F E AT U R E S

St. John’s Wort and the Treatment of Mild

to Moderate Depression
A Systematic Review
■ Kimberly Clement, MS, APRN ■ Catherine R. Covertson, PhD, RNC
■ Mary Jane Johnson, PhD, APRN ■ Karen Dearing, PhD, APRN

A systematic review of randomized controlled trials was conducted to determine the efficacy of St. John’s Wort
(SJW) in the treatment of mild to moderate depression. The Boyak and Lookinland Methodological Quality Index
was used to evaluate the studies. Despite methodological concerns, all studies demonstrated a significant drop in
the Hamilton Depression Rating Scale scores for clients taking SJW compared with placebo or pharmaceutical
antidepressants. Practitioners may find SJW a viable complementary treatment alternative to traditional medical
treatment. The results should encourage further research to validate these findings and seek the most appropriate
preparations and dosing for this popular herb. KEY WORDS: CONSORT guidelines, depression, Hypericum
perforatum, randomized controlled trial, St. John’s Wort, systematic review Holist Nurs Pract 2006;20(4):197–203

Depressive disorders affect approximately States as an alternative treatment over pharmaceutical

19 million Americans.1 Major depression is second
only to cardiovascular disease as a cause of disability
worldwide.2 An estimated 15% of people will suffer
from depression at some time in their lives, and the
incidence may be as high as 25% in women.3
Estimated annual costs in the United States alone
are $44 billion for lost production time4 and
$26 billion for treatment.5 Medications used for the
treatment of depressive disorders include selective
serotonin reuptake inhibitors, tricyclic antidepressants,
and monoamine oxidase inhibitors. Although effective
pharmaceutical antidepressants exist, some people
prefer to self-treat depression with herbal remedies,
citing a need to have personal control of their health,
concerns about prescription drug risks, barriers to
traditional healthcare, and increased awareness of
herbal preparations with improvement in depressive
symptoms with usage.6–8
St. John’s Wort (Hypericum perforatum) is the most
common herbal supplement for mild to moderate
depression. It is used more than any other
antidepressant in Europe and is accepted in the United
From the Central Utah Medical Clinic (Ms Clement); and the College of
Nursing, Brigham Young University, Provo, Utah (Dr Covertson).
Corresponding author: Catherine R. Covertson, PhD, RNC, College of Nurs-
ing, Brigham Young University, 500D SWKT, Provo, UT 84602 (e-mail:
catherine coverston@byu.edu).
medications.9 Therefore, it is important for
practitioners to be knowledgeable enough to educate
their clients about the efficacy, recommended dosages,
contraindications, and potential side effects of St.
John’s Wort (SJW) in the treatment of mild to
moderate depression. A systemic review of the
literature was conducted to better understand the use of
SJW in the treatment of mild to moderate depression.
BACKGROUND
The likely causes and risk factors of depression are
multifactorial. Depressive disorders have a hereditary
component including higher incidence of depression
in families and higher concordance rates with
depression in twins. Life changes, lifestyle,
personality, and psychological and environmental
factors as well as nutritional deficiencies have also
been linked as possible etiology of depression7,8
Alterations in the neurotransmitters, serotonin (5 HT),
noradrenaline, adrenaline, and dopamine that regulate
mood, emotional behavior, anxiety, aggression, and
sleep patterns have also been implicated.10
People of all ages, races, and social classes are at
risk for developing a depressive illness and can
become clinically depressed. Clinical depression
usually occurs for the first time between the ages of 20

