NIH
Press Release:
Study Shows St. John's Wort Ineffective for Major Depression of Moderate
Severity
An extract of the
herb St. John's wort was no more effective for treating major depression
of moderate severity than placebo, according to research published in the
April 10 issue of the Journal of the American Medical Association.1
The randomized, double-blind trial compared the use of a standardized
extract of St. John's wort (Hypericum perforatum) to a placebo for
treating major depression of moderate severity. The multi-site trial,
involving 340 participants, also compared the FDA-approved antidepressant
drug sertraline (Zoloft®) to placebo as a way to measure how sensitive the
trial was to detecting antidepressant effects.
"Many Americans use
dietary supplements like St. John's wort for depression without consulting
a physician," says principal investigator Jonathan R.T. Davidson, M.D.,
professor of psychiatry and director of the Anxiety and Traumatic Stress
Program at Duke University Medical Center. "We felt there was a need to
conduct a trial that could help us determine where St. John's wort fits in
the overall management of depression."
The trial, funded
jointly by the National Center for Complementary and Alternative Medicine
(NCCAM), the National Institute of Mental Health (NIMH), and the Office of
Dietary Supplements (ODS), all components of the National Institutes of
Health, was launched in response to growing use of St. John's wort in the
United States and a need for more definitive data on its use for different
types of depression. Although several smaller European studies have
suggested that St. John's wort is useful in treating mild to moderately
severe depression, experts who reviewed those studies concluded that they
had limitations and more rigorous trials were needed before firm
conclusions could be drawn. Thus, NCCAM and its partners launched one of
the first large-scale, multi-site clinical trials of St. John's wort in
the United States.
"Our commitment is
to apply exacting scientific methods to studying popular complementary and
alternative medicine practices and to publish the results of such studies
in critical peer-reviewed journals, so that the public and practitioners
can make the most informed decisions about them," says Stephen E. Straus,
M.D., NCCAM Director. "This study represents one of our first 'downpayments'
on this commitment."
"St. John's wort is
taken by many people for the relief of mild to moderate depression," notes
Paul M. Coates, Ph.D., Director of ODS. "It is important to assess the
efficacy and safety of this and other commonly used dietary supplement
ingredients."
According to NIMH,
major depression affects approximately 9.9 million American adults age 18
and older in a given year and is a leading cause of disability in the
United States. A person experiencing a major depressive episode, according
to the American Psychiatric Association's Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition (DSM-IV), suffers from a
depressed mood or loss of interest in normal activities that lasts most of
the day nearly every day for at least 2 weeks; this mood can last longer
if untreated. Other than depressed mood or loss of interest, symptoms
include at least four of the following: significant weight loss or gain,
sleep disturbances, agitation or unusual slowness, fatigue or loss of
energy, feelings of worthlessness or guilt, lack of concentration, or
recurrent thoughts of death or suicide.
"Major depression is
a serious public health concern. Determining whether an herbal product,
such as St. John's wort, can work as a treatment is important," said
Richard K. Nakamura, Ph.D., Acting Director, NIMH. "We are always seeking
treatment options to add to the list of proven medications and
psychotherapies available to those suffering from depression."
Study participants'
initial diagnosis and severity of depression were confirmed using three
primary measures: the DSM-IV depression criteria, the Hamilton
Depression Scale (HAM-D), and the Global Assessment of Functioning Scale
(GAF). Participants who met DSM-IV criteria for major depression,
who had initial HAM-D scores of 20 or higher, and who had at least
moderately severe major depression according to the GAF, were recruited
from 12 academic or community psychiatric research clinics across the
country. The study was conducted in two phases. The first 8-week phase, or
acute phase, measured the number of people whose depression responded to
treatment with St. John's wort (from 900 mg to 1500 mg per day),
sertraline (50 mg to 100 mg per day), or placebo; this phase was the
primary focus of the study. A second, or continuation, phase offered
patients who had responded to their initial treatment another 18 weeks of
therapy, which enabled researchers to gather data on longer-term use of
the treatments. The preparation of St. John's wort used in this study is
one sold and produced in Europe and used in many earlier, smaller
depression trials.
