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Meta-Analysis
. 2016 Oct 10;10(10):CD011286.
doi: 10.1002/14651858.CD011286.pub2.

S-adenosyl methionine (SAMe) for depression in adults

Ilaria Galizia  1 , Lucio Oldani, Karine Macritchie, Erica Amari, Dominic Dougall, Tessa N Jones, Raymond W Lam, Guido Jacopo Massei, Lakshmi N Yatham, Allan H Young
Affiliations
Meta-Analysis

S-adenosyl methionine (SAMe) for depression in adults

Ilaria Galizia et al. Cochrane Database Syst Rev. .

Abstract

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.

Search methods: We searched the Cochrane Common Mental Disorders Group's Specialised Register (CCMDCTR Studies and Reference Register), MEDLINE, EMBASE, PsycINFO, international trial registers ClinicalTrials.gov and the World Health Organization trials portal (ICTRP). We checked reference lists, performed handsearching and contacted experts in the field. The CCMDCTR literature search was last updated on 5 February 2016.

Selection criteria: Randomised controlled trials comparing SAMe with placebo or antidepressants in adults with a diagnosis of major depression.

Data collection and analysis: Two authors independently performed extraction of data and assessment of risk of bias. We contacted trialists of included studies for additional information.

Main results: This systematic review included eight trials comparing SAMe with either placebo, imipramine, desipramine or escitalopram. We accepted trials that used SAMe as monotherapy or as add-on therapy to selective serotonin reuptake inhibitors (SSRIs), and we accepted both oral and parenteral administration. The review involved 934 adults, of both sexes, from inpatient and outpatient settings.The trials were at low risk of reporting bias. We judged the risk of selection, performance, detection and attrition bias as unclear or low, and one study was at high risk of attrition bias.There was no strong evidence of a difference in terms of change in depressive symptoms from baseline to end of treatment between SAMe and placebo as monotherapy (standardised mean difference (SMD) -0.54, 95% confidence interval (CI) -1.54 to 0.46; P = 0.29; 142 participants; 2 studies; very low quality evidence). There was also no strong evidence of a difference in terms of drop-out rates due to any reason between SAMe and placebo, when used as monotherapy (risk ratio (RR) 0.88, 95% CI 0.61 to 1.29; P = 0.52; 142 participants; 2 studies; low quality evidence).Low quality evidence showed that the change in depressive symptoms from baseline to end of treatment was similar between SAMe and imipramine, both as monotherapy (SMD -0.04, 95% CI -0.34 to 0.27; P = 0.82; 619 participants; 4 studies). There was also no strong evidence of a difference between SAMe and a tricyclic antidepressant in terms of drop-outs due to any reason (RR 0.61, 95% CI 0.28 to 1.31; P = 0.2; 78 participants; 3 studies; very low quality evidence).There was little evidence of a difference in terms of change in depressive symptoms from baseline to end of treatment between SAMe and escitalopram, both as monotherapy (MD 0.12, 95% CI -2.75 to 2.99; P = 0.93; 129 participants; 1 study; low quality evidence). There was no strong evidence of a difference between SAMe and escitalopram in terms of drop-outs due to any reason (RR 0.81, 95% CI 0.57 to 1.16; P = 0.26; 129 participants; 1 study; low quality evidence).There was low quality evidence that SAMe is superior to placebo as add-on to SSRIs in terms of change in depressive symptoms from baseline to end of treatment (MD -3.90, 95% CI -6.93 to -0.87; P = 0.01; 73 participants; 1 study). There was no strong evidence of a difference between SAMe and placebo as adjunctive therapy to an SSRI in terms of drop-outs due to any reason (RR 0.70, 95% CI 0.31 to 1.56; P = 0.38; 73 participants; 1 study; very low quality evidence).For all comparisons, secondary outcome measures of response and remission rates were consistent with these primary outcome measures.With regard to all extractable measures of the acceptability of SAMe, the quality of the evidence was low to very low. 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.The specific adverse effects were not detailed in most of the included studies. There were two reports of mania/hypomania recorded for 441 participants in the SAMe arm.

