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Are St John's wort and SSRI antidepressants really ineffective in depression?

We were pleased to see a review by Wong in Aust J Herbal Med 24:3;97 (2012) appraising the quality of the most recent St John's wort (SJW) study by Rapaport et al (2011). The author raises some interesting points which deserve further exploration. Thus we provide a reply to the Wong paper in order to 1) respond to the critique of the Rapaport study, 2) address the reasons why SJW and antidepressant depression studies are increasingly not demonstrating efficacy over placebo, and 3) summarise the results of our new data exploring response patterns of SJW compared with placebo and antidepressants.

First it should be clarified that the search methods outlined by Wong was for 'major depression' and clearly the study reviewed concerned 'minor depression'. Further Wong chose to review the Rapaport et al (2011) paper stating that the Sarris, Fava, Schweitzer and Mischoulon (2012) was a reanalysis of SJW data and not an 'original' paper. This is incorrect as the data presented in this paper were data that had not been previously presented before, i.e. continuation data.

The critiqued Rapaport study revealed that SJW was no more effective than placebo (and the antidepressant citalopram) in treating minor depression in a sample of 73 participants. This is potentially due to an overinflated placebo response and also the likelihood of 'minor' depression not being effectively treated by pharmacological interventions (Fournier 2010). Regardless, the assertion by Wong that 'the study was not conducted with a superiority of research due to several limitations in the research methods' is highly questionable. The study design was methodologically sound and the SJW preparation used had been thoroughly scrutinised and vetted by NCCAM prior to awarding of funding. Regarding the sample size, the study was powered to assess the difference between both active treatments and placebo. The main flaw of the report, we recognise, was the failure to detail the standardisation of the SJW extract used. Several recent studies comparing SJW against placebo or selective serotonin reuptake inhibitors (SSRIs) have yielded equivocal results, with neither SJW nor the active drug separating from placebo.

So does this mean that SJW and antidepressants are not effective in reducing depression, or is there another explanation? It should be noted that in antidepressant randomised controlled trials (RCTs) of clinical depression, the placebo response rate in depressive disorders has been gradually increasing by approximately 7% per decade over the past four decades (Walsh 2002). In recent RCTs the average placebo response rate in major depressive disorder (MDD) trials may in fact be as high as 35-45%, with the average drug-placebo difference being only a modest 11-20% (Khan 2002, Yang 2005). This pattern is also apparent with SJW, with a meta-analysis by Werneke, Horn and Taylor (2004) showing, compared with previous meta-analyses, a reduced relative risk for response to SJW in treating MDD of 1.73 (CI 95% = 1.40, 2.14).

So why is a high placebo response rate occurring (and thus obfuscating the true effect of medications) and what are the potential solutions? Possible contributing factors to this problem raised by Fava and colleagues (2003) include study design flaws, diagnostic misclassification and inclusion or exclusion criteria issues, outcome measures with poor sensitivity, measurement and data entry errors, participants' depression oscillating and usually getting better due to 'regression to mean', and high attrition rates reducing statistical power. Another simple explanation concerns a potentially modifiable issue: due to increased competition to recruit participants and the sometimes inflated financial compensation to both researchers and patients, the study's 'strict' inclusion criteria may not be adhered to. Participants may be recruited with 'minor depression', potentially occurring due to psychosocial factors, and these participants may not be the ideal candidates for a biological intervention.

Proposed solutions have focused on selecting patients with particular characteristics such as increased illness severity or non-transient endogenous depression, use of specific sensitive outcome measures and modifying trial length and design, for example with placebo run-in periods.

Whilst a common anecdotal belief concerning antidepressant response time purports that 'medications take several weeks or months to work', the data do not support this. In fact, among trials that ultimately detect a difference between the active medication and placebo, a statistically significant difference is usually apparent as early as week 2, and almost always by week 4 of treatment (Posternak 2005; Walsh 2002). Interestingly Posternak and Zimmerman (2005) have proposed nearly identical response patterns for both placebo and antidepressants. In reviewing 76 double blind RCTs they found that drug-placebo differences were most pronounced during the first two weeks of treatment and diminished in a stepwise fashion thereafter. Critically more than 80% of the improvement on placebo was noted to occur, on average, in the first half of 6 week trials. Thus if patients experience an antidepressant effect from medication, this occurs shortly after initiation of the treatment, and in studies using placebo this perceived antidepressant response may also occur in the first few weeks.

