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 S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: efficacy and effects of histamine and carnitine as moderators of response. 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 (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women. 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. Affective illness and S-adenosyl methionine: a preliminary report. Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial. Efficacy of S-adenosyl-L-methionine in speeding the onset of action of imipramine S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial. S-Adenosyl-L-Methionine Augmentation in Patients with Stage II Treatment-Resistant Major Depressive Disorder: An Open Label, Fixed Dose, Single-Blind Study 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 Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. Risperidone for Treatment-Refractory Major Depressive Disorder SAMe and sexual functioning. Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. Treatment-resistant depression in adolescents: is the addition of cognitive behavioral therapy of benefit? The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. Monoamine oxidase inhibitors revisited: what you should know. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Committee for Medicinal Products for Human Use (CHMP) assessment on efficacy of antidepressants
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 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 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 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 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 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 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 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 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 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 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 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 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 Context Does augmentation with an atypical antipsychotic improve symptoms in patients with major depression that is suboptimally responsive to antidepressant monotherapy ? Contribution This double-blind r and omized trial found that 6 weeks of treatment with risperidone improved symptoms more than placebo in 274 adults with major depression that was suboptimally responsive to antidepressant monotherapy . Risperidone , compared with placebo , result ed in more remissions ( 25 % vs. 11 % ) , as well as more cases of somnolence ( 5 % vs. 2 % ) and dry mouth ( 5 % vs. 1 % ) . Caution The trial duration was short , and 19 % of risperidone recipients did not complete treatment . Implication Risperidone augmentation may improve symptoms in some patients with suboptimal response to antidepressant monotherapy . The Editors Major depressive disorder is the leading cause of disability worldwide ( 1 ) , affecting nearly 121 million people . It is associated with increased overall mortality ( 2 , 3 ) ; premature cardiovascular-related death ( 4 , 5 ) ; and morbidity , including disability , lost productivity , and decreased wages , compared with individuals without depression ( 6 ) . Selective serotonin reuptake inhibitors ( SSRIs ) and serotoninnorepinephrine reuptake inhibitors are generally considered first-line treatments for depression . Despite a sufficient dose and duration of antidepressant treatment , symptoms do not resolve in 30 % to 40 % of patients with major depressive disorder ( 710 ) . Remission , defined as the virtual absence of depressive symptoms , is important because it is associated with improved patient prognosis and functioning relative to response ( generally defined as 50 % reduction in symptoms ) ( 11 , 12 ) . In an effort to improve the therapeutic efficacy of antidepressant monotherapy , several pharmacologic strategies to modulate different or additional neurotransmitters ( 1315 ) are commonly used , despite a paucity of evidence from r and omized clinical trials . These strategies include switching monotherapy within ( 10 , 1618 ) or between antidepressant classes ( 10 , 1921 ) , combination regimens consisting of 2 antidepressants ( 2226 ) , and augmentation of antidepressants with nonst and ard treatmentsfor example , thyroid hormone ( 27 ) ; S-adenosyl-l-methionine ( 28 ) ; lithium ( 29 ) ; cyclooxygenase-2 inhibitors ( 30 ) ; or an atypical antipsychotic ( 3133 ) , such as risperidone . Findings of several open-label studies ( 3135 ) suggest that atypical antipsychotic augmentation provides benefit in major depressive disorder that is suboptimally responsive to antidepressant monotherapy . Risperidone , whose activity includes blockade of certain serotonin and dopamine receptors , is considered an atypical antipsychotic . It is approved in the United States for treatment of bipolar mania and schizophrenia and in other countries for additional uses . The efficacy of risperidone has also been studied for various psychoses and behavioral disorders , including treatment-resistant depression and anxiety spectrum disorders ( 34 , 3639 ) . We hypothesized that low-dose risperidone augmentation would reduce symptoms of major depressive disorder , enhance clinical response and remission rates , and reduce disability and improve quality of life compared