title: Cost of depression in Europe. S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: efficacy and effects of histamine and carnitine as moderators of response. Bioavailability of S-adenosyl methionine and impact on response in a randomized, double-blind, placebo-controlled trial in major depressive disorder. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. S-adenosylmethionine (SAM-e) for the treatment of depression in people living with HIV/AIDS The thyrotropin response to thyrotropin‐releasing hormone as a predictor of response to treatment in depressed outpatients Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. 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. 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 The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials The influence of S-adenosylmethionine (SAM) on prolactin in depressed patients. Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine Components of variance and intraclass correlations for the design of community-based surveys and intervention studies: data from the Health Survey for England 1994. Short-term spontaneous improvement rates in depressed outpatients. 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. Clinically useful measures of effect in binary analyses of randomized trials. S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. S‐adenosylmethionine blood levels in major depression: changes with drug treatment S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Effect of s-adenosyl-l-methionine (SAMe) upon depressive symptoms. S-adenosylmethionine treatment of depression: a controlled clinical trial. External validity of randomised controlled trials: “To whom do the results of this trial apply?” Affective illness and S-adenosyl methionine: a preliminary report. Results and possible developments of the clinical use of S-adenosyl-L-methionine (SAMe) in psychiatry. A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. The switch mechanism and the bipolar/unipolar dichotomy. Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial. Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial.
abstract: BACKGROUND Depression is one of the most disabling diseases , and causes a significant burden both to the individual and to society . WHO data suggests that depression causes 6 % of the burden of all diseases in Europe in terms of disability adjusted life years ( DALYs ) . Yet , the knowledge of the economic impact of depression has been relatively little research ed in Europe . AIMS OF THE STUDY The present study aims at estimating the total cost of depression  in Europe based on published epidemiologic and economic evidence . METHODS A model was developed to combine epidemiological and economic data on depression in Europe to estimate the cost . The model was populated with data collected from extensive literature review s of the epidemiology and economic burden of depression in Europe . The cost data was calculated as annual cost per patient , and epidemiologic data was reported as 12-month prevalence estimates . National and international statistics for the model were retrieved from the OECD and Eurostat data bases . The aggregated annual cost estimates were presented in Euro for 2004 . RESULTS In 28 countries with a population of 466 million , at least 21 million were affected by depression . The total annual cost of depression in Europe was estimated at Euro 118 billion in 2004 , which corresponds to a cost of Euro 253 per inhabitant . Direct costs alone totalled dollar 42 billion , comprised of outpatient care ( Euro 22 billion ) , drug cost ( Euro 9 billion ) and hospitalization ( Euro 10 billion ) . Indirect costs due to morbidity and mortality were estimated at Euro 76 billion . This makes depression the most costly brain disorder in Europe , accounting for 33 % of the total cost . The cost of depression corresponds to 1 % of the total economy of Europe ( GDP ) . DISCUSSION Our cost results are in good agreement with previous research findings . The cost estimates in the present study are based on model simulations for countries where no data was available . The predictability of our model is limited to the accuracy of the input data employed . As there is no earlier cost-of-illness study conducted on depression in Europe , it is , however , difficult to evaluate the validity of our results for individual countries and thus further research is needed . CONCLUSION The cost of depression poses a significant economic burden to European society . The simulation model employed shows good predictability of the cost of depression in Europe and is a novel approach to estimate the cost-of-illness in Europe . IMPLICATION S FOR HEALTH CARE PROVISION AND POLICIES : Health and social care policy and commissioning must be evidence -based . The empirical results from this study confirm previous findings , that depression is a major concern to the economic welfare in Europe which has consequences to both healthcare providers and policy makers . One important way to stop this explosion in cost is through increased research efforts in the field . Moreover , better detection , prevention , treatment and patient management are imperatives to reduce the burden of depression and its costs . Mental healthcare policies and better access to healthcare for mentally ill are other challenges to improve for Europe . IMPLICATION S FOR FURTHER RESEARCH This study has identified several research gaps which are of interest for future research . In order to better underst and the impact of depression to European society long-term prospect i ve epidemiology and cost-of-illness studies are needed . In particular data is lacking for Central European countries . On the basis of our findings , further economic evaluations of treatments for depression are necessary in order to ensure a cost-effective use of European healthcare budgets OBJECTIVE To assess the antidepressant efficacy of S-adenosyl methionine ( SAMe ) , a naturally occurring methyl donor , versus the selective serotonin reuptake inhibitor ( SSRI ) escitalopram and a placebo control ; and to determine whether serum histamine or carnitine levels modified treatment response . METHODS We examined a sub sample ( n=144 ) from one site of a two-site study of adults with diagnosed Major Depressive Disorder ( MDD ) , recruited from 4/13/05 to 12/22/09 , who consented to the additional blood draw for serum