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One of the most widely used herbal treatments for depression received a hard blow in April when the Journal of the American Medical Association printed the results of a study that concludes St. John’s wort is not effective for major depression.1
The Vanderbilt University study, which included 200 adult outpatients diagnosed with major depression, criticizes two dozen clinical trials, concluding that "most have significant flaws in design and do not enable meaningful interpretation," wrote the study’s lead author, Richard C. Shelton, MD, of the Vanderbilt School of Medicine in Nashville, TN. Shelton’s subjects were randomized to receive 900 mg of St. John’s wort daily or placebo for eight weeks. Nonresponders in the St. John’s wort group were increased to 1,200 mg after four weeks.
All participants scored at least 20 of a possible score of 52 on the 21-item Hamilton Rating Scale for Depression (HAM-D), indicating major depression. Secondary measurements included the Beck Depression Inventory, the Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression-Severity and Improvement scales (CGI-S and CGI-I).
"There was no significant difference in rate of change in HAM-D scores between the St. John’s wort group and the placebo group for those patients with relatively less severe initial depression. . . ." Shelton wrote. "Unlike previous studies, St. John’s wort extract failed to produce significant differences vs. placebo on any of the outcome measures used. . . ." The St. John’s wort efficacy rate was 32%, and the placebo rate was 21%, short of the difference needed for statistical power, he added.
The researchers concede that St. John’s wort "could be effective for less severely depressed patients" since results showed improvement in 20.3% of the active ingredient patients and 11.8% of placebo-treated subjects.
The study immediately drew heavy fire from clinicians who have used St. John’s wort and found it effective against longstanding mild-to-moderate depression. "There is plenty of evidence that St. John’s wort is helpful in mild-to-moderate depression and even some evidence that it can help in severe cases," says Adrian Fugh-Berman, MD, assistant clinical professor at George Washington University School of Medicine and Health Sciences in Washington, DC. She says the Vanderbilt study is "a well-designed trial," but calls the conclusions "deficient."
"The single positive finding in this trial was a higher remission rate among the treated group. Although remission rates were low, the authors should not have dismissed this finding: Remission is of clearer benefit to the patients than an improvement in HAM-D scores," says Fugh-Berman. She also criticizes the authors for unsporting behavior. "The desire that one’s research will supersede all other research in the field probably is common, but most authors are better at keeping such uncollegial thoughts under wraps."
Fugh-Berman commends the design of the study. "The attention to details is laudable. For example, care was taken to mask the taste and smell of the verum treatment; individual lots of the treatment were analyzed to ensure consistency; a dose increase was built in; and HAM-D assessments were videotaped and reviewed by an independent assessor," writes Fugh-Berman in the June issue of Alternative Therapies in Women’s Health.
Although some colleagues disagree, Fugh-Berman also says she approves of the study population, which she says "appears to have been selected to represent an appropriate level of depression for comparison with previous St. John’s wort studies." Yet she roundly criticizes Shelton’s dismissal of other studies as poorly designed, for example, those which include patients rated mildly depressed with scores of less than 18 on the HAM-D scale. "Deliberate inclusion of mildly depressed subjects is hardly a design flaw."
St. John’s wort is one of the most widely studied of all herbal remedies. It is currently the subject of a three-year multicenter study sponsored by the U.S. National Institutes of Health where it is being compared to placebo and to the selective serotonin reuptake inhibitor (SSRI) sertraline (marketed under the brand name Zoloft).
Herbal Medicine, an expanded version of the German Commission E monographs (Blumenthal, Goldberg, Brinckman. Austin, TX: American Botanical Council; 2000) lists 65 primary references on the efficacy of St. John’s wort, several of them naming Fugh-Berman as lead author or co-author.
In 1984, The German Commission E approved the internal use of St. John’s wort for mild-to-moderate depressive states, restlessness, anxiety, and irritability. The German government also licenses its use for nervous excitement and sleep disturbances. However, because the St. John’s wort monograph was written in the 1980s, the Commis-sion’s monograph does not include data from recent studies reporting potential interactions with prescription and over-the-counter drugs.
