AAD  Vol.7 No.4 , December 2018
The Efficacy and Safety of Yokukansankachimpihange for Treating Behavioral and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease: An Open-Label Pilot Study
Abstract: Previous clinical trials have demonstrated the efficacy of yokukansan, a traditional Japanese medicine, for the treatment of behavioral and psychological symptoms of dementia (BPSD). However, less evidence is available for the treatment of BPSD with yokukansankachimpihange (YKSCH), which consists of yokukansan and two additional herbal ingredients. The present study was conducted to investigate the efficacy and safety of YKSCH for treating BPSD in patients with Alzheimer’s disease (AD). We enrolled outpatients with mild-to-moderate AD who exhibited BPSD and obtained a Neuropsychiatric Inventory (NPI) score of >3 including subscale scores for “agitation”, “anxiety”, “irritability”, and “sleep and night-time behavior change”. A daily YKSCH dose of 7.5 g was administered for 12 weeks with concomitant administration of anti-dementia medication. BPSD was evaluated using the NPI at baseline and every 4 weeks during the intervention. We also examined apathy using the Japanese translation of the Apathy Scale, the short version of the Japanese version of the Zarit Caregiver Burden Interview, and the Modified Crichton Rating Scale for Predicting Activities of Daily Living. Cognitive dysfunction was evaluated using the Mini Mental State Examination and the AD Assessment Scale-Cognitive (Japanese version). Five participants were enrolled. The NPI total score tended to decrease between the baseline and 8-week evaluations during the YKSCH intervention (Wilcoxon signed rank test, P = 0.063). In terms of the NPI subscale scores, “apathy”, “agitation”, “delusions, and “sleep and night-time behavior change” decreased after the intervention in those who exhibited each symptom at baseline. There were no significant differences in the other scores examined. No serious adverse events were observed. YKSCH could ameliorate BPSD in patients with mild-to-moderate AD with agitation, anxiety, irritability, and sleep and night-time behavior change, and it was well-tolerated.
Cite this paper: Arita, R. , Yoshino, T. , Ohgishi, M. , Hamaguchi, T. , Horiba, Y. , Sawai, K. , Funaki, K. , Tabuchi, H. , Oka, M. , Yoshizaki, T. , Watanabe, K. and Mimura, M. (2018) The Efficacy and Safety of Yokukansankachimpihange for Treating Behavioral and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease: An Open-Label Pilot Study. Advances in Alzheimer's Disease, 7, 141-152. doi: 10.4236/aad.2018.74010.

[1]   Yatawara, C., Hiu, S., Tan, L. and Kandiah, N. (2018) Neuropsychiatric Symptoms in South-East Asian Patients with Mild Cognitive Impairment and Dementia: Prevalence, Subtypes, and Risk Factors. International Journal of Geriatric Psychiatry, 33, 122-130.

[2]   Beeri, M.S., Werner, P., Davidson, M. and Noy, S. (2002) The Cost of Behavioral and Psychological Symptoms of Dementia (BPSD) in Community Dwelling Alzheimer’s Disease Patients. International Journal of Geriatric Psychiatry, 17, 403-408.

[3]   Kamiya, M., Sakurai, T., Ogama, N., Maki, Y. and Toba, K. (2014) Factors Associated with Increased Caregivers’ Burden in Several Cognitive Stages of Alzheimer’s disease. Geriatrics & Gerontology International, 14, 45-55.

[4]   Steele, C., Rovner, B., Chase, G.A. and Folstein, M. (1990) Psychiatric Symptoms and Nursing Home Placement of Patients with Alzheimer’s Disease. American Journal of Psychiatry, 147, 1049-1051.

[5]   Iwasaki, K., Satoh-Nakagawa, T., Maruyama, M., Monma, Y., Nemoto, M., et al. (2005) 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. Journal of Clinical Psychiatry, 66, 248-252.

[6]   Mizukami, K., Asada, T., Kinoshita, T., Tanaka, K., Sonohara, K., et al. (2009) A Randomized Cross-Over Study of a Traditional Japanese Medicine (Kampo), Yokukansan, in the Treatment of the Behavioral and Psychological Symptoms of Dementia. International Journal of Neuropsychopharmacology, 12, 191-199.

[7]   Monji, A., Takita, M., Samejima, T., Takaishi, T., Hashimoto, K., et al. (2009) Effect of Yokukansan on the Behavioral and Psychological Symptoms of Dementia in Elderly Patients with Alzheimer’s Disease. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33, 308-311.