Authors' conclusions: Given the absence of high quality evidence and the inability to draw firm conclusions based on that evidence, the use of SAMe for the treatment of depression in adults should be investigated further. Future trials should be in the form of large randomised controlled clinical trials of high methodological quality, with particular attention given to randomisation, allocation concealment, blinding and the handling of missing data. Comparator antidepressants from all classes should be used. Adverse events should be detailed for each participant, bearing in mind that induction of mania is of particular interest.

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Conflict of interest statement

Dr Karine Macritchie has no conflicts of interest relevant to this review, but has attended educational symposia and conferences sponsored by several pharmaceutical companies. She has received a non‐promotional educational grant from Sanofi‐Synthélabo to support research. She has been employed at the University of Edinburgh on an award from the Translational Medicine Research Collaboration ‐ a consortium made up by the Universities of Aberdeen, Dundee, Edinburgh and Glasgow, the four associated National Health Service (NHS) Health Boards, Scottish Enterprise and Pfizer (formerly Wyeth).

Dr Ilaria Galizia, Dr Lucio Oldani, Ms Erica Amari, Dr Jacopo Massei, Dr Dominic Dougall and Dr Tessa Jones have no conflicts of interest to declare.

Dr Lam has been a speaker for, sat on advisory boards for, or has received research funds from: Advanced Neuromodulation Systems Inc, AstraZeneca, BrainCells Inc, Biovail, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Research Foundation, Eli Lilly, Janssen, Litebook Company Ltd, Lundbeck, Lundbeck Institute, Mathematics of Information Technology and Advanced Computing Systems, Michael Smith Foundation for Health Research, Servier, Takeda, UBC Institute of Mental Health/Coast Capital Savings and Wyeth.

Dr Lakshmi Yatham has received grants from and has been a speaker or member of advisory boards for AstraZeneca, Lilly, Janssen, Bristol Myers Squibb, Pfizer, Novartis, GlaxoSmithKline (GSK), Sanofi, Servier and Scherring Plough.

Professor Allan Young has no conflicts of interest relevant to this review, but he has received honoraria for lectures from Eli Lilly, AstraZeneca, Sanofi, GSK, Sanofi‐Aventis, Pfizer, Janssen, Servier, BMS, Biovail and Wyeth. He has been a member of advisory boards for Eli Lilly, AstraZeneca, Sanofi, GSK, Sanofi‐Aventis, Pfizer, Janssen, Servier, BMS and Wyeth. He has received research support from SMRI, MRC (UK), CIHR, NIH, Wellcome Trust (UK) and the following foundations: the University of British Columbia‐Vancouver General Hospital Foundations, BC Credit Unions, CoastCapital Savings and the Kelty Patrick Dennehy Foundation.

