THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE

Volume 14, Number 7, 2008, pp. 841–846

© Mary Ann Liebert, Inc.
DOI: 10.1089/acm.2008.0010

The Beneficial Effects of the Herbal Medicine

Free and Easy Wanderer Plus (FEWP) and Fluoxetine
on Post-Stroke Depression

Lian-Tao Li, Ph.D.,1,2 Shu-Hua Wang, Ph.D.,3 Hong-You Ge, Ph.D., M.D.,4 Jing Chen, B.Sci.,3
Shou-Wei Yue, Ph.D.,1 and Mei Yu, M.D.2

Abstract

Objectives: Depression occurs frequently in post-stroke patients and appears to be associated with impairment
of their rehabilitation and functional recovery. In this study, we evaluated the efficacy and tolerability of the
herbal drug, Free and Easy Wanderer Plus (FEWP), in patients affected by post-stroke depression (PSD).
Methods: One hundred fifty (150) moderately to severely depressed patients as determined by a score 20 on
the Hamilton Depression Scale (HDS) after a single ischemic or hemorrhagic stroke were randomly divided
into the FEWP group (n  60), the fluoxetine group (n  60), and the placebo group (n  30). The FEWP, flu-
oxetine, and placebo were administered to the patients over a period of 8 weeks. Depression was evaluated by
HDS and the Barthel Index (BI) before, during, and after the treatment.
Results: Significantly higher clinical response rates were observed in both the FEWP and fluoxetine groups
compared to the placebo group (60% and 65.5% versus 21.4%, 2  15.9, p  0.01) and there was no difference
in the response rates between the FEWP group and the fluoxetine group at the end of this study (60% versus
65.5%, 2  0.38, p  0.05). Compared to fluoxetine, FEWP produced significantly greater improvement in de-
pression at week 2 (15% versus 3.3%, 2  4.9, p  0.05). Furthermore, FEWP produced significantly greater
improvement in the activities of daily living (ADL) than fluoxetine at the end of this trial (BI: 43.8  5.6 versus
40.7  3.7, p  0.01).
Conclusions: FEWP showed good efficacy, safety, and tolerability in PSD patients. We conclude that FEWP is
well tolerated and may be a useful therapeutic option in patients with PSD.

Introduction
I t has been reported that more than 65% of patients with
severe depression and anxiety receive some type of alter-
native therapy, including herbal products.1 Some kinds of
herbal extracts and constituents have been shown to have
psychotropic effects in animal models.2 Free and Easy Wan-
derer Plus (FEWP) (Jinan Pharmaceutical, Jinan, Shandong,
China) is a well known Chinese herbal formula which has
been used to alleviate mood symptoms for a long time. The
original Chinese name is Jia-Wei-Xiao-Yao-San, which means
the patient with mood disorder will feel easy and be free of
mind-wandering after taking this medicine.3 Open clinical
trials have shown the efficacy of FEWP for bipolar mood dis-
orders;4 and case studies have reported the beneficial effect
of FEWP in patients with panic disorder,5 premenstrual dys-
phoric disorder,6,7 and climacteric symptoms.8 Zhang et al.
also found that FEWP with carbamazepine resulted in a sig-
nificantly greater clinical response rate in depressed sub-
jects.9 These results suggest that the effects of FEWP on the
improvement of mood disorders are associated with multi-
ple central transmitter systems and these studies also led to
the hypothesis that FEWP may also have therapeutic effects
in post-stroke depression (PSD). However, the therapeutic
efficacy of FEWP against PSD has not yet been confirmed in
rigorous clinical studies. This trial was conducted to deter-
mine whether FEWP was beneficial to patients with PSD or
not.

1Department of Rehabilitation, Qilu Hospital of Shandong University, Jinan, China.

2Shan
Dong Medical College, Jinan, China.
3Department of Neurology, Qilu Hosptital of Shandong University, Jinan, China.
4Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aal-

borg University, Aalborg, Denmark.