Two primary outcomes
were measured during the first phase of the trial: improvements in the
HAM-D scores, indicated by a reduction in score, and complete response to
treatment, indicated by overall reduction in both the HAM-D score to
normal levels and Clinical Global Impressions-Improvement Scale (CGI-I)
score. The researchers found that HAM-D scores among patients taking St.
John's wort dropped about 8.7 points on average versus approximately 9.2
points for placebo and 10.5 points for sertraline. They also found that
approximately 24 percent of patients taking St. John's wort had full
responses to treatment versus about 32 percent for placebo and 25 percent
for sertraline. The differences in these rates of response were not large
enough to be statistically significant. However, additional analyses of
the data showed that those taking sertraline improved significantly more
than those on placebo and on St. John's wort on the CGI-I, a secondary
measure of improvement. In spite of this finding, the overall response to
sertraline on the primary measures was not superior to that of placebo, an
outcome which is not uncommon in trials of approved antidepressants. In
fact, this apparent lack of efficacy occurs in up to 35 percent of trials
of antidepressants.
"Overall, we found
that patients taking either St. John's wort or placebo had similar rates
of response according to scales commonly used for measuring depression,"
says Dr. Davidson. "And, although sertraline produced no greater effect
than placebo on the primary measures, it fared better than placebo on the
Clinical Global Impressions-Improvement scale and produced results
consistent with its known benefits."
1 Hypericum Depression
Trial Study Group. Effect of Hypericum perforatum (St. John's
wort) in major depressive disorder: a randomized, controlled trial.
JAMA, 2002; 287:1807-1814. Full-text of the article is available on
the JAMA website at www.jama.com.
The Coordinating Center for the St. John's wort trial was
led by Dr. Davidson and his colleagues at the Duke University Medical
Center Department of Psychiatry and Behavioral Sciences, the Duke
Clinical Research Institute, and the Research Triangle Institute.
Background on St. John's Wort and Depression
1. What is St. John's wort?
St. John's wort (Hypericum perforatum in Latin) is a
long-living, wild-growing plant with yellow flowers. Extracts of
the plant have been used for centuries in efforts to treat mental
disorders as well as nerve pain. In ancient times, doctors and
herbalists (specialists in herbs) wrote about its use as a
sedative and treatment for malaria as well as a balm for wounds,
burns, and insect bites. Today, St. John's wort is used for
treating mild to moderate depression, anxiety, or sleep disorders.
St. John's wort remains among the top-selling botanical products
in the United States and many brands are now available and sold
over the counter as dietary supplements.
2. Does St. John's wort have side effects or
interact with prescription medications?
The most common side effects of St. John's wort include dry mouth,
dizziness, gastrointestinal symptoms, increased sensitivity to
sunlight, and fatigue. Research from the National Institutes of
Health (NIH) reveals that St. John's wort may reduce the
effectiveness of several drugs by speeding up activity in a key
pathway responsible for their breakdown. The end result is that
blood levels of these drugs decrease because the body breaks them
down faster making the drugs less effective. St. John's wort
especially affects indinavir, a protease inhibitor used to treat
HIV infection. It may also affect cyclosporine, a drug used to
help prevent organ transplant rejection, and other drugs that work
through this same pathway in the body, such as birth control pills
and medications for heart disease and depression. The U.S. Food
and Drug Administration (FDA) issued a Public Health Advisory on
February 10, 2000, warning physicians of these potential adverse
interactions and advising them to alert their patients (see
www.fda.gov/cder/drug/advisory/stjwort.htm).
3. What was the St. John's wort extract used
in this trial?