Figures

1
1
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 S‐adenosyl methionine versus placebo as monotherapy, Outcome 1 Efficacy. Change in mean scores from baseline to end of treatment on the depression rating scale (negative value = improvement).
1.2
1.2. Analysis
Comparison 1 S‐adenosyl methionine versus placebo as monotherapy, Outcome 2 Acceptability. Participants dropping out of treatment during study period for any reason.
1.3
1.3. Analysis
Comparison 1 S‐adenosyl methionine versus placebo as monotherapy, Outcome 3 Acceptability. Participants dropping out of treatment during study period because of adverse effects.
1.4
1.4. Analysis
Comparison 1 S‐adenosyl methionine versus placebo as monotherapy, Outcome 4 Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
1.5
1.5. Analysis
Comparison 1 S‐adenosyl methionine versus placebo as monotherapy, Outcome 5 Efficacy. Remission, defined as a depression rating scale score within normal range at end of study.
1.6
1.6. Analysis
Comparison 1 S‐adenosyl methionine versus placebo as monotherapy, Outcome 6 Acceptability. Participants experiencing specific adverse effects: mania or hypomania.
1.7
1.7. Analysis
Comparison 1 S‐adenosyl methionine versus placebo as monotherapy, Outcome 7 Acceptability. Participants experiencing specific adverse effects: headache.
1.8
1.8. Analysis
Comparison 1 S‐adenosyl methionine versus placebo as monotherapy, Outcome 8 Acceptability. Participants experiencing specific adverse effects: flatulence.
1.9
1.9. Analysis
Comparison 1 S‐adenosyl methionine versus placebo as monotherapy, Outcome 9 Acceptability. Participants dropping out for any reasons other than adverse effects.
2.1
2.1. Analysis
Comparison 2 S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 1 Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
2.2
2.2. Analysis
Comparison 2 S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 2 Acceptability. Participants dropping out of treatment during study period for any reason.
2.3
2.3. Analysis
Comparison 2 S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 3 Acceptability. Participants dropping out of treatment during study period because of adverse effects.
2.4
2.4. Analysis
Comparison 2 S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 4 Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
2.5
2.5. Analysis
Comparison 2 S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 5 Acceptability. Participants experiencing troublesome adverse effects of any nature.
2.6
2.6. Analysis
Comparison 2 S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 6 Acceptability. Participants experiencing specific adverse effects: mania or hypomania.
2.7
2.7. Analysis
Comparison 2 S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 7 Acceptability. Participants dropping out for any reasons other than adverse effects.
3.1
3.1. Analysis
Comparison 3 S‐adenosyl methionine versus SSRI antidepressant agent as monotherapy, Outcome 1 Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
3.2
3.2. Analysis
Comparison 3 S‐adenosyl methionine versus SSRI antidepressant agent as monotherapy, Outcome 2 Acceptability. Participants dropping out of treatment during study period for any reason.
3.3
3.3. Analysis
Comparison 3 S‐adenosyl methionine versus SSRI antidepressant agent as monotherapy, Outcome 3 Acceptability. Participants dropping out of treatment during study period because of adverse effects.
3.4
3.4. Analysis
Comparison 3 S‐adenosyl methionine versus SSRI antidepressant agent as monotherapy, Outcome 4 Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
3.5
3.5. Analysis
Comparison 3 S‐adenosyl methionine versus SSRI antidepressant agent as monotherapy, Outcome 5 Efficacy. Remission, defined as a depression rating scale score within normal range at end of study.
3.6
3.6. Analysis
Comparison 3 S‐adenosyl methionine versus SSRI antidepressant agent as monotherapy, Outcome 6 Acceptability. Participants dropping out for any reasons other than adverse effects.
4.1
4.1. Analysis
Comparison 4 S‐adenosyl methionine versus placebo as adjunctive treatment to SSRI, Outcome 1 Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
4.2
4.2. Analysis