with continued antidepressant monotherapy . Preliminary data suggest that persons with a confirmed suboptimal response to previous treatment may respond to risperidone augmentation within 4 to 6 weeks ( 38 ) . We therefore conducted a large , multicenter , double-blind , placebo-controlled trial to assess the clinical efficacy of risperidone augmentation from the clinician and patient perspectives and to evaluate tolerability in patients with major depressive disorder who continue to experience symptoms despite an adequate trial of st and ard antidepressants . Methods Design Consenting persons entered a 4-week prospect i ve open-label run-in period during which they received their current antidepressant monotherapy at the dosages recommended in product labeling , so that we could confirm an insufficient response to st and ard monotherapy . The run-in period was followed by a 6-week double-blind treatment phase ; during this phase , patients who continued to experience depressive symptoms , defined as a Clinical Global ImpressionSeverity of illness ( CGI-S ) score of 4 or greater and a Carroll Depression Scale ( 40 ) score of 20 or greater , were r and omly assigned to receive risperidone augmentation therapy or placebo . A 4-week follow-up phase of open-label risperidone augmentation therapy was available to participants who completed at least 4 weeks of double-blind treatment ( results not shown ) . Setting and Participants Out patients 18 to 65 years of age who had received antidepressant monotherapy for at least 4 weeks and met the Diagnostic and Statistical Manual of Mental Disorders , fourth edition ( 41 ) , criteria for unremitting major depressive disorder ( single or recurrent episodes ) and a CGI-S score of 4 or more ( 42 ) at the start of both the open-label and double-blind phases were eligible . The CGI-S is scored on a scale of increasing intensity from 1 to 7 , with 4 representing moderate illness . We recruited participants by using various methods , including media advertisements , and enrolled persons from 75 public and private primary care ( n= 41 ) and psychiatric ( n= 34 ) centers in the United States between 19 October 2004 and 17 November 2005 . Ethical approval was obtained from the institutional review board of each site , and written informed consent was obtained from all patients . Exclusion criteria were pregnancy ; serious suicidal risk or serious medical or neurologic illness ; active substance or alcohol use disorders ; or current treatment with a tricyclic antidepressant , monoamine oxidase inhibitor , mood stabilizer , antiepileptic , or a central ly acting agent for attention deficit disorder/attention deficit hyperactivity disorder or narcolepsy . R and omization and Interventions Patients who were eligible for r and omization continued their st and ard antidepressant regimen and dosage and were assigned to receive risperidone or placebo . Tablets were identical in appearance . The investigators , study staff , and patients were blinded to the treatment assignment . The r and omization code was central ly generated and administered by a telephone interactive voice response system , was stratified by antidepressant class ( SSRI or non-SSRI ) and center , and occurred in r and om permuted blocks . An independent statistician provided the r and omization codes . The dosing schedule was 0.25 mg for the first 3 days , 0.5 mg on days 4 to 15 , and 1.0 mg on days 16 to 28 . On day 29 , patients with insufficient treatment response in the opinion of the investigator could continue augmentation at the current dosage , have the dosage increased to 2 mg/d , or discontinue double-blind treatment . Concomitant medications were allowed as necessary for medical conditions . Sedative agents ( zolpidem , 2.5 to 10 mg/d , or zaleplon , 5 to 20 mg/d , as needed ) were allowed for insomnia . During double-blind treatment , benztropine mesylate was permitted as needed for potential treatment-emergent motor effects . Measurements and Outcomes At each visit ( end of the open-label phase and weeks 1 , 2 , 4 , and 6 ) , trained personnel administered the grid version of the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) ( 43 , 44 ) and the CGI-S ( 42 ) , both clinician-rated instruments . Scores on the HRSD-17 range from 0 to 52 ; higher scores indicate more severe depression . Patients also independently rated their response by using the telephone interactive voice response system at baseline and weekly thereafter . Other patient-reported outcomes were scores on 3 vali date d instruments : the Quality of Life Enjoyment and Satisfaction Question naire ( Q-LES-Q ) ( 45 ) , the Patient Global Improvement Scale ( 7-point rating from 1 [ very much improved ] to 7 [ very much worse ] ) , and the Sheehan Disability Scale ( SDS ) . Change in HRSD-17 total score from baseline to study end was the a priori primary efficacy measure . Response ( 50 % reduction in HRSD-17 total score from baseline ) and remission ( HRSD-17 total score 7 ) were assessed at each time point . Secondary measures were changes in the CGI-S , Q-LES-Q , SDS , and Patient Global Improvement Scale scores . Follow-up Patients underwent physical examination , including assessment of vital signs , at regular intervals . Research staff maintained records of trial medication and assessed treatment compliance by matching doses taken with the number of treatment days . To assess adverse effects , patients were interviewed at each study visit with open-ended questions about potential adverse events ; spontaneous reports were also taken into account . All adverse events were recorded , and the investigator assessed each event for severity and relationship to the study drug ( probable , possible , not related ) . Statistical Analysis A sample of 116 patients per group was anticipated to have 90 % power to detect an arbitrary difference in change in mean HRSD-17 total score of 3.0 units , assuming a common SD of 7.0 using a 2-group t test and a 2-sided significance level of 0.05 . We also assumed that approximately 30 % of the participants would not complete double-blind treatment and planned for 332 persons to undergo r and omization . We further assumed that during the open-label run-in phase , 30 % of participants would discontinue the study and 20 % would respond to st and ard antidepressant treatment and therefore be ineligible for r and omization ; thus , we sought 592 persons for the open-label run-in phase . All analyses were performed by using SAS , version 8.2 ( SAS Institute , Cary , North Carolina ) , and statistical analysis personnel were blinded to patient group assignment . Baseline patient characteristics were summarized by using descriptive statistics . Efficacy and safety analyses were based on the intention-to-treat population ( that is , all persons who underwent r and omization and received at least 1 dose of medication in the double-blind phase ) . BACKGROUND Sexual dysfunction is a known side effect of antidepressant treatment ( ADT ) , affecting up to 58 - 73 % of those who receive ADT , potentially affecting antidepressant adherence . Consequently , it is vital to develop novel treatments that target antidepressant-induced sexual dysfunction . METHODS We examined whether adjunctive S-adenosyl-l-methionine ( SAMe ) is associated with greater improvement in sexual functioning than adjunctive placebo by measuring changes in sexual functioning using the Massachusetts General Hospital-Sexual Functioning Question naire ( MGH-SFQ ) during a 6-week , single-center , r and omized , double-blind trial of SAMe augmentation for SSRI/SNRI- nonresponders . RESULTS Controlling for the degree of arousal dysfunction at baseline as well as the degree of change in HDRS-17 scale scores during the course of the study , men treated with adjunctive SAMe  demonstrated significantly lower arousal dysfunction at endpoint than those treated with adjunctive placebo . In addition , controlling for the degree of erectile dysfunction at baseline as well as the degree of change in HDRS-17 scale scores , men treated with adjunctive SAMe demonstrated significantly lower erectile dysfunction at endpoint than those treated with adjunctive placebo . CONCLUSIONS In the present study , we have observed that adjunctive SAMe can have positive benefit on male arousal and erectile dysfunction , independent of improvement in depressive symptoms . These findings are preliminary , and warrant replication . CLINICAL TRIALS.GOV IDENTIFIER : NCT00093847 ; titled ' Optimizing the Effectiveness of Selective Serotonin Reuptake Inhibitors ( SSRIs ) in Treatment-Resistant Depression ' , accessible at : http:// clinical trials.gov/ct2/show/NCT00093847 IMPORTANCE High placebo responses have been observed across a wide range of pathologies , severely impacting drug development . OBJECTIVE To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder ( MDD ) . DESIGN , SETTING , AND PARTICIPANTS In this study involving 2 placebo lead-in phases followed by an open antidepressant administration , we performed a single-blinded 2-week crossover r and omized clinical trial of 2 identical oral placebos ( described as having either active or inactive fast-acting antidepressant-like effects ) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or , in some cases , another agent as clinical ly indicated . The volunteers ( 35 medication-free patients with MDD at a university health system ) were studied with positron emission tomography and the µ-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment . In addition , 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment , with instructions that the compound may be associated with the activation of brain systems involved in mood improvement . This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect . MAIN OUTCOMES AND MEASURES Changes in depressive symptoms in response to active placebo  and antidepressant . Baseline and activation measures of µ-opioid receptor binding . RESULTS Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment ( r = 0.48 ; P = .02 ) . Reductions in depressive symptoms after 1 week of active placebo treatment , compared with the inactive , were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion , stress regulation , and the pathophysiology of MDD , namely , the subgenual anterior cingulate cortex , nucleus accumbens , midline thalamus , and amygdala ( nucleus accumbens : r = 0.6 ; P < .001 ) . Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response , predicting 43 % of the variance in symptom improvement at the end of the antidepressant trial . CONCLUSIONS AND RELEVANCE These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses , conferring illness resiliency , during open administration . TRIAL REGISTRATION clinical trials.gov Identifier : NCT02178696 OBJECTIVE This study compared the efficacy and safety of paroxetine and imipramine with that of placebo in the treatment of bipolar depression in adult out patients stabilized on a regimen of lithium . METHOD In a double-blind , placebo-controlled study , 117 out patients with DSM-III-R bipolar disorder , depressive phase , were r and omly assigned to treatment with paroxetine ( N=35 ) , imipramine ( N=39 ) , or placebo ( N=43 ) for 10 weeks . In addition to lithium monotherapy , patients may have received either carbamazepine or valproate in combination with lithium for control of manic symptoms . Patients were stratified on the basis of trough serum lithium levels determined at the screening visit ( high : > 0.8 meq/liter ; low : < /=0.8 meq/liter ) . Primary efficacy was assessed by change from baseline in scores on the Hamilton Rating Scale for Depression and the Clinical Global Impression illness severity scale . RESULTS Differences in overall efficacy among the three groups were not statistically significant . For patients with high serum lithium levels  , antidepressant response at endpoint also did not significantly differ from placebo . However , both paroxetine and imipramine were superior to placebo for patients with low serum lithium levels . Compared to imipramine , paroxetine result ed in a lower incidence of adverse events , most notably emergence of manic symptoms . CONCLUSIONS Antidepressants may not be useful adjunctive therapy for bipolar depressed patients with high serum lithium levels . However , antidepressant therapy may be beneficial for patients who can not tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium 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 Background Many young people with major depression fail first-line treatments . Treatment-resistant depression has various definitions in the literature but typically assumes nonresponse to medication . In young people , cognitive behavioral therapy ( CBT ) is the recommended first-line intervention , thus the definition of treatment resistance should be exp and ed . Therefore , our aim was to synthesize the existing evidence of any interventions for treatment-resistant depression , broadly defined , in children and adolescents and to investigate the effectiveness of CBT in this context . Methods We used Cochrane Collaboration methodology , with electronic search es of Medline , PsycINFO , Embase , and the Cochrane Depression Anxiety and Neurosis Group trials registers . Only r and omized controlled trials were included , and were assessed for risk of bias . Meta- analysis was undertaken where possible and appropriate . Results Of 953 articles retrieved , four trials were eligible for inclusion . For one study , only the trial registration document was available , because the study was never completed . All other studies were well conducted with a low risk of bias , although one study had a high dropout rate . Two studies assessed the effect of adding CBT to medication . While an assertive trial of antidepressants does appear to lead to benefit , when compared with placebo , there was no significant advantage , in either study , or in a meta- analysis of data from these trials , that clearly demonstrated an additional benefit of CBT . The third trial showed little advantage of a tricyclic antidepressant over placebo in the context of an inpatient admission . Conclusion Few r and omized controlled trials have investigated interventions for treatment-resistant depression in young people , and results from these show modest benefit from antidepressants with no additional benefit over medication from CBT . Overall , there is a lack of evidence about effective interventions to treat young people who have failed to respond to evidence -based interventions for depression . Research in this area is urgently required BACKGROUND Many questions remain regarding the use of atypical neuroleptics as antidepressant augmentation agents . To date , there have been no reports in the literature regarding the effectiveness of these drugs when trials of one or more of them have failed previously as antidepressant augmentation . METHOD This retrospective chart review was conducted to determine the effectiveness of olanzapine , risperidone , quetiapine , and ziprasidone when given in a fee-for-service setting as anti-depressant augmentation agents to patients with treatment-resistant , nonpsychotic major depressive disorder ( DSM-IV ) . Prospect i ve ( Global Assessment of Functioning [ GAF ] ) along with retrospective ( Clinical Global Impressions-Improvement [ CGI-I ] and -Severity of Illness scales ) ratings were completed for each patient . Analyses were conducted in an attempt to identify factors that appeared to correlate with response , including order of administration and Thase-Rush staging of treatment resistance . RESULTS In this study of 76 medication trials in 49 patients , the overall response rate based on the CGI-I ratings was 65 % ( 32/49 ) . Individual rates of response were 57 % ( 21/37 ) for olanzapine , 50 % ( 7/14 ) for risperidone , 33 % ( 6/18 ) for quetiapine , and 10 % ( 1/10 ) for ziprasidone . None of the differences between neuroleptics in rates of response were significant . The difference between baseline and final GAF scores was statistically significant only in the olanzapine ( p < .001 ) and risperidone ( p = .047 ) groups . Rates