April 10

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News Stories on Human ResearchProtection and
Commentary by Vera Hassner Sharav

April 10, 2002

For Relief of ModeratelySevere Depression, Study Shows No Significance Difference Among Placebo, Zoloftand 
St. Johns Wort — JAMA 


The findings of a major government sponsored, 14-site,controlled clinical trial, comparing anti-depression treatments– serrtraline(Zoloft) vs. Hypericum perforatum (St John’s wort) vs. placebo–are reported inthe current Journal of American Medical Association (JAMA).

The findings reported by prominent investigators:"Full response occurred in 31.9% of the placebo-treated patients vs. 23.9%of the H perforatum–treated patients and 24.8% of sertraline-treated patients."

The authors also acknowledge: "An increasing numberof studies have failed to show a difference between active antidepressants andplacebo.  Many of the presumed factors underlying this phenomenon werecarefully attended to in this study, e.g., adherence to quality control by ratertraining, treatment adherence monitoring, inclusion of experiencedinvestigators, and carefully defined entry criteria. Despite all of this,sertraline failed to separate from placebo on the 2 primary outcomemeasures"

Yet, in their conclusion, these prominent leaders ofpsychiatry (too numerous to list at the head of the article) ignore theirnegative findings that the antidepressant drug, Zoloft, and St. John’s wort wereless effective than placebo. The investigators pretend that Zoloft was not partof the 3-arm trial:

"This study fails to support the efficacy of Hperforatum in moderately severe major depression. The result may be due to lowassay sensitivity of the trial, but the complete absence of trends suggestive ofefficacy for H perforatum is noteworthy. "

An accompanying JAMA editorial (by a past president of theAmerican College of Neuropsychopharmacology) draws the same confoundingconclusion.

"The current study on the use of St John’s wort inthe treatment of MDD is the second one within a year to conclude that St John’swort is not effective. These trials were conducted because, even though StJohn’s wort is widely used for the treatment of major depression and depressivesymptoms, its efficacy has not been clearly established, despite more than 20randomized trials, most of which are considered to have had seriousmethodological flaws"

The actual findings of 20 studies in Germany foundSt.John’s wort effective. The findings reported by the investigators reportingin JAMA, show that placebo had a higher number of subjects whose depression wasrelieved than eitherZoloft or St. John’s wort — 31.9% _ 24.8%_ 23.9 % respectively.

How could these prominent authors and editorial reviewersdraw a conclusion that ignores a key finding of the study, namely, that Zoloftwas no better than a placebo in treating moderately severe depression?

Perhaps their conclusion was reached through alchemy. Tothis observer, it is a clear indication that there is no such thing as unbiasedreporting of clinical findings in psychiatry. The incredible list of theauthors’ financial ties to industry that append the article speaks for itself.One must also question JAMA editors’ judgment in failing to seek an independentscientist –not a psychiatrist–to evaluate the research findings.



Vol. 287 No. 14, April 10, 2002

Effect of Hypericum perforatum (St John’s Wort) inMajor Depressive Disorder
A Randomized Controlled Trial

Hypericum Depression Trial Study Group

Context Extracts of Hypericum perforatum (St John’s wort)are widely used for the treatment of depression of varying severity. Theirefficacy in major depressive disorder, however, has not been conclusivelydemonstrated.

Objective: To test the efficacy and safety of awell-characterized H perforatum extract (LI-160) in major depressive disorder.

Design and Setting: Double-blind, randomized,placebo-controlled trial conducted in 12 academic and community psychiatricresearch clinics in the United States.

Participants: Adult outpatients (n = 340) recruitedbetween December 1998 and June 2000 with major depression and a baseline totalscore on the Hamilton Depression Scale (HAM-D) of at least 20.

Interventions: Patients were randomly assigned toreceive H perforatum, placebo, or sertraline (as an active comparator) for 8weeks. Based on clinical response, the daily dose of H perforatum could rangefrom 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week8 could continue blinded treatment for another 18 weeks.

