A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients.

Abstract

This randomized, observer-blind, controlled trial examined the efficacy and safety of the traditional Chinese herbal medicine Yi-Gan San (YGS, Yokukan-San in Japanese) in the improvement of behavioral and psychological symptoms of dementia (BPSD) and activities of daily living (ADL).
Fifty-two patients with mild-to-severe dementia (24 men and 28 women, mean +/- SD age = 80.3 +/- 9.0 years) according to DSM-IV criteria were investigated. Participants were randomly assigned to the YGS group (N = 27) or control (drug-free) group (N = 25) and treated for 4 weeks. The Neuropsychiatric Inventory (NPI) for the assessment of BPSD, the Mini-Mental State Examination (MMSE) for cognitive function, and the Barthel Index for ADL were administered at baseline and the end of the treatment. The frequency of extrapyramidal symptoms (EPS) and other adverse events was recorded. If patients showed insufficient response to treatment after 1 week, tiapride hydrochloride, a dopamine D(1) selective neuroleptic, was added to the regimen. Data were collected from January 2004 to March 2004.
All participants in both groups completed the trial. In the control group, 11 patients required treatment with tiapride hydrochloride. Significant improvements in mean +/- SD NPI (from 37.9 +/- 16.1 to 19.5 +/- 15.6) and Barthel Index (from 56.4 +/- 34.2 to 62.9 +/- 35.2) scores were observed in the YGS group, but not in the control group. MMSE results were unchanged in both groups. EPS were not observed in either group, but dizziness and impaired postural sway were observed in 6 patients treated with tiapride hydrochloride.
Yi-Gan San improves BPSD and ADL. Follow-up studies using a double-blinded, placebo-controlled design are recommended.

Full text

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Yi-Gan San for Improvement of BPSD and ADL in Dementia
J Clin Psychiatry 66:2, February 2005249 248
ehavioral and psychological symptoms of dementia
(BPSD) are commonly seen in patients with Alz-
heimer’s disease (AD) and other forms of senile demen-
tia. BPSD are a significant burden to caregivers and a
major reason for the early institutionalization of AD pa-
tients.1 Moreover, they consistently relate to poor perfor-
mance of activities of daily living (ADL).2 Pharmacologic
interventions including antipsychotics3 and acetylcholine
esterase inhibitors (AChEIs)4 have been investigated, but
drug-induced extrapyramidal symptoms (EPS) and other
adverse events are not uncommon consequences among
elderly people.5
For millennia, herbal medicines have been used with
apparent safety and efficacy in Asia, including present-
day China, Korea, Taiwan, and Japan, for alleviating vari-
ous symptoms of senile dementia. We have previously
reported the clinical efficacy and safety of such medicines
in cognitive function and ADL in AD.6,7
Yi-Gan San (YGS, Yokukan-San in Japanese, Pulvis
depressionis efficientiae) was developed in 1555 by Xue
Kai as a remedy for restlessness and agitation in children.
Prompted by the increasing life expectancy of the Japa-
nese population, geriatricians have begun to use this tradi-
tional regimen for BPSD in the elderly. For example,
A Randomized, Observer-Blind, Controlled Trial
of the Traditional Chinese Medicine Yi-Gan San for
Improvement of Behavioral and Psychological Symptoms
and Activities of Daily Living in Dementia Patients
Koh Iwasaki, M.D., Ph.D.; Takuma Satoh-Nakagawa, M.D., Ph.D.;
Masahiro Maruyama, M.D., Ph.D.; Yasutake Monma, M.N.; Miyako Nemoto, M.D.;
Naoki Tomita, M.D.; Haruko Tanji, M.D., Ph.D.; Hironori Fujiwara, Ph.D.;
Takashi Seki, M.D., Ph.D.; Masahiko Fujii, M.D., Ph.D.;
Hiroyuki Arai, M.D., Ph.D.; and Hidetada Sasaki, M.D., Ph.D.
Objective: This randomized, observer-blind,
controlled trial examined the efficacy and safety
of the traditional Chinese herbal medicine Yi-Gan
San (YGS, Yokukan-San in Japanese) in the im-
provement of behavioral and psychological symp-
toms of dementia (BPSD) and activities of daily
living (ADL).