197
198 HOLISTIC NURSING PRACTICE • JULY/AUGUST 2006
and 50, yet people older than 65 may be especially
vulnerable. Boys and girls are affected equally until
adolescence, after which females have more
depression than males throughout life.11
Despite effective medications, one study
determined that about 16% of prescription drug
patients use herbal remedies for various reasons.9 In
the same study, concurrent use of herbal supplements
was 22% for patients on fluoxetine.9 Some individuals
believe natural herbs are safer than traditional
medicine and pose less health risks and side effects.
However, whereas the Food and Drug Administration
(FDA) mandates that side effects of drugs are
disclosed with prescriptions, herbal apothecaries are
not regulated under the FDA and do not have to
disclose this information. Therefore, people may be
less knowledgeable about the potential adverse
reactions to herbs.
St. John’s Wort
St. John’s Wort is used widely in Europe and is used
more than any other antidepressant in Germany, thus
arousing interest in the United States.9 Although sales
have declined in recent years,12 SJW continues to be a
popular herbal remedy in the United States, and its
retail sales in the US mainstream market in 2001 were
approximately $24 million.13 The market share of
SJW in Europe is increasing.11 In 1999, approximately
130 million daily doses were prescribed in Germany,
triple the number of doses prescribed in 1993.9
Profile of St. John’s Wort
St. John’s Wort is a perennial herb that grows wildly in
Europe, Western Asia, North Africa, and America.
The herb has been used for centuries in many countries
for numerous health problems.14 Historically, the herb
was gathered for the feast of St. John the Baptist. The
herb would be hung on homes on St. John’s Feast Day
to protect against demons and their spells, and also
against harm and sickness to livestock. It is a sparse,
taut, red shrub with blossoms, which, when rubbed
between the fingers, releases a blood-like sap, for
which it is also known as Andro Haimon (Mars blood).
This red liquid contains the active components.15
Over the past 2000 years, prominent medical
herbalists, writers, and folk healers have singled out
SJW for its many medical properties. The primary
ancient medical herbalists including Hippocrates,
Pliny, Dioscurides, and Galen wrote about the
medicinal properties of SJW, noting its use as a
wound-healing agent, diuretic, and antimalarial agent.
It has also been used in Europe for the treatment of
anxiety, neuralgia, and menopausal neurosis.9 In the
13th century, SJW was mentioned in the medicinal
plants list of the Medical School of Salerno as herba
demonis fuga or “the herb that chases away the devil.”
In 1525, it was established by Paracelsus for the
treatment of depression, melancholy, and
overexcitability. Throughout the years, SJW has been
documented repeatedly for different medicinal uses
but has become a mainstream herb for the treatment of
depression.15 The increasing use of SJW for the
treatment of mild to moderate depression, as well
as the increasing interest in documenting its efficacy
through research, has led to this review of SJW in the
treatment of mild to moderate depression.
Overview of preparations and dosing
for St. John’s Wort
St. John’s Wort is available as standardized extracts,
tea leaves, dry extracts in tablet or capsule form, and
oil infusions for topical use.16 Hyperforin seems to be
the main active ingredient. However, it is thought that
other components have a synergistic effect in treating
depression. Preparation standards are 0.3% hypercin
at 900 mg daily in 3 doses of 300 mg. Alternatively,
standardization of hyperforin is 2% to 4.5% with the
same dosing.17 For depression, response time varies
from 2 to 6 weeks, and the herb should be continued
for at least 6 months after symptom remission.17
Although it has been thought that SJW functioned
as a monoamine oxidase inhibitor, it does not seem to
be the case. Rather, it appears to inhibit uptake of
several neurotransmitters including serotonin,
dopamine, noradrenaline, γ -aminobutyric acid, and
L-glutamate. Other effects are available in the cited
texts. The German Commission stated that there are
no contraindications. However, recent reports of
interaction with conventional medications indicate
that SJW may interact with other antidepressants, oral
contraceptives, and anticoagulants. Adverse effects
include skin reactions, breakthrough bleeding for
women taking oral contraceptives, gastrointestinal
complaints, and lowered levels of plasma
cyclosporine.17
RESEARCH METHODS
An electronic search was conducted to identify studies
from 1998 to 2004 in the following databases:

MEDLINE, CINAHL, Alt-Health Watch, PubMed,
and Cochrane. The search terms used were St. John’s
Wort, Hypericum perforatum, herbal remedies, herbs,
depression, and mild to moderate depression. The
search was limited to randomized controlled trials
(RCTs) published in English. References in the
articles were reviewed for additional relevant studies.
The inclusion criteria were RCTs between the years
1998 and 2005; diagnosis of trial subjects was mild to
moderate depression; and 1 or 2 parallel treatments
compared with SJW. Articles were excluded if they
were not in English, used adolescents, pregnant or
lactating women, or subjects who were severely
depressed or had suicidal ideations. Studies that
compared severe depression and the use of SJW with
another drug or placebo were also excluded. Six
articles met the inclusion criteria.
Methodological Quality Index
The Boyack and Lookinland Methodological Quality
Index (MQI) tool was developed to score research
reports based on the Consolidated Standards of
Reporting Trials (CONSORT) guidelines. The
CONSORT statement,18 developed in the 1990s and
revised in 1999, provides direction for standardized
reporting of RCTs. These guidelines also provide
transparency to research reports so that practitioners
can make wise decisions based on the quality of the
study without having to make assumptions about
missing elements. Following the CONSORT
guidelines requires the writer to speak to all elements,
even if they were not done, so that there is no
confusion in the evaluation of the study.
The MQI is used to extract 5 different categories of
data identified in the CONSORT guidelines: methods,
outcomes, treatment effect, magnitude or reported
differences, and summary to determine study design
and method quality.19 The MQI was used to review all
of the 6 RCTs, thus allowing comparison of the
studies to each other.
The result of the MQI evaluation is a percentage
score relative to adherence to RCT study quality
guidelines, with 100% indicating perfect adherence to
the CONSORT criteria as defined in the MQI. To
calculate the percentage of each study, the number of
the individual score in an RCT was divided by the
total possible score. If any criterion was not
applicable to a study, the denominator was reduced,
adjusting the total score.19
Two independent reviewers (CC and KC) using the
Boyack and Lookinland MQI extracted data from the
St. John’s Wort and Depression 199
articles for the review. Both individuals reviewed the
studies independently and arrived at scoring
consensus.
STUDY DESCRIPTIONS
Study characteristics
Six studies were reviewed. All of the studies were
double-blinded RCTs. Five studies were multicentered
(with one study being single centered). The average
MQI score for the 6 studies was 56% (range =
46%–66%) (Table 1).
Patient characteristics
Patient sample sizes ranged from 30 to 324. All studies
included men and women ranging from 18 to 70 years
old. In the studies that gave gender ratios, female
percentages were higher, reflecting the trend of more
women than men reporting depressive symptoms. For
example, one study reviewed had 79.4% women and
20.6% men in the SJW group while the parallel group
had 69.4% women and 30.6% men.20 All of the
studies used evaluation tools and clinical history to
diagnose the patient’s depression level (Table 1).
Tools used to assess depression
in the evaluated RCTs
No serum test can evaluate one’s level of depression;
therefore, psychometric instruments were used to
evaluate the severity of depression. All of the RCT’s
used psychometric tools to measure depression. The
most commonly used tools were the Hamilton
Depression Rating Scale (HAM-D), the Clinical
Global Impressions (CGI) scale, and the Depression
Scale.20–25
The HAM-D is a 17-item scale developed in 1960.
It is the most widely used tool for the clinical
assessment of depression. It is well validated, used by
the FDA in clinical trials, and considered highly
reliable. The HAM-D is scored by giving 2 points if a
symptom is present and 0 points if the symptom is
absent. However, it allows for additional points to be
added, based on the severity of the symptom. A
HAM-D score of more than 25 indicates severe
depression, whereas a score of 14 to 25 indicates mild
to moderate depression.26 A total score of 7 or less
indicates symptomatic remission and implies to the
clinician that the treatment used is working.27 The
17-item scale is filled out by the provider interviewing
200 HOLISTIC NURSING PRACTICE • JULY/AUGUST 2006