841
842
PSD is a common disorder, affecting 30% to 50% of hemi-
plegic patients within 1 year of their cerebral infarction.10–13
PSD has been associated with a poor outcome of rehabil-
itation therapy, such as worsened function,10,14 worsened
quality of life,15 as well as an increased risk of subsequent
mortality.16 Controlled treatment trials have shown the
advantage of tricyclic antidepressants.17,18 However, the side
effects of tricyclic antidepressants limit their use, especially
in older patients with multiple disorders, and many authors
advise the use of selective serotonin reuptake inhibitors
(SSRI).11,19–22 In addition to citalopram,19 a controlled study
of a small number of patients showed the advantages of flu-
oxetine in early PSD.23 But no advantages of fluoxetine could
be observed in another study of the fluoxetine treatment of
PSD patients within 2 weeks after stroke:24 The limitation of
that study was a high degree of spontaneous recovery dur-
ing early rehabilitation therapy, which may have improved
the depression, making it difficult to evaluate the efficiency
of fluoxetine in the early stages of stroke recovery. There-
fore, a large sample size of PSD patients within 6 weeks af-
ter stroke is needed to observe the efficiency of fluoxetine.
PSD is generally believed to exert a negative effect on re-
habilitation.10,11,25 Effective treatment of depression is be-
lieved to contribute to the recovery of stroke-induced
deficits. One study demonstrated that fluoxetine improved
motor performance and modulated cerebral activation in pa-
tients recovering from stroke.26 In a trial comparing fluoxe-
tine and nortriptyline, Dam et al. also reported an improve-
ment of motor function and activities of daily living (ADL)
in the fluoxetine group.20 It is still unknown if FEWP will
not only improve the depressive condition, but also improve
the functional independence of the patients with PSD. In this
double-blind and placebo-controlled study, we evaluated the
effects of FEWP on PSD compared with fluoxetine and
placebo.
Patients and Methods
Study setting
This study was conducted in Qilu Hospital of Shandong
University from March 2006 to September 2007. The study
protocol was approved by the Medical Ethical Committee of
Qilu Hospital in conformity with the Declaration of Helsinki
and its subsequent amendment. All participants signed an
informed consent document before entering the study and
the treatment period lasted 8 weeks.
TABLE 1. BASELINE CHARACTERISTICS
FEWP
Age, years 68.5  4.10
M/F 28/32
Time since stroke, weeks 4.83  0.57
Left-side lesions 35
Right-side lesions 25
BI 28.5  6.40
MMSE 27.3  2.30
Baseline HDS 25.2  3.80
Values are mean  standard deviation.
FEWP, Free and Easy Wanderer Plus; BI, Barthel Index; MMSE, Mini-Mental State Examination; HDS, Hamilton Depression Scale; NS not
significant.
p  0.05.
LI ET AL.
Subjects
One hundred fifty (150) patients with PSD within 6 weeks
after their strokes were included in this trial. Each patient
was evaluated by a neuropsychiatrist specialized in clinical
and psychiatric evaluation. General baseline characteristics
of the patients entering the trial are shown in Table 1.
The inclusion criteria for this study were: presence of a re-
cent (6 weeks) single ischemic or hemorrhagic stroke, doc-
umented by cerebral computed tomograph scanning or mag-
netic resonance imaging before this study; presence of major
or minor depression, with a Hamilton Depression Scale
(HDS) score over 20; and lack of treatment with antidepres-
sants during the 2 weeks prior to this study.
Exclusion criteria were: a Mini-Mental State Examination
score 23; a history of psychiatric illness other than depres-
sion; severe aphasia; and abnormal thyroid function,
epilepsy, or chronic alcoholism.
Preparation of herbal medicine and placebo
FEWP is a combination of 11 herbal drugs. To determine
the quality of the herbal preparations, the content of some
known chemical constituents was evaluated using high per-
formance liquid chromatography (HPLC) with electrochem-
ical detection calculated based on a tablet derived from 3 g
crude herbal mixture (Table 2). The shelf life of FEWP is 1
year.The placebo and herbal preparations were prepared by
Jinan Pharmaceutical (Jinan, Shandong, China) as described
by Zhang.9 The water extract of the crude herbal materials
was processed as described in the Pharmacopoeia of the Peo-
ple’s Republic of China, 2000 Edition.27 The resulting pow-
der was formed into tablets, with each tablet containing 3 g
of the crude herbal mixture. Both the placebo and herbal
tablets were prepared to be identical to the fluoxetine tablets
(Suzhou Pharmaceuticals, China) in shape, size, and color.
To minimize the effects of the distinctive smell of herbal
preparations on double blinding, the fluoxetine, placebo, and
herbal tablets were all contained in blister packs consisting
of plastic films and aluminum foils. There were 6 tablets in
each blister pack (in fluoxetine group, the blister packs,
which consisted of 1 fluoxetine and 5 placebo tablets, were
distributed to patients in the morning). The tablets were
taken twice daily and each time a blister pack was distrib-
uted to the patient by a physician who was not involved in
this trial. Neither the examiners involved nor the patients
were aware of the type of the administered medications.
OF THE PATIENTS ENTERING THE TRIAL
Fluoxetine Placebo p
69.2  3.50 67.8  3.90 NS
25/35 17/13 NS
4.75  0.70 4.82  0.67 NS
31 12 NS
29 18 NS
29.3  5.60 30.3  7.20 NS
27.0  2.30 27.9  1.90 NS
25.5  3.10 24.3  2.90 NS
FEWP AND FLUOXETINE IN POST-STROKE DEPRESSION 843