Comparison 4 S‐adenosyl methionine versus placebo as adjunctive treatment to SSRI, Outcome 2 Acceptability. Participants dropping out of treatment during study period for any reason.
4.3
4.3. Analysis
Comparison 4 S‐adenosyl methionine versus placebo as adjunctive treatment to SSRI, Outcome 3 Acceptability. Participants dropping out of treatment during study period because of adverse effects.
4.4
4.4. Analysis
Comparison 4 S‐adenosyl methionine versus placebo as adjunctive treatment to SSRI, Outcome 4 Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
4.5
4.5. Analysis
Comparison 4 S‐adenosyl methionine versus placebo as adjunctive treatment to SSRI, Outcome 5 Efficacy. Remission, defined as a depression rating scale score within normal range at end of study.
4.6
4.6. Analysis
Comparison 4 S‐adenosyl methionine versus placebo as adjunctive treatment to SSRI, Outcome 6 Acceptability. Participants experiencing specific adverse effects: headache.
4.7
4.7. Analysis
Comparison 4 S‐adenosyl methionine versus placebo as adjunctive treatment to SSRI, Outcome 7 Acceptability. Participants experiencing specific adverse effects: diarrhoea.
4.8
4.8. Analysis
Comparison 4 S‐adenosyl methionine versus placebo as adjunctive treatment to SSRI, Outcome 8 Acceptability. Participants dropping out for any reasons other than adverse effects.
5.1
5.1. Analysis
Comparison 5 Sensitivity analyses. S‐adenosyl methionine versus placebo as monotherapy, Outcome 1 Sensitivity analysis for imputation of continuous efficacy data (assumption: missing participants had same mean change as other participants). Efficacy. Change in mean scores from baseline to end of treatment on the depression rating scale (negative value = improvement).
5.2
5.2. Analysis
Comparison 5 Sensitivity analyses. S‐adenosyl methionine versus placebo as monotherapy, Outcome 2 Sensitivity analysis for imputation of dichotomous data (assumption: 'best‐case' scenario). Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
5.3
5.3. Analysis
Comparison 5 Sensitivity analyses. S‐adenosyl methionine versus placebo as monotherapy, Outcome 3 Sensitivity analysis for the imputation of SD (using correlation coefficient of 0.4). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
5.4
5.4. Analysis
Comparison 5 Sensitivity analyses. S‐adenosyl methionine versus placebo as monotherapy, Outcome 4 Sensitivity analysis (excluding studies with high levels of missing data). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
5.5
5.5. Analysis
Comparison 5 Sensitivity analyses. S‐adenosyl methionine versus placebo as monotherapy, Outcome 5 Sensitivity analysis (excluding studies with high levels of missing data). Acceptability. Participants dropping out of treatment during study period for any reason.
5.6
5.6. Analysis
Comparison 5 Sensitivity analyses. S‐adenosyl methionine versus placebo as monotherapy, Outcome 6 Sensitivity analysis (excluding studies with high levels of missing data). Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
5.7
5.7. Analysis
Comparison 5 Sensitivity analyses. S‐adenosyl methionine versus placebo as monotherapy, Outcome 7 Sensitivity analysis (excluding studies with high levels of missing data). Acceptability. Participants dropping out for any reasons other than adverse effects.
6.1
6.1. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 1 Subgroup analysis (oral administration of SAMe). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
6.2
6.2. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 2 Subgroup analysis (parenteral administration of SAMe). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
6.3
6.3. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 3 Subgroup analysis (oral administration of SAMe). Acceptability. Participants dropping out of treatment during study period for any reason.
6.4
6.4. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 4 Subgroup analysis (parenteral administration of SAMe). Acceptability. Participants dropping out of treatment during study period for any reason.
6.5
6.5. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 5 Subgroup analysis (oral administration of SAMe). Acceptability. Participants dropping out of treatment during study period because of adverse effects.
6.6