TABLE 1. General characteristics of studies∗

Design/treatment/ Patient
Authors outcomes characteristics Instruments MQI

Woelk21 R, DB, M 6 wk Depression HAM-D, CGI Score: 57%

Total (N = 324) Mild: 189/324; Baseline/endpoint Strengths: M, sample size, power
SJW (n = 157) Moderate: 135/324 HAM-D analysis
250 mg 2 × d No breastfeeding or SJW: 22.4/12 Weaknesses: <6 mo
IMI (n = 167) pregnant woman, thyroid IMI: 22.1/12.75
75 mg 2 × d disorders or bipolar
Placebo 2 × d
Schrader25 R, DB, M, 6 wk 65% Women HAM-D, CGI, Score: 54%
Total (N = 240) Mean age: 46.5 Visual analog scale Strengths: M, wash out, sample
SJW (n = 126) No hx substance abuse, Baseline/endpoint size
250 mg 2 × d dementia, suicidal HAM-D Weaknesses: No power analysis,
FLUO (n = 114) ideation, thyroid or SJW: 19.65/11.54 <6 mo
20 mg/d parathyroid disorders, FLUO: 19.50/12.20
Parkinson’s disease,
pregnant or
breastfeeding woman
Brenner et al23 R, DB, single Women 19/men 11 HAM-D, CGI, DS MQI score: 51%
centered, 7 wk Age: 21–65 Baseline/endpoint Strengths: Blinding/concealment
Total (N = 30) No pregnant or HAM-D Weaknesses: Single centered,
SJW (n = 15) breastfeeding woman, SJW: 21.3 ± 3.2/ small sample size, no power
600 mg/d for 1 wk hx severe depression or 12.7 ± 6.7 analysis, <6 mo
then 900 mg/d attempted suicide SER: 21.7 ± 2.7/
SER (n = 15) 12.5 ± 5.6
50 mg/d for 1 wk
then 75 mg/d
Kalb et al24 R, DB, M, 6 wk Male/female HAM-D, CGI, DS Score: 63%
Total (N = 72) Age:18–65 Baseline/endpoint Strengths: M
SWJ (n = 37) HAM D >16 HAM-D Weaknesses: Small sample size,
3 × 300 mg/d No suicidal tendency, SJW: 19.7 ± 3.4/ no power analysis done, <6 mo
Placebo (n = 35) organic brain syndrome, 8.9 ± 4.3
major psychiatric Placebo: 20.1 ± 2.6/
diseases, tx with 14.4 ± 6.8
depressive medication in
last 6 wk, substance
abuse, pregnancy,
lactation
Behnke et al22 R, DB, M, 6 wk Male/female HAM-D, CGI, DS Score: 46%
Total (N = 70) Age: 18–70 Baseline/endpoint Strengths: M
SWJ (n = 35) No pregnant or lactating HAM-D Weaknesses: Small sample size,
150 mg 2 × d woman, suicide risks, SJW: 20.0 ± 3.2/9.9 no power analysis, <6 mo
FLU0 (n = 35) dementia, chronic FLUO: 20.7 ± 2.9/7
20 mg 2 × d alcohol or drug use,
severe cardiac, liver, or
respiratory problems
Gastpar et al20 R, DB, M, 24 wk Male/female HAM-D, CGI, DS Score: 66%
Total (N = 241) Age:18–70 Baseline/endpoint Strengths: M, power analysis
SJW (n = 123) Depression score 20–24 HAM-D Weaknesses: Trial period 24 wk
612 mg/d on Ham-D and SJW: 22.0 ± 1.1/
SER (n = 118) diagnosis of mild to 8.3 ± 5.5
50 mg/d moderate depression; SER: 22.1 ± 1.1/
no pregnant woman 8.1 ± 5.6

∗
R indicates randomized; DB, double blind; M, multicentered; SJW, St. John’s Wort; IMI, imipramine; FLUO, fluoxetine; SER, sertraline; HAM-D, the
Hamilton Depression Rating Scale; CGI, the Clinical Global Impressions scale; DS, Depression Scale; MQI, Methodological Quality Index; tx, patient
care; and hx, patient history.