TABLE 2. THE FORMULATION OF FREE AND EASY WANDERER PLUS

Full scientific name Herbal materials % Constituent mg/tablet

Bupleurum chinense DC Dry root 7.3 Saikosaponin 0.70

Atractylodes macrocephala Koidz Dry root and stem 7.3 Atractylenolide 0.17
Zingiber officinale rose Fresh root 4.9
Angelica sinensis (Oliv) Diels Dry root 9.8 Ferulic acid 0.03
Lilium brownii (Lily bulb) Squamous bulb 24.3
Rehmannia glutinosa Dry root 12.2 Catalpol 4.40
Paeonia lactiflora Pall Peeled, dry root 9.8 Paeonilflorin 1.20
Salvia miltiorrhiza Dry root 9.8 Tanshinone and salvianolic 31.5 and 15.6
Poria cocos Wolf Dry sclerotium 7.3
Mentha haplocalyx Briq Dry stem and leaf 4.9
Glycyrrhiza uralensis Fisch Dry root 2.4 Glycyrrhizic acid 0.60

Study procedures in the FEWP group complained of nausea for several days,
but this side effect disappeared later. Six (6) patients in the
A computer-generated randomization was carried out by a
fluoxetine group and 3 in the placebo group reported nau-
physician who was not involved in the evaluation of patients.
sea; 4 patients in the fluoxetine group and 2 in the placebo
The 150 patients who met the entry criteria were divided into
group reported insomnia. The drug-induced nausea was at-
a FEWP group (n  60), a fluoxetine group (n  60), and a
tenuated by massage and no patient left the study owing to
placebo group (n  30). During the 8-week trial, FEWP (18 g,
side effects of medication. Two (2) patients in the fluoxetine
twice daily), fluoxetine plus placebo (referred to as fluoxetine
group withdrew from the study because of a second stroke
monotherapy), and placebo (18 g, twice daily) were adminis-
and 2 patients in the placebo group did not complete the
tered to patients in the three groups. Fluoxetine was initiated
study because of aggravated symptoms of depression; all
at 20 mg taken once daily and escalated to a maximum of 40
these patients withdrew after 4 weeks of the trial.
mg/day based on the patient’s response and tolerability. The
There was a significant decrease of HDS mean scores at
use of benzodiazepines for the treatment of insomnia was per-
week 2 in the FEWP group compared with either the placebo
mitted but did not exceede 14 days cumulatively.
(21.2  4.3 versus 24.7  3.3, p  0.01) or the fluoxetine
All patients received 8 weeks (5 days a week) of rehabili-
group (21.2  4.3 versus 24.3  2.0, p  0.01).The difference
tation, consisting of 1 to 2 hours of individual physical ther-
in HDS scores between the fluoxetine and the placebo groups
apy, 2 hours of occupational therapy, and 1 hour of speech
was not significant (24.7  3.3 versus 24.3  2.0, p  0.05)
therapy (if needed) per day. The major techniques used were
(Fig. 1).
as described by Bobath.28

Assessments
HDS and Barthel Index (BI) scores were calculated at base-
line, week 2, week 4, and at the end of the trial.29,30 The mea-
sure of clinical response was defined as a 50% reduction
in the HDS score compared with the baseline score.
Side effects and tolerability were assessed by recording
adverse events monitored at each visit after the completion
of a baseline physical examination of vital signs, laboratory
tests, and electrocardiogram. All adverse events—reported,
elicited, or observed—were recorded on the case report form,
including the date and time of onset, duration, severity, re-
lationship to study drug, and action taken.

