NIMH St. John's wort study RFP outlines eight-week trial for "major depressive disorder".

ST. JOHN's WORT DEPRESSION ACUTE TREATMENT STUDY will compare the safety and clinical efficacy of eight weeks of daily treatment with 900 mg standardized Hypericum perforatum, or St. John's wort, a botanical dietary supplement commonly used as an antidepressant, to placebo in patients found to suffer from a major depressive disorder. The three-arm trial, sponsored by the National Institute of Mental Health, will include an examination in the third arm of patients receiving eight weeks of treatment with a prescription selective serotonin re-uptake inhibitor (SSRI) antidepressant "to document the sensitivity of the trial," NIMH said. However, "this trial will not have sufficient power to compare SSRI to Hypericum," the study protocol states.

The proposed study is outlined in a request for proposals issued June 6 by NIMH in conjunction with the National Institutes of Health Office of Alternative Medicine. The NIH Office of Dietary Supplements also is a co-sponsor. Research proposals are due July 21. Each study arm will contain 112 subjects, the RFP estimates -- a total of 336 study participants. The document stipulates that the research contract will last three years, with an option for two additional years.

Those patients who respond to the randomly assigned treatment Hypericum in the eight-week acute treatment phase will continue to receive treatment for an additional 18 weeks "to determine if acute efficacy of Hypericum can be maintained long-term," the RFP states.

"Patients treated with Hypericum (900 mg/day) will achieve significantly lower final...scores" on the Hamilton Rating Scale for Depression (HAM-D) "at week eight (or endpoint) than patients treated with placebo," the research hypothesis states. "Adverse events will not differ significantly between the Hypericum and placebo groups, and Hypericum will be better tolerated than the SSRI," it predicts. In the long-term, patients treated with St. John's wort are expected to have fewer relapses than those treated with placebo, NIMH states. One episode of depression frequently leads to other, often more severe, episodes of the disease.

Treatment non-responders and subjects who relapse "will be discontinued from the original randomization treatment and will be referred for further treatment as clinically appropriate" -- including "standard open-label medication," the RFP states. Open-label treatment of non-responders and relapsers during the six-month term of the study "will more closely approximate the ethical, real-life treatment of depression and will provide preliminary information about the nature of the non-responders, e.g., are they nonresponsive only to study medication," the document adds. This group of patients will be "followed until their current episodes [have] been stabilized."

The study population will include males and females age 18 and older, selected from an "outpatient sample of patients with current major depressive disorder" diagnosed through several depression severity scales. Among other criteria, individuals excluded from the study will be: those judged to be suicidal or homicidal; pregnant women or women not using a "medically acceptable" means of birth control; those suffering from "serious or unstable illness"; patients with a history of seizure disorder; those with untreated thyroid disorder; patients who have failed to respond to at least one adequate antidepressant trial; anyone who has been in psychotherapy for two months or less at enrollment; and anyone using an Rx or nonprescription "psychotropic" substance (including St. John's wort, kava or valerian).

After screening, participants will enter a one-week "placebo lead-in period during which no psychotropic medication will be allowed." Baseline assessment of depression will be done at the end of the first week. "Patients who improve by showing a 25% decrease in their [depression rating] or experience suicidal ideation or psychotic symptoms between the screen and baseline visits will be excluded from the study," the RFP states.

After baseline evaluation, eligible patients will be randomized to one of the three study arms. At weekly visits, participants will be administered a myriad of rating instruments to monitor depression severity and reaction to treatment (including the HAM-D; Clinical Global Impressions; Beck Depression Inventory; Kellner's Symptom Questionnaire; Treatment Emergent Symptom Scale; and Global Assessment Scale).

Participants will receive blood count tests, urinalyses and urine toxicology screens, "clinical chemistry" bloodwork and electrocardiograms during screening, at week eight and at week 26 (or early discontinuation) to monitor for safety and adverse events. Weight, oral temperature, pulse and blood pressure will be recorded at weeks one, two, four, eight, 14 and 26. Physical exams will be performed at screen, week eight and at endpoint (week 26 or early discontinuation).

The "primary test of outcome will be based on the assessment of the differences between the Hypericum and placebo groups in depression severity between baseline and week eight or endpoint (relapse)," the RFP states. The HAM-D score at endpoint will serve as the "primary dependent measure." All other efficacy measures will serve as secondary outcome measures, as will the number of respondents at endpoint.

Full responders will include those who: exhibit a 50% reduction in HAM-D score from baseline; have a final Hamilton score of eight; and have a CGI-Improvement rating of one or two. Partial responders will be patients who meet at least one of the three criteria.

During the continuation phase of the study, patients will continue receiving the treatment they were administered in the acute phase. They will have monthly visits and be able to contact investigators by telephone between visits to report "significant" changes in mood or side effects.

The draft protocol notes that Hypericum "has been used since the time of ancient Greece for its many medicinal properties," and that "modern usage" includes the treatment of wounds, kidney and lung ailments, insomnia and depression. The plant contains hypericin, "a red pigment," and "similar compounds, which have been assumed to be the primary active constituent(s) in this plant genus." The RFP notes that Hypericum "has become increasingly popular in Germany," where it is prescribed for depression.

The protocol also points to the meta-analysis of 23 Hypericum trials covering 1,757 patients, appearing in the August 1996 issue of the British Medical Journal. Conducted by Klaus Linde, et al., Ludwig Maximilians Universitat, Munich, the meta-analysis concluded that Hypericum is significantly superior than placebo in the treatment of mild to moderate depression ("The Tan Sheet" Aug. 5, 1996, p. 16). The researchers also concluded that the herb may work as well as other standard antidepressant treatments and produce fewer side effects.

The RFP notes that side effects, although mild, have included dry mouth, dizziness, constipation, "other unspecified gastrointestinal symptoms" and confusion. Fewer than 2% of those taking the herb discontinue use due to side effects. There are no data that assess the "potential for a fatal overdose with Hypericum," the draft states; "further post-marketing surveillance studies could provide more information on the overall toxicity of Hypericum as has been done with other antidepressants," the document concludes. The draft protocol also reviews the ingredients and pharmacokinetics of the botanical, and suggests possible ways that Hypericum "exerts its activity" -- such as affecting dopamine or serotonin receptors.