While the pattern of antidepressant and placebo response has been studied, this has not yet occurred with SJW. In view of this we examined post hoc the conditional probability (the probability of an event occurring assuming another event has already occurred) of response to SJW compared with placebo and antidepressants via an analysis of a pooled sample of MDD patients from two 8 week RCTs comparing SSRIs versus SJW (The Hypericum Depression Trial Study Group study 2002 and the Fava et al study 2005). From a pooled total of 483 patients included in the intent-to-treat analyses, for the 149 patients who were classified as responders (>50% reduction on Hamilton Depression Rating Scale) at week 8, the conditional probabilities of early partial response revealed that in participants who ultimately respond to SJW, an initial partial response occurs early (Sarris et al in submission). This pattern is mirrored for placebo and antidepressant medication.

Another recent reanalysis of the Hypericum Depression Trial Study group study by Chen et al (2011) found that patient belief with regard to what treatment they had received appeared to have a significant impact on overall response, independent of actual treatment received. Further comparative study of SJW and placebo response patterns should clarify the most effective way to use SJW for mood disorders.

The take home messages from our commentary is that future depression studies need to have careful inclusion and exclusion criteria which are adhered to, and that clinicians prescribing SJW are advised to be aware that if no response occurs within one month of treatment it is unlikely the individual will respond to SJW. In this case reconsideration of the treatment strategy is needed. This may involve clinicians taking more assertive measures by switching interventions, augmenting treatment or referring appropriately.


Chen JA, Papakostas GI, Youn SJ, Baer L, Clain AJ, Fava M, Mischoulon D. 2011. Association between patient beliefs regarding assigned treatment and clinical response: reanalysis of data from the Hypericum Depression Trial Study Group. J Clin Psychiat 72:12;1669-76.

Fava M, Alpert J, Nierenberg AA, Mischoulon D, Otto MW, Zajecka J, Rosenbaum JF. 2005. A double-blind, randomized trial of St John's wort, fluoxetine, and placebo in major depressive disorder. J Clin Psychopharmacol 25:5;441-7.

Fava M, Evins AE, Dorer DJ, Schoenfeld DA. 2003. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother Psychosom 72:3;115-27.

Fournier J, DeRubeis R, Hollon S, Dimidjian S, Amsterdam J, Shelton R, Fawcett J. 2010. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 303:1;47-53.

Hypericum Depression Trial Study Group. 2002. Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. JAMA 287:14;1807-14.

Khan A, Khan S, Brown WA. 2002. Are placebo controls necessary to test new antidepressants and anxiolytics? Int J Neuropsychopharmacol 5:3;193-7.

Posternak MA, Zimmerman M. 2005. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiat 66:2; 148-58.

Rapaport MH, Nierenber g AA, Howland R, Dording C, Schettler PJ, Mischoulon D. 2011. The treatment of minor depression with St. John's Wort or citalopram: failure to show benefit over placebo. J Psychiatr Res 45:7;931-41.

Sarris J, Fava M, Schweitzer I, Mischoulon D. 2012. St John's wort (Hypericum perforatum) versus sertraline and placebo in major depressive disorder: continuation data from a 26 week RCT. Pharmacopsychiatry In Press.

Walsh BT, Seidman SN, Sysko R, Gould M. 2002. Placebo response in studies of major depression: variable, substantial, and growing. [Meta-Analysis Review]. JAMA 287:14;1840-47.

Werneke U, Horn O, Taylor D. 2004. How effective is St John's wort? The evidence revisited. J Clin Psychiat 65:5;611-17.

Wong S. 2012. Evidence based naturopathic literature review: Hypericum perforatum. Aust J Herbal Med 24:3;97-9.

Yang H, Cusin C, Fava M. 2005. Is there a placebo problem in antidepressant trials? Curr Top Med Chem 5:11;1077-86.

Jerome Sarris PhD, MHSc (1,2) *, Isaac Schweitzer MD (1), David Mischoulon MD, PhD (3)

(1.) Department of Psychiatry, The University of Melbourne, Melbourne, Victoria, Australia

(2.) Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Victoria, Australia

(3.) Depression Clinical and Research Unit, Massachusetts General Hospital, Department of Psychiatry, Harvard Medical School, Boston, USA

* Corresponding author: Dr Jerome Sarris, The Melbourne Clinic, Department of Psychiatry The University of Melbourne, 2 Salisbury St, Richmond, Melbourne, Australia Ph: +613 94209350 email:

This paper provides a reply to the Wong (AJHM 24:3;97-9) critique of the Rapaport et al (2011) study which found no significant difference between St John's wort, citalopram and placebo in treating minor depression. Additionally we address the reasons why St John's wort and antidepressant depression studies are increasingly not demonstrating efficacy over placebo, and provide potential solutions.
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Title Annotation:Commentary
Author:Sarris, Jerome; Schweitzer, Isaac; Mischoulon, David
Publication:Australian Journal of Herbal Medicine
Article Type:Report
Geographic Code:8AUST
Date:Dec 1, 2012
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