Yokukansan treatment of chronic renal failure patients
receiving hemodialysis, with behavioral and psychologicalsymptoms of dementia: An open-label study
11123
Makoto Hayashi, MD , Akio Mantani, MD, PhD , Hidenori Sumiyoshi, MD , Satoshi Nishiyama, MD , Soh Fujiwaki, MD ,Shoichiro Ohta, MD, PhD 4, Yoshikazu Masuda, MD1, Youhei Tomita, MD1, Naofumi Tarumoto, MD1, Shigeto Yamawaki, MD, PhD
1Department of Psychiatry, Yoshida General Hospital, Akitakata-shi, Hiroshima, Japan 2Division of Psychiatry, Kurayoshi Hospital, Tottori, Japan 3Division of Psychiatry, Hoyu Hospital, Hiroshima, Japan 4Department of Laboratory
Medicine, Saga Medical School, Saga, Japan 5Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hi roshima University, Hiroshima, Japan

Individuals with end-stage chronic renal failure (CRF) have 2- to 7- fold higher prevalence ofcognitive impairment and dementia compared with the general population (1). Moreover, thefrequency of cognitive impairment of patients undergoing hemodialysis is significantly higher
than the general population, with cognitive impairment thought to be an independent predictor ofmortality in dialysis patients (2). Behavioral and psychological symptoms of dementia (BPSD)
are a significant burden to caregivers, and often relate to poor performance on activities of dailyliving (ADL), but despite this a strategy to treat BPSD has not been successfully established.
Treating BPSD in CRF patients by using neuroleptics is often complicated because hemodialysis
decreases the plasma concentration of neuroleptics by 20-25%, thereby inhibiting the affectivityof the drug. The time required for neuroleptics to reach steady state is also lengthened whencompared to results seen in normal cases. Urinary potassium excretion is significantly
decreased in CRF patients, therefore hyperkalemia is a common and critical problem in thissubset of people (3). Excessive potassium must be removed by hemodialysis so hyperkalemia in
CRF patients can be avoided, and some CRF patients require cation exchange resins, inaddition to hemodialysis, to facilitate intestinal excretion of potassium despite the serious sideeffects (4).
Yokukansan (YKS) is an herbal medicine, which was developed as a remedy for restlessness
and agitation in children. Several clinical studies have revealed the efficacy of YKS for BPSD
with Lewy bodies (5), borderline personality disorders, tardive dyskinesia of schizophrenia, andsleep disturbance. The main adverse reaction of YKS is hypokalemia. Conversely, YKS might be
an ideal alternative to the above-mentioned potassium-removing agents in the CRF patient.
The authors evaluated the efficacy and safety of YKS for CRF patients receiving hemodialysis
with BPSD. Our clinical study suggested that YKS was effective and safe for BPSD in
hemodialysis patients.

receiving hemodialysis prior to Yokukansan treatment
Age, mean ± SD, years
Sex, NDiagnosis, N

68.0 ± 7.3

male

7female4AD8VD

3MMSE score

10.5 ± 6.0

Anti-psychotic use
haloperidole, N

6risperidone, N

3quetiapine, N

2perospirone, N

1

Number of antipsychotics, mean ± SD, N

1.18 ± 0.72

Dose of antipsychotic ‡, mean ± SD, mg/day

164.2 ± 152.4

AD; Alzheimer ’s disease, VD; vascular dementia, MMSE; Mini-Mental State Examination, ‡;chlorpromazine equivalent

Figure1; Comparison of NPI, serum K concentration before and after YKS treatment (N=11)mEq/l )

Introduction

Table 1: Demographics and clinical characteristics of 11 subjects diagnosed with dementia

Methods
Subjects

Subjects were recruited after a preliminary psychiatric interview and further assessment inYoshida General Hospital, Kurayoshi Hospital, Miyoshi Clinic, Hiroshima, Japan. All subjects wererequired to be diagnosed with CRF and receiving hemodialysis 3 times a week. Inclusion criteria
were as follows; less than 20 points on the Mini-Mental State Examination, or diagnosis ofdementia according to a structured clinical interview using the DSM-IV criteria. Patients withmajor medical or neurological illness were excluded. The local Institutional Review Board
approved this study. Before being recruited, participants gave their written, informed consent.