Main Outcome Measures: Change in the HAM-D totalscore from baseline to 8 weeks; rates of full response, determined by the HAM-Dand Clinical Global Impressions (CGI) scores.

Results: On the 2 primary outcome measures, neithersertraline nor H perforatum was significantly different from placebo. The randomregression parameter estimate for mean (SE) change in HAM-D total score frombaseline to week 8 (with a greater decline indicating more improvement) was –9.20(0.67) (95% confidence interval [CI], –10.51 to –7.89) for placebo vs –8.68(0.68) (95% CI, –10.01 to –7.35) for H perforatum (P = .59) and –10.53(0.72) (95% CI, –11.94 to –9.12) for sertraline (P = .18). Full responseoccurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum–treatedpatients (P = .21) and 24.8% of sertraline-treated patients (P = .26).Sertraline was better than placebo on the CGI improvement scale (P = .02), whichwas a secondary measure in this study. Adverse-effect profiles for H perforatumand sertraline differed relative to placebo.

Conclusion: This study fails to support theefficacy of H perforatum in moderately severe major depression. The result maybe due to low assay sensitivity of the trial, but the complete absence of trendssuggestive of efficacy for H perforatum is noteworthy.

JAMA. 2002;287:1807-1814
Placebo in Clinical Trials for Depression
Complexity and Necessity
David J. Kupfer, MD; Ellen Frank, PhD

Within the last several years, the long-simmering debateabout the ethical issues surrounding placebo administration in randomizedclinical trials has reached new levels of intensity. The report of the NationalBioethics Advisory Commission included specific recommendations for studiesinvolving more than minimal risk, including the use of placebo controls inclinical trials.[1]At a time of increased interest in drug discovery in medicineand the potential need for definitive randomized clinical trials, thecontroversy over the ethical issues places an appropriate burden on thescientific community to justify the use of placebo controls.[2,3] One argumentis that placebo administration is not appropriate if effective treatment for acondition exists and that assessment of efficacy can be conducted with activecontrols. Another view is that placebo controls may be necessary to determinethe assay sensitivity of a trial and are ethical if patients provide informedconsent and are not harmed. [4]

Treatment of depression, a well-recognized and worldwidepublic health problem, [5] represents a special opportunity to highlight severalkey issues in the "placebo controversy" and to demonstrate why for theforeseeable future placebo-controlled trials will be necessary. While thetreatment of depression has been marked by major successes with the introductionof new classes of antidepressants and their "uptake" by clinicians andpatients,[6] newer antidepressants will continue to be developed. These newproducts may target specific subtypes of depression, may provide more completerecovery and sustained remission, and may have reduced adverse effects andfaster onset of action. These products will require proof of efficacy and Foodand Drug Administration approval. A better understanding of the many alternativeor complementary treatments for depression, such as nonprescription herbalcompounds, also contributes to the need to determine when placebo controls areappropriate.

Two articles in this issue of THE JOURNAL,one from the Hypericum Depression Trial Study Group [7] and another from Walshet al[8] on placebo response, focus attention on the key issues. The firstreport examines the efficacy of St John’s wort (Hypericum perforatum) in majordepressive disorder (MDD) in a 3-arm clinical trial.[7] This study provides anopportunity to comment on the role of placebo and whether placebo efficacy rates"interfere" with the establishment of the efficacy of new treatments.The second report addresses the problems of placebo in depression trials using a20-year perspective. Walsh and colleagues [8] describe how placebocharacteristics and clinical response levels have changed.