[8]   Okahara, K., Ishida, Y., Hayashi, Y., Inoue, T., Tsuruta, K., et al. (2010) Effects of Yokukansan on Behavioral and Psychological Symptoms of Dementia in Regular Treatment for Alzheimer’s Disease. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 34, 532-536.

[9]   Matsuda, Y., Kishi, T., Shibayama, H. and Iwata, N. (2013) Yokukansan in the Treatment of Behavioral and Psychological Symptoms of Dementia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Human Psychopharmacology, 28, 80-86.

[10]   Furukawa, K., Tomita, N., Uematsu, D., Okahara, K., Shimada, H., et al. (2017) Randomized Double-Blind Placebo-Controlled Multicenter Trial of Yokukansan for Neuropsychiatric Symptoms in Alzheimer’s Disease. Geriatrics & Gerontology International, 17, 211-218.

[11]   Japanese Society of Neurology (2017) Practice Guideline for the Treatment of Dementia 2017. Igaku-Shoin, Tokyo. (In Japanese)

[12]   Magome, A. (2011) Effect of Yokukansankachimpihange on Dementia—Including the Point of View of Oriental Medicine. Psychiatry, 18, 108-114. (In Japanese with English Abstract)

[13]   Katsumoto, E., Ishida, T., Kinoshita, K., Shimizu, M., Tsutsumi, T., et al. (2016) Efficacy and Safety of Yokukansankachimpihange on BPSD. Japanese Journal of Medicine and Pharmaceutical Science, 73, 846-853. (In Japanese with English Abstract)

[14]   Miyazawa, J. (2009) Study of the Clinical Efficacy of Yokukansankachimpihange on Alzheimer’s Disease. Psychiatry, 14, 535-542. (In Japanese with English Abstract)

[15]   Fujita, N., Yoshida, M., Yomoda, S. and Itomura, M. (2013) Effect of Yokukansankachimpihange on Cognitive Ability, an Open Randomized Controlled Trial. Psychiatry, 23, 130-138. (In Japanese with English Abstract)

[16]   McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D. and Stadlan,E.M. (1984) Clinical Diagnosis of Alzheimer’s Disease: Report of the NINCDS—ADRDA Work Group under the Auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology, 34, 939.

[17]   Cummings, J.L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D.A. and Gornbein, J. (1994) The Neuropsychiatric Inventory: Comprehensive Assessment of Psychopathology in Dementia. Neurology, 44, 2308.

[18]   Folstein, M.F., Folstein, S.E. and McHugh, P.R. (1975) “Mini-Mental State”: A Practical Method for Grading the Cognitive State of Patients for the Clinician. Journal of Psychiatric Research, 12, 189-198.

[19]   Tsumura & Co. (2013) Kampo-Preparation: TSUMURA Yokukansankachimpihange Extract Granules for Ethical Use. 5th Version, Tsumura & Co., Tokyo.

[20]   Starkstein, S.E., Mayberg, H.S., Preziosi, T.J., Andrezejewski, P., Leiguarda, R., et al. (2006) Reliability, Validity, and Clinical Correlates of Apathy in Parkinson’s Disease. The Journal of Neuropsychiatry and Clinical Neurosciences, 4, 134-139.

[21]   Okada, K., Kobayashi, S., Yamagata, S., Takahashi, K. and Yamaguchi, S. (1997) Poststroke Apathy and Regional Cerebral Blood Flow. Stroke, 28, 2437-2441.

[22]   Arai, Y., Tamiya, N. and Yano, E. (2003) The Short Version of the Japanese Version of the Zarit Caregiver Burden Interview (J-ZBI_8): Its Reliability and Validity. The Japan Geriatrics Society, 40, 497-503. (In Japanese with English Abstract)

[23]   Hasegawa, K., Honma, A., Takeda, M., Udaka, F., Imai, Y., et al. (2003) Evaluating the Family or Caregiver Impression of Donepezil on Alzheimer’s Disease. Does Donepezil Help the Communication between Patients and Their Family? Geriatric Medicine, 41, 733-743. (In Japanese)

[24]   Rosen, W.G., Mohs, R.C. and Davis, K.L. (2006) A New Rating Scale for Alzheimer’s Disease. The American Journal of Psychiatry, 141, 1356-1364.

[25]   Marin, R.S. (2006) Apathy: A Neuropsychiatric Syndrome. The Journal of Neuropsychiatry and Clinical Neurosciences, 3, 243-254.

[26]   Starkstein, S.E., Petracca, G., Chemerinski, E. and Kremer, J. (2001) Syndromic Validity of Apathy in Alzheimer’s Disease. American Journal of Psychiatry, 158, 872-877.