Method: Fifty-two patients with mild-to-severe
dementia (24 men and 28 women, mean ± SD
age = 80.3 ± 9.0 years) according to DSM-IV
criteria were investigated. Participants were
randomly assigned to the YGS group (N = 27)
or control (drug-free) group (N = 25) and treated
for 4 weeks. The Neuropsychiatric Inventory
(NPI) for the assessment of BPSD, the Mini-
Mental State Examination (MMSE) for cognitive
function, and the Barthel Index for ADL were
administered at baseline and the end of the treat-
ment. The frequency of extrapyramidal symptoms
(EPS) and other adverse events was recorded. If
patients showed insufficient response to treatment
after 1 week, tiapride hydrochloride, a dopamine
D1 selective neuroleptic, was added to the regi-
men. Data were collected from January 2004
to March 2004.
Results: All participants in both groups com-
pleted the trial. In the control group, 11 patients
required treatment with tiapride hydrochloride.
Significant improvements in mean ± SD NPI
(from 37.9 ± 16.1 to 19.5 ± 15.6) and Barthel
Index (from 56.4 ± 34.2 to 62.9 ± 35.2) scores
were observed in the YGS group, but not in the
control group. MMSE results were unchanged
in both groups. EPS were not observed in either
group, but dizziness and impaired postural sway
were observed in 6 patients treated with tiapride
hydrochloride.
Conclusion: Yi-Gan San improves BPSD and
ADL. Follow-up studies using a double-blinded,
placebo-controlled design are recommended.
(J Clin Psychiatry 2005;66:248–252)
Received May 18, 2004; accepted Aug. 12, 2004. From the
Department of Geriatrics and Complementary Medicine (Advanced
Research Center for Asian Traditional Medicine), Graduate School
of Medicine (Drs. Iwasaki, Fujiwara, Seki, and Arai) and the
Department of Geriatrics and Respiratory Medicine, School of Medicine
(Drs. Satoh-Nakagawa, Maruyama, Nemoto, Tomita, Tanji, and Sasaki),
Tohoku University, Sendai City; the Department of Nursing, Graduate
School of Medicine, Yamagata University, Yamagata City (Mr. Monma);
and Yamagata Kohsei Hospital, Yamagata City (Dr. Fujii), Japan.
This study is partly supported by the research fund of Institute
of Kampo Medicine (Japan).
Corresponding author and reprints: Hiroyuki Arai, M.D., Ph.D.,
Department of Geriatric and Complementary Medicine (Advanced
Research Center for Asian Traditional Medicine), Graduate School
of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba Ward,
Sendai City, Miyagi pref., Japan (e-mail: QFG03604@nifty.com).
B

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Iwasaki et al.
250 249 J Clin Psychiatry 66:2, February 2005
Tahara et al.8 reported 2 cases in an extended care
unit who were successfully treated with YGS for BPSD.
Tsunekawa and colleagues9 reported the efficacy of a
YGS derivative (Yi-Gan San jia Chenpi Banxia, Pulvis
depressionis efficientiae cum Pinellia et aurantio) in 7
cases of demented elderly patients with nighttime dis-
turbance, disinhibition, eating disturbance, anxiety, hal-
lucinations, irritability, and insomnia. Such detailed case
observations, depending on the traditional Chinese medi-
cine studied, can offer hints at new treatments for cur-
rently incurable diseases. Therefore, based upon these
observations, we designed a randomized, observer-blind,
controlled trial to assess the efficacy and safety of YGS in
the improvement of BPSD and ADL.
METHOD
Participants
All subjects were recruited from 3 centers for long-
term care located in the prefectures of Yamagata, Iwate,
and Miyagi, Japan. Data were collected from January
2004 to March 2004. The diagnosis of dementia was made
for a total of 60 patients according to Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV) criteria.10 The physical condition of all patients
had been stable for the past year. At baseline, each patient
received a uniform evaluation, which included a medical
history, physical and neurologic examination, and brain
computed tomography scan, as well as the Mini-Mental
State Examination (MMSE)11 to assess cognitive function
and the Barthel Index for ADL (higher scores indicate bet-
ter performance).12 BPSD were assessed and evaluated
using the Neuropsychiatric Inventory (NPI: lower scores
indicate better performance).13
We included patients who satisfied the following crite-
ria: (1) dementia of Alzheimer’s disease (DSM-IV), vas-
cular dementia (as defined by the NINDS-AIREN Inter-
national Workshop),14 dementia with Lewy bodies,15 or
Alzheimer’s disease with cerebrovascular disease; (2) an
MMSE score of < 24; and (3) concomitant BPSD with an
NPI score of > 6 on at least one of the delusion, halluci-
nation, violent behavior, or apathy subscales. The exclu-
sion criteria were (1) major medical illness such as neo-
plastic disease, acute inflammation, or any other disease
that would be likely to prevent completion of this study;
(2) other types of dementia (such as Korsakoff syn-
drome); (3) delirium due to drug use, metabolic intoxica-
tion, or inflammation; (4) an MMSE score ≥ 24; (5) neu-
roleptic treatment at baseline; and (6) AChEI (donepezil)
therapy within 1 year.
