Major depression is typically treated with antidepressant medications. Although newer antidepressants (SSRIs, selective serotonin reuptake inhibitors) are better tolerated than older drugs (e.g., tricyclic antidepressants), they still have many unwanted side effects. Extracts of St. John’s wort (SJW, Hypericum perforatum, Clusiaceae) are prescribed in Germany to treat depression. The purpose of this systematic review was to investigate whether extracts of SJW are more effective than placebo and as effective as standard antidepressants in the treatment of major depression, and whether they have fewer adverse effects than standard antidepressant drugs. Similar reviews have been published by the Cochrane Collaboration in the past. This review is an update, including the latest published studies.

Electronic databases were searched through July 8, 2008 to find appropriate studies. Reference lists were also searched. Only randomized, double-blind clinical trials were included in this review. Patients were required to have major depression (meeting DSM-IV or ICD-10 criteria). Trials in children (less than 16 years of age) were not eligible. Studies evaluating combination herbal products and trials using inappropriate synthetic drugs (e.g. benzodiazepines) or a dosage of an antidepressant below the lower thresholds recommended in current guidelines were excluded. Experimental and control treatments had to be administered for a duration of at least 4 weeks. Trials that measured only physiological parameters were excluded.

A total of 79 relevant studies were identified and 29 trials (conducted on a total of 5489 patients) met the inclusion criteria, including 18 placebo-controlled studies and 17 active-controlled studies. (Active controls are usually conventional pharmaceutical drugs approved and used for the indication being tested in the trial.) The severity of major depression was described as mild to moderate in 19 trials and moderate to severe in 9 trials (one trial did not classify severity). Eighteen trials were from German-speaking countries, four from the United States, two from the United Kingdom, and one each from Brazil, Canada, Denmark, France, and Sweden. Many different SJW preparations were used in the trials. The range of daily doses varied between 240 and 1800 mg of SJW extract, but most trials used 500-1200 mg. The active comparators were the conventional pharmaceutical antidepressants fluoxetine (6 trials, dosage 20-40 mg), sertraline (4 trials, 50-100 mg), imipramine (3 trials, 100-150 mg), citalopram (1 trial, 20 mg), paroxetine (1 trial, 20-40 mg), maprotiline (1 trial, 75 mg), and amitriptyline (1 trial, 75 mg). Treatment duration lasted 4 weeks (1 trial), 6 weeks (19 trials), 7 weeks (1 trial), 8 weeks (5 trials) or 12 weeks (4 trials).

The methodological quality of each trial was assessed by at least 2 independent reviewers using Jadad scales, and the majority of studies were of high quality (Jadad score of 5 out of 5). The report contains a table listing all of the included trials and their Jadad scores (a method of evaluating the design quality of a clinical trial). Data were extracted from the reports and a meta-analysis was conducted. The main outcome measure for assessing effectiveness was the response rate according to the Hamilton Rating Scale for Depression (HAMD), the Montgomery Åsberg Depression Rating Scale (MADRS), or Clinical Global Impression Index (CGI) scales. The main outcome measure for adverse effects (AEs) was the number of patients who dropped out due to AEs.

In the placebo-controlled studies, patients receiving SJW were significantly more likely to be treatment responders (responder rate ratio = 1.48; 95% CI: 1.23 – 1.77), but study results were highly heterogeneous. Variables affecting the heterogeneity were baseline depression values (higher values had smaller effect size), precision of the study (more precise studies had smaller effect size), and country of origin (trials from German-speaking countries reported more positive findings). Remission rates (HAMD score < 8 or < 7) were significantly higher in patients receiving SJW than in those receiving placebo (ratio = 2.77; 95% CI: 1.80 – 4.26).

In comparator trials, an analysis based on the HAMD revealed no differences between the groups (RR = 1.01; 95% CI: 0.93 – 1.09). Analysis based on the CGI also found no relevant differences (RR = 1.01; 95% CI: 0.94 – 1.09). Studies from German-speaking countries reported findings that were slightly more favorable to SJW. However, in the multivariable meta-regression analysis, trials with patients having higher HAMD baseline values had less favorable results (P = 0.010), while country of origin and precision had no significant influence in comparator trials.

The number of patients dropping out for AEs was similar among patients receiving SJW and placebo (OR = 0.92; 95% CI: 0.45 – 1.88). Patients treated with SJW were less likely to drop out of the study due to AEs than patients treated with either older or newer (SSRIs) pharmaceuticals. More patients treated with older pharmaceuticals had AEs than those taking SSRIs. Despite the documented safety of SJW extracts with respect to lack of AEs, there was a short note mentioning the potential of adverse drug interactions for which SJW is increasingly well known, although such interactions were not detected in the clinical trials in this review.

Overall the findings support the use of SJW for treatment of major depression. It appears that SJW is effective and safe.

The authors of this 147-page report conclude:

Patients suffering from depressive symptoms who wish to use a St. John’s wort product should consult a health professional. Using a St. John’s wort extract might be justified, but important issues should be taken into account: St. John’s wort products available on the market vary to a great extent. The results of this review apply only to the preparations tested in the studies included, and possibly to extracts with similar characteristics. Side effects of St. John’s wort extracts are usually minor and uncommon. However, the effects of concomitant drugs might be compromised.

In previous versions of this Cochrane review (published in 1998 and 2005), included trials were not restricted to patients with major depression, whereas the inclusion criteria of the present review were restricted to patients with major depression. This is not to say that SJW is ineffective in depressed patients who are not classified as having major depression. Rather, this restriction may make the results more generalizable.

A probable limitation of the review’s results is that the authors concluded that the results pertain only to preparations evaluated in the review; the clinical results cannot be projected onto non-clinicallytested SJW preparations. A table shows that the following commercial SJW preparations were used: Hypericum extract LI160 (aka Jarsin®, produced by Lichtwer Pharma, Berlin, Germany), HYP611 (aka Felis® 650, produced by Biocur Arzneimittel GmbH, Holzkirchen, Germany), STW3-1 (Steigerwald Arzneimittelwerk, Darmstadt, Germany), STW3IV (Steigerwald), STW3-VI (Steigerwald) LoHyp-57 (Dr. Werner Loges and Co, GmbH, Winsen, Germany), WS5572 (W. Schwabe Pharmaceuticals, Karlsruhe, Germany), WS5573 (Schwabe), WS5570 (Schwabe), Iperisan (Laboratorio Marjan, Sao Paulo, Brazil), STEI 300 (Steiner Arzneimittel, Berlin, Germany), ZE117 (Max Zeller Sohn, Romanshorn, Switzerland), and Psychotonin forte (Steigerwald).

—Heather S. Oliff, PhD