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Letter to the Editor

Failed Studies Should Not Be Used to Malign Good Treatments

Patricia L. Gerbarg, MD; Philip R. Muskin, MD; Teodoro Bottiglieri, PhD; and Richard P. Brown, MD

Published: November 24, 2014

See Reply by Mischoulon et al and Article by Mischoulon et al

Failed Studies Should Not Be Used to Malign Good Treatments

To the Editor: The recent double-blind, randomized, placebo-controlled trial of S-adenosylmethionine (SAMe) versus escitalopram in major depressive disorder (MDD) was reported as a failed trial by Mischoulon and colleagues.1 In intent-to-treat samples, no significant differences were found in response rates: 36% for SAMe, 34% for escitalopram, and 30% for placebo. The remission rates of 28% for SAMe, 28% for escitalopram, and 17% for placebo suggested that both active treatments produced "a more robust ‘ true’ effect"1(p374) compared to placebo.

Mischoulon and colleagues discuss possible reasons for the failure of antidepressants with established records of efficacy (SAMe and escitalopram) to exceed placebo. They note that Iovieno and Papakostas2 observed that placebo response rates ≥ 30% correlated with lower risk ratio of response to antidepressants versus placebo. Rutherford and Roose3 also reported worse performance of drug versus placebo in studies with placebo response rates ≥ 30%, as seen in this Mischoulon study. Nearly 60% of subjects had low levels of depression severity (pretreatment Hamilton Depression Rating Scale score ≥ 19), increasing the difficulty of demonstrating a significant drug versus placebo effect.

Despite the fact that the SAMe response rate was equal to that of escitalopram, discussion of the results gave unequal treatment to the 2 antidepressants. Mischoulon and colleagues state that the sample size was only two-thirds the number for which the study was powered, a "major limitation"; however, they write that the sample "is large enough to provide a conclusive statement about the efficacy of SAMe as a monotherapy for MDD"1(p375) [our emphasis]. How can one make a conclusive statement from a failed trial? No such statement was made about escitalopram, though it performed no better than SAMe. They speculate, "SAMe may be better suited as an augmentation therapy than as a monotherapy."1(p375) Bias is introduced and then is driven home by suggestions that further trials will be needed to clarify SAMe’s potential antidepressant effect and its place in treating depression. According to the US Department of Health and Human Services Agency for Healthcare Research and Quality 2002 report,4 SAMe has already proven efficacy as a monotherapy in depression, based on 13 randomized, placebo-controlled trials and 19 randomized trials comparing it with standard antidepressants (imipramine, amitriptyline, clomipramine, nomifensine, minaprine, and desipramine).5-9 The manner in which researchers discuss study results impacts clinical practice and can be particularly damaging in the case of less well-known or less conventional treatments. Publications must be impartial in order to avoid introducing errors of bias into clinical decision making.

This study highlights the growing threats to validity in large, expensive antidepressant trials that appear to have excellent methodology (eg, high Jadad scores), and yet produce no useful information. The answers would more likely be found in problems with the patient selection process and the heterogeneity within patient groups with respect to genomic and metabolic biomarkers.10 At the very least, until the true causes of invalidity are identified, such studies should not be used to create unwarranted doubt about the efficacy of highly beneficial treatments such as SAMe.


1. Mischoulon D, Price LH, Carpenter LL, et al. A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-l-methionine (SAMe) versus escitalopram in major depressive disorder. J Clin Psychiatry. 2014;75(4):370-376. PubMed doi:10.4088/JCP.13m08591

2. Iovieno N, Papakostas GI. Correlation between different levels of placebo response rate and clinical trial outcome in major depressive disorder: a meta-analysis. J Clin Psychiatry. 2012;73(10):1300-1306. PubMed doi:10.4088/JCP.11r07485

3. Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013;170(7):723-733. PubMed doi:10.1176/appi.ajp.2012.12040474

4. US Departments of Health and Human Services Agency for Healthcare Research and Quality (AHRQ). (2002). S-adenosyl-l-methionine for treatment of depression, osteoarthritis, and liver disease. Summary, Evidence Report/Technology Assessment: Number 64. AHRQ Publication No. 02-E033. Updated August 2002. Accessed October 8, 2007.

5. Bottiglieri T. Folate, vitamin B12, and S-adenosylmethionine. Psychtr Clin North Am. 2013;36(1):1-13. doi:10.1016/j.psc.2012.12.001 PubMed.

6. Brown RP, Gerbarg PL. Herbs and nutrients in the treatment of depression, anxiety, insomnia, migraine, and obesity. J Psychiatr Pract. 2001;7(2):75-91. PubMed doi:10.1097/00131746-200103000-00002

7. Brown RP, Gerbarg PL, Bottiglieri T. S-Adenosylmethionine in depression: biochemical and clinical evidence. Psychiatr Ann. 2002;32(1):29-44. doi:10.3928/0048-5713-20020101-07

8. Brown RP, Gerbarg PG, Muskin PR. In: Tasman A, Kay J, Lieberman J, eds. Alternative Treatments in Psychiatry in Psychiatry. 3rd ed. Chapter 108. London, UK: John Wiley & Sons; 2008:2318-2353.

9. Brown RP, Gerbarg PL, Muskin PR. How to Use Herbs, Nutrients, and Yoga in Mental Health Care. New York, NY: W W Norton & Company; 2009.

10. Papakostas GI, Shelton RC, Zajecka JM, et al. Effect of adjunctive l-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry. 2014;75(8):855-863. PubMed doi:10.4088/JCP.13m08947

Patricia L. Gerbarg, MD

Philip R. Muskin, MD

Teodoro Bottiglieri, PhD

Richard P. Brown, MD

Author affiliations: Department of Psychiatry, New York Medical College, Valhalla (Dr Gerbarg); Department of Psychiatry, Columbia University Medical Center, New York (Drs Muskin and Brown), New York; and Center of Metabolomics, Institute of Metabolic Disease, Baylor Research Institute, Baylor University, Dallas, Texas (Dr Bottiglieri).

Potential conflicts of interest: Dr Bottiglieri has received research support from Pamlab/Nestle Health Science and honoraria from Pamlab/Nestle Health Science and Xymogen, and has stock options in Methylation Sciences Inc, Vancouver, Canada. Drs Gerbarg, Muskin, and Brown report no financial or other relationship relevant to the subject of this letter.

Funding/support: None reported.

J Clin Psychiatry 2014;75(11):e1328 (doi:10.4088/JCP.14lr09266).

© Copyright 2014 Physicians Postgraduate Press, Inc.

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