of discontinuation did not vary significantly between agents , though trends were present . Crossover trials from one atypical neuroleptic to another in the event of nonresponse appeared to be effective . CONCLUSIONS Although limited by its design , this study suggests atypical neuroleptic augmentation of antidepressants may be a viable option in treatment-resistant major depressive disorder Efficacy Although clinicians often view MAOIs as more difficult to prescribe than agents in other classes , there is little doubt about their efficacy . In bipolar depression , for example ( where impactful treatments are few and far between ) , response rates with tranylcypromine have been reported to exceed 80 % , and this agent may be more efficacious than TCAs such as imipramine , particularly in patients with anergic , motor-retarded features.4 MAOIs also may yield better antidepressant efficacy than TCAs in chronic depression and dysthymia.5 In refractory major depression , response rates of at least 40%–50 % have been reported for both tranylcypromine and phenelzine , with comparable head-to-head efficacy.6 It was therefore surprising that , in the Sequenced Treatment Alternatives to Relieve Depression ( STAR*D ) trials , patients r and omly assigned to tranylcypromine ( a fourth-level intervention following nonresponse to an SSRI and 2 other interventions ) obtained a meager 6.9 % remission rate.7 However , low mean dosing of tranylcypromine in that study ( < 40 mg/d ) quite likely underestimated optimal MAOI benefits for advanced forms of treatment-resistant depression . Studies from the 1970s and 1980s made MAOIs virtually synonymous with treatment for atypical depression , with reports of superiority to TCAs ( review ed by Henkel et al8 ) . MAOIs are also often thought of for anxious depression on the basis of an older literature comparing phenelzine with tricyclics such as amitriptyline.9,10 Much of this literature focused on pre – DSM-III constructs such as “ neurotic ” or “ reactive ” depressions that may also relate to atypical depression . Excitement surrounding such apparent differential therapeutics was largely dissipated by the rapid ascension of SSRIs , which essentially replaced TCAs as the antidepressants of first choice by the early 1990s . Whereas MAOIs were clearly superior to TCAs , there was little reason to view them as superior to SSRIs , which were substantially safer OBJECTIVE Studies have reported that countries with high rates of fish oil consumption have low rates of depressive disorder . The authors studied a specific omega-3 fatty acid , the ethyl ester of eicosapentaenoic acid ( E-EPA ) , as an adjunct to treatment for depressive episodes occurring in patients with recurrent unipolar depressive disorder who were receiving maintenance antidepressant therapy . METHOD Twenty patients with a current diagnosis of major depressive disorder participated in a 4-week , parallel-group , double-blind addition of either placebo or E-EPA to ongoing antidepressant therapy .  Seventeen of the patients were women , and three were men . RESULTS Highly significant benefits of the addition of the omega-3 fatty acid compared with placebo were found by week 3 of treatment . CONCLUSIONS It is not possible to distinguish whether E-EPA augments antidepressant action in the manner of lithium or has independent antidepressant properties of its own BACKGROUND Recent publications have raised questions over the efficacy and clinical ly relevant effects of antidepressants that have been approved for the treatment of major depression . In this context , the European Commission requested that the European Medicines Agency ( EMEA ) and its scientific committee ( CHMP ) issue an opinion on these data under Article 5(3 ) of Regulation ( EC ) No 726/2004 . FINDINGS Results from a recent meta- analysis [ Kirsch , I. , Deacon , B.J. et al. , ( 2008 ) Initial severity and antidepressant benefits : a meta- analysis of data su bmi tted to the Food and Drug Administration . PLoS Med . 5(2 ) , e45 . ] have question ed the clinical relevance of the use of some antidepressants in treating major depression . This analysis focused only on statistically significant mean differences versus placebo in changes in a rating scale ( such as the Hamilton Depression Rating Scale ) . This , however , would not be an adequate basis for the evaluation of clinical relevance and , from a regulatory perspective , would not be sufficient to grant an antidepressant the approval needed to allow it onto the market . Improvements that are both statistically significant ( based on improvements in vali date d rating scales between baseline and study end ) and clinical ly relevant ( based on responder rates ) need to be shown in short-term studies . In addition , these short-term results need to be confirmed in a r and omised withdrawal study to demonstrate the maintenance of an antidepressant 's effects . CONCLUSIONS The CHMP concluded that the approval of antidepressants for the treatment of patients with major depression is based on data that provide robust and sufficient evidence of clinical ly meaningful benefits for patients with major depression . Therefore , the CHMP is of the opinion that , as no public health concerns have been identified , no regulatory action is necessary on the basis of Kirsch et al. 's findings
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 .