6.6. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 6 Subgroup analysis (parenteral administration of SAMe). Acceptability. Participants dropping out of treatment during study period because of adverse effects.
6.7
6.7. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 7 Subgroup analysis (oral administration of SAMe). Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
6.8
6.8. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 8 Subgroup analysis (parenteral administration of SAMe). Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
6.9
6.9. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 9 Subgroup analysis (parenteral administration of SAMe). Acceptability. Participants experiencing troublesome adverse effects of any nature.
6.10
6.10. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 10 Subgroup analysis (oral administration of SAMe). Acceptability. Participants experiencing troublesome adverse effects of any nature.
6.11
6.11. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 11 Subgroup analysis (oral administration of SAMe). Acceptability. Participants dropping out for any reasons other than adverse effects.
6.12
6.12. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 12 Subgroup analysis (parenteral administration of SAMe). Acceptability. Participants dropping out for any reasons other than adverse effects.
6.13
6.13. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 13 Sensitivity analysis for imputation of continuous efficacy data (assumption: missing participants had same mean change as other participants). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
6.14
6.14. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 14 Sensitivity analysis for imputation of dichotomous data (assumption: 'best‐case' scenario). Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
6.15
6.15. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 15 Sensitivity analysis for imputation of SD (using correlation coefficient of 0.4). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
6.16
6.16. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 16 Sensitivity analysis (excluding studies with high levels of missing data). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
6.17
6.17. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 17 Sensitivity analysis (excluding studies with high levels of missing data). Acceptability. Participants dropping out of treatment during study period for any reason.
6.18
6.18. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 18 Sensitivity analysis (excluding studies with high levels of missing data). Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
6.19
6.19. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 19 Sensitivity analysis (excluding studies with high levels of missing data). Acceptability. Participants experiencing troublesome adverse effects of any nature.
6.20
6.20. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 20 Sensitivity analysis (excluding De Vanna 1992). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
6.21
6.21. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 21 Sensitivity analysis (excluding Bell 1994, as at high risk of bias). Acceptability. Participants dropping out of treatment during study period for any reason.
6.22
6.22. Analysis
Comparison 6 Sensitivity and subgroup analyses. S‐adenosyl methionine versus tricyclic antidepressant agent as monotherapy, Outcome 22 Sensitivity analysis (excluding Bell 1994, as at high risk of bias). Efficacy. Response to treatment, defined as a ≥ 50% reduction in depression score from baseline to end of treatment.
7.1
7.1. Analysis
Comparison 7 Sensitivity analysis. S‐adenosyl methionine versus SSRI antidepressant agent as monotherapy, Outcome 1 Sensitivity analysis for imputation of SD (using correlation coefficient of 0.4). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
8.1
8.1. Analysis
Comparison 8 Sensitivity analysis. S‐adenosyl methionine versus placebo as adjunctive treatment, Outcome 1 Sensitivity analysis for imputation of SD (using correlation coefficient of 0.4). Efficacy. Change in mean scores from baseline to end of treatment on depression rating scale (negative value = improvement).
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Update of