[27]   Hurt, C., Bhattacharyya, S., Burns, A., Camus, V., Liperoti, R., et al. (2008) Patient and Caregiver Perspectives of Quality of Life in Dementia: An Investigation of the Relationship to Behavioral and Psychological Symptoms in Dementia. Dementia and Geriatric Cognitive Disorders, 26, 138-146.

[28]   Starkstein, S.E., Jorge, R., Mizrahi, R. and Robinson, R.G. (2006) A Prospective Longitudinal Study of Apathy in Alzheimer’s Disease. Journal of Neurology, Neurosurgery, and Psychiatry, 77, 8-11.

[29]   Vilalta-Franch, J., Calvo-Perxas, L., Garre-Olmo, J., Turro-Garriga, O. and Lopez-Pousa, S. (2013) Apathy Syndrome in Alzheimer’s Disease Epidemiology: Prevalence, Incidence, Persistence, and Risk and Mortality Factors. Journal of Alzheimer’s Disease, 33, 535-543.

[30]   Dauphinot, V., Delphin-Combe, F., Mouchoux, C., Dorey, A., Bathsavanis, A., et al. (2015) Risk Factors of Caregiver Burden among Patients with Alzheimer’s Disease or Related Disorders: A Cross-Sectional Study. Journal of Alzheimer’s Disease, 44, 907-916.

[31]   Rosenberg, P.B., Lanctot, K.L., Drye, L.T., Herrmann, N., Scherer, R.W., et al. (2013) Safety and Efficacy of Methylphenidate for Apathy in Alzheimer’s Disease: A Randomized, Placebo-Controlled Trial. Journal of Clinical Psychiatry, 74, 810-816.

[32]   Herrmann, N., Rothenburg, L.S., Black, S.E., Ryan, M., Liu, B.A., et al. (2008) Methylphenidate for the Treatment of Apathy in Alzheimer Disease: Prediction of Response Using Dextroamphetamine Challenge. Journal of Clinical Psychopharmacology, 28, 296-301.

[33]   Feldman, H., Gauthier, S., Hecker, J., Vellas, B., Xu, Y., et al. (2005) Efficacy and Safety of Donepezil in Patients with More Severe Alzheimer’s Disease: A Subgroup Analysis from a Randomized, Placebo-Controlled Trial. International Journal of Geriatric Psychiatry, 20, 559-569.

[34]   Sepehry, A.A., Sarai. M. and Hsiung, G.R. (2017) Pharmacological Therapy for Apathy in Alzheimer’s Disease: A Systematic Review and Meta-Analysis. Canadian Journal of Neurological Sciences, 44, 267-275.

[35]   Mizoguchi, K., Tanaka, Y. and Tabira, T. (2010) Anxiolytic Effect of a Herbal Medicine, Yokukansan, in Aged Rats: Involvement of Serotonergic and Dopaminergic Transmissions in the Prefrontal Cortex. Journal of Ethnopharmacology, 127, 70-76.

[36]   Ueda, T., Ugawa, S., Ishida, Y. and Shimada, S. (2011) Geissoschizine Methyl Ether has Third-Generation Antipsychotic-Like Actions at the Dopamine and Serotonin Receptors. European Journal of Pharmacology, 671, 79-86.

[37]   Jung, U.J., Leem, E. and Kim, S.R. (2014) Naringin: A Protector of the Nigrostriatal Dopaminergic Projection. Experimental Neurology, 23, 124-129.

[38]   Kim, H.D., Jeong, K.H., Jung, U.J. and Kim, S.R. (2016) Naringin Treatment Induces Neuroprotective Effects in a Mouse Model of Parkinson’s Disease in Vivo, but Not Enough to Restore the Lesioned Dopaminergic System. The Journal of Nutritional Biochemistry, 28, 140-146.

[39]   Ohsawa, M., Tanaka, Y., Ehara, Y., Makita, S. and Onaka, K. (2017) A Possibility of Simultaneous Treatment with the Multicomponent Drug, Ninjin’yoeito, for Anorexia, Apathy, and Cognitive Dysfunction in Frail Alzheimer’s Disease Patients: An Open-Label Pilot Study. Journal of Alzheimer’s Disease Reports, 1, 229-235.

[40]   Kudoh, C., Arita, R., Honda, M., Kishi, T., Komatsu, Y., et al. (2016) Effect of Ninjin’yoeito, a Kampo (Traditional Japanese) Medicine, on Cognitive Impairment and Depression in Patients with Alzheimer’s Disease: 2 Years of Observation. Psychogeriatrics, 16, 85-92.