April 18, 2001 (Volume 285, Number 15)

Effectiveness of St. John's Wort in Major Depression: A Randomized Controlled Trial

Shelton RC, Keller MB, Gelenberg A, et al.
JAMA. 2001;285:1978-1986

Herbal remedies for a number of medical conditions remain popular. Although many previous studies involving herbal medicines were methodologically flawed, more recent research has been of good quality. This particular study sought to confirm previous research showing that St. John's wort was an effective, safe treatment for depression.

The research was carried out at 11 academic medical centers. All participants were older than 18 years of age and had a diagnosis of major depressive disorder (without psychotic features) of at least 4 weeks' duration. All participants also had a score of at least 20 on the Hamilton Depression (HAM-D) Scale, a standardized instrument for rating symptoms of depression. Patients who previously failed to respond to an antidepressant were excluded from the study. Similarly, patients who experienced a 25% or greater improvement on the HAM-D after a 1-week run-in period on placebo were also excluded. The initial median HAM-D score for enrolled participants was 22.

Two hundred participants were randomized to receive either placebo (n = 98) or St. John's wort (n = 102) at a beginning dosage of 900 mg/day. Double blinding in the study was adequate. Several different instruments that measure depression and anxiety were used to assess participants during the 8-week study period. The dose of St. John's wort was increased to 1200 mg/day at week 4 if participants showed no previous improvement. Response to therapy was defined as a HAM-D score of 12 or less.

The therapies were compared using multiple statistical methods, including an intent-to-treat analysis. Overall, treatment with St. John's wort failed to demonstrate a significant effect over placebo in any of the outcome measures used. There was a time effect seen in both the St. John's wort and placebo groups, with 26.5% of the St. John's wort group and 18.6% of placebo group responding to therapy by week 8. However, this difference was not statistically significant. Further subanalyses of patients with milder depression also did not demonstrate an advantage of St. John's wort over placebo. There was a difference in remission rates between the 2 treatments, but these rates were very low overall.

Both placebo and St. John's wort were well-tolerated. The only symptoms identified were abdominal discomfort and headaches -- these occurred in > 10% of all participants. Headaches were more common in participants using St. John's wort.

The failure of St. John's wort to improve depression in this study stands in stark contrast to previous work that demonstrated the herbal medicine more effective than placebo and as effective as some tricyclic antidepressants. Although more research on the subject is pending, it would not seem prudent at this time to recommend St. John's wort to patients suffering from major depressive disorder.

British Medical Journal
September 2000 (Volume 321, Number 7260)

Comparison of St. John's Wort and Imipramine for Treating Depression: Randomised Controlled Trial

Woelk H
BMJ. 2000;321:536-539

This is the largest controlled trial examining the treatment of mild and moderate depression with Hypericum perforatum (St. John's wort) thus far. It was conducted by Dr. Woelk from the Giessen University, Germany and it took place in 40 different outpatient settings, including psychiatric, internal medicine, and general medicine clinics.

The goal was to compare the efficacy and tolerability of hypericum 250 mg twice daily vs imipramine 75 mg twice daily. The 6-week, randomized, double-blind study included 324 patients with an ICD-10 diagnosis of mild to moderate depression, without suicidal ideation, substance misuse, or other relevant concomitant medical condition. Patients were assessed with the HAM-D scale at weeks 1, 3, and 6; clinicians also completed the Clinical Global Impression scale, and patients completed a global impression scale that rated efficacy and tolerability.

In terms of efficacy, there was no significant difference between the 2 groups, except for the anxiety-somatization subscale of the Hamilton Scale in which the group receiving St. John's wort showed a significant advantage. The most significant difference was seen in terms of tolerability -- patients taking St. John's wort tolerated treatment better than those on imipramine, as measured by self-report scale (unfortunately data were not provided). In addition, although only 3% of those taking St. John's wort withdrew from the study because of adverse events (mainly dry mouth), the imipramine group had a 16% withdrawal rate due to adverse events.

Although no drug-drug interactions were observed in this study, caution should be exercised when considering hypericum for patients who are taking cyclosporin, digoxin, indinavir, or theophylline.

The authors conclude that treatment with St. John's wort for mild to moderate depression "is therapeutically equivalent to imipramine, but is better tolerated by patients." They suggest that in view of these results (as well as previous research), St. John's wort should be considered as a first-line treatment for mild to moderate depression, "especially in the primary care setting."

It is not clear to this reviewer why hypericum was compared with imipramine, instead of doing so with the more widely used and better-tolerated group of selective serotonin reuptake inhibitors (SSRIs). The NIH recently funded a study comparing hypericum with sertraline and placebo, but results will not be available for another 2-3 years. (PS)

[excerpted from www.medscape.com ]