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Yi-gan san

Scientific Name(s): Angelica acutiloba Kitagawa, Atractylodes lancea De Candolle, Bupleurum falcatum Linne, Cnidium officinale Makino, Glycyrrhiza uralensis Fisher, Poria cocos Wolf, Uncaria rhynchophilla Miquel
Common Name(s): TJ-54, Tsumura, Ukgansan, Yi-gan san, Yoku-kan-san, Yokukan-san, Yokukansan

Medically reviewed by Drugs.com. Last updated on Sep 2, 2019.

Clinical Overview

Use

Yi-gan san has been used for centuries as a traditional herbal medicine to treat agitation and restlessness in children and has often been administered to both the mother and infant. In Japan, it is approved for neurosis, insomnia, night cry in children, and irritability in children. Increasingly, yi-gan san is being used for a variety of psychological and psychiatric conditions associated with dementia, personality disorder, schizophrenia, sleep disorders, traumatic brain injury, and Charles Bonnet syndrome. There is limited clinical data indicating its usefulness in chronic urticaria and tardive dyskinesia.

Dosing

According to the prescribing information for the Japanese commercial product (TJ-54), the usual adult dosage of yi-gan san formulation is 7.5 g/day given orally in 2 or 3 divided doses. The dosage may be adjusted based on patient age, body weight, and symptoms for the relief of symptoms of nervousness (ie, neurosis, insomnia, night crying in children, irritability). This dose has also been used in clinical studies for treatment of behavioral and psychological symptoms of dementia, tardive dyskinesia, aggressive dream-enacting behavior, and visual hallucinations. Doses of the yi-gan san formulation ranging from 2.5 to 7.5 g/day have been studied in females with borderline personality disorder.

Yi-gan san dosages of 2.5 g once or twice daily (evening and/or bedtime) as an adjunct to psychotropic regimens have been used to treat restless leg syndrome (RLS) and abnormal night eating behavior. A dosage of 2.5 g 3 times daily as an adjunct to antipsychotic treatment has been used to manage treatment-resistant schizophrenia.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Since 1555, yi-gan san has been used in breast-feeding mothers, infants, and children; however, information regarding safety and efficacy in pregnancy and lactation is lacking. According to Japanese product labeling, the safety of yi-gan san has not been established.

Interactions

Coadministration of glycyrrhiza-, glycyrrhizinic acid-, or glycyrrhizinate-containing preparations may lead to pseudoaldosteronism, hypokalemia, and myopathy.

Adverse Reactions

Reversible adverse effects reported include sedation, nausea, vomiting, diarrhea, epigastric discomfort, hypokalemia, and leg edema. Clinically important adverse reactions are interstitial pneumonia, pseudoaldosteronism, heart failure, myopathy or rhabdomyolysis, hepatic dysfunction and jaundice, and skin hypersensitivity (ie, rash, redness, pruritus). Use caution in patients with extremely weak GI tracts, as adverse effects including anorexia, nausea, vomiting, diarrhea, and epigastric distress may occur.

Toxicology

No data are available.

Scientific Family

  • Compositae
  • Leguminosae
  • Polyporaceae
  • Rubiaceae
  • Umbelliferae

Botany

Yi-gan san is an herbal formulation used in traditional East Asian medicine. Yi-gan san is composed of a ratio of 4:4:3:3:3:2:1.5 of the following 7 dried medicinal herbs: Atractylodis Lanceae Rhizoma (rhizome of A. lancea De Candolle, Compositae), Poria (sclelrotium of P. cocos Wolf, Polyporaceae [also known as Hoelen]), Cnidii Rhizoma (rhizome of C. officinale Makino, Umbelliferae), Angelicae Radix (root of A. acutiloba Kitagawa, Umbelliferae), Uncaria Uncis Cum Ramulus (hook of U. rhynchophilla Miquel, Rubiaceae), Bupleuri Radix (root of B. falcatum Linne, Umbelliferae), and Glycyrrhizae radix (root and stolon of G. uralensis Fisher, Leguminosae).1, 2

Cnidium monnieri rootstock as well as Uncaria sinensis and Angelica sinensis root have also been used in place of C. officinale and A. acutiloba, respectively.3