histamine and carnitine levels . After washout , eligible subjects were r and omized to SAMe ( 1600 - 3200mg/daily ) , escitalopram ( 10 - 20mg/daily ) , or matching placebo for 12 weeks of double-blind treatment ( titration at week 6 in non-response ) . RESULTS On the primary outcome of the Hamilton Depression Rating Scale ( HAMD-17 ) , a significant difference in improvement was observed between groups from baseline to week 12 ( p=0.039 ) . The effect size from baseline to endpoint was moderate to large for SAMe versus placebo ( d=0.74 ) . SAMe was superior to placebo from week 1 , and to escitalopram during weeks 2 , 4 , and 6 . No significant effect was found between escitalopram and placebo or SAMe  . Response rates ( HAMD-17≥50 % reduction ) at endpoint were 45 % , 31 % , and 26 % for SAMe , escitalopram , and placebo , respectively ; while remission rates ( HAM-D≤7 ) were 34 % for SAMe ( p=0.003 ) , 23 % for escitalopram ( p=0.023 ) , and 6 % for placebo . No correlation between baseline histamine level and reduction of HAMD-17 score was found for either the SAMe or escitalopram  groups . Baseline carnitine levels were also not found to moderate response to either treatment . LIMITATIONS While SAMe appears to be an effective antidepressant agent , the overall findings from the parent study ( which showed no significant difference between groups due to site differences ) must be taken into consideration . CONCLUSIONS These preliminary results provide encouraging evidence for the use of SAMe in the treatment of MDD . Histamine and carnitine serum level may not necessarily moderate response to SAMe 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 Cerebrospinal fluid ( CSF ) S-adenosylmethionine ( SAM ) levels were significantly lower in severely depressed patients than in a neurological control group . The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM , indicating that it crosses the blood-brain barrier in humans . These observations provide a rational basis for the antidepressant effect of SAM , which has been confirmed in several countries . CSF SAM levels were low in a group of patients with Alzheimer 's dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment Background This study reports on clinical data from an 8-week open-label study of 20 HIV-seropositive individuals , diagnosed with Major Depressive Disorder ( DSM-IV ) , who were treated with SAM-e ( S-Adenosylmethionine ) . SAM-e may be a treatment alternative for the management of depression in a population reluctant to add another " pill " or another set of related side effects to an already complex highly active antiretroviral therapy ( HAART ) regimen . Methods The Hamilton Rating Scale for Depression ( HAM-D ) and the Beck Depression Inventory ( BDI ) were used to assess depressive symptomatology from 1,2,4,6 and 8 weeks after initiation of treatment with SAM-e . Results Data show a significant acute reduction in depressive symptomatology , as measured by both the HAM-D and the BDI instruments . Conclusions SAM-e has a rapid effect evident as soon as week 1 ( p < .001 ) , with progressive decreases in depression symptom rating scores throughout the 8 week study We evaluated the predictive value of the thyrotropin ( TSH ) response to thyrotropin‐releasing hormone ( TRH ) in 32 depressed out patients completing a double‐blind placebo‐controlled trial of s‐adenosyl‐l‐methionine ( SAMe )  , which failed to show any significant difference between SAMe and placebo . Treatment response was defined as the change in Hamilton Rating Scale for Depression ( HRSD‐24 ) score between baseline and the end of the six‐week trial . Subjects with TSH response outside the normal range ( 7–25 uU/ml ) had a significantly greater response than patients with a normal response . There was also a significant correlation between absolute deviations from the mean TSH response ( 16 uU/ml ) and changes in HRSD‐24 scores 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 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 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 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Twenty subjects entered a double-blind placebo-controlled trial of  SAM in depression .  Prolactin concentrations were measured before and after 14 days ' treatment . There was a highly significant fall in prolactin concentrations in the SAM-treated group 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 The authors estimated components of variance and intraclass correlation coefficients ( ICCs ) to aid in the design of complex surveys and community intervention studies by analyzing data from the Health Survey for Engl and 1994 . This cross-sectional survey of English adults included data on a range of lifestyle risk factors and health outcomes . For the survey , households were sample d in 720 postal code sectors nested within 177 district health authorities and 14 regional health authorities . Study subjects were adults aged 16 years or more .  ICCs and components of variance were estimated from a nested r and om-effects analysis of variance . Results are presented at the district health authority , postal code sector , and household levels . Between-cluster variation was evident at each level of clustering . In these data , ICCs were inversely related to cluster size , but design effects could be substantial when the cluster size was large . Most ICCs were below 0.01 at the district health authority level , and they were mostly below 0.05 at the postal code sector level . At the household level , many ICCs were in the range of 0.0 - 0.3 . These data may provide useful information for the design of epidemiologic studies in which the units sample d or allocated range in size from households to large administrative areas The objectives of the present report were : a ) to determine the spontaneous remission rate in depressed out patients who do not receive antidepressant medication ; b ) to develop a novel method for obtaining a control group that can be used to gauge the effectiveness of antidepressant medication in clinical practice ; and c ) to compare response rates from the present sample with outcomes of depressed patients in our practice who were treated with antidepressant medications .  