The St. John's wort extract used in this study was LI-160,
manufactured by Lichtwer Pharma, AG (Berlin, Germany). It was
selected because it is a well-characterized and well-studied
extract of St. John's wort that had published literature
supporting its possible efficacy in treating depression. The
entire supply of St. John's wort extract used in the study came
from one batch and was standardized to between 0.12 and 0.28
percent hypericin. Hypericin is thought to be one of the primary
active ingredients in St. John's wort.
4. What is major depression?
Major depressive disorder, also known as major depression, is the
most common type of depressive illness. Symptoms usually develop
over days, weeks, or months. They can cause distress and/or
interfere with the ability to work, study, sleep, eat, and enjoy
once-pleasurable activities. The description of a person
experiencing a major depressive episode, as found in the
Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition (DSM-IV), is that of someone who may feel sad,
irritable, hopeless, discouraged, tired, worthless, or guilty much
of the time. The person also often cannot think clearly,
concentrate, or make decisions. This depressed mood lasts most of
the day nearly every day for a period of at least 2 weeks.
Untreated, the depression can last for 6 months or longer. Other
than depressed mood and/or loss of interest or pleasure, symptoms
include at least four of the following:
- Significant weight gain or loss
- Disturbance of normal sleeping patterns
(insomnia, hypersomnia)
- Agitation or unusual slowness
- Fatigue or loss of energy nearly every day
- Feelings of worthlessness or guilt
- Diminished ability to think or concentrate
- Recurrent thoughts of death or suicide.
Major depression can vary in degree from mild to
moderate to severe. In mild cases, there may be some
significant distress or interference with daily activities at
work, at home, and in social life. In moderate depression,
problems and impairments in these areas are more pronounced. If
the depression is severe, the person may lose completely the
ability to function.
5. Are there proven treatments for major
depression?
Fortunately, major depression can be successfully treated.
Treatments that have been scientifically proven include a variety
of antidepressant medications approved by the FDA and certain
psychotherapies, such as cognitive-behavioral therapy and
interpersonal therapy. A first step toward getting treatment for
depression is a complete physical examination and evaluation by a
doctor. The physician can rule out medical conditions, such as a
viral infection or thyroid disorder, that can cause the same
symptoms as depression.
6. Why did NIH fund a trial of St. John's
wort?
There is considerable public interest in the possibility that St.
John's wort may be an effective treatment for depression. These
claims are based on findings from research studies conducted in
Europe; however, these studies had several limitations. According
to the researchers who led this NIH study, important issues have
been raised regarding the existing studies, including: limited
information about the use of St. John's wort in clinically defined
major depression; lack of placebo-controlled trials that have
included a separate, selective serotonin reuptake inhibitor (SSRI)
antidepressant arm; and absence of data regarding long-term use of
the extract. In addition, there were concerns that many of the
studies had smaller numbers of participants.
Because of the growth in Americans' use of St.
John's wort in recent years and the need to answer important
remaining questions about the herb's efficacy and long-term use
for depression, NIH launched a large study of St. John's wort in
1997. This 4-year, $6 million study was sponsored by the National
Center for Complementary and Alternative Medicine (NCCAM), the
National Institute of Mental Health (NIMH), and the NIH Office of
Dietary Supplements (ODS). The main purpose of the trial was to
determine whether a well-standardized extract of St. John's wort
is effective in the treatment of adults suffering from major
depression of moderate severity.
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About the Trial
7. How many people participated in the trial,
and what were their characteristics?
There were 340 participants in the trial. The average age of
participants entering the study was approximately 42 years. Nearly
two-thirds were female (65.9 percent). The ethnic composition of
the group was approximately 76 percent White, 10 percent
Black/African American, 8 percent Hispanic, and 6 percent "other."
8. How were participants selected?
Eligible participants were men and women ages 18 and older with
depression who were confirmed prior to entering the study as
having a diagnosis of major depressive disorder as defined by the
DSM-IV. In addition, to be eligible, participants had to
have at least a moderate level of depressive symptoms as measured
by the Hamilton Depression Scale (HAM-D), and at least a moderate
level of functional impairment from depression on the Global
Assessment of Functioning Scale (GAF) of the DSM-IV.
