Potential Application of Yokukansan as a Remedy for Parkinson’s Disease

Table 1

Clinical studies on the effects of YKS on PD-like symptoms in multiple neurological disorders.

Symptom	Participants (number)	Design	Intervention	Comparison	Outcome		Reference
					Primary	Secondary
Sleep	12 with AD and 1 with frontotemporal dementia (n= 13)	Open-label trial	YKS (5-7.5 g/day) for 8 weeks	None	Improved Sleep Disorder Inventory per NPI	Improved wake after sleep onset and total NPI scores; No change in MMSE	[5]
	5 with dementia	Open-label trial	YGS (2.5g) for 4 weeks	None	PSG; total sleep time, sleep efficiency, stage 2 sleep ↑ and the number of arousals and periodic limb movements ↓; Improved PSQI		[6]
	20 healthy adult males	Double-blind trial	YKSCH (7.5 g/day) for 3 days	Anchu-san	PSG; total sleep time, sleep efficiency, and stage 2 sleep ↑; Sleep latency and stage 3+4 sleep ↓		[7]
	3 with rapid eye movement sleep; behavior disorder	Case report	YGS (7.5 g/day) + clonazepam (0.5 mg/day)	None	Suppression of RBD		[8]
			YGS (7.5 g/day) + clonazepam (0.25 mg/day)
			YGS(2.5 g/day)
	25 with PD	Open-label trial	YKS (7.5 g/day) for 12 weeks	None	NPI total score ↓; Improved subscale including hallucinations, anxiety, and apathy	No significant change in UPDRS part III and Hoehn–Yahr classification	[2]
	7 with PD; 7 with PDD; (n=14)	Open-label trial	YKS (7.5 g/day) for 4 weeks	None	NPI total score ↓; improved subscale including hallucinations; MMSE improved slightly in PDD; No change in UPDRS III and ADL		[9]
	90 with dementia	Randomized rater-blinded trial	YKS (2.5-7.5 g/d) for 8 weeks	Risperidone or fluvoxamine	NPI-NH ↓	No change in MMSE, FIM, and drug-induced Extra-Pyramidal Symptoms Scale	[10]
	103 with dementia	Randomized cross-over trial	YKS (7.5 g) for 4 weeks	None	NPI total score ↓; improved subscale including delusions, hallucinations, agitation/aggression, depression, anxiety, and irritability/lability; No change in MMSE and ADL		[11]
	5 with dementia	Open-label trial	YGS (2.5 g) for 4 weeks	None	NPI-NH total score ↓; improved subscale including delusions,; hallucinations, agitation/aggression, anxiety, and irritability/lability; No change in MMSE		[6]
Neuropsychiatry	52 with dementia	Randomized, observer-blind, controlled trial	YGS (7.5 g/day) for 4 weeks	Drug-free	NPI-NH total score ↓; improved subscale including hallucinations, agitation/aggression, irritability/lability and aberrant motor activity; Barthel index ↑; No change in MMSE		[12]
	145 with AD	Randomized double-blind placebo-controlled trial	YKS (7.5 g/day) for 4 weeks	Placebo-control	No significant difference in total NPI-Q scores	Improved NPI subscale including agitation/aggression and hallucinations; No change in MMSE	[13]
	61 with AD	Randomized, non-blinded, parallel-group comparison trial	YKS (7.5 g/day) + donepezil for 4 weeks	Active comparator	NPI total score ↓; improved subscale including agitation/aggression and irritability/lability; No significant difference in MMSE, DAD, ZBI, or SDS		[14]
	29 with AD	Open-label trial	YKS (7.5 g/day) for 4 weeks	None	NPI total score ↓	Clinically decreased subscale including hallucinations, agitation, anxiety, irritability, and abnormal behaviors; No significant difference in MMSE, DAD, ZBI, or SDS	[15]
	15 with AD	Randomized controlled trial	YKS(2.5 g) for 12 weeks + sulpiride (50 mg/day)	Control	NPI total score ↓; No change in MMSE and ADL		[16]
	13 with vascular dementia	Open-label clinical trial	YKS (7.5 g/day) for 4 weeks	None	NPI total score ↓; significantly improved subscale including agitation; No change in MMSE, ADL, DAD, or UPDRS		[17]
	40 with schizophrenia	Open-label clinical trial	YKS (2.5–7.5 g/day) for 4 weeks	None	Significantly improved BPRS, CGI-S, and PANSS; Slightly decreased Simpson-Angus scale, Barnes Akathisia scale, and AIM		[18]
Cognition	1 with schizophrenia	Case report	YKS (5.0 g/day) for 3 months	None	Markedly improved cognitive functions in daily life and BACS–J		[19]
Pain	10 with neuropathic pain	Open-label clinical trial		None	Markedly decreased VAS and PS		[20]
Tardive dyskinesia	22 with schizophrenia	Open-label trial	YGS (7.5 g/day) for 12 weeks	None	Significantly decreased AIMS total scores and all PANSS subscales; Substantial changes in CGI		[21]

NPI=neuropsychiatric inventory, MMSE=MINI-Mental State Examination, YGS=Yi-Gan San, PSG=polysomnography, ADL=the Barthel Index for activities of daily living, PDD=PD with dementia, NPI-NH=The Nursing Home version of Neuropsychiatric Inventory, PSQI=the Pittsburgh Sleep Quality Index, FIM=daily life function measured by Functional Independence Measure, DAD=Disability Assessment for Dementia, SDS=Self-rating Depression Scale, ZBI=Zarit Burden Interview, BPRS=psychiatric rating scale, CGI-S=clinical global impression scale-severity, PANSS=positive and negative syndrome scale, AIM=involuntary movement scale, BACS–J=Brief Assessment of Cognition in Schizophrenia, Japanese Version, VAS=visual analogue scale, and PS=pain score.