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References

References to studies included in this review

Bell 1988 {published data only}
    1. Bell KM, Plon L, Bunney WE Jr, Potkin SG. S‐adenosylmethionine treatment of depression: a controlled clinical trial. American Journal of Psychiatry 1988;145(9):1110‐14. - PubMed
    1. Potkin SG, Bell K, Plon L, Bunney WE Jr. Rapid antidepressant response with SAMe. A double‐study. Alabama Journal of Medical Sciences 1988;25(3):313‐6. - PubMed
Bell 1994 {published data only}
    1. Bell KM, Carreon D, Plon L, Bunney We Jr, Potkin SG. Oral S‐adenosylmethionine in the treatment of depression: a double‐blind comparison with desipramine. Study report. BioResearch File 1990:53‐4.
    1. Bell KM, Potkin SG, Carreon D, Plon L. S‐adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurologica Scandinavica 1994;154(Suppl 1):15‐8. - PubMed
Delle Chiaie 2000a {published data only}
    1. Delle Chiaie R, Pancheri P, Scapicchio P. 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 multicentrum studies. American Journal of Clinical Nutrition 2002;76(5):1172‐6. - PubMed
    1. Delle Chiaie R, Pancheri P, Scapicchio P. Mc3: multicentre, controlled efficacy and safety trial of oral S‐adenosyl‐methionine (SAMe) vs oral imipramine in the treatment of depression. International Journal of Neuropsychopharmacology 2000;3(Suppl 1):S230.
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Delle Chiaie 2000b {published data only}
    1. Delle Chiaie R, Pancheri P, Scapicchio P. Efficacy and tolerability of oral and intramuscular s‐adenosyl‐l‐methionine 1,4‐butanedisulfunate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. American Journal of Clinical Nutrition 2002;76(5):1172‐6. - PubMed
    1. Delle Chiaie R, Pancheri P, Scapicchio P. Mc4: multicentre, controlled efficacy and safety trial of intramuscular S‐adenosylmethionine (SAMe) versus oral imipramine in the treatment of depression. International Journal of Neuropsychopharmacology 2000;3(Suppl 1):S230.
    1. Delle Chiaie R, Pancheri P, Scapicchio P. S‐adenosyl‐methionine (SAMe) in major depression: two multicenter trials versus imipramine. 154th Annual Meeting of the American Psychiatric Association; 2001 May 5‐10, New Orleans. 2001:NR499.
    1. Delle Chiaie R, Pancheri P, Scapicchio P. S‐adenosyl‐methionine (SAMe) in major depression: two multicenter trials versus imipramine. 155th Annual Meeting of the American Psychiatric Association; 2002 May 18‐23; Philadelphia, PA. 2002.
    1. Pancheri P, Scapicchio P, Delle Chiaie R. 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. International Journal of Neuropsychopharmacology 2002;5(4):287‐94. - PubMed
De Vanna 1992 {published data only}
    1. Vanna M, Rigamonti R. Oral S‐adenosyl‐l‐methionine in depression. Current Therapeutic Research, Clinical and Experimental 1992;52(3):478‐85.
Kagan 1990 {published data only}
    1. Kagan BL, Sultzer L, Rosenlicht N, Gerner RH. Oral S‐adenosylmethionine in depression: a randomized, double‐blind, placebo‐controlled trial. American Journal of Psychiatry 1990;147(5):591‐5. - PubMed
Mischoulon 2014 {published data only}
    1. Fava M. A double‐blind, placebo‐controlled study of the alternative therapy S‐adenosyl‐l‐methionine (SAMe) versus escitalopram in major depressive disorder. clinicaltrials.gov/show/NCT00101452 (accessed 3 August 2016). [http://clinicaltrials.gov/show/NCT00101452]
    1. Gerbarg PL, Muskin PR, Bottiglieri T, Brown RP. Failed studies should not be used to malign good treatments [NCT00101452]. Journal of Clinical Psychiatry 2014;75(11):e1328. - PubMed
    1. Mischoulon D, Price LH, Carpenter LL, Tyrka AR, Papakostas GI, Fava M. Dr. Mischoulon and colleagues reply [NCT00101452]. Comment on failed studies should not be used to malign good treatments. Journal of Clinical Psychiatry 2014;75(11):e1328‐9. - PubMed
    1. Mischoulon D, Price LH, Carpenter LL, Tyrka AR, Papakostas GI, Fava M, et al. A double‐blind, randomized, placebo‐controlled clinical trial of S‐adenosyl‐l‐methionine (SAMe) versus escitalopram in major depressive disorder. Journal of Clinical Psychiatry 2014;75(4):370‐6. - PMC - PubMed
    1. Sarris J, Papakostas GI, Vitolo O, Fava M, Mischoulon D. S‐adenosylmethionine (SAMe) versus escitalopram and placebo in major depression RCT: efficacy and effects of histamine and carnitine as moderators of response. Journal of Affective Disorders 2014;164:76‐81. - PubMed
Papakostas 2010a {published data only}
    1. Mischoulon D, Alpert JE, Arning E, Bottiglieri T, Fava M, Papakostas GI. Bioavailability of S‐adenosyl methionine and impact on response in a randomized, double‐blind, placebo‐controlled trial in major depressive disorder [NCT00093847]. Journal of Clinical Psychiatry 2012;73(6):843‐8. - PMC - PubMed
    1. Papakostas GI. S‐Adenosyl methionine (SAMe) augmentation of selective serotonin reuptake inhibitors (SSRIs) for treatment‐resistant depression (TRD). clinicaltrials.gov/show/NCT00093847 (accessed 3 August 2016). [http://clinicaltrials.gov/show/NCT00093847]
    1. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S‐adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double‐blind, randomized clinical trial. American Journal of Psychiatry 2010;167(8):942‐8. - PubMed