Individuals with severe symptoms who were in need of
hospitalization, at high risk for suicide, or having any signs of
psychosis (such as hallucinations or delusions) were excluded.
These eligibility criteria provided a well-defined group of
participants that would represent adults with major depression
whose symptoms were significant, though not completely
incapacitating.
9. What are some of the primary
characteristics of this trial?
This trial had three treatment arms. Participants were assigned at
random to one of three treatments for an initial 8 weeks: St.
John's wort, an SSRI antidepressant medication--sertraline
(Zoloft®), or placebo (inactive pills that looked exactly like St.
John's wort or sertraline tablets). This was a double-blind study,
meaning neither the participants nor the clinical staff knew which
treatments were being assigned. Participants who responded well to
their assigned treatment could continue on it for an additional 4
months during the trial's second, or continuation, phase. This
phase allowed researchers to gather additional data on the safety
and longer-term effects of the treatments. This was the first
trial to include a long-term followup phase studying the use of
St. John's wort. Participants had regular followup visits to
monitor symptoms and any side effects. If participants experienced
significant worsening of depression, suicidality, or psychosis,
they were withdrawn from the study; offered FDA-approved treatment
with at least three followup visits, based on need; and referred
to a psychiatrist not involved in the study for care.
To determine the efficacy of St. John's wort for
major depression, the group of participants assigned to St. John's
wort was compared to the group assigned to placebo during the
first 8 weeks of treatment. Two primary outcomes were measured:
- improvements in the HAM-D total score,
indicated by a reduction to normal levels in score;
- complete response to treatment, the
percentage of participants essentially free of symptoms of
depression, also called "in remission."
A complete response was determined by both a reduction in the
HAM-D score and the clinician's overall estimate of improvement,
as measured by the Clinical Global Impressions-Improvement Scale
(CGI-I). In addition to the tests already mentioned, several
secondary measures of efficacy were used, including
clinician-rated and patient-self-administered scales.
10. What are the main results of this trial?
The trial found no statistically significant difference between
St. John's wort and placebo on improvement in HAM-D scores or
percentage of complete responses. The percentage of participants
in remission from major depression at the end of the 8-week
initial treatment phase was approximately 24 percent for St.
John's wort and about 32 percent for placebo. Overall, the
percentage of participants who improved either partially or
completely was about 38 percent for St. John's wort and 43 percent
for placebo. These findings suggest that St. John's wort is not
effective for the treatment of major depression in adults with a
moderate level of symptoms. This conclusion is supported by
another recently reported placebo-controlled study (Shelton, et
al., 2001).
The study also found no significant difference between sertraline
and placebo on either primary outcome, with about 25 percent of
the participants on sertraline reaching remission as compared to
about 32 percent on placebo. The rate of response overall was
about 49 percent for sertraline and 43 percent for placebo, but
this difference was not statistically significant. At the same
time, additional planned analyses of the data did show that
sertraline was superior to placebo on other secondary tests of
efficacy, such as the CGI-I alone. The results of the sertraline
versus placebo comparison indicate that the sensitivity of this
study to antidepressant effects was limited. In other words, even
two treatments (sertraline and placebo) previously proven to
differ in efficacy for major depression were found not to differ
on the primary measures used in this study.
11. Why did sertraline have no greater effect
than placebo?
The authors offer possible explanations as to why sertraline was
not superior to placebo overall in this study. First, it is known
that 35 percent of studies of approved, active antidepressants do
not show greater efficacy of the antidepressant over placebo.
Second, it is possible that the dose range for sertraline of 50 to
100 milligrams (mg) per day during the first 8 weeks, chosen to
ensure effective treatment while minimizing side effects, may not
have been adequate despite extensive discussions among study
designers to find the best possible dose range.
