment at those sites. Subjects at the Depression Clinical and Research Program were referred clinically or responding to study advertisements. Subjects were required to be on a stable (>=4 weeks), minimally adequate dose of an SSRI or venlafaxine (fluoxetine/paroxetine/citalopram >=20 mg/d, escitalopram >=10 mg/d, sertraline >=50 mg/d, or venlafaxine >=75 mg/d). They needed to meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for current major depressive disorder and have a HAM-D-17 19 score of >=14 at screening and baseline visits. Exclusions included active suicidality, bipolar disorder, psychosis, and pregnancy as well as repeated antidepressant resistance (>3 adequate antidepressant trials) during the current major depressive disorder episode, and use of concomitant dietary supplements with putative antidepressant or mood-stabilizing activity.Treatment
Eligible subjects were evaluated weekly for 4 weeks and had a final visit at the end of week 6. Based upon doses used in previous SAMe clinical trials for depression, osteoarthritis, and cirrhosis,10,12 SAMe tosylate (Nature Made® supplied by Pharmavite, LLC) was started at 400 mg bid and was increased to 800 mg bid after 2 weeks. Subjects could remain on or return to the initial dose based upon clinical judgment. SSRI and venlafaxine doses could be lowered within the therapeutic range, if clinically indicated, while subjects requiring an increased antidepressant dose were discontinued.Efficacy, Tolerability, and Safety Measures
Response was defined as a 50% reduction in HAM-D-17 score from baseline to end point. Remission was defined as a final HAM-D-17 score of <=7. Secondary efficacy measures included the Montgomery Asberg Depression Rating Scale 20 and the Clinical Global Impressions-Severity and Improvement scales 21 and the 90-item Kellner Symptom Questionnaire (SQ).22 Paired t tests were conducted on baseline and end point assessments. The primary assessment of tolerability was the number of dropouts attributed to side effects. Sexual dysfunction at baseline and end point was assessed by the validated Massachusetts General Hospital Sexual Function Questionnaire.23Pretreatment and posttreatment serum homocysteine levels were measured given the interrelationship between SAMe and homocysteine in the 1-carbon cycle and concern about the increased risk of vasoocclusive disease with hyperhomocysteinemia.24 Baseline serum B12, homocysteine, and serum and red blood cell folate were also determined to evaluate the hypothesis that low folate and/or high homocysteine would be associated with a favorable response to SAMe augmentation based on their links in the 1-carbon cycle.11
RESULTS
Thirty of 45 subjects who were screened were eligible for the study and proceeded to baseline evaluation. The mean age for all patients was 48.4 ± 13.0 (SD) years and the gender distribution was 22/30 (73.3%) females. The mean duration of the current major depressive episode was 20.3 ± 29.0 months. The mean number of lifetime major depressive episodes was 4.0 ± 3.8. The mean age of onset of major depressive disorder in years was 28.7 ± 11.5. The mean total HAM-D-17 and Clinical Global Impressions-Severity scores during the baseline visit were 17.7 ± 4.2 (median 17.0, range 14 to 26) and 4.0 ± 0.7, respectively. Overall, 10 patients enrolled had a major depressive episode resistant to fluoxetine (mean dose 43.0 ± 21.1 mg), 2 to sertraline (mean dose 150.0 ± 70.7 mg), 13 to citalopram (mean dose 48.4 ± 32.6 mg), 1 to escitalopram (20 mg), 1 to paroxetine (40 mg), and 3 to venlafaxine (mean dose 200.0 ± 86.6 mg). The mean duration of the failed SSRI/venlafaxine trial was 14.5 ± 14.4 months (median 11.5 months; range 2 to 55 months). All but 4 patients had failed to respond to SSRI/venlafaxine doses higher than the required minimum to enroll in the study, and all patients had failed to respond to an SSRI trial at least twice as long as the minimally required 4 weeks.Twenty-three (76.6%) of 30 subjects completed the 6-week trial. The most common adverse events are listed in Table 1. Two subjects (6.6%) discontinued early because of intolerance of study treatment. No patient experienced a serious adverse event including serotonin syndrome.
