Effect of s-adenosyl-l-methionine (SAMe) upon depressive symptoms. Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial. Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. 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 Venlafaxine Preliminary results of a randomized controlled trial carried out with a fixed combination of S-adenosyl-L-methionine and betaine versus amitriptyline in patients with mild depression A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. S-adenosylmethionine treatment of depression: a controlled clinical trial. Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. S-Adenosyl-L-Methionine Augmentation in Patients with Stage II Treatment-Resistant Major Depressive Disorder: An Open Label, Fixed Dose, Single-Blind Study Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. Affective illness and S-adenosyl methionine: a preliminary report. A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. Bioavailability of S-adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder. Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine
Abstract SAMe is a methyl donor involved in methylation processes generally , including the Central Nervous System . Thirty depressed patients were studied in a double blind trial . The Hamilton Depression Rating Scale was used for symptom evaluation . The drug ( 45 mg i.m . daily ) appeared to have a rapid and beneficial effect mainly upon depressed mood , suicidal tendencies , retardation and performance . Improvement was observed in 80 % of the cases in 4–6 days . Studies are now in progress to clarify the biological mechanism involved in SAMe 's antidepressive action OBJECTIVE The aim of this study was to examine whether gender differences may have affected treatment response to S-adenosyl methionine ( SAMe ) in a recent failed r and omized clinical trial ( RCT ) for adults with major depressive disorder . METHODS Data from a 2-site , 12-week , double-blind RCT ( n=189 ) assessing the efficacy of SAMe vs. placebo and a comparator selective serotonin reuptake inhibitor ( escitalopram )  were subjected to post-hoc analyses to evaluate effects of patient gender on treatment response . RESULTS When assessing the efficacy outcomes within each gender separately , SAMe was superior to placebo among males ( n=51 ) , but not among females ( n=62 ) . Males showed a significant reduction of depression severity from baseline to study endpoint on the 17-item Hamilton Depression Rating Scale ( 4.3 point difference ; p=0.034 ; d=0.95 ) , while females did not show significant change . This finding emerged despite equivalence on baseline measures of depression severity between the gender groups . CONCLUSION RESULTS of this secondary data analysis suggest that gender might impact the antidepressant efficacy of SAMe , with greater therapeutic effect found in males . The underlying mechanism is still relatively unknown . Further work is needed to replicate this observation in independent sample s. Clinical trials.gov identifier : NCT00101452 S-adenosyl-L-methionine ( SAMe ) is a naturally occurring substance which is a major source of methyl groups in the brain and has been found in previous studies to be an effective antidepressant . The aim of this study was to assess the efficacy of oral SAMe in the treatment of depressed postmenopausal women in a 30-day double-blind placebo-controlled r and omized trial . During the course of the study , 80 women , between the ages of 45 and 59 , who were diagnosed as having DSM-III-R major depressive disorder or dysthymia between 6 and 36 months following either natural menopause or hysterectomy , underwent 1 week of single-blind placebo washout , followed by 30 days of double-blind treatment with either SAMe 1,600 mg/day or placebo . There was a significantly greater improvement in depressive symptoms in the group treated with SAMe compared to the placebo group from day 10 of the study . Side effects were mild and transient Methylation has been implicated in the etiology of psychiatric illness . Parenteral S-adenosylmethionine , a methyl group donor , has been shown to be an effective antidepressant . The authors studied the antidepressant effect of oral S-adenosylmethionine in a r and omized , double-blind , placebo-controlled trial for 15 in patients with major depression . The results suggest that oral S-adenosylmethionine is a safe , effective antidepressant with few side effects and a rapid onset of action .  S-Adenosylmethionine induced mania in a patient with no history of mania . S-Adenosylmethionine may be useful for patients who can not tolerate tricyclic anti-depressants . These findings support a role for methylation in the pathophysiology of depression 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 out patients 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 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 , r and omized , observational study enrolled 64 individuals with a diagnosis of mild depression according to the Zung Self-Rating Depression Scale . After r and omization , 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 S-adenosyl-L-methionine ( SAMe ) is a natural substance which constitutes the most important methyl donor in transmethylation reactions in the central nervous system . Several clinical trials have shown that SAMe possesses an antidepressant activity . This multicentre study was carried out to confirm both efficacy and safety of SAMe in the treatment of major depression .  