The current study [7] on the use of St John’s wort in thetreatment of MDD is the second one within a year [9] to conclude that St John’swort is not effective. These trials were conducted because, even though StJohn’s wort is widely used for the treatment of major depression and depressivesymptoms, its efficacy has not been clearly established, despite more than 20randomized trials, most of which are considered to have had seriousmethodological flaws.[9-11] Both of the recent trials were multicenterrandomized, double-blind, placebo-controlled trials with a standardized extractof St John’s wort. The previous 8-week trial by Shelton et al [9] showed nosignificant difference between St John’s wort extract and placebo on any of thedepression outcome measures. Response rates in the intention-to-treat analysiswere also not significantly different (26.5% for St John’s wort vs 18.6% forplacebo). The second study[7] reported in this issue, also included a largemulticenter population of outpatients with MDD, but differed in that a selectiveserotonin reuptake inhibitor (SSRI), sertraline, was included as an activecontrol in addition to testing St John’s wort extract (hypericum) and placebo.From this 8-week clinical trial, the authors conclude that neither sertralinenor hypericum was significantly different from placebo on the 2 primary outcomemeasures, the Hamilton Depression Scale (HAM-D) and the Clinical GlobalImpression Scale (CGI-I). The overall response rates (including partial and fullresponse) were 38.1% for hypericum, 43.1% for placebo, and 48.6% for sertraline.

As the authors point out, their study represents anexcellent example of why it is critical to include both placebo and activecomparators in trials of agents for which efficacy is unproven. Without aplacebo control, one might prematurely conclude that hypericum has efficacycomparable to an SSRI, in this case, sertraline. However, without sertraline asthe active comparator, the conclusion, as in the previously published trial,would be that St John’s wort extract is not efficacious in MDD. Before drawingconclusions, the low assay sensitivity of this new trial must be acknowledged.It is likely that the study was underpowered given the assumption of a 20%drug-placebo difference in full response rates. In addition, while relativelyhigh doses of hypericum (1500-1800 mg/d) were permitted, the maximum acute doseof sertraline (100 mg/d) almost certainly contributed to its low effect size andfailure to separate out from placebo or hypericum. The overall placebo responsewas high compared with the previous hypericum vs placebo study[9] demonstratingthe variability in placebo response from trial to trial. A recent review ofplacebo controls in depression trials[12] made a series of recommendations toenhance documentation of treatment vs placebo efficacy, including greateremphasis on effect size, rather than significance levels alone.

Walsh and colleagues [8] have approached the placeboresponse issue for major depression studies in a careful review of controlledtrials between 1981 and 2000 in which outpatients with MDD were randomlyassigned to medication or placebo. In the 75 trials meeting this criterion, themean (SD) proportion of patients in the placebo group who responded was 29.7%(8.3%). Since many investigations involved more than 1 active antidepressant,the greater response with an active drug in such trials was used to calculatethe overall active treatment response rate (50.0% [9.0%]). The average effectsize across studies for maximum proportion responding to a medication was 0.43(0.22). The authors conclude that the response to placebo is highly variable,substantial, and has increased significantly in recent years as shown by thehigh positive correlation with the year of publication. While the response ratefor antidepressant medication has also increased in the last 20 years, theassociation between response rate and year of publication was more statisticallyrobust for placebo than for active medication. Walsh et al note that the changein placebo response rate does not appear to be directly explained by changes instudy characteristics such as patient age, placebo lead-in, or minimum requiredHAM-D score. It is difficult to disagree with their contention that since theaverage rate of response has changed over time, the use of a historical standardas a valid benchmark of efficacy rates would be a poor choice.

Both of these reports, from different perspectives, pointto the continuing set of problems inherent in clinical trials for majordepression. Based on an extensive consensus development panel process convenedin September 1999, and on summaries of presentations at that conference,including those by Lavori [13] and Rush,[14] a National Depressive andManic-Depressive Association Consensus Statement on the use of placebo inclinical trials of mood disorders [15] concluded that placebo has a definiterole in mood disorder studies and that findings of equivalence between a newdrug and standard treatment are not evidence of efficacy unless the new drug isalso significantly more effective than placebo. Since this report expresses theconsensus of an interdisciplinary group of clinical researchers,biostatisticians, bioethicists, and consumers, it is likely that the use ofplacebo-controlled trials in developing interventions will continue. It is alsonoteworthy that all the stakeholders are now much more sensitized to thenecessity of seeking newer strategies for shorter durations in drug-placebotrials to minimize risks, as well as to the need for alternate research designs,when appropriate.