Intervention
Of the 60 patients enrolled according to the criteria
above, 8 subjects were excluded because of inflamma-
tion (2 cases), use of neuroleptics (5 cases), and drug-
induced delirium (1 case). Therefore, 52 patients with
mild-to-severe dementia (24 men and 28 women, mean ±
SD age = 80.3 ± 9.0 years, MMSE score of 0–23) were
investigated. Written informed consent was obtained
from participants or their families following a detailed
explanation of the study. The Institutional Review Board
of Tohoku University (Sendai City, Japan) approved
the study. The patients were stratified for NPI, MMSE,
Barthel Index, age, and sex and then randomly assigned
to the YGS treatment group (N = 27) or the control
group (N = 25) using a random number table. Patient
characteristics are shown in Table 1. There was no sig-
nificant difference in the characteristics between the 2
groups.
The mixture of dried plants—4.0 g of Atractylodis
Lanceae rhizoma, 4.0 g of Hoelen, 3.0 g of Cnidii rhi-
zoma, 3.0 g of Angelicae radix, 2.0 g of Bupleuri radix,
1.5 g of Glycyrrhizae radix, and 3.0 g of Uncariae ramu-
lus et uncus—was added to 700 mL of distilled water and
boiled for 1 hour, filtered, and then concentrated to 300
mL. This decoction was lyophilized to yield 4.5 g of dry
extract and was added to 3.0 g lactate to yield a total of
7.5 g of powder for 1 day’s use. This powder is registered
in the Pharmacopoeia of Japan as the Kampo Medicine
TJ-54 Yokukan-San and was provided by Tsumura Co,
Ltd (Tokyo, Japan). The quality was standardized based
on the Good Manufacturing Practice defined by the Min-
istry of Health and Welfare of Japan. Moreover, Tsumura
Co, Ltd, standardized the quality of its TJ-54 Yokukan-
San by 3D-HPLC (high-performance liquid chroma-
tography) analysis.
Participants in the YGS group each received 2.5 g
of YGS powder (1.5 g of extract) 3 times a day before
meals for 4 weeks. If patients showed insufficient re-
sponse to the treatment after 1 week, 25 mg of tiapride
hydrochloride, a dopamine D1 selective classical neuro-
leptic, was added to the regimen.
Table 1. Baseline Characteristics of 52 Patients
With Dementiaa
YGS
Group
13:14
77.0 ± 9.6
Control
Group
11:14
84.0 ± 6.7
Characteristic
Sex, N, male:female
Age, mean ± SD, y
Diagnoses, N
Alzheimer’s disease
Vascular dementia
Alzheimer’s disease with CVD
Dementia with Lewy bodies
Duration of illness, mean ± SD, mo
Test scores, mean ± SD
Neuropsychiatric Inventory
Mini-Mental State Examination
Barthel Index
aThere were no significant differences between groups for any of the
characteristics.
Abbreviations: CVD = cerebrovascular disease, YGS = Yi-Gan San.
14
6
1
6
16
3
2
4
67.0 ± 6.366.0 ± 9.1
37.9 ± 16.1
13.2 ± 8.5
56.4 ± 34.2
33.6 ± 20.1
11.3 ± 9.6
55.4 ± 31.0

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Yi-Gan San for Improvement of BPSD and ADL in Dementia
J Clin Psychiatry 66:2, February 2005251 250
Outcome Measure and Statistical Analysis
A trained nurse performed the NPI, MMSE, and
Barthel Index tests in a manner blinded to treatment
status. All scales were examined at baseline and at the end
of the 4-week interventions. Statistical analyses of the
NPI, MMSE, and Barthel Index results were performed
using repeated-measures analysis of variance and the
Fisher protected least significant difference test. The fre-
quency of EPS was measured according to the Barnes
Akathisia Scale16 (Japanese edition). However, as will be
described later, none of the participants showed EPS dur-
ing the observation period. Therefore, we analyzed the in-
cidence of adverse events freely noted in both groups by
χ2 test. Results were considered to be statistically signifi-
cant at p < .05. Data are expressed as mean ± SD.