By using a naturalistic design , prospect i ve assessment s were made on all depressed out patients . Twenty-five patients who met full criteria for a major depressive episode ended up not taking antidepressant medication for a variety of reasons . " Response " rates to a no-treatment trial were determined with st and ard outcome criteria using the Clinical Global Impression-Improvement scale . Eight patients ( 32.0 % ) had a positive response , 5 patients ( 20.0 % ) had a partial response , and 12 patients ( 48.0 % ) were nonresponders to a no-treatment trial . These response rates were higher than expected , but significantly lower than what we had found in a cohort of depressed patients who underwent an antidepressant trial ( p = .02 ) . Likewise , treatment-resistant patients fared better on  pharmacotherapy  , though this difference was not statistically significant . These results suggest that the occurrence of spontaneous remissions may be common in clinical practice , and therefore the specific short-term benefits of antidepressant medication in clinical practice may frequently be overestimated . Despite the high rate of spontaneous remission in our sample , the present study allowed us to confirm the effectiveness of antidepressant medication in clinical practice using a novel method for obtaining a control comparison group 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 The results of a r and omized clinical trial can be reported using relative and /or absolute estimators of treatment effect . These various measures convey different information , and the choice can influence the physician 's appreciation of the size of treatment effect and , subsequently , treatment decisions . We compare the estimators with respect to the clinical ly relevant information conveyed to physicians , and identify which clinical questions can and can not be answered directly by each . We also identify opportunities for misinterpretation when one estimator is substituted for another , or when an estimator is mislabeled . Clinical ly important questions are addressed most directly by reporting both relative and absolute effects using relative risk and its complement , relative risk reduction , and risk difference and its reciprocal , number needed to treat . This is true of estimates of treatment effect derived from a single trial and also from meta- analysis of a group of trials . Because the control group 's risk affects the numerical value of the odds ratio , the odds ratio can not substitute for the risk ratio in conveying clinical ly important information to physicians . This is especially important when large treatment effects are shown in trials carried out in population s at high baseline risk 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 Introduction ‐ The relationship between plasma levels of S‐adenosylmethionine ( SAMe ) , an endogenous methyl donor , and clinical response were studied in patients with a DSM‐III‐R diagnosis of major depression . Material and methods ‐ A double‐blind r and omized protocol comparingoral SAMe with oral desipramine , involving a total of 26 patients , was employed . Results ‐At the end of the 4‐week trial , 62 % of the patients treated with SAMe and 50 % of the patients treated with desipramine had significantly improved . Regardless of the type of treatment , patients witha 50 % decrease in their Hamilton Depression Scale ( HAM‐D ) score showed a significant increase in plasma SAMe concentration . Conclusion ‐ The significant correlation between plasma SAMe levels and the degree of clinical improvement in depressed patients regardless of the type of treatment suggests that SAMe may play an important role in regulating mood 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 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 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 In making treatment decisions , doctors and patients must take into account relevant r and omised controlled trials ( RCTs ) and systematic review s. Relevance depends on external validity ( or generalisability)--ie , whether the results can be reasonably applied to a definable group of patients in a particular clinical setting in routine practice . There is concern among clinicians that external validity is often poor , particularly for some pharmaceutical industry trials , a perception that has led to underuse of treatments that are effective . Yet research ers , funding agencies , ethics committees , the pharmaceutical industry , medical journals , and governmental regulators alike all neglect external validity , leaving clinicians to make judgments . However , reporting of the determinants of external validity in trial publications and systematic review s is usually inadequate . This review discusses those determinants , presents a checklist for clinicians , and makes recommendations for greater consideration of external validity in the design and reporting of RCTs 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 Experimental work on the acute , chronic , and fetal toxicity of SAMe was carried out by Stramentinoli and his colleagues ( 19 ) . The intravenous LD50 in rats is more than 2000 mg/kg , or the equivalent of 140–150 g in a man of 70 kg . In man , on the other h and , clinical trials have revealed a definite action of the substance in the CNS with doses as little as 80/zg/kg ; the largest dose so far administered intravenously to humans is 0.5 g daily and has produced no visible 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 During open trials of intravenous and oral S-adenosyl methionine ( SAM ) and a placebo-controlled trial of intravenous SAM in 29 patients , 25 patients had SAM and four had placebo ( 27 courses of SAM , two of the patients receiving two trials a piece ) . Nine of 11 bipolar patients ( all SAM-treated ) switched into elevated mood state ( hypomania , mania and euphoria ) and two did not respond . Six endogenous unipolar patients improved and five did not . No non-endogenous patient or placebo patient responded for more than 14 days . No unipolar patient switched into elated mood . In eleven ( 38 % ) trials and nine ( 33 % ) patients there was a switch from depression to elation . Biochemical data from the cerebrospinal fluid of eight patients suggested that the role of the dopaminergic system should be further explored 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 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
target: 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: 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 .