Kampo therapy as an alternative to pharmacotherapy using antipsychotic medicines for behavioral and psychological symptoms of dementia (BPSD)
This review article was presented by the author in Symposium of the 22nd Annual Meeting of Japanese Psychogeriatric Society in Osaka, 15–16 November 2007.
Dr Katsuyoshi Mizukami MD, Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Email: email@example.com
The behavioral and psychological symptoms of dementia (BPSD), including aggression, agitation, screaming, wandering, hallucinations, and delusions, occur in 50–90% of patients with dementia, and have a negative impact on the activity of daily living (ADL) of patients, as well as caregivers. Patients with severe BPSD often require management with antipsychotic medicines. However, an increased mortality rate has been reported in patients with dementia taking antipsychotic medicine and, thus, there is an urgent need to develop safer treatments for BPSD. Kampo medicines are an alternative to antipsychotic medicines and several Kampo medicines have been reported to be effective in the treatment of BPSD. Oren-gedoku-to has been reported to be effective for the treatment of irritability and sullenness in patients with vascular dementia, as well as improving excitement, depression, anxiety, and restlessness of patients with cerebrovascular lesions. Choto-san has been reported to be effective in the treatment of delirium, insomnia, and hallucinations/delusions in patients with vascular dementia. Toki-syakuyaku-san has been reported to improve emotional lability, restlessness, and sleep disturbances in patients with dementia. Yokukan-san has been reported to be effective for hallucinations, agitation/aggression, irritability/lability, and aberrant motor activity, as well as being effective in the treatment of visual hallucinations in patients with dementia with Lewy bodies (DLB). A multicenter randomized crossover study confirmed that Yokukan-san is effective in the treatment of BPSD and is well-tolerated. Kampo medicines do not induce extrapyramidal or anticholinergic symptoms and have no adverse effects on ADL or cognitive function. Thus, Kampo therapy is recommended for patients who cannot tolerate treatment with neuroleptics, patients who have extrapyramidal symptoms and gait disturbance, and patients with DLB. In future, to confirm the effectiveness of Kampo medicines in the treatment of BPSD, further studies, such as randomized control trials, are needed. In addition, basic studies are required to elucidate the processes by which Kampo medicines are metabolized, as well as any interactions between Western and Kampo medicines.
The behavioral and psychological symptoms of dementia (BPSD), including aggression, agitation, screaming, wandering, hallucinations, and delusions, occur in 50–90% of patients with dementia1–3 and have a negative impact on the quality of life (QOL) of patients, as well as their caregivers.4 Moreover, these symptoms are frequently the primary cause of hospitalization or institutionalization.5
Although non-pharmacological interventions, such as environmental interventions, should be the first-line treatment for BPSD,6 patients with severe BPSD often require management using antipsychotic medicines.3,7 However, antipsychotic medications may induce extrapyramidal symptoms and have adverse effects on cognitive function and activities of daily living (ADL). Recently, an increased mortality rate has been reported for patients with dementia taking both atypical8 and conventional9 antipsychotic medicines. Thus, there is an urgent need for the development of safer treatments for BPSD.
KAMPO MEDICINES FOR BPSD
Kampo medicines, Japanese herbal medicines, are an alternative to antipsychotics and are known to allow patients to maintain a favorable QOL.10 Thus, Kampo therapy is suitable for the treatment of BPSD in elderly patients. However, thus far, there have been few reports of the treatment of BPSD with Kampo medicines. In the present paper, several Kampo medicines that have been reported to be effective in the treatment of BPSD are reviewed (Table 1).
Table 1. Kampo medicines for behavioral and psychological symptoms of dementia
|Dementia type||AD, DLB, VaD||VaD||VaD||AD, VaD|
|Symptoms improved||Agitation, irritability, hallucination, abberant motor behavior||Sleep disturbance, delirium, hallucination, delusion||Irritability, depression, anxiety||Lability, restlessness, sleep disturbance|
|Effect on cognitive function||None||Improvement is reported||Improvement is reported||Improvement is reported|
|Adverse reactions reported||Gastrointestinal symptoms hypokalemia||Gastrointestinal symptoms||Gastrointestinal symptoms, liver dysfunction||Gastrointestinal symptoms|
Oren-gedoku-to, which is composed of four crude drugs (Scutellariae radix, Coptidis rhizoma, Gardeniae fructus, and Phellodendri cortex), is routinely used for the treatment of hypertension, gastritis, skin itching, irritability, and insomnia in patients with a robust constitution.
Two previous studies have demonstrated the effectiveness of Oren-gedoku-to in treating BPSD. One study was a multicenter open trial that went for 12 weeks, involved 43 patients (average age 70.4 years), 32 with vascular dementia (VaD) and 11 with Alzheimer's disease (AD), and investigated the effects of 7.5 g Oren-gedoku-to daily on BPSD.11 The results of that study demonstrated that Oren-gedoku-to improves irritability and sulleness in patients as well as ADL. Adverse reactions were observed in three of 43 patients (one patient discontinued therapy because of liver dysfunction). This study shows that Oren-gedoku-to is particularly effective for BPSD in patients with VaD.