History

Traditional herbal medicines have been used for centuries in China, Japan, Taiwan, Korea, and Vietnam. Japanese traditional herbal medicine (Kampo) has its origins in traditional Chinese medicine and was introduced to Japan in the fifth century. In Kampo medicine, one herbal formula prescription is often used to treat a wide variety of symptoms—a practice referred to as Ibyodochi. Yokukansan, a commonly used Kampo medicine, was developed in 1555 as a treatment for agitation and restlessness in children and was often administered to both mother and child concomitantly. It has been used in Japan for insomnia, screaming attacks, sleep terrors, neurosis, irritability in children, borderline personality disorder, schizophrenia-related diseases, and behavioral and psychological symptoms of dementia. Increasingly, beneficial effects in psychiatric disorders, including schizophrenia and tardive dyskinesia, are being reported.1, 4, 5, 6, 7 The name "yokukansan" originally meant "medicine suppressing the liver"; the liver was considered an organ that stabilized mental activities and alleviated involuntary muscle movement. Based on Kampo-specific philosophies of health and disease, its use is considered appropriate in patients with the following conditions: impatience or frequent anger, irritability, excitability, insomnia, neurotic symptoms, muscular tics or convulsions, and/or blepharospasm; tight overall pulse quality (pulse diagnosis); abdominal tension that is not weak and tenderness/discomfort in the hypochondrium on palpation and pulsation at the upper navel region (abdominal diagnosis).2, 6

In 1986, yokukansan was approved in Japan by the Ministry of Health, Labor, and Welfare as a covered prescription under Japan's National Health Insurance. The commercial product Tsumura yokukansan [TJ-54]) is a mixed extract in packages of 2.5 g per unit. The usual adult dosage is 7.5 g/day of extract granules (containing 3.25 g of the previously described crude herbs) given orally in 2 or 3 divided doses, with adjustments made based on patient age, body weight, and symptoms. It is indicated for the relief of symptoms of nervousness (ie, neurosis, insomnia, night cry in children, irritability). Its use is based on the patient's "SHO" (ie, patient constitution and symptoms according to Kampo diagnosis).8

Chemistry

Yi-gan san is a formulation of 7 dried herbs and contains multiple components with biological effects that can impact signaling pathways in cells; at least 25 ingredients have been identified and the interactions among these ingredients may play a role in its actions.7, 9, 10 Representative chemical constituents include hinesol and beta-eudesmol from Atractylodis Lanceae Rhizoma; eburicoic acid from Poria; cnidilide, ligustilide, and ferulic acid from Cnidii Rhizoma; indole and oxyindole alkaloids from Uncariae Uncis cum Ramulus; ligustilide from Angelicae Radix; saikosaponin A, C, and D from Bupueri Radix; and glycyrrhizin from Glycyrrhizae Radix.2, 11

Animal and neurobiology studies have demonstrated that yokukansan has antipsychotic properties; in a zinc-deficient rat model, yokukansan inhibited the increased release of glutamate. G. uralensis and its main metabolite, 18beta-glycyrrhetinic acid, have been shown to provide neuroprotective effects by crossing the blood-brain barrier and ameliorating astrocyte glutamate transporter dysfunction.5 Yi-gan san also protects dopaminergic neurons from the Parkinson disease–inducing compound methyl-phenylpyridine-methyl-phenyltetrahydropyridine toxicity.9 Compounds contained only in U. rhynchophylla have been found to have affinity for serotonin receptors (ie, 5-hydroxytryptamine [5-HT] 1A, 2A, 2C, and 7). A corynanthean-type alkaloid, geissoschizine methyl ether, had high blood-brain barrier permeability, exhibiting 5-HT1A receptor partial agonist activity and 5-HT2A, 5-HT2C, and 5-HT7 receptor antagonist activity. Activation of the 5-HT1A receptor has been suggested to decrease extrapyramidal symptoms and increase dopaminergic neurotransmission in the frontal cortex. Geissoschizine methyl ether may also have partial agonist/antagonist activity at the cloned dopamine D2Long receptors with low intrinsic activity and partial activation.5

In Kampo medicine, the mechanisms of action related to yi-gan san's calming effects are related to the attenuation of glutamate release, uptake, and transport, as well as the inhibition of N-methyl-D-aspartate (NMDA) receptors. Yi-gan san also activates the gamma-aminobutyric acid-A (GABA-A) receptor, which accounts for its use for management of insomnia. Actions related to signal mediation of G protein–coupled receptors, the largest superfamily of cell-surface receptors, lead to pharmacological uses related to aggressive behavior, memory disturbance, and head twitch. These effects result from actions on 5-HT and muscarinic receptors.7