Statistical analysis
One-way analysis of variance (ANOVA) was used to com-
pare the difference in HDS and BI among the 3 groups at
each measured point; the Chi-square (2) test was used to
compare the difference in the response rate between groups.
Values were expressed as mean  standard deviation and
statistical significance was defined as p  0.05.
FIG. 1. Variations of Hamilton Depression Scale (HDS)
Results scores in patients treated with Free and Easy Wanderer Plus
(FEWP), fluoxetine, and placebo, compared to baseline. *In-
No serious side effects were observed. No patients dicates HDS scores significally decreased in the FEWP group
dropped out from the FEWP treatment, although 2 patients compared with the fluoxetine and placebo groups.
844 LI ET AL.

At week 4 and week 8, HDS mean scores were signifi-

cantly decreased in both the FEWP and fluoxetine groups
when compared to placebo. The HDS mean scores were:
18.1  3.5 at week 4 and 14.6  2.6 at week 8 in the FEWP
group; 18.8  3.3 at week 4 and 14.5  2.4 at week 8 in the
fluoxetine group; and 21.7  3.4 at week 4 and 18.7  3.9 at
week 8 in the placebo group. Both the FEWP and fluoxetine
scores were superior to placebo at week 4 (F  11.8, p  0.01)
and week 8 (F  24, p  0.01), but the HDS mean scores were
not significantly different between the FEWP and fluoxetine
groups.
The difference in the percentage of responders was sig-
nificant at week 2: 15% in the FEWP group versus 3.3% in
the fluoxetine group (2  4.9, p  0.05) and 0% in the
placebo (Fig. 2). There was no significant difference in the
percentage of responders between the FEWP and fluoxetine
groups at week 4 (26.7% versus 23.3%, 2  0.18, p  0.05)
and week 8 (60% versus 65.5%, 2  0.38, p  0.05).
At the end of the study, BI scores had increased from base-
line values to 43.8  5.6, 40.8  3.7, and 38.4  5.8 in the
FEWP, fluoxetine, and placebo groups, respectively. The BI
scores were statistically different between these three groups
(FEWP versus placebo, p  0.01; fluoxetine versus placebo, FIG. 3. Evolution of Barthel Index (BI) scores during treat-
p  0.05; FEWP versus fluoxetine, p  0.01), but no differences ment with Free and Easy Wanderer Plus (FEWP), fluoxetine,
were seen at weeks 2 and 4 among these 3 groups (Fig. 3). or placebo. *Indicates a significant difference of BI score in
the FEWP group compared with the fluoxetine and placebo
Discussion group at the end of this trial.