the patient, and evaluates guilt, sleep, mood
disturbance, work activities, suicidal ideation, anxiety,
and somatic symptoms.21
The CGI is a 3 item 7-point Likert-type scale (1 =
“very much improved” to 7 = “very much worse”)
used to assess severity of depression and changes in
the clinical condition over time.21 Lower scores
indicate patient improvement. The 3 items evaluated
are severity of illness, global improvement, and
efficacy index. The CGI allows the clinician to rate
how much the patient’s illness has improved or
worsened since an initial assessment was done. The
benefits of this scale are that it has been effective in
measuring efficacy in drug treatment trials, is simple
to use, and is sensitive to change. Lower numbers
indicate patient improvement.21
The Depression Scale is a self-diagnosing tool used
by patients to evaluate the level of depression. This
questionnaire was developed by Von Zerssen in the
1970s, and is a scale that uses adjectives to describe
the level of depression a person may be experiencing.
Subjects are asked to rate 16 items on a 4-point scale.20
Treatment characteristics
Several preparations of SJW were reported among the
studies. Preparations included Ze 117, a 50%
ethanolic extract with a drug ratio of 4–7:123 ; SJW
WS 5572, which is hydroalcholic with a drug ratio
2.5–5.0:1.5% hyperforin22 ; and extracts with no
preparation or drug ratios reported.20,22
Dosages and dosage frequency varied as well. The
dosage frequency ranged from daily to 3 times per
day. Total dosages ranged from 300 to 900 mg/d, with
a range of 150 mg 2 times daily22 to 300 mg 3 times
daily.24 One study used 600 mg daily for 1 week, and
then 900 mg daily for the rest of the study.20,23
Another study used 150 mg of SJW 2 times daily.20
Patients in 2 studies took 250 mg twice daily21,25 ;
dosage in another study was 300 mg 3 times daily.20
One study used 600 mg daily for 1 week, and then
900 mg daily for the rest of the study.23 The longest
study used 612 mg daily.20
The drugs used in the comparison arm were another
area where difference was present. One study
compared the antidepressant imipramine (75 mg
daily) with SJW and a placebo,21 while another
compared SJW extract with a placebo only.24 Four
studies compared SJW with pharmacologic
antidepressants only. Antidepressants used were
sertraline, 50 mg daily for 1 week, and then 75 mg
St. John’s Wort and Depression 201
daily23 ; sertraline 50 mg daily20 ; and fluoxetine 20 mg
daily.22,25 Study lengths ranged from 6 to 24 weeks.
Four of the 6 studies were for 6 weeks and one study
was for 7 weeks.20,22–25 The longest study was
reviewed at 12 weeks and 24 weeks, respectively.20
Clinical outcomes
The 6 studies reviewed showed SJW to be
significantly effective in lowering depression, as
demonstrated by a reduction in HAM-D scores. In one
study comparing SJW with a placebo, the HAM-D
score dropped for SJW from 19.7 ± 3.4 to 8.9 ± 4.3
and the placebo score dropped from 20.1 ± 2.6 to
14.4 ± 6.8.24 When SJW was compared with
sertraline, the baseline of SJW was 21.3 ± 3.2 and
dropped to 12.7 ± 6.7. The baseline of sertraline was
21.7 ± 2.7 and dropped to 12.5 ± 5.6.23 Another
study compared SJW to fluoxetine. The baseline score
of SJW in this study was 19.65 and dropped to 11.54.
The baseline of fluoxetine was 19.50 and dropped to
12.20.25 The studies demonstrated that the decrease in
the HAM-D scores for patients taking SJW was
significantly greater than for those patients receiving
placebo, and equivalent to those on antidepressants,
suggesting that SJW is a viable therapeutic alternative.
DISCUSSION
The average individual study MQI score was 56%
(range = 46%–66%), indicating important elements of
a well-designed RCT were either not done or not
reported. Studies failed to earn points in the areas of
study length, power analysis, and blinding of subjects
and researchers. If the elements were both done and
reported, the scores would have increased, thus
leading to greater trust in the outcomes reported. To
receive the highest points possible for the study
length, the trials should be 3 years in length.19
Notwithstanding the likelihood that longer studies are
more apt to uncover difference, the decrease of
HAM-D score was accomplished despite short study
lengths.
Power analysis was done in 4 of the 6 studies.
Insufficient power increases the probability of a type II
error, resulting in findings that suggest SJW was not
effective in lowering mild to moderate depression
when, in fact, it was. This did not occur, as all the
studies demonstrated efficacy of SJW in the treatment
of mild to moderate depression.
202 HOLISTIC NURSING PRACTICE • JULY/AUGUST 2006
Blinding subjects and researchers was another weak
area in the reports. Only one of the studies gave
accurate descriptions of how the medications were
blinded to subjects.24 In most of the studies, it was not
clear how the subjects were blinded; how medications
and herbal preparations were kept and disbursed to the
patients; whether the medications and herbal
preparations were different in taste, smell, or texture;
or whether the preparation of the medications
eliminated bias on the part of those distributing the