Taken together, the 2 reports in this issue of THEJOURNAL return full circle to the placebo response and understanding itsmechanisms of action 16] and highlight the perplexing complexity of the placeboand its ability to cause "mischief" in scientific inquiry. This may benature’s way of providing clues to fundamental aspects of the healing process,even as advances in medicine and the discovery of new therapies take place. Itis important to learn from, rather than dismiss, the variability of thetherapeutic response.

Author/Article Information

Author Affiliations: Department of Psychiatry, Universityof Pittsburgh Medical School, Western Psychiatric Institute and Clinic,Pittsburgh, Pa.

Corresponding Author and Reprints: David J. Kupfer, MD,Department of Psychiatry, University of Pittsburgh Medical School, WesternPsychiatric Institute and Clinic, 3811 O’Hara St, Pittsburgh, PA 15213 (e-mail:kupferdj@msx.upmc.edu). Editorials represent the opinions of the authors and THEJOURNAL and not those of the American Medical Association.

1. Research Involving Persons With Mental Disorders That May AffectDecision-Making Capacity. Rockville, Md: National Bioethics Advisory Commission;December 1998. Available at: http://bioethics.georgetown.edu/nbuc/capacity/TOC.htm
Accessed February 28, 2002.

2. Rothman KJ, Michels KB. The continuing unethical use ofplacebo controls. N Engl J Med. 1994;331:394-398.

3. Charney DS. The use of placebos in randomized clinicaltrials of mood disorders. Biol Psychiatry. 2000;47:687-688.

4. Temple R, Ellenberg SS. Placebo-controlled trials andactive-control trials in the evaluation of new treatments, part I: ethical andscientific issues. Ann Intern Med. 2000;133:455-463.

5. Murray JL, ed, Lopez AD, ed. The Global Burden OfDisease: A Comprehensive Assessment of Mortality and Disability From Diseases,Injuries, and Risk Factors in 1990 and Projected to 2020. Geneva, Switzerland:World Health Organization; 1998.

6. Olfson M, Marcus SC, Druss BN, Elinson L, Tanielian T,Pincus HA. National trends in the outpatient treatment of depression. JAMA.2002;287:203-209.

7. Hypericum Depression Trial Study Group. Effect ofHypericum perforatum (St John’s wort) in major depressive disorder: a randomizedcontrolled trial. JAMA. 2002;287:1807-1814.

8. Walsh BT, Seidman SN, Sysko R, Gould M. Placeboresponse in studies of major depression: variable, substantial, and growing.JAMA. 2002;287:1840-1847.

9. Shelton RC, Keller MB, Gelenberg A, et al.Effectiveness of St John’s wort in major depression: a randomized controlledtrial. JAMA. 2001;285:1978-1986.

10. Linde K, Ramirez T, Mulrow CD, et al. St. John’s wortfor depression: an overview and meta-analysis of randomized clinical trails. BMJ.1996;313:253-258.

11. Linde K, Mulrow CD. St. John’s wort for depression [CochraneDatabase of Systematic Reviews]. Oxford, England: Cochrane Library, UpdateSoftware; 2000; issue 2.

12. Schatzberg AF, Kraemer HC. Use of placebo controlgroups in evaluating efficacy of treatment of unipolar major depression. BiolPsychiatry. 2000;47:736-744.

13. Lavori PW. Placebo control groups in randomizedtreatment trials: a statistician’s perspective. Biol Psychiatry.2000;47:717-723.

14. Rush AJ. The use of placebos in unipolar majordepression: the current status. Biol Psychiatry. 2000;47:745-747.

15. Charney DS, Nemeroff CB, Lewis L, et al. NationalDepressive and Manic-Depressive Association Consensus Statement on the use ofplacebo in clinical trials of mood disorders. Arch Gen Psychiatry.2002;59:262-270.

16. Lasagna L. Placebos and controlled trials underattack. Eur J Clin Pharmacol. 1979;15:373-374.

© 2002 American Medical Association. All rights reserved.

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