Clinical Briefs

St John’s Wort and Major Depression

With Comments from Russell H. Greenfield, MD

Dr. Greenfield, Medical Director, Carolinas Integrative Health Carolinas HealthCare System Charlotte, NC, Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC, is Executive Editor of Alternative Medicine Alert.

Source: Szegedi A, et al. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St. John’s wort): Randomized controlled double blind non-inferiority trial versus paroxetine. BMJ 2005;330:503.

Goal: To evaluate the efficacy of a standardized extract of St John’s wort for moderate-to-severe depression as compared with paroxetine.

Design: Multicenter phase III randomized, double-blind, controlled, double-dummy non-inferiority trial.

Subjects: Two hundred fifty-one outpatient adults (18-70 years) with single or recurrent acute unipolar major depression persisting for two weeks to one year recruited from 21 German psychiatric primary care centers (data available for analysis on 188 subjects). Subjects had to score > 22 on the Hamilton depression scale and > 2 points on the item for "depressive mood."

Methods: Subjects underwent a single-blind placebo run-in phase of 3-7 days during which time they received three placebo tablets of hypericum and one of paroxetine. They were then randomized to six weeks of either 900 mg hypericum (standardized to 3-6% hyperforin and 0.12-0.28% hypericin) or 20 mg paroxetine daily plus an identically matched placebo for the other agent (i.e., three tablets of hypericum plus placebo paroxetine capsule or one capsule of paroxetine plus three placebo hypericum tablets). If at least 20% improvement in total depression score was not noted after two weeks of treatment, doses were increased to either 1,800 mg hypericum or 40 mg paroxetine daily. Primary outcome measure was decrease in Hamilton depression score after six weeks compared to baseline. Secondary outcome measures included results of the Montgomery-Asberg depression rating scale, clinical global impressions, and the Beck depression inventory. Assessments were made at baseline and at 4 and 6 weeks.

Results: Compared to baseline values, by day 42 Hamilton depression scores had decreased by 57% in the hypericum group and by 45% in the paroxetine group. Those patients who were switched to higher dosages at week 2 showed significant responses during weeks 3-6. Regardless of dose, substantial symptom relief was achieved with treatment in each group. Statistical analysis of validated rating scales showed the hypericum extract to be superior to paroxetine at almost all of the centers. The number of adverse events was higher for paroxetine than for hypericum (mainly gastrointestinal in nature).

Conclusion: Six weeks of hypericum extract WS 5570 is at least as effective as paroxetine in the treatment of adults with moderate-to-severe major unipolar depression.

Study strengths: Method of blinding; use of multiple validated rating tools; comparison to standard form of therapy.

Study weaknesses: All participants were Caucasian, limiting generalizability; assessment of compliance (counting tablets); short duration of trial; three-quarters of the authors have ties to the manufacturer of the hypericum extract utilized.

Of note: Participants were not allowed to use other psychotropic agents or engage in psychotherapy during the trial; all assessments were made by psychiatrists and psychologists familiar with the protocol; mean age and average duration of episode were higher in the hypericum group; more than half the participants in each group were severely depressed; after two weeks, 57% of those in the hypericum group and 48% in the paroxetine group were switched to the higher dosage; 14% dropout rate in hypericum group and 23% dropout rate in the paroxetine group; two serious complications occurred in the hypericum group, though they were felt to be unrelated to the agent (one hypertensive crisis, one psychotic decompensation due to social problems); there was no increase in adverse effects with higher dosages of the agents, including photosensitivity; an ongoing continuation phase will be reported at a later date.

We knew that: Therapeutic effectiveness of St. John’s wort for severe major depression has been in doubt; standardized extracts of St. John’s wort have been shown effective in treating mild-to-moderate depression, and to be as effective as fluoxetine and some antidepressants in this regard; a placebo control was not used for these severely depressed patients for ethical reasons; St. John’s wort has been reported to lower levels of a number of pharmaceutical agents, including cyclosporine, warfarin, theophylline, indinavir, and irinotecan.

Comments: Regarding either conventional methods of care or complementary modalities, industry involvement in research is a given in today’s environment. While it is cause for especially careful assessment before drawing conclusions, as well as for investigation by other centers, industry involvement alone does not nullify positive results. At a time when the benefits of antidepressant therapy are being challenged by fears of frightening side effects (i.e., increased suicide risk), practitioners and patients alike are likely to seek out safe alternatives. A single trial of short duration, in a clinical situation where placebos have also been reported to offer significant benefit, is not sufficient to mandate change in the long-term management of depression. Potential drug interactions do loom large when considering the use of hypericum. However, the study is clean, and the results compelling enough to open the possibility that St. John’s wort may be a viable option for those with major depression, a clinical recommendation that previously would have been cause for alarm in many professional circles.

What to do with this article: Keep a hard copy in your file cabinet.