SAMe was given intramuscularly ( i.m . ) at a dose of 400 mg/d , double-blind , vs. 150 mg/d oral Imipramine ( IMI ) in patients with a diagnosis of major depressive episode , with a baseline score on the 21-item Hamilton Depression Rating Scale ( HAMD ) of > or=18 . A total of 146 patients received SAMe whereas 147 received IMI  for a period of 4 wk . The two main efficacy measures were endpoint HAMD score and percentage of responders to Clinical Global Impression ( CGI ) at week 4 . Secondary efficacy measures were the final Montgomery-Asberg Depression Rating Scale ( MADRS ) scores and the response rate intended as a fall in HAMD scores of at least 50 % with respect to baseline . The analysis of safety and tolerability was conducted in all treated patients . SAMe and IMI did not differ significantly on any efficacy measure , either main or secondary . Adverse events were significantly less in patients treated with SAMe compared to those treated with IMI . These data show 400 mg/d i.m . SAMe to be comparable to 150 mg/d oral IMI in terms of antidepressive efficacy , but significantly better tolerated . These findings suggest interesting perspectives for the use of SAMe in depression OBJECTIVE Despite the progressive increase in the number of antidepressants , many patients with major depressive disorder continue to be symptomatic . Clearly , there is an urgent need to develop better tolerated and more effective treatments for this disorder . The use of S-adenosyl methionine ( SAMe ) , a naturally occurring molecule that serves as a methyl donor in human cellular metabolism , as adjunctive treatment for antidepressant nonresponders with major depressive disorder represents one such effort toward novel pharmacotherapy development . METHOD Participants were 73 serotonin reuptake inhibitor ( SRI ) nonresponders with major depressive disorder enrolled in a 6-week , double-blind , r and omized trial of adjunctive oral SAMe ( target dose : 800 mg/twice daily ) . Patients continued to receive their SRI treatment at a stable dose throughout the 6-week trial . The primary outcome measure for the study was the response rates according to the 17-item Hamilton Depression Rating Scale ( HAM-D ) . RESULTS The HAM-D response and remission rates were higher for patients treated with adjunctive SAMe ( 36.1 % and 25.8 % , respectively ) than adjunctive placebo ( 17.6 % versus 11.7 % , respectively ) . The number needed to treat for response and remission was approximately one in six and one in seven , respectively . There was no statistically significant difference in the proportion of SAMe- versus placebo-treated patients who discontinued the trial for any reason ( 20.6 % versus 29.5 % , respectively ) , due to adverse events ( 5.1 % versus 8.8 % , respectively ) , or due to inefficacy ( 5.1 % versus 11.7 % , respectively ) . CONCLUSIONS These preliminary results suggest that SAMe can be an effective , well-tolerated , and safe adjunctive treatment strategy for SRI nonresponders with major depressive disorder and warrant replication The antidepressant properties of S-adenosylmethionine , an endogenous methyl donor , were studied in in patients who met the DSM-III criteria for major depression . Nine patients given intravenous S-adenosylmethionine and nine given low oral doses of imipramine  were compared in a double-blind design for 14 days . The S-adenosylmethionine produced superior results by the end of the first week of treatment . By the end of the second week , 66 % of the S-adenosylmethionine patients had a clinical ly significant improvement in depressive symptoms , compared to 22 % of the imipramine patients . Side effects appeared to be fewer with S-adenosylmethionine than with imipramine during the last 5 days of the study BACKGROUND Major depressive disorder ( MDD ) is often accompanied by significant cognitive impairment , and there are limited interventions specific to this particular symptom . S-adenosyl methionine ( SAMe ) , a naturally occurring molecule which serves as a major methyl-donor in human cellular metabolism , is required for the synthesis and maintenance of several neurotransmitters that have been implicated in the pathophysiology and treatment of cognitive dysfunction in MDD . METHODS This study is a secondary analysis of a clinical trial involving the use of adjunctive SAMe for MDD . Forty-six serotonin-reuptake inhibitor ( SRI ) non-responders with MDD enrolled in a 6-week , double-blind , r and omized trial of adjunctive oral SAMe  were administered the self-rated cognitive and physical symptoms question naire ( CPFQ ) , a vali date d measure of cognitive as well as physical symptoms of MDD , before and after treatment . RESULTS There was a greater improvement in the ability to recall information ( p=0.04 ) and a trend toward statistical significance for greater improvement in word-finding ( p=0.09 ) for patients who received adjunctive SAMe than placebo . None of the remaining five items reached statistical significance . CONCLUSION These preliminary