The second study was a multicenter control trial that again went for 12 weeks and compared the effects of treatment between 7.5 g Oren-gedoku-to and 1500 mg Ca hopantenate daily for BPSD in 148 patients with cerebral vascular lesions.12 The results showed that treatment with Oren-gedoku-to improved feelings of excitement, depression, anxiety, and restlessness in the patients, although no significant difference was observed between the two treatments. Oren-gedoku-to also showed a beneficial effect on ADL, such as wearing clothes and eating, as well as cognitive function assessed using the Hasegawa Dementia Scale (P < 0.01 vs Ca hopantenate). In this study, adverse effects were observed in four of 76 patients (gastrointestinal symptoms, headache etc.).12
An experimental study has demonstrated that Oren-gedoku-to increases cerebral blood flow in the area surrounding the ischemic core and promotes collateral circulation in the margins of the ischemic area.13 These pharmacological actions of Oren-gedoku-to may be associated, in part, with its effects on BPSD in patients with cerebral vascular lesions.
Choto-san is composed of 11 crude drugs: Gypsum fibrosum, Uncariae uncis cum ramulus, Aurantii nobilis pericarpium, Ophiopogonis tuber, Pinelliae tuber, Poria, Chrysanthemi flos, Ginseng radix, Saposhnikoviae radix, Glycyrrhizae radix, and Zingiberis rhizoma. Choto-san is commonly used for cerebrovasucular symptoms, such as headache, dizziness, and vertigo, as well as hypertension in elderly patients with a deficient constitution.
A multicenter randomized placebo-controlled trial was conducted in order to investigate the effectiveness and safety of Choto-san for BPSD in patients with vascular dementia.14 That study involved 139 patients with VaD (average age 76.6 years) and compared the effects of 7.5 g Choto-san daily with that of placebo on BPSD over a period of 12 weeks. Choto-san improved delirium (P < 0.05 at 8 weeks), insomnia (P < 0.001 at 12 weeks), and hallucinations/delusions (P < 0.001 at 12 weeks) compared with controls. Choto-san also improved ADL (wearing clothes; P < 0.05), although there was no effect on cognitive function. Mild adverse effects, such as gastrointestinal symptoms and eruption, were observed in five patients. The results of this study suggest that Choto-san is effective for the treatment of BPSD in patients with VaD.
Experimental studies have demonstrated that Choto-san has pharmacological actions protecting against ischemic brain lesions.15,16 In addition, Uncariae uncis cum ramulus, one of the components of Choto-san, acts on serotonin 5-HT1A receptors17 and has an activating effect on the cholinergic neurotransmitter system.18 Thus, it is possible that these pharmacological actions on ischemic lesions and several neurotransmitter systems may contribute, in part, to the improvemebnt of BPSD in patients with VaD who are treated with Choto-san.
Toki-shyakuyaku-san contains six crude drugs: Paeoniae radix, Atractylodis lanceae rhizoma, Alismatis rhizoma, Poria, Cnidii rhizoma, and Angelicae radix. This medicine is commonly used for the treatment of women's physical conditions, such as amenorrhea, infertility, and menopausal syndrome, in patients with a deficient constitution.
The effects of Toki-shyakuyaku-san on BPSD have been reported following a multicenter open-label 12-week trial.19 That trial included 80 patients with dementia (average age 78.4 years; 40 with VaD, 38 with AD, and two with mixed-type dementia). The results indicated that Toki-syakuyaku-san improves emotional lability, restlessness, and sleep disturbances compared with baseline (P < 0.01). In addition, Toki-syakuyaku-san improved ADL and cognitive function (especially orientation and attention). Minimal adverse effects were observed in two patients.
An experimental study demonstrated that Toki-syakuyaku-san activates cholinergic and dopaminergic neurons, receptors, and protein synthesis.20 In addition, Angelicae radix, a component of Toki-syakuyaku-san, reportedly acts on the GABAergic system.21 These pharmacological actions on the brain are presumably associated with the clinical effectiveness of Toki-shyakuyaku-san in the treatment of BPSD.
Yokukan-san is composed of seven crude drugs: Atractylodis lanceae rhizoma, Poria, Cnidii rhizoma, Uncariae uncis cum ramulus, Angelicae radix, Bupleuri radix, and Glycyrrhizae radix.
Yokukan-san was originally used for the treatment of emotional lability and agitation in infants. Hara first reported that Yokukan-san and its allied drugs are effective in treating emotional disorders in elderly patients.22 He reported that, of 48 elderly patients treated with Yokukan-san, marked improvement was observed in 32 patients (67%), an improvement was observed in 11 patients (23%), and no effect was observed in only two patients. Hara selected patients with sho (Kampo diagnosis) indicating that they were suitable for Yokukan-san or Yokukan-san-ka-chinpi-hange treatment. Accordingly, his study suggests that sho is useful in predicting the effectiveness of these medicines.
