Is St. John’s wort an effective treatment for major depression?

BACKGROUND: A meta-analysis of 23 randomized trials published in 1996 found St. John’s wort (SJW) to be effective for treating depressive disorders. However, the trials have been criticized for such flaws as lack of standard diagnostic criteria, short duration, wide dose variation, failure to blind, lack of placebo use, and suboptimal doses of comparison antidepressants. This trial aimed to address those concerns.

POPULATION STUDIED: Patients with major depressive disorder according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition were recruited from 11 academic medical centers’ psychiatry outpatient clinics, and 200 met criteria for randomization. Treatment and control groups were similar, with a mean age of 41.4 years, 64% women, and 85% white. This was the first episode of major depression for 35% of the sample. Patients were excluded for risk of suicide, psychotropic medicine use, history of treatment-resistant depression, or recent enrollment in psychotherapy. Other conditions that led to exclusion were cognitive disorders, posttraumatic stress disorder, eating disorders, substance use disorder, panic disorder, bipolar or psychotic disorders, and borderline, antisocial, or schizotypal personality disorders.

STUDY DESIGN AND VALIDITY: This study was a multisite placebo-controlled trial. Allocation of assignment was concealed. The taste and smell of SJW were masked by using an odorless SJW extract. All patients received placebo for 1 week, and 16 patients were excluded either because they experienced a 25% improvement on the Hamilton Rating Scale for Depression (HAM-D) while taking placebo or had very low HAM-D scores after 1 week. Patients were then randomized to receive either 300 mg of SJW extract or an identical placebo tablet 3 times daily. At 4 weeks the dose increased to 4 times daily if no improvement occurred. The subjects were followed up for 8 weeks. The researchers addressed many of the concerns about previous studies by using standard diagnostic techniques and a standardized drug dose. The use of a placebo run-in period decreases the overall response rate of both groups. Therefore, it should not affect statistical significance in comparing the 2 groups, but the response rate may appear lower than the results seen in clinical practice. This study had the power to detect a 17.5% difference in response between SJW and placebo. Smaller differences may exist but may not be clinically meaningful.

OUTCOMES MEASURED: The researchers measured efficacy of treatment using standard assessment tools. The primary measure of efficacy was the difference in the rate of improvement between SJW and placebo on total HAM-D scores over 8 weeks. The researchers also looked for differences in response (50% improvement in HAM-D scores) and remission (a HAM-D score of ≤7 and a clinical global impression score of 1-2), and they did a subgroup analysis of patients with mild depression (HAM-D scores <23).

RESULTS: Of the 98 patients completing the placebo run-in and randomized to SJW, 80 completed the trial compared with 87 of 100 placebo-assigned patients. Both intention-to-treat and completer analysis were performed for all measures of effect. The rate of improvement over time was not significantly different between SJW and placebo (P=.58). The 26.5% clinical response for SJW was not significantly better at 8 weeks than the 18.6% response for placebo (P=.15). Remission rates were significantly higher for SJW compared with placebo in the intention-to-treat analysis (14.3%; 95% confidence interval [CI], 8.6%-22.8% vs 4.9%; 95% CI, 2.0%-11.3%, P=.02; number needed to treat=11). The only significant adverse outcome was headache, which occurred in 41% of patients taking SJW (number needed to harm=7).