data suggest that SAMe can improve memory-related cognitive symptoms in depressed patients , and warrant replication We investigated the efficacy of S-Adenosyl-L-Methionine ( SAMe ) augmentation in patients with treatment-resistant depressive disorder ( TRD ) . Thirty-three out patients with major depressive episode who failed to respond to at least 8 weeks of treatment with two adequate and stable doses of antidepressants were treated openly with fixed dose of SAMe ( 800 mg ) for 8 weeks , added to existing medication . The primary outcome measure was the change from baseline in total score on Hamilton Rating Scale for Depression ( HAM-D ) . The Clinical Global Impression of Improvement ( CGI-I ) was rated at the endpoint . Patients with a reduction of 50 % or more on HAM-D total score and a CGI-I score of 1 or 2 at endpoint were considered responders ; remission was defined as a HAM-D score ≤7 . Secondary outcome measures included the Snaith-Hamilton Pleasure Scale ( SHAPS ) and the Sheehan Disability Scale ( SDS ) . At 8 weeks , a significant decrease in HAM-D score was observed with response achieved by 60 % of the patients and remission by 36 % . Also a statistically significant reduction in SHAPS and SDS was observed . Our findings indicate that SAMe augmentation may be effective and well tolerated in stage II TRD . However , limitations of the present study must be considered and further placebo-controlled trials are needed BACKGROUND S-Adenosyl-L-methionine ( SAMe ) , a natural compound , is the most important methyl donor in the central nervous system . In several clinical trials , SAMe showed antidepressant activity . OBJECTIVE Two multicenter studies were conducted in patients with a diagnosis of major depressive episode [ baseline score on the 21-item Hamilton Depression Rating Scale ( HAM-D ) > or=18 ] to confirm the efficacy and safety of SAMe in the treatment of major depression . In the first study ( MC3 ) , 1600 mg SAMe/d was given orally ; whereas , in the second study ( MC4 ) , 400 mg SAMe/d was given intramuscularly . In both studies , the effects of SAMe were compared with those of 150 mg imipramine/d given orally in a double-blind design . DESIGN In  MC3 , 143 patients received oral SAMe and 138 patients received imipramine for 6 wk . In  MC4 , 147 patients received SAMe intramuscularly and 148 patients received imipramine for 4 wk . In both studies the 2 main efficacy measures were the final HAM-D score and the percentage of responders to Clinical Global Impression at the endpoint . Secondary efficacy measures were the endpoint Montgomery-Asberg Depression Rating Scale scores and the percentage of responders , responders being those patients showing a decrease in HAM-D score of > or=50 % from baseline . RESULTS In both studies , the results of SAMe and imipramine treatment did not differ significantly for any efficacy measure . However , significantly fewer adverse events were observed in the patients treated with SAMe . CONCLUSIONS The antidepressive efficacy of 1600 mg SAMe/d orally and 400 mg SAMe/d intramuscularly is comparable with that of 150 mg imipramine/d orally , but SAMe is significantly better tolerated We report a pilot study of S-adenosyl-methionine ( SAM ) in 13 depressed patients with Parkinson 's disease . All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects .  SAM was administered in doses of 800 to 3600 mg per day for a period of 10 weeks . Eleven patients completed the study , and 10 had at least a 50 % improvement on the 17-point Hamilton Depression Scale ( HDS ) . One patient did not improve . Two patients prematurely terminated participation in the study because of increased anxiety . One patient experienced mild nausea , and another two patients developed mild diarrhea , which resolved spontaneously . The mean HDS score before treatment was 27.09 + /- 6.04 ( mean + /- st and ard deviation ) and was 9.55 + /- 7.29 after SAM treatment ( p < 0.0001 ) . Although uncontrolled and preliminary , this study suggests that SAM is well tolerated and may be a safe and effective alternative to the antidepressant agents currently used in patients with Parkinson 's disease S-Adenosyl methionine may well have an antidepressant action beyond a placebo effect but this is virtually confined to endogenous depression . This should be subjected to further study . Our own double-blind placebo-controlled study is still incomplete . The indications are that SAM specifically affects folate , dopamine , and serotonin metabolism as well as activating and switching brain mechanisms . This suggests exciting prospect s for further investigations . SAM is a nontoxic physiological metabolite virtually free of side effects OBJECTIVE To examine the comparative antidepressant efficacy of S-adenosyl-L-methionine ( SAMe ) and escitalopram in a placebo-controlled , r and omized , double-blind clinical trial . METHOD One hundred eighty-nine out patients ( 49.7 % female , mean [ SD ] age = 45 [ 15 ] years ) with DSM-IV-diagnosed major depressive disorder ( MDD ) were recruited from April 13 , 2005 , to December 22 , 2009 , at the Massachusetts General Hospital and at Butler Hospital . Patients were r and omized for 12 weeks to SAMe 1,600 - 3,200 mg/d , escitalopram 10 - 20 mg/d , or placebo . Doses were escalated at 6 weeks in the event of nonresponse . The main outcome measure was the 17-item Hamilton Depression Rating Scale ( HDRS-17 ) . Tolerability was assessed by the Systematic Assessment for Treatment of Emergent Events-Specific Inquiry ( SAFTEE-SI ) . RESULTS All 3 treatment arms demonstrated a significant improvement of about 5 - 6 points in HDRS-17 scores ( P < .001 for all ) , and no significant differences were observed between the treatment arms ( P > .05 for all ) . Response rates in the intent-to-treat sample were 36 % for SAMe , 34 % for escitalopram , and 30 % for placebo .  