The use of herbal medicine in psychiatric practice has in-

creased tremendously in the past decade.31,32 However, the
therapeutic efficacy of Chinese herbs against PSD has not yet
been confirmed in rigorous clinical studies. This fluoxetine
and placebo-controlled study is the first investigation on the
FIG. 2. Variations of responder percentages during treat-
ment with Free and Easy Wanderer Plus (FEWP), fluoxetine,
or placebo. *Indicates a significant difference in the FEWP
group compared with fluoxetine and placebo at week 2.
efficacy of FEWP in antidepressant treatment within 6 weeks
following a stroke.
By the end of 6 weeks after a stroke, most of the intensive
care and many therapeutic efforts of medicine are finished.
Some patients begin to accept the remaining permanent im-
pairment although rehabilitation efforts are not yet completed;
this stress may lead to a depressive mood in stroke patients. In
this study, the efficacy of FEWP in the treatment of PSD also
provided evidence to support the effects of FEWP on mood dis-
orders associated with depression, as recorded in the ancient
Chinese pharmacopoeia. Furthermore, it is also consistent with
the results shown in several open and clinical case studies.4–8
The traditional FEWP has been found to have a slow on-
set of therapeutic function, after at least 8 weeks of treatment
for mood disorders.33 Interestingly, we have noticed a
shorter onset time of therapeutic effect (2 weeks) than con-
ventional antidepressant therapies.34 The FEWP used in this
study is a combination of lily bulb, Rehmannia glutinosa, and
Salvia miltiorrhiza with traditional FEW, so it may not only
share some common components with traditional FEW in its
mechanism of antidepressant actions, but also some other
components we suppose are likely to be related to the func-
tion of lily bulb, although there is no research evidence of its
pharmacological mechanisms for the improvement of de-
pression. Lily bulb is an effective antidepressive herb and is
also the main component of Baihe Dihuang decoction, a tra-
ditional antidepressant formula that has been used in China
for more than 2000 years. The combination of lily bulb with
the traditional FEW may account for the rapid onset of ther-
apeutic effects in this study, with a significantly better effect
than fluoxetine after 2 weeks of treatment.
Fluoxetine improved PSD in 65.5% of patients at the end
of this trial. This result is consistent with the results of other
studies.20 FEWP showed effects similar to those of fluoxe-
FEWP AND FLUOXETINE IN POST-STROKE DEPRESSION
tine in the improvement of PSD at the end of this study.
However, the response latency of FEWP was shorter than
fluoxetine in the improvement of PSD.
It is widely believed that PSD has a negative impact on
rehabilitation.10,11,25 ADL is evaluated by the BI score (range,
0 to 100; the higher the score, the greater the independence
in ADL)30 and depression is associated with poorer ADL
abilities in post-stroke subjects.14 Effective treatment of this
depression is believed to contribute to the recovery of stroke-
induced deficits. This study also showed that FEWP and flu-
oxetine generally facilitate ADL recovery in post-stroke pa-
tients undergoing rehabilitation; furthermore, the efficacy of
fluoxetine on the improvement of ADL in this study is con-
sistent with the results published by Pariente26 and Dam.20
This study also showed that the efficacy of FEWP and flu-
oxetine seems to be related, at least in part, to improvement
of motor function, in addition to the natural course of the ill-
ness, although Wiart hypothesizes that in the early stage of
stroke, spontaneous improvement and rehabilitation may
lead to the improvement of motor function rather than the
improvement of depression itself.23 Furthermore, the efficacy
of FEWP is superior to fluoxetine in the improvement of mo-
tor function because the difference in BI scores between the
FEWP and fluoxetine groups was also significant.
Apparently, the potential effects of herbs are another im-
portant factor that may account for the efficacy of FEWP in
the improvement of ADL. Catalpol, found extensively in the
roots of R. glutinosa, is truly neuroprotective, rather than sim-
ply delaying the onset of neuronal damage, and might be of
therapeutic value for the treatment of global cerebral isch-
emia.35 The neuroprotective function of catalpol has been
proved in other studies.36–38 S. miltiorrhiza is another well
known traditional Chinese herb used for the treatment of
cerebrovascular diseases including stroke. S. miltiorrhiza ex-
tracts such as tanshinone and salvianolic acid have shown
marked neuron-protective effects; the neuroprotective effects
of salvianolic acid B and tanshinones IIA and IIB have been
reported.39–43 The putative herb–drug interaction may also
explain the enhanced efficacy and tolerability in PSD patients
treated with the herb therapy. There are no experimental
data in animals about the effect of FEWP, although some
components of FEWP, such as Poria cocos and Zingiber offic-
inale, were shown to possess antidepressant effects in mice.44
Most patients completed this trial. The dropout rate was
much lower than the usual dropout rate of 25–35% in most
clinical studies on depression but it was consistent with the
study of Davidson.45 In our study, drug-induced nausea was
attenuated by massage, which may partly account for the low
dropout rate; furthermore, after receiving the treatment, pa-
tients may have been more motivated to recover from stroke.
Conclusion
The traditional Chinese medicine FEWP offers benefits in
improving PSD. The long-term use of FEWP also can bene-
fit the patient by reducing side effects and improving BI
scores. The findings of the present trial suggest that FEWP
can be considered as an alternative for the treatment of PSD.
Acknowledgments
This study (30772684) was supported by the Natural Sci-
ence Foundation of Shandong province, People’s Republic of
845
China. None of the authors or the departments involved in
the study has financial ties with the companies producing the
medications used in this study. The authors thank Yong-hui
Wang, MD, for the randomization and coding of FEWP, flu-
oxetine, and placebo. We also thank physician Xin-li Ding,
MD, and nurses Xiu-lian Xu, BS, and Lin liu, BS, who were
responsible for dispatching the medicines and recording the
times and doses of taking medicine each day in this study.
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Shan Dong Medical College
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