Iwasaki et al. have reported the effects of Yokukan-san in the treatment of BPSD.23,24 They conducted a 4-week observer-blinded randomized comparative study of Yokukan-san on 52 elderly patients with BPSD (including AD, VaD, mixed type, and dementia with Lewy bodies (DLB)) and reported that Yokukan-san administration significantly improved BPSD comapred with controls who did not received treatment (P < 0.001).23 In that study, Neuropsychiatric Inventory subscales significantly improved with regard to hallucinations, agitation/aggression, irritability/lability, and aberrant motor activity. In addition, patients, who received Yokukan-san exhibited improved ADL, as assessed by the Barthel Index. Two patients were oversedated with 7.5 g Yokukan-san daily, but this adverse effect disappeared after the dose was reduced to 5 g daily.23 Their next study was an open-label trial of the effects of Yokukan-san on BPSD of patients with DLB.24 Iwasaki et al. found that BPSD of DLB significantly improved from baseline following 4 weeks administration of Yokukan-san (P < 0.0008). In addition, visual hallucinations disappeared in 11 of 13 DLB patients within 2 weeks.24 The ADL of patients was improved following administration of Yokukan-san (P < 0.0027). Only one patient discontinued Yokukan-san because of drowsiness. Both studies reported that Yokukan-san had no adverse effects on cognitive function, as assessed using the Mini-Mental State Examination.
In our study,25 Yokukan-san was found to be effective in the treatment of irritability, excitement, and insomnia, as well as depression. For some patients, 5 g Yokukan-san daily was effective for BPSD. It is difficult for patients who have both depression and agitation to be treated with Western medicines, because combination therapy of antipsychotics and antidepressants increases the risk of adverse reactions. For such patients, Yokukan-san appears to be useful because it improves both depression and agitation.
To further assess the effectiveness and safety of Yokukan-san for BPSD, we conducted a multicenter randomized crossover study between October 2005 and April 2007.26 That study involved 106 patients (AD, mixed-type dementia, and DLB) who were randomly assigned to Group A (Yokukan-san treatment to no treatment) and Group B (no treatment to Yokukan-san treatment). The period of administration of Yokukan-san and no treatment was 4 weeks each. The results of this study also suggested that Yokukan-san is effective in the treatment of BPSD and that it is well tolerated. However, because Glycyrrhizae radix, a component of Yokukan-san, contains glycyrrhizin, which has a facilitating action on potassium excretion in the renal tubules, we need to be careful of the development of hypokalemia during Yokukan-san administration.
The mechanism underlying the effects of Yokukan-san on BPSD remains to be determined. Regulatory effects on neurotransmitter systems by Uncariae uncis cum ramulus and Angelicae radix, components of Yokukan-san, are thought to contribute to the improvements in various psychiatric and behavioral symptoms.
CONCLUSIONS REGARDING KAMPO THERAPY FOR BPSD
The benefit of Kampo medicines is safety, because Kampo medicines do not induce extrapyramidal or anticholinergic symptoms and have no adverse effects on ADL or cognitive function. In fact, some studies have demonstrated that Kampo therapy improves ADL and cognitive function (Table 2). In addition, the pharamacological actions of Kampo medicines, such as the protective effects against ischemic damage of Oren-gedoku-to and Choto-san, the free radical-scavenging activity27 and prevention of neuronal apoptosis20 of Toki-syakuyaku-san, and the inhibitory effects of Uncariae uncis cum ramulus (a component of Choto-san and Yokukan-san) on β-amyloid protein fibril aggregation,28 are favorable for elderly patients with dementia.
Table 2. Benefits of Kampo therapy
| Does not cause extrapyramidal symptoms|
| No anticholinergic effect|
| No adverse effects on ADL and cognitive function|
| Protects against ischemic damage|
| Prevents neuronal apoptosis|
| Radical-scavenging activity|
| Inhibitory effect on β-amyloid protein fibril aggregation|
Because of their safety profile, Kampo medicines are recommended for patients who have difficulties with treatments involving antipsychotic medicines, including those patients who are intolerant of treatment with antipsychotic medicines, patients who have physical complications (including parkinsonism, gait disturbance, urinary disturbance, and emaciation), and patients with DLB (Table 3).
Table 3. Indications for the use of Kampo medicines
|Patients suitable for treatment with Kampo medicines:|
|• Those who have physical complications (including parkinsonism, gait disturbance, urinary disturbance, and emaciation)|
|• Those who are intolerant of treatment with antipsychotic medicines|
|• Patients with dementia with Lewy bodies|
However, Kampo therapy for BPSD has some issues that remain to be resolved. First, there is still little evidence regarding the effectiveness and safety of Kampo therapy, and further studies, such as randomized controlled trials, are needed. Second, basic studies are required to elucidate the pharmacology of the Kampo medicines, particularly metabolic processes and metabolizing enzymes. In addition, little is known regarding interactions between Western and Kampo medicines. In order to avoid critical interactions, this matter should also be investigated.