Those recommendations notwithstanding, several studies, including one by Fugh-Berman, suggest mild serotonin syndrome might result from mixing St. John’s wort with SSRIs.2 A review from Thomas Jefferson University in Philadelphia notes several studies that warn St. Johns wort may accelerate liver enzyme activity via cytochrome P450.3 Studies have reported potential herb-drug interactions in patients taking theophylline, cyclosporine, warfarin, and ethinyl estradiol/desogestrel.
Other research suggests that St. John’s wort induces CYP3A4 isozyme activity, which is responsible for the metabolism of such commonly used drugs as: protease inhibitors, nonsedating antihistamines, calcium channel blockers, 3-hydroxy-3-methlyglutaryl coenzyme A reductase inhibitors, benzodiazepines, estrogens, macrolide antibiotics, carbamazepine, cyclosporine, carbamazepine, ketoconazole, and cortisone.
The authors of the Thomas Jefferson review, who noted at least six "well-designed" clinical studies showing the efficacy of St. John’s wort, also are less than enthusiastic about the Vanderbilt study. Jeffrey Greeson, MS, a research associate at Thomas Jefferson and lead author of the review, says he believes the differences between the placebo group and the St. John’s wort group are significant, despite Shelton’s conclusions. Statistically, Greeson says, the Vanderbilt study comes close to clinical significance. "At worst, there is a strong trend, so let’s not throw the baby out with the bath water. While their conclusion is scientifically acceptable, to me, it suggests St. John’s wort is superior to the placebo." Particularly since the Vanderbilt study addresses patients with major depression, Greeson says, he would have expected even less positive results.
Daniel A. Monti, MD, professor of psychiatry at Thomas Jefferson Medical School and a practitioner at the university’s Center for Integrative Medicine, says he thinks the use of St. John’s wort may be effective for some patients with mild-to-moderate depression, but "in severe cases, I go straight to a pharmacological agent." His advice to clinicians: If patients are philosophically opposed to taking pharmacological agents, let them try St. John’s wort and see if it works.
And a second caveat in view of possible herb-drug interactions: Always ask patients to tell you all the drugs, herbs, and supplements they are taking. Monti and Greeson both suggest that any patient taking St. John’s wort should be under the supervision of a physician, particularly if the patient is taking any conventional drugs, whether prescription or over-the-counter. Monti says the Vanderbilt study does contribute to the scientific literature on St. John’s wort; particularly, it underscores the likelihood that St. John’s wort isn’t terribly effective for severe depression.
And in written remarks, Jerry Cott, PhD, former chief of psychopharmacology at the National Institute of Mental Health in Bethesda, MD, said the Vanderbilt study should, at least, be considered "neutral — one that simply fails to show effectiveness rather than proving the test drug doesn’t work. Since no active treatment group, i.e., no active pharmaceutical drug, was used in the design of the study to compare to St. John’s wort and the placebo, the [Vanderbilt] study may simply have lacked the sensitivity to detect a difference," he wrote.
Cott suggested the presence of subjects on active medication would show if the study has sensitivity depending on whether the known antidepressant was effective. He also noted that in 25 years of research on psychopharmacological agents, he has never seen a study on depression with such low placebo response. "One possible interpretation is that the extremely low placebo response rate could invalidate the study." He noted that the Vanderbilt investigative team routinely has seen placebo response rates of 30% to 50% in other studies. "So why the difference now?" he asked.
(Editor’s note: Vanderbilt investigators were unavailable for comment.)
1. Shelton, RC, Keller MB, Gelenberg A et al. Effective-ness of St. John’s wort in major depression. JAMA 2001; 285:1978-86.
2. Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355:134-138.
3. Greeson JM, Sanford B, Monti DA. St. John’s wort (Hypericum perforatum): A review of current pharmacological, toxicological, and clinical literature. Psychopharmacology 2001; 153:402-414.