12. What is sertraline?
Sertraline is an FDA-approved antidepressant of the type known as
a selective serotonin reuptake inhibitor (SSRI). Serotonin is a
neurotransmitter, a chemical messenger in the brain, that is
thought to be in low supply in individuals suffering from
depression. An SSRI, such as sertraline, works by blocking the
reuptake of serotonin in the nerve cells in the brain, thus making
more serotonin available for proper brain function.
13. Why was sertraline used in the trial?
Sertraline was included in this trial to provide a third "active"
control arm to aid in assessing the trial's overall validity. That
is, whether the study measured antidepressant effects and not the
impact of unrelated factors, such as the effect of a patient
withdrawing from the study before the treatment could work. By
having a third trial arm with sertraline and comparing it to
placebo, the researchers could also measure how sensitive the
trial was to detecting any antidepressant effects of St. John's
wort. If sertraline would prove superior to placebo in this study,
as expected, then the study's ability to detect antidepressant
effects would be confirmed. In addition, the researchers chose to
use an SSRI because there is a lack of placebo-controlled trials
of St. John's wort that included an SSRI arm.
14. Who provided the extracts and drugs used
in the trial?
Lichtwer Pharma donated the St. John's wort extract in tablet form
together with matched placebo. Pfizer Inc. donated the supply of
sertraline and its matching placebo.
15. What dose of St. John's wort was used in
the NIH study?
The starting dose of St. John's wort was 900 mg per day (given in
300 mg tablets, three times a day). That dose could be increased
up to 1500 mg per day in the first 6 weeks of the study until the
end of the first phase of the trial at 8 weeks. During the second
phase of the trial, after 8 weeks, the dose could be increased to
1800 mg per day. The average dose of St. John's wort in the
initial 8 weeks of the study was about 1300 mg per day.
16. What dose of sertraline was used in the
NIH study?
The average dose of sertraline in this study was 75 mg per day.
The starting dose was 50 mg per day and could be increased to 100
mg per day in the first phase of the study. During the second, or
continuation, phase of the trial the dose could be increased to
150 mg per day. The range of dosages was comparable to that used
in clinical practice.
17. What were the most common side effects
for St. John's wort or sertraline in the study?
St. John's wort was generally well tolerated. However, people who
were taking the extract did experience more sexual dysfunction,
general swelling, and urinary frequency than those taking placebo.
Side effects for those taking sertraline included sexual
dysfunction, sweating, nausea, and diarrhea.
18. Who conducted the study?
The principal investigator for this study was Jonathan R.T.
Davidson, M.D., professor of psychiatry and director of the
Anxiety and Traumatic Stress Program at Duke University Medical
Center, Durham, NC. Dr. Davidson is an expert in clinical research
on conventional as well as complementary and alternative medical
treatments for mood and anxiety disorders. Dr. Davidson and his
collaborators in the Department of Psychiatry and Behavioral
Sciences, the Duke Clinical Research Institute, and the Research
Triangle Institute, coordinated the entire study.
19. Who else was involved in the NIH St.
John's wort trial?
The scientific aspects of the study were monitored by NIMH and
NCCAM staff with the input of an independent group of advisors who
were consulted regularly on the protocol and study progress before
and during the course of the project. This group included the
following: four professors of psychiatry at different universities
with specific expertise in the treatment of depression; a
professor of pharmacology with expertise in clinical research,
pharmacokinetics, and metabolism; a professor of statistics; an
expert in botanical medicinal products; and an advocate for people
with depression. The study's safety and data quality were
monitored on a quarterly basis by the NIMH Data and Safety
Monitoring Board, a group including experts in clinical studies
and patient representatives. In addition, this study was monitored
by the FDA under an Investigational New Drug application filed by
Lichtwer Pharma.
20. Where did the study take place?
The study took place in 12 community and academic psychiatric
research centers across the United States. The sites and lead
investigators were as follows:
- Dean Foundation, Middleton, WI (Leslie
Taylor, M.D.)