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TABLE 1. Common Side Effects of SAMe 800 to 1600 mg/d*--------------------------------------------------------------------------------
There was a significant but modest (4.9%) decrease in pretreatment to posttreatment homocysteine levels (from 8.2 ± 2.5 to 7.8 ± 2.3 µmol/L, t test; df = 22; P = 0.003). There was also a small but significant reduction in Massachusetts General Hospital Sexual Function Questionnaire scores reflecting improvement, (22.8 ± 6.4 vs. 20.6 ± 7.3; df = 29; P = 0.02). There was no significant weight change over 6 weeks (183.1 ± 55.3 lb vs. 183.9 ± 56.8 lb, respectively; P > 0.05).
Intent-to-treat (ITT) analysis with last observation carried forward indicated a significant decrease in depression severity from baseline to end point as measured by the HAM-D-17 (17.7 ± 4.2 to 10.0 ± 6.6, df = 29; P < 0.0001), the Montgomery Asberg Depression Rating Scale (23.2 ± 6.2 to 13.9 ± 8.4, df = 29; P < 0.0001), and the Beck Depression Inventory (18.8 ± 5.4 to 12.2 ± 8.6, df = 29; P = 0.0002). There was also a significant decrease in Clinical Global Impressions-Severity scores, baseline to end point (4.0 ± 0.7 to 2.7 ± 1.2, df = 29; P < 0.0001). At end point, there were 15 (50.0%) responders and 13 (43.3%) remitters in the ITT analysis. At end point, there were 13 (56.5%) responders and 11 (47.8%) remitters in the completer analysis. Figure 1 presents mean HAM-D-17 scores by week for ITT and completer group samples.
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FIGURE 1. Change in mean HAM-D-17 scores. P < 0.0001 paired t test for all postbaseline HAM-D-17 severity assessments when compared to baseline HAM-D-17 severity for both ITT and Completer Analysis.--------------------------------------------------------------------------------
There was also a statistically significant improvement in baseline to end point SQ-depression scores (13.2 ± 4.9 vs. 7.5 ± 5.3, respectively, t test; df = 29; P = 0.001) and SQ-anxiety scores (12.2 ± 4.9, vs. 8.0 ± 5.6, respectively; df = 29; P = 0.012), but not SQ-anger/hostility scores (8.2 ± 5.6 vs. 5.8 ± 5.8, respectively; df = 29; P = 0.14), SQ-somatic symptom scores (10.6 ± 5.5 vs. 9.1 ± 6.1; P > 0.05), or SQ-somatic well-being scores (1.7 ± 1.9 vs. 2.7 ± 2.8, respectively, P > 0.05) in the ITT sample.
Low baseline folate (<=5.65) or B12 (<=148.1) levels, or elevated homocysteine levels (>=13.2) were not associated with positive clinical response to SAMe augmentation in this limited sample (P > 0.05 for all analyses); similarly, mean levels of folate, B12, or homocysteine did not differ between responders and nonresponders.
DISCUSSION
Consistent with the earlier findings of Chinchilla et al 14 who combined parenteral SAMe with fluoxetine, the combination of oral enteric-coated SAMe with SSRIs or venlafaxine for antidepressant augmentation was generally well tolerated. Additionally, there was evidence for a slight decrease in serum homocysteine consistent with the limited previous literature 25,26 as well as reduction of sexual dysfunction on SSRIs (perhaps related to the putative dopaminergic enhancement by SAMe 27,28). Preliminary evidence for efficacy were ITT response and remission rates comparable to those recently reported for bupropion augmentation of SSRIs or venlafaxine 29 as well as for switching to other antidepressants such as venlafaxine or mirtazapine after initial treatment resistance.30,31 Response and remission rates exceeded those in a very similar previous trial we conducted on folinic acid.8 Limitations of this study are its small sample size, lack of a placebo control, unblinded assessments, and inclusion of subjects whose antidepressant monotherapy had not been prospectively optimized. In addition, stability studies were not conducted on the SAMe tablets used for this trial and dose-finding studies are needed to identify whether the higher and therefore more costly doses used in this study are, in fact, necessary for efficacy. Nevertheless, within the limits of an uncontrolled trial, the results of this preliminary study suggest that the combination of SAMe with antidepressants deserves further scrutiny as a potentially safe and effective addition to the growing armamentarium of treatment approaches to resistant depression.ACKNOWLEDGMENTS
This study was funded by Pharmavite, LLC, a distributor of SAMe products. We also thank Marc Alan Pfeffer, MD, PhD, and Courtney Vitale of Partners Research and Education Program (PREP) for their support in conducting this study.REFERENCES
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