Remission rates were 28 % for SAMe , 28 % for escitalopram , and 17 % for placebo . No comparisons between treatment groups attained significance ( P > .05 for all ) . Tolerability was good , with gastrointestinal side effects ( 19 % for stomach discomfort and 20 % for diarrhea ) as the most common in the SAMe arm . Significant differences were observed between treatment groups for dizziness , anorgasmia , diminished mental acuity , and hot flashes ( P < .05 for all ) . CONCLUSIONS The results fail to support an advantage over placebo for either the investigational treatment SAMe or the st and ard treatment escitalopram for MDD . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00101452 OBJECTIVE To characterize the impact of S-adenosyl methionine ( SAMe ) on homocysteine and potential risk of adverse cardiovascular effects by examining plasma levels of SAMe , S-adenosyl homocysteine ( SAH ) , total homocysteine ( tHCY ) , methionine ( MET ) , and 5-methyltetrahydrofolate ( 5-MTHF ) in 35 of 73 patients from a 6-week r and omized double-blind , placebo-controlled trial of SAMe augmentation in serotonin reuptake inhibitor partial responders with DSM-IV major depressive disorder ( MDD ) , published in 2010 . METHOD Subjects were r and omized from June 4 , 2004 , until August 8 , 2008 , to adjunctive placebo or SAMe 800 - 1600 mg/d for 6 weeks . Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm ( by paired t test ) and between treatment arms ( by independent sample s t test ) . Univariate analysis of variance and Fisher Protected Least Significant Difference were carried out to compare posttreatment levels of each one-carbon cycle intermediate . Secondary outcome measures included associations between clinical improvement and change in plasma intermediate levels , examined by linear regression ( for change in Hamilton Depression Rating Scale scores ) and logistic regression ( for response or remission ) . RESULTS We found significant differences in pretreatment plasma levels of tHCY ( P = .03 ) between the SAMe and placebo arms . Following 6 weeks of treatment , plasma SAMe ( P = .002 ) and SAH ( P < .0001 ) levels increased significantly in the SAMe arm ; no intermediates in the placebo group changed significantly . Posttreatment plasma SAMe ( P = .0035 ) , SAH ( P < .0001 ) , and tHCY ( P = .0016 ) levels differed significantly between the SAMe and placebo groups . No significant associations were found between plasma intermediate levels and clinical improvement , response , or remission . CONCLUSIONS Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects , the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected . Our findings , however , have some significant limitations and should be interpreted with caution . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00093847 A double-blind clinical trial was carried out to evaluate the efficacy of S-adenosyl-L-methionine ( SAMe ) in speeding the onset of action of imipramine ( IMI ) . SAMe is a naturally occurring substance that has been shown to possess antidepressant activity with a rapid mode of onset and minimal side effects . Sixty-three out patients with moderate to severe depression were included in the study . After an initial 1-week placebo period , only 40 patients entered the active treatment phase . During the first 2 weeks of the trial , half of these patients received 200 mg/day of SAMe intramuscularly , while the other half received placebo . Simultaneously , oral IMI was administered to all patients at a fixed dose of 150 mg/day . The onset of clinical response was determined by evaluating patients every second day . By the end of week 2 , the parenteral treatment was suppressed and IMI was adjusted according to individual needs . Depressive symptoms decreased earlier in the patients who were receiving the SAMe-IMI combination than in those who were receiving the placebo-IMI combination
SAMe was not different from placebo and established antidepressants .
The exception was that compared to imipramine , fewer participants experienced troublesome adverse effects when treated with parenteral SAMe .
BACKGROUND Depression is a recurrent illness with high rates of chronicity , treatment-resistance and significant economic impact .
There is evidence in the literature that S-adenosyl methionine ( SAMe ) , a naturally occurring compound in the human body , has antidepressant efficacy .
This product may be an important addition to the armamentarium of antidepressant agents .
OBJECTIVES To assess the effects of SAMe in comparison with placebo or antidepressants for the treatment of depression in adults .