Extracts of Hypericum perforatum (St. John's wort) are used to treat depression, although there is some conflicting evidence about their efficacy. Potential risks associated with the use of unregulated agents such as Hypericum include drug interactions. In addition, patients with depression may be inadequately treated. Several studies and a meta-analysis determined that Hypericum was more effective than placebo and as effective as amitripty-line, imipramine, and fluoxetine in the treatment of mild to moderate depression. Other studies did not show that Hypericum is better than placebo in the treatment of depression. There is a lack of trials that compare Hypericum with selective serotonin reuptake inhibitors, insufficient evidence about ongoing treatment, and only partial information about using this agent in the treatment of clinically defined depression. The Hypericum Depression Trial Study Group addressed some of these issues.

In a randomized, double-blind, placebo-controlled trial, patients were given either Hypericum, sertraline, or placebo. Each agent was used for at least eight weeks and continued for up to 18 weeks in some patients. Adult patients who met the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., for major depression were included. Patients were excluded if they had attempted suicide in the past year; were pregnant or breastfeeding; had liver disease; or elevated liver enzymes; had a history of seizure disorders, psychotic disorders, or substance abuse; and certain other criteria.

Patients were randomly assigned to Hypericum (900 mg per day of extract standardized to 0.12 percent to 0.28 percent in three divided doses), sertraline (50 mg per day in three divided doses), or placebo three times daily. After three to four weeks, the doses could be increased to 1,200 mg for Hypericum and 75 mg for sertraline. If the patient was still showing mild to moderate illness, these doses could be increased to 1,500 mg and 100 mg, respectively. Maximum drug doses after the eight-week trial were 1,800 mg and 150 mg, respectively. If adverse effects occurred, the doses could be reduced.

The efficacy end points included a decrease in the Hamilton Depression Scale (HAM-D) score and the incidence of full response at the end of the trial. The Clinical Global Impression (Improvement) scale (CGI-I) was used secondarily to assess response. A full response was defined as a HAM-D score of 8 or less and a CGI-I score of 1 (very much improved) or 2 (much improved). Partial response was defined as a decrease in the HAM-D score of at least 50 percent, with a total score of 9 to 12, and a CGI-I score of 1 or 2. After eight weeks of treatment, a relapse was defined as a HAM-D score of at least 20 and a CGI-I score or 4 or more.

There were 340 patients randomized to one of the three treatment groups. The groups were similar at baseline. Just over one quarter of the patients were withdrawn from each of the three groups before completing the eight-week trial. The rates of full response did not differ between the Hypericum group and the placebo group at the end of the trial. When the CGI-I scores were compared, the sertraline group fared better than the placebo group and the Hypericum group.

Overall, of the two main outcome measures, neither Hypericum nor sertraline was superior to placebo. Sertraline showed more improvement on the CGI-I scale than Hypericum did. For some reason, only about one third of patients in the sertraline group who experienced partial response had their medication increased to the maximum possible dose; slightly more than one half of the Hypericum and placebo groups had their doses maximized. The authors speculate that this may be part of the reason that the sertraline-treated patients did not seem to show as much improvement as expected.

The authors conclude that the use of Hypericum cannot be supported unless future trials clearly show its efficacy. Antidepressant medications have been proved clinically efficacious, and Hypericum should not be used as a replacement for proven agents in patients with major depression.