Figure2; Comparison of the symptoms of NPI before and after YKS treatment (N=11)

Procedure

Prior to YKS treatment, all patients were assessed for age, past history, family history, name anddose of antipsychotics already administered. After assessment, 7.5 g of YKS powder was added
to ongoing therapy with antipsychotics. Participants were asked about adverse events, sideeffects, and medication compliance every week. Neuropsychiatric Inventory (NPI) criteria before
and after 4-week YKS treatment were compared. ADL of participants were evaluated using theBathel index. Rating scale scores were confirmed by an independent researcher. Participants
were assessed by field researchers.

Statistical analysis

Parametric data are reported as meanSD. The Wilcoxon signed-ranks test was used tocompare mean differences in parametric data at baseline and at week 4. A probability value ofless than 0.05 was considered statistically significant. Statistical analysis of data was carried out
using Statcel (2nd edition) on Excel for Windows.

A total of 12 patients were recruited for the present trial. A 79-year-old male patient who satisfied
the diagnostic criteria of Alzheimer’s dementia dropped out from the study, because he and his
family preferred to use quetiapine a week after the initiation of YKS treatment. He continued totake YKS 7.5 g/day and quetiapine 50-100 mg/day together for 4 weeks and did not experience
any adverse reactions.
The other 11 patients completed the 4-week observation period (Table 1). Analysis of the meanscore for NPI scale revealed a significant improvement during the period of YKS administration(25.3
17.6 vs 8.36
4.46; p = 0.0069; Figure 1). Delusions and feelings of agitation weresignificantly improved (Figure 2). The mean score for the Bathel index showed no significant
difference during the period of YKS administration (47.621.2 vs 50.4
22.1; p = 0.1441).
Laboratory parameters were within the range at baseline and remained in the reference range forthe whole sample throughout the 4-week trial. Mean level of serum potassium was 3.890.56mEq/l at baseline and 3.78
0.46 mEq/l at week 4, which was still within the normal range(Figure 2). Subjects reported a few mild and transient adverse events, including nausea (1 case)and tiredness (1 case), however, no subjects had severe adverse reactions necessitating
discontinuation from the study.

Conclusions
We showed that a traditional Chinese herbal medicine, YKS, significantly improved the symptomsof BPSD in CRF patients receiving hemodialysis without critical side effects. The
pharmacokinetics of the ingredients contained in YKS need to be elucidated for more precise
usage of YKS against BPSD in CRF patients.

Night time behaviors

Irritability

Disinhibition

ApathyEuphoria

Anxiety

Agitation

Depression

Results

Hallucinations

Medical and disease history, physical examination, body weight, blood pressure, andelectrocardiograms were assessed at baseline. Laboratory studies included a baseline screening
for liver disease, metabolic dysfunction, electrolyte imbalance, anemia, adequate blood cell andplatelet count, and presence of illegal drugs. A medical review was performed, together withassessment of body weight and blood pressure and a review of adverse events and concomitant
medications at the end of the trial.

Delusions

Safety assessments

References
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therapy. Nephron 2002; 91:344-347.
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3. Abraham SC, Bhagavan BS, Lee LA, et al: Upper gastrointestinal tract injury in patients receiving
kayexalate (sodium polystyrene sulfonate) in sorbitol: clinical, endoscopic, and histopathologic findings.
Am J Surg Pathol 2001; 25: 637
4. Khedr E, Abdelwhab S, El-Sharkawy M, et al: Prevalence of hyperkalemia among hemodialysis patientsin Egypt. Ren Fail 2009; 31: 891-898.
5. Iwasaki K, Maruyama M, Tomita N, et al: Effects of the traditional Chinese herbal medicine Yi-Gan San forcholinesterase inhibitor-resistant visual hallucinations and neuropsychiatric symptoms in patients withdementia with Lewy bodies. J Clin Psychiatry 2005; 66:1612-1613.