drugs or evaluating the results. Therefore, it is
unknown whether either the researchers or the patients
could identify what they were receiving. This is a
serious breach, as a lack of blinding may lead to
performance bias on the part of either the subjects or
the researchers, raising questions about the
researchers’ conclusions.
Differences in extracts and dosing also confound
the results when examined as a whole. Only 2 of the
studies used the same dosages of SJW; yet, not
necessarily the same extract, thus decreasing
comparability of the studies.21,25 Although it would be
easier to compare studies using the same extract and
the dosage to determine whether SJW is effective,
even with these differences the studies point to SJW as
useful in the treatment of mild to moderate depression.
Future studies evaluating SJW for treatment of mild
to moderate depression should be designed to attend
carefully to the expectations of RCTs and the required
CONSORT guideline elements should all be addressed
in the published report. When reviewing future studies
on the use of SJW for depression, practitioners who
evaluate studies using the CONSORT guidelines can
be more certain of their decision as to whether or not
SJW is effective in lowering depression levels. Along
with confirming or refuting the efficacy of SJW in the
treatment of mild to moderate depression, research
should utilize the German Commission E Monographs
that provide guidelines for manufacturing and
development of herbal medicines. Translated into
English, the American Botanical Council has
recommended the adoption of these standardized
preparations and dosage recommendations for clinical
research in the United States.16
Despite flaws in the research reports, all of the
studies demonstrated a significant difference in the use
of SJW versus placebo, and equivalent response to the
HAM-D between SJW and pharmaceutical
antidepressants. Those suffering from mild to
moderate depression who would rather not try
psychotropic medicine may have success with SJW.
On the basis of this review, SJW doses as low as
300 mg daily have demonstrated significant drops in
the HAM-D score, and can be used as an alternative as
long as the patient has only mild to moderate
depression and is not taking other contraindicated
medications including antidepressants,
immunosuppressive drugs such as cyclosporine,
coumadin, and digoxin.3 There is no indication in the
literature that SJW is appropriate for patients with
severe depression, and practitioners should be
prepared to counsel those patients regarding
appropriate treatment.
NURSING IMPLICATIONS
Depression is one of the major diagnoses practitioners
will encounter in any healthcare setting. It is important
for practitioners to utilize the appropriate screening
tools and should have the knowledge of not only
pharmaceutical treatments but also complementary
treatments that may be helpful.
It is estimated that one third of adults use herbal
remedies, yet two-thirds do not reveal this to their
health providers.3 Although this may be because
patients do not feel they need to tell their care provider,
it is just as likely because patients perceive that their
healthcare provider will not be supportive of their
choice. Care providers should create relationships and
environments that encourage disclosure, so patients
can receive the best treatment with the least risk.
Side effects of SJW are minimal when not used
concomitantly with other medications. The most
common side effects are dry mouth, headache,
dizziness, and gastrointestinal upsets.20,21 Patients
using oral contraceptive, loperamide, and theophylline
should be monitored closely as SJW can interfere with
these medications and can cause their increased or
decreased levels in the body making them toxic or less
effective.13
The preference of many people for herbal treatment
is often augmented by the perceived low cost of herbal
remedies. The cost of SJW varies because of the
extracts used and dosages recommended. Because
SJW is not regulated by the FDA, it is not always
known exactly how much SJW may actually be in the
capsule taken. After reviewing the price at a local
health food store, the approximate cost for SJW was
between $10 and $13 per month at 300 mg daily. In
checking with a local discount pharmacy, we found
generic forms of antidepressants costing from $10 to

$20 per month while nongeneric forms ranged
between $40 and $80.00 per month. Although the price
difference between generic antidepressants and SJW is
not large, patients who prefer herbal supplements to
medication, and who respond well to SJW, may find
this a realistic alternative for treatment of depression.
With a relatively low cost and low risk of adverse
reactions when taken alone, SJW may be a good
choice for mild to moderate depression. It is the
practitioner’s responsibility to educate patients and
teach families about the risk factors involved with the
medications they are taking. Staying current with the
research is one way nurse practitioners can serve their
patients well and provide appropriate and safe
treatment.
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