RESULTS
All participants in both groups completed the trial.
Significant improvements in the scores for both the NPI
(from 37.9 ± 16.1 to 19.5 ± 15.6, p < .001; Figure 1) and
the Barthel Index (from 56.4 ± 34.2 to 62.9 ± 35.2,
p < .05; Figure 2) were observed in the YGS group,
whereas these scores did not change significantly in
the control group (NPI from 33.6 ± 20.1 to 31.0 ± 20.8;
Barthel Index from 55.4 ± 31.0 to 51.7 ± 32.6). On the
NPI subscales, significant improvements in hallucina-
tions, agitation/aggression, irritability/lability, and aber-
rant motor activity were observed in the group treated
with YGS (Figure 3). Nighttime disturbance showed a
tendency to improve (p = .06). MMSE results did not
Figure 1. NPI Total Scores of 52 Patients With Dementia at
Study Baseline and Endpoint
Mean ± SD Score
60
50
40
30
20
10
0
Group
YGS
(N=27)
Control
(N=25)
p< .001
Baseline
Endpoint
Abbreviations: NPI = Neuropsychiatric Inventory, YGS = Yi-Gan San.
Figure 2. Barthel Index Scores of 52 Patients With Dementia
at Study Baseline and Endpoint
Abbreviation: YGS = Yi-Gan San.
Mean ± SD Score
100
80
60
40
20
0
Group
YGS
(N=27)
Control
(N=25)
p< .05
Baseline
Endpoint
Mean ±SD Score
12
10
8
6
4
2
0
Delusions
Hallucinations
Agitation/
Aggression
Dysphoria
Anxiety
Euphoria
Apathy
Disinhibition
Irritability/
Lability
Aberrant Motor
Activity
Nighttime
Disturbance
Eating
Disturbance
YGS Group, Baseline (N = 27)
YGS Group, Endpoint (N = 27)
Control Group, Baseline (N = 25)
Control Group, Endpoint (N = 25)
*
*
*
*
†
Figure 3. NPI Subscale Scores of 52 Patients With Dementia at Study Baseline and Endpoint
*p < .05.
†p = .06.
Abbreviations: NPI = Neuropsychiatric Inventory, YGS = Yi-Gan San.

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Iwasaki et al.
252 251J Clin Psychiatry 66:2, February 2005
change in either group (YGS group, from 13.2 ± 8.5 to
11.7 ± 7.6; control group, from 11.3 ± 9.6 to 12.0 ± 6.9).
In the control group, 11 patients had to be treated with
tiapride hydrochloride. None of the patients in the YGS
group required such additional therapies. EPS listed in the
Barnes Akathisia Scale were not observed in either group,
but dizziness and impairment of postural sway were ob-
served in 6 cases treated with tiapride hydrochloride in
the control group. No treatment-emergent adverse events
were seen in either group during the observation period,
but 2 participants who continued YGS therapy after the
trial seemed to become oversedated. However, among
these patients, the treatment was well tolerated when the
dose was reduced from 4.5 g to 3.0 g per day.
DISCUSSION
Behavioral and psychological symptoms have a seri-
ous impact on the quality of life of dementia patients, as
well as their caregivers. Recent trials demonstrated that
AChEIs may also be useful, but are not completely effec-
tive.17,18 Use of neuroleptics is also common in treating
patients with BPSD, but neuroleptics have the drawback
of being associated with EPS in elderly patients.3 More-
over, neuroleptic treatment is a major risk factor for aspi-
ration pneumonia19 and falls20 in elderly patients. Tiapride
hydrochloride is widely used in Japan for the treatment of
mild BPSD, but as shown in this study, the drug lacks
efficacy and causes dizziness and postural imbalance,
which can lead to falls. Thus, an effective drug therapy for
BPSD has not previously been established.
