Treatment of Major Depression With St. John's Wort (Hypericum)
Treatment of Major Depression With St. John's Wort (Hypericum)
The purpose of this trial is to study the acute efficacy and safety of a standardized extract
 of the herb Hypericum perforatum (St. John's Wort), called hypericum for purposes of this
 trial, in the treatment of patients with major depression.

 Clinical depression is a serious medical disorder that can be debilitating and can lead to
 suicide. There is growing public interest in claims that hypericum may be an effective
 treatment for depression. Although it is widely prescribed in Europe, no studies of its
 long-term use have been conducted, and published studies have treated different types of
 patients and have used several different doses. The toxicity and side effects of hypericum
 appear to be substantially less than those of standard tricyclic antidepressant medications,
 and thus hypericum may be more acceptable to patients. In addition, the cost is significantly
 less than standard antidepressant medications. Published studies assessed acute efficacy and
 lasted between 4 and 12 weeks (most being 4-6 weeks). The longer-term effects of hypericum
 have not been evaluated. There is a need for a large-scale, controlled clinical trial to
 assess whether Hypericum has a significant therapeutic effect in patients with clinical
 depression.

 Patients are assigned randomly (like tossing a coin) to receive St. John's wort, Sertraline
 (Zoloft), or a placebo (sugar pill) for 8 weeks. This is a double-blind study, meaning
 neither the patient nor the doctor will know which treatment is being assigned. Patients who
 respond well to the treatment will continue on the assigned treatment for an additional 4
 months. Patients will have regular follow-up visits to monitor their symptoms and any side
 effects they experience.
This trial will determine the acute antidepressant efficacy of a standardized extract of
 hypericum (St. John's Wort) for the treatment of major depressive disorder.

 For this trial, the primary efficacy analysis will be evaluated at 8 weeks. For observational
 purposes, a 4-month double blind continuation (6 months total treatment) in treatment
 responders would enable an approximation of the effectiveness of maintenance treatment with
 this medication. No published studies have included a selective serotonin re-uptake inhibitor
 (SSRI) comparator. While this trial will not compare the efficacy of hypericum to an SSRI,
 having an SSRI arm of sertraline (Zoloft) will allow an evaluation of the validity of the
 trial.

 336 eligible patients will be randomly assigned to double-blind treatment with hypericum,
 sertraline, or placebo following a one-week placebo lead-in period (between screening and
 baseline). All treatment groups will consist of 112 patients and will be followed for an
 eight-week period. Treatment responders will be continued on the randomly assigned treatment
 arm for an additional 18 weeks.
Inclusion Criteria:

 -  Major depression assessed by Structured Clinical Interview for DSM-IV Axis I Disorders
 (SCID; First et al, 1995)

 -  Minimum score greater than or equal to 20 on the 17-item Hamilton Depression (HAM-D)
 Scale at screen and at baseline

 -  GAF of 60 or less (moderate symptoms) at screen and at baseline

 -  HAM-D cannot decrease by 25% or more between screening and baseline

 -  Capacity to give informed consent and to follow study procedures.

 -  Abstinence or effective method of contraception throughout the study

 Exclusion Criteria:

 -  Scores greater than 2 on the "suicide" item of HAM-D, or history of suicide attempt(s)
 in the past 12 months

 -  Current suicidal or homicidal risk, as determined by the investigator

 -  Women of childbearing age who are pregnant, planning pregnancy in the next 6 months,
 breast-feeding, or not using medically acceptable means of birth control (hormonal
 treatment such as birth control pill, injection or implant, IUD, or double barrier of
 condom and diaphragm together is acceptable; primary use of condom, sponge or
 diaphragm alone (single barrier) is not acceptable because these may carry a higher
 rate of failure when used alone

 -  Clinically significant liver disease (such as hepatitis, cirrhosis, etc); or
 clinically significant elevation of liver enzyme tests (two times the upper limit of
 normal; asymptomatic Gilbert's syndrome is not an exclusion). 4. Serious or unstable
 medical illness. 5. History of seizure disorder (other than febrile).

 -  Any of the following DSM-IV diagnoses by SCID: current (within past 6 months) alcohol
 or other substance abuse disorder; schizophrenia, schizo-affective, or other psychotic
 disorder; bipolar disorder; current panic disorder or obsessive compulsive disorder;
 history of psychotic features of affective disorder (mood congruent or incongruent)

 -  Clinical or laboratory evidence of untreated or unstable thyroid disorder

 -  Failed to respond to at least two adequate antidepressant trials (defined as 6 weeks
 or more treatment with either greater than or equal to 150 mg imipramine, or tricyclic
 equivalent), or greater than or equal to 60 mg of phenelzine, or MAOI equivalent, or
 greater than or equal to 100 mg of sertraline, or its SSRI equivalent

 -  Have taken sertraline or any form of hypericum during this current episode of
 depression at any dose level, daily, for at least one month, within the past 6 months

 -  Current (within past 6 months) use of other prescription or non-prescription drugs,
 including anticonvulsants and other medications with significant psychotropic
 properties, antiretroviral medications, cyclosporine, digoxin, coumadin, dietary
 supplements, natural remedies, and botanical preparations (eg, hypericum, kava,
 valerian)

 -  Have had other investigational drugs within 30 days or other psychotropic medication
 within 21 days of baseline (6 weeks for fluoxetine)

 -  Known allergy or hypersensitivity to the study medications

 -  Positive drug urine screen

 -  Have been in psychotherapy for 2 months or less at the time of enrollment into the
 study

 -  Receiving psychotherapies which are specifically designed to treat depression, eg,
 interpersonal psychotherapy during the study period

 -  Mental retardation or cognitive impairment, or any disorder that might interfere with
 their ability to consent or follow study procedures and requirements