- Duke Medical Center, Durham, NC (Murali P.
Doraiswamy, M.D. and Richard Weisler, M.D.)
- Eastside Medical Center, New York, NY (Ram K.
Shrivastava, M.D.)
- Emory University, Atlanta, GA (Charles B.
Nemeroff, M.D., Ph.D. and Jeffrey Kelsey, M.D., Ph.D.)
- Harbor-UCLA Medical Center, Torrance, CA (Khae-Ming
Lin, M.D.)
- Feighner Research Institute, San Diego, CA
(John P. Feighner, M.D.)
- McLean Hospital, Belmont, MA (Jonathan O.
Cole, M.D.)
- Seattle Clinical Research Center, Seattle, WA
(Peter D. Londborg, M.D.)
- Stanford University, Palo Alto, CA (Alan F.
Schatzberg, M.D. and Charles Debattista, M.D.)
- University of Cincinnati, Cincinnati, OH
(Paul Keck, M.D.)
- University of South Florida, Tampa, FL (David
V. Sheehan, M.D.)
- University of Texas Southwestern Medical
Center, Dallas, TX (Madhukar H. Trivedi, M.D.)
21. How long did it take to complete the
trial?
Recruitment of participants took place from December 1998 to June
2000. Analysis of results was completed in 2001, and the paper was
submitted for publication in late 2001.
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Conclusion and Future Research
22. Should St. John's wort be used for major
depression?
At this time, it is not known what role St. John's wort should
play in the management of depression. The results of this study
indicate that St. John's wort is not effective in treating major
depression of moderate severity.
23. Will NIH conduct more research on St.
John's wort?
NCCAM, NIMH, and ODS are planning to conduct a study of the
efficacy and safety of St. John's wort for the treatment of minor
depression.
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For Additional Reading
Hypericum Depression Trial Study Group. Effect of
Hypericum perforatum (St. John's wort) in major depressive
disorder: a randomized, controlled trial. JAMA, 2002;
287:1807-14.
Shelton RC, Keller MB, Gelenberg AJ, et al.
Effectiveness of St. John's wort in major depression. JAMA,
2001; 285:1978-86.
Linde K, et al. St. John's wort for depression -
an overview and meta-analysis of randomized clinical trials. Br.
Med J, 1996; 313:253-8.
American Psychiatric Association. Diagnostic
and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV).
Washington, DC: American Psychiatric Press, 1994.
NCCAM, St. John's Wort Fact Sheet, available
online at
nccam.nih.gov/fcp/factsheets/stjohnswort/stjohnswort.htm,
updated April 2002.
NIMH depression information available at
www.nimh.nih.gov/publicat/depressionmenu.cfm.
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The Coordinating Center for the St. John's wort
trial was led by Dr. Davidson and his colleagues at the Duke
University Medical Center Department of Psychiatry and Behavioral
Sciences, the Duke Clinical Research Institute, and the Research
Triangle Institute. For more Duke University Medical Center news
visit
www.dukemednews.duke.edu.
The National Center for Complementary and
Alternative Medicine (NCCAM) is dedicated to exploring complementary
and alternative medical (CAM) practices in the context of rigorous
science, training CAM researchers, and disseminating authoritative
information to the public and professionals. For additional
information on CAM, call toll free 1-888-644-6226 or visit
nccam.nih.gov.
The National Institute of Mental Health (NIMH) is
committed to reducing the burden of mental illness through research
on mental disorders and the underlying basic science of brain and
behavior. For more information about depression or other mental
health disorders, call NIMH Public Inquiries at (301) 443-4513 or
visit www.nimh.nih.gov.
The Office of Dietary Supplements (ODS), whose
mission is to explore the potential role of dietary supplements to
improve health care, promotes the scientific study of dietary
supplements through conducting and coordinating scientific research
and compiling and disseminating research results. For more
information call ODS at 301-435-2920 or visit
dietary-supplements.info.nih.gov.
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