In the present study, we showed that a traditional Chi-
nese herbal medicine, YGS, significantly improved BPSD
without significantly influencing cognitive function as as-
sessed by the MMSE. In our daily clinical experience, the
effect of YGS usually begins within 1 or 2 weeks of treat-
ment. In addition to having a rapid onset of action, YGS
also caused no serious adverse events. YGS has been used
as a mild sedative. Aizawa et al.21 reported that a YGS
derivative was effective in the treatment of insomnia.
Sedatives tend to have unfavorable effects on cognitive
function,22 but in the present study, MMSE results did
not significantly change in the YGS group. Because the
MMSE is not a sensitive measure of cognitive function,
and due to a rather short-term observation period (2
months), we could not fully assess the influence of YGS
on cognitive function.
Two cases seemed to become overly sedated when
treated with the full daily dose (4.5 g) of YGS. However,
in these patients, YGS was well tolerated when the dose
was reduced to 3.0 g. One of these 2 patients briefly dis-
continued YGS therapy. Her NPI score had decreased
from 25 at baseline to 8 with YGS treatment, but it in-
creased to 10 after 1 month of abstention from treatment.
Delusions and apathy were also diminished by YGS treat-
ment but relapsed during the drug-free period. When YGS
treatment (3.0 g per day) was resumed at the family’s re-
quest, these symptoms vanished again. Symptoms seemed
to be closely related to treatment status (on/off) in this
case.
This study was performed in a single-blinded manner,
i.e., the observer who collected the data was blinded to the
treatment. A double-blind study could not be performed
because we could not develop an adequate placebo, due to
the distinctive taste and smell of YGS. The possibility of a
placebo effect cannot be completely excluded, although
it is unlikely considering the cognitive level of these pa-
tients. A more rigorous double-blind, placebo-controlled
design is needed for follow-up studies.
Several prior studies have investigated the mechanism
of action of YGS. Egashira and colleagues23 found that
YGS improved the scopolamine-induced disruption of
spatial cognition in rats. Indeed, YGS derivatives have
been reported to increase both choline acetyltransferase
activity and acetylcholine levels in experimental ani-
mals.24,25 YGS may therefore enhance cholinergic trans-
mission by mechanisms similar to those of AChEIs. It
remains to be determined whether YGS improves cogni-
tive function. Although YGS has been reported to increase
choline acetyltransferase, in our study, because the MMSE
is not a sensitive measure of cognitive function, and due
to a rather short-term observation period (2 months), we
could not fully assess the influence of YGS on cognitive
function.
YGS is not a simple preparation of medicine, as it con-
tains many ingredients. It has multiple biological effects,
and the interactions between ingredients can be important.
The hooks of Uncariae sinensis contain oxyindole and in-
dole alkaloids, known for their protective effects against
glutamate-induced neuronal death in cultured cerebellar
granule cells.26 On the other hand, Angelicae radix, an-
other important herb in YGS, is known for its effects on γ-
aminobutyric acid (GABA) and serotonin receptors.27 It is
known that receptors of neurotransmitters such as GABA-
A α1 subunits decrease in the AD brain, while receptors
of excitatory neurotransmitters such as glutamate are re-
tained.28 Zubenko et al.29 showed that BPSD were associ-
ated with a significant reduction of serotonin in the pre-
subiculum, which was accompanied by reduced levels of
serotonin and 5-hydroxyindoleacetic acid in the remaining
regions. Therefore, actions of the serotonergic system may
also account for some of the therapeutic effects of YGS.
Each herbal constituent of YGS plays a particular role,
and the preparation was carefully devised so that the com-
ponents would act in an interlocking manner. Thus, the
benefits of YGS may be attributable to the preparation as a
whole rather to the sum of each of its ingredients. These
pharmacologic properties of YGS, a traditional Chinese
medicine, most likely account for its versatile physiologic
effects and safety.

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Yi-Gan San for Improvement of BPSD and ADL in Dementia
J Clin Psychiatry 66:2, February 2005 253252
YGS was approved by the Ministry of Health and
Welfare of Japan as an ethical-use drug for medical treat-
ments in 1986. YGS has not been marketed in the United
States; however, all of the herbs contained in YGS can
be obtained in the United States. It may therefore be pos-
sible to perform similar studies on this herbal mixture in
the United States. In summary, our randomized, observer-
blind, controlled trial suggests that YGS therapy is a well-
tolerated and effective remedy that improves BPSD and
ADL.
Drug names: donepezil (Aricept), scopolamine (Transderm Scop).
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