Radioligand assays revealed that all 8 chemical constituents of Glycyrrhizae Radix (ie, glycyrrhizin, liquiritin, liquiritigenin, liquiritinapioside, isoliquirtin, isoliquiritigenin, glycycoumarin, 18beta-glycyrrhetinic acid) and 6 of the 7 alkaloids of Uncaria hook (ie, geissoschizine methyl ether, hirsuteine, hirsutine, isoorynoxeine, isorhyncophylline, rhynchophylline) had specific binding affinity for and antagonist activity against the alpha2A adrenoceptor.12

Genomic studies in mice have revealed several mechanisms by which yokukansan affects cellular signaling pathways, including down-regulation of microRNA and glucocorticoid receptor proteins in the brain, augmentation of gene expression in the cysteine-glutamate transporter system, suppression of NMDA receptors, and inhibition of hydrogen peroxide-induced apoptosis.10, 13, 14, 15, 16

Uses and Pharmacology

Cellular stress/Apoptosis

Experimental data

One of the major mechanisms of programmed cell death, or apoptosis, is oxidative stress caused by reactive oxygen species (ROS), which play a critical role in neurodegenerative disorders. The main intracellular ROS is hydrogen peroxide. Pretreatment of rat pheochromocytoma cells (PC12) with one of the most potent constituents of yokukansan, YGS40, prevented hydrogen peroxide–induced cytotoxicity and protected the cell line from hydrogen peroxide–triggered mitochondrial membrane potential loss and apoptosis.15

Another important mechanism of neuronal cell death is glutamate-mediated cellular toxicity. Yokukansan, as well as several of its individual constituents, prevented glutamate-induced cell death at 24 hours in a concentration-dependent manner in PC12 cells as well as in human keratinocytes. Yokukansan geissoschizine methyl ether, hirsuteine, hirsutine, and procyanidin B1 demonstrated cytoprotective effects in PC12 cells. Increased gene expression of system Xc- subunits in the cysteine/glutamate antiporter system, as well as prevention of glutamate-induced reduction of glutathione was demonstrated in the PC12 cell line. However, peripheral glutamate signaling was affected in human keratinocytes via extracellular glutamate control, suppression of NMDA receptors, messenger RNA expression, and glutamate transport activation.10, 16

The effect of yokukansan and its individual constituents on endoplasmic reticulum stress, the associated unfolded protein response, and subsequent cell death was investigated in human and murine neuroblastoma cells. Yokukansan resulted in a reduction of endoplasmic reticulum stress–induced cell death and familial Alzheimer disease-linked cell death. These effects resulted from modulation of gene expression in both survival and apoptotic pathways (ie, upregulation of GR P78/Bip expression, inhibition of C/EBP homologous protein gene) as well as inhibition of caspase-4 activation. Cnidii Rhizoma (Senkyu) was particularly effective, specifically its ferulic acid component. Long-term or high-dose treatment with yokukansan had a neurotoxic effect; however, longer exposure to Senkyu or ferulic acid did not induce neurotoxicity.11

Autism spectrum disorder

Animal data

Because serotonin (5-HT) is one of the earliest expressed neurotransmitters, genetic or heritable aberrancy in 5-HT metabolism is thought to have an impact on neurodevelopmental processes; abnormalities of genes related to 5-HT synthesis have been reported in individuals with autism. Additionally, parents of autistic children are more likely to have 5-HT–related mental disorders such as depression or obsessive-compulsive disorder. The effect of yokukansan on behavior and brain metabolism during breast-feeding was investigated in an animal model of neurodevelopmental disorders in which BrdU-rats showed impaired social interaction between males and females, and also exhibited sexual dimorphism in dopamine and 5-HT metabolism. Yokukansan was administered using mother-infant coadministration (MICA) and child-only treatment methods. Compared with controls, modulation of grooming behavior during adulthood occurred with yokukansan regardless of administration method. In contrast, MICA of yokukansan reduced latency of pup movement, whereas administration to only the pup was associated with disruption of coordination in locomotor behavior and rearing, and resulted in altered levels of serotonin and its metabolite in the cerebellum.4

Clinical data

Research reveals no clinical data regarding use of yi-gan san in autism.

Dementia

Animal data

Research reveals no animal data regarding use of yi-gan san in dementia.

Clinical data

A meta-analysis of randomized controlled trials assessing the effect of yi-gan san for treatment of behavioral and psychological symptoms in patients with dementia identified 4 eligible studies (N = 236) published up to July 2012. Mean age of participants was 78.6 years, and diagnoses included Alzheimer disease, dementia with Lewy bodies, and/or vascular dementia. Yi-gan san 7.5 g/day for 4 or 12 weeks was compared with usual care in all 4 studies; usual care was not defined. Yi-gan san was significantly more efficacious in reducing Neuropsychiatric Inventory (NPI) scores (P = 0.0009); results were similar in trials that included only patients with Alzheimer disease and those with mixed dementia. Significant differences were also observed in subscale scores of delusions (P = 0.0009), hallucinations (P < 0.00001), and agitation/aggression (P = 0.0007). Although patients receiving yi-gan san experienced significantly improved activities of daily living scores compared with those receiving usual care (P = 0.04), Mini Mental State Examination (MMSE) scores did not differ between groups. Extrapyramidal symptoms were reported in 1 patient; hypokalemia, possibly due to yi-gan san, was reported in 2 patients. Discontinuation rates did not differ between groups.1 The American Psychiatric Association (APA) guideline watch for the treatment of patients with Alzheimer disease and other dementias (2014) did not find enough definitive new evidence to change the 2007 guideline recommendations for alternative agents, including yi-gan san.36

An 8-week, single-blinded, randomized comparator trial assessed efficacy and tolerability of yokukusan, fluvoxamine, and risperidone for the treatment of behavioral and psychological symptoms of dementia in elderly Japanese inpatients with dementia (N = 82). Patients had a mean age of approximately 82 years, an MMSE score less than 19, and Alzheimer disease, vascular dementia, or dementia with Lewy bodies. After at least a 1-week washout of all psychotropic medications, patients were randomized to a flexible oral regimen of either yokukusan (2.5 to 7.5 g/day), risperidone (0.5 to 2 mg/day), or fluvoxamine (25 to 200 mg/day); mean dose at study end was 7.02 g/day, 1.1 mg/day, and 83.02 mg/day, respectively. All 3 drugs improved NPI-Nursing Home scores with no differences among groups. Neither MMSE scores nor Functional Independence Measure scores changed from baseline in the 3 treatment groups. Severe adverse effects occurred in 3 yokukasan patients (fracture, head injury, fall with contusion), 3 with fluvoxamine (hallucination and delusion, refusal to eat, fall with contusion), and 5 with risperidone (fall with contusion, oversedation, swallowing difficulty, stridor, sudden death). Muscle rigidity occurred in more than 19% of risperidone patients compared with 0% in yokukasan-treated patients.17

Opioid tolerance and physical dependence

Animal data

Prolonged oral administration of yokukansan inhibited morphine tolerance and physical dependence in mice.12 However, amelioration of morphine withdrawal symptoms was only observed after long-term (3 weeks) exposure and not after single-dose administration, suggesting the involvement of neuroadaptive processes. At a dose of 1 g/kg, but not 0.5 g/kg, yokukansan significantly reduced development of morphine tolerance and the naloxone-precipitated withdrawal signs of jumps and weight loss, without affecting the analgesic effects of morphine. The inhibitory effects on withdrawal symptoms were attenuated by the alpha-2 adrenoreceptor antagonist yohimbine, but not by the alpha-1 adrenoreceptor antagonist prazosin. Additionally, membrane expression of alpha-2A adrenoreceptor in the pons/medulla was decreased during morphine withdrawal; this reduction was prevented with repeated administration of yokukansan 1 g/kg. Radioligand binding assays revealed that yokukansan exhibits specific binding to alpha-2a adrenoreceptor but not alpha-2b adrenoreceptor, alpha-2c adrenoreceptor, alpha-1 adrenoreceptor, beta adrenoreceptors, or norepinephrine transporter; yokukansan demonstrated only antagonistic properties and no agonistic activity at alpha-2a adrenoreceptor. Of the 7 herbs that comprise yokukansan, only Glycyrrhiza radix and Uncaria hook bound to alpha-2a adrenoreceptor. All 8 chemical constituents of Glycyrrhiza radix (ie, glycyrrhizin, liquiritin, liquiritigenin, liquiritinapioside, isoliquirtin, isoliquiritigenin, glycycoumarin, 18beta-glycyrrhetinic acid) showed antagonistic binding. All but 1 of the 7 alkaloids of Uncaria hook (ie, geissoschizine methyl ether, hirsuteine, hirsutine, isoorynoxeine, isorhyncophylline, rhynchophylline) bound specifically to alpha-2a adrenoreceptor. Oral administration of Glycyrrhiza radix (75 mg/kg), glycyrrhizin (9.6 mg/kg), Uncaria hook (150 mg/kg), geissoschizine methyl ether (150 mcg/kg), and yokukansan without Uncaria hook herb (850 mg/kg) for 3 weeks inhibited naloxone-precipitated morphine withdrawal jumps compared with controls.

Clinical data

Research reveals no clinical data regarding use of yi-gan san for opioid tolerance and dependence.

Borderline personality disorder

Clinical data

An open-label, pilot study evaluated the efficacy and tolerability of yi-gan san in 22 female adult patients with borderline personality disorder. Previous antipsychotics, antidepressants, mood stabilizers, and benzodiazepines were discontinued and, after a 1- to 2-week washout period, patients received monotherapy with yi-gan san 2.5 to 7.5 g/day for 12 weeks. By week 12 of yi-gan san therapy, patients showed significant improvement on clinician- and self-rated scales. The average daily dose of yi-gan san by the end of the study was 6.4 g/day. Mild and transient headache, nausea, and tiredness were reported in 3 cases.18

Schizophrenia

Animal data

In rat models of schizophrenia, yokukansan suppressed microglial activation and promoted neurogenesis in the hippocampal dentate gyrus and one of the active constituents of Uncaria hook (geissoschizine methyl ether) increased formation of new oligodendrocytes after cuprizone-induced demyelination. Additionally, geissoschizine methyl ether attenuated the decrease in myelin basic protein immunoreactivity caused by cuprizine.19, 20

Clinical data

In a double-blind, placebo-controlled trial that evaluated use of yi-gan san for treatment-resistant schizophrenia (N = 120), patients were randomized to placebo or yi-gan san 2.5 g 3 times daily for 4 weeks as an adjunct to their regular antipsychotic treatment. Patients were 20 to 59 years of age, had a diagnosis of schizophrenia for at least 3 years, and had a history of treatment resistance to at least 2 antipsychotics that included at least one second-generation agent (ie, greater than 600 mg/day of chlorpromazine equivalent). Overall Positive and Negative Syndrome Scale (PANSS) scores did not differ between groups, with a difference observed only in the excitement/hostility subscale score of the PANSS with adjunctive yi-gan san therapy compared with placebo. Yi-gan san was well tolerated.21 A review of 5 clinical trials published between 2008 and 2013 by the same author documented average yi-gan san dosages of 5.2 to 6.7 g/day for 4 weeks and 7.5 g/day for 2 or 12 weeks in patients with schizophrenia.5

Sleep disorders

Animal data

Research reveals no animal data regarding use of yi-gan san for sleep disorders.

Clinical data

Several case reports have been documented by the same author for the successful use of yi-gan san in the treatment and/or management of sleep disorders in elderly patients with a variety of diagnoses. In an 81-year-old male admitted for dementia with Lewy bodies, yi-gan san 2.5 g 3 times daily was effective in treating behavioral and psychological symptoms of dementia as well as improving total sleep time from 352 to 504 minutes, sleep efficacy from 48% to 79%, number of awakenings from 148 to 45, stage II non-rapid eye movement (REM) and REM sleep, and periodic limb movements from 70/hour to 28/hour.22

Adjunctive use of yi-gan san 2.5 g twice daily (in the evening and at bedtime) in addition to pramipexole or clonazepam was effective for treatment of RLS in 3 elderly patients 62 to 80 years of age. Patients' diagnoses included uterine carcinoma with multiple bone metastases that resulted in chemotherapy-induced iron-deficient anemia, colon polyposis with anemia, and renal failure with artificial dialysis and subsequent anemia. Yi-gan san administered in combination with pramipexole (approximately 0.5 mg/day) in 2 of the patients and in combination with clonazepam (1 mg/day) in the third patient resolved unpleasant leg sensations and sleep disturbances and was well tolerated.23 Similarly, a 50-year-old man with a 16-year history of schizophrenia had nocturnal eating/drinking syndrome and RLS suspected to be induced by aripiprazole, which was part of his psychotropic regimen that also included quazepam, brotizolam, ramelteon, and trazodone. Aripiprazole was replaced with paliperidone, and 10 days after adding yi-gan san 2.5 g at bedtime to the patient's regimen, his sleep and leg pain/discomfort improved; at 1 month, the patient's Pittsburgh Sleep Quality Index sleep score improved from 10/21 to 7/21 and total sleeping time increased from 6 to 9 hours per night. Additionally, his abnormal night eating behavior resolved. Yi-gan san was well tolerated, with no adverse effects reported.24

Improvements in dream-enacting behaviors were observed with yi-gan san therapy in 3 elderly patients 60 to 87 years of age with idiopathic REM sleep behavior disorder in which physical or aggressive sleep behavior was documented as harmful or annoying to the family. In 2 of these patients, clonazepam was only partially effective, and higher doses led to intolerable adverse effects; however, the addition of yi-gan san 7.5 