America has not been kind to St. John’s Wort. In Europe, this flowering bush that blooms around June 24 (St. John’s Day), has been all the rage for about 2000 years. It was first mentioned by the Roman Pliny the Elder in the first century, and over the past two millennia it has been used for a variety of ills, including diarrhea, urinary problems, demonic exorcism, and more recently, for melancholia. It is well-loved in Germany to this day, where it is prescribed by physicians seven times more frequently than Prozac for depression.
But once in America, its magic wore off, at least in the hands of our psychiatric researchers. Recently, two high-profile studies have been published in JAMA (1,2), both of which reported negative results for St. John’s Wort’s efficacy in the treatment of depression. The first study (1) by Shelton et. al., reported a 26% response rate for St. John’s Wort (hereafter referred to as “SJW”) vs. an 18% response rate for placebo, a non-statistically significant difference, though they did report a significantly higher remission rate on SJW (14% vs. 5%). In the second study (2), response rates did not differ significantly among any of the three treatments tested: SJW (response rate 24%), Zoloft (25%), or placebo (32%), although Zoloft outperformed placebo on a secondary scale of severity (the CGI scale).
The media response to these two studies has been significant, and would indicate to the uninformed that St John’s Wort has finally undergone definitive controlled trials proving that it is ineffective for depression. This would be an unfortunate conclusion, because over 30 other controlled trials of SJW have been published in Europe, and each one has reported a benefit of SJW in depression. (3,4,5). These studies have been criticized for methodological flaws (1), but a close look at the nature of these flaws is important, since even imperfect studies can help physicians make decisions about treatment.
To begin with, all 30 studies were randomized, double blind, controlled trials. In each study, patients were randomly assigned to receive either SJW or a control medication, usually placebo, and in other cases a standard antidepressant. The major criticisms of these studies are two-fold: first, that different definitions of depression were used in different studies, making it difficult to generalize the findings to specific diagnostic groups; and second, that the studies were sometimes conducted by primary care physicians rather than by experienced psychiatrists.
While these are valid criticisms, they hardly constitute fatal flaws. Primary care physicians do by far the majority of diagnosis and treatment of depression in the U.S., and claims that they miss psychiatric diagnoses are often overstated (6). There is no reason to presume that this is different in German-speaking countries. With regard to differences in diagnostic criteria, while it is possible that some of the “depressed” patients in the European trials would not have met all our DSM-4 criteria, recall that these trials were all randomized and controlled, so that any bias should apply equally to both groups.
A further important point is that the two negative JAMA studies were themselves far from perfect. In the study by Shelton et al (1) the placebo response rate was only 18%, far lower than the typical 40 to 50% placebo response seen in most antidepressant trials. The implication is that this group of patients was atypically treatment unresponsive, and therefore not a fair test of SJW, which is supposed to work best in mild to moderate depression.
The second JAMA study (2) inspires even less confidence, since Zoloft performed no better than placebo, even at a relatively robust dose of 100mg daily. Many would consider this a failed study, since an agent that we know is effective (Zoloft) could not outperform placebo.
Finally, buried in the media hoopla surrounding the JAMA studies was a recent very impressive randomized controlled trial of SJW vs. placebo (5) which was of sufficient methodological rigor to pass the stringent peer review standards of the American Journal of Psychiatry. In this study of depressed outpatients, SJW beat placebo in response rates (53% vs. 42%, p
The TCR verdict, after a close perusal of the evidence to date, is that St. John’s Wort probably works for mild to moderate depression, and that its very benign side effect profile (little incidence of sexual dysfunction or weight gain) should prompt us to suggest it to patients, especially those who are reluctant to take an SSRI. (This herbal is not completely benign, however; there have been case reports of drug-drug interactions, specifically an induction of the metabolism of a protease inhibitor used to treat HIV (7).
The cynic in TCR suspects that the enthusiasm with which the two negative JAMA articles have been received reflects political and economic pressures that make St. John’s Wort an unpalatable alternative to current treatments. No pharmaceutical company can profit much from an herbal product, and psychiatrists are not overjoyed about promoting an alternative that any consumer can purchase without a prescription.
TCR VERDICT:Give this poor immigrant a job!
1. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St. John’s Wort in major depression: A randomized controlled trial. JAMA. 2001;285:1978-1986.
2. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John’s Wort) in major depressive disorder: A randomized controlled trial. JAMA. 2002;287:1807-1814.
3. Linde K, Ramirez G, Mulrow CD, et. al. St. John’s Wort for depression–an overview and meta-analysis of randomized controlled trials. British Medical Journal. 1996;313:253-258.
4. Brenner R, Azbel V, Madhusoodanan S, et. al. Comparison of an extract of Hypericum (LI 160) and sertraline in the treatment of depression: A doubleblind, randomized pilot study. Clinical Therapeutics. 2000;22:411-419.
5. Lecrubier Y, Clerc G, Didi R, et.al. Efficacy of St. John’s Wort Extract WS 5570 in major depression: A double-blind, placebo-controlled trial. American Journal of Psychiatry. 2002;159:1361-1366.
6. Coyne JC, Schwenk TL, Fechner-Bates S. Nondetection of depression by primary care physicians reconsidered. Gen Hosp Psychiatry 1995;17(1):3-12.
7. Piscitelli S, et al. Indinavir concentrations and St. John’s Wort. Lancet. 2000:355-547-548.