References to studies excluded from this review

Agnoli 1975 {published data only}
    1. Agnoli A, Fazio C, Andreoli V. Neuropsychiatric disorders and transmethylations: therapeutic effects of S adenosyl L methionine [Disturbi neuropsichiatrici e transmetilazioni: effetti terapeutici della S adenosil l metionina]. Clinica Terapeutica 1975;75(6):567‐79. - PubMed
Agnoli 1976 {published data only}
    1. Agnoli A, Andreoli V, Casacchia M, Cerbo R. Effect of S‐adenosyl‐l‐methionine (SAMe) upon depressive symptoms. Journal of Psychiatric Research 1976;13(1):43‐54. - PubMed
Agnoli 1978 {published data only}
    1. Agnoli A, Andreoli VM, Casacchia M, Maffei F, Fazio C. Results and possible developments of the clinical use of S‐adenosyl‐L‐methionine (SAMe) in psychiatry. Monographien aus dem Gesamtgebiete der Psychiatrie 1978;18:170‐82. - PubMed
Alvarez 1984 {published data only}
    1. Alvarez E, Udina C, Guillamat R. Double blind study on the antidepressant activity of sulfoadenosyl‐L‐methionine (SAMe): clinical and biological factors [Estudio doble ciego sobre la efectividad antidepresiva del SAMe; factores clínicos y biológicos]. Revista del Departamento de Psiquiatría de la Facultad de Medicina de Barcelona 1984;11(4):275‐88.
Bambling 2015 {published data only}
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Bottiglieri 1986 {published data only}
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Bottiglieri 1990 {published data only}
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Del Vecchio 1978 {published data only}
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Di Pierro 2015 {published data only}
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Lanaia 1977 {published data only}
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Mantero 1976 {published data only}
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Muscettola 1982 {published data only}
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Rabassini 1979 {published data only}
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Salmaggi 1991 {published data only}
    1. Salmaggi P, Bressa GM, Nicchia G, Coniglio M, Greca P, Grazie C. Double‐blind, placebo‐controlled study of S‐adenosyl‐L‐methionine in depressed postmenopausal women. Psychotherapy and Psychosomatics 1993;59(1):34‐40. - PubMed
    1. Salmaggi P, Bressa GM, Niccia G, Coniglio M, Greca P, Grazie C. Oral S‐adenosylmethionine (SAMe) in the treatment of menopausal depressive disorder (MDD): a double‐blind placebo controlled trial. European Journal of Clinical Investigation 1991;21(2 pt 2):58.
Sarris 2015b {published data only}
    1. Sarris J, Stough C, Bousman C, Murphy J, Savage K, Smith DJ, et al. An adjunctive antidepressant nutraceutical combination in treating major depression: study protocol, and clinical considerations. Advances in Integrative Medicine 2015;2(1):49‐55.
Scarzella 1978 {published data only}
    1. Scarzella R, Appiotti A. A double‐blind clinical comparison of SAMe vs clomipramine in depressive disorders [Confronto clinico in doppio cieco della SAMe versus clorimipramina nelle sindromi depressive]. Rivista Sperimentale di Freniatria 1978;102:359‐65.
Schifano 1993 {published data only}
    1. Schifano F, Garofoli F. Dothiepin vs S‐adenosylmethionine (SAMe) for the treatment of major depression in weaned alcoholics: a pilot study. European Neuropsychopharmacology 1993;3(3):330.
Thomas 1987 {published data only}
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References to studies awaiting assessment

Quiros 1982 {published data only}
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References to ongoing studies

ACTRN12613001299796 {published data only}
    1. Sarris J. Nutraceuticals as monotherapy treatments in major depressive disorder: a double‐blind, randomised, placebo‐controlled trial, 2013. www.anzctr.org.au/ACTRN12613001299796.aspx (accessed 3 August 2016). [www.anzctr.org.au/ACTRN12613001299796.aspx]
    1. Sarris J, Murphy J. The efficacy of S‐adenosyl methionine (SAMe) and a combination nutraceutical as monotherapy treatments in major depressive disorder: a double‐blind, randomised, placebo‐controlled trial. www.anzctr.org.au/ACTRN12613001299796.aspx (accessed 3 August 2016).
ACTRN12613001300763 {published data only}
    1. Sarris J. The efficacy of S‐adenosylmethionine (SAMe) and a combination nutraceutical as adjunctive treatments in depression: a double‐blind, randomized, placebo‐controlled trial, 2013. www.anzctr.org.au/ACTRN12613001300763.aspx (accessed 3 August 2016). [www.anzctr.org.au/ACTRN12613001300763.aspx]
NCT01912196 {published data only}
    1. MSI Methylation Sciences, Inc. A double‐blind, placebo‐controlled, randomized add‐on study of MSI‐195 (Methylation Sciences Inc. S‐adenosyl‐L‐methionine, SAMe) for patients with major depressive disorder (MDD) who have had an inadequate response to current antidepressant therapy, 2013. clinicaltrials.gov/show/NCT01912196 (accessed 3 August 2016). [clinicaltrials.gov/show/NCT01912196]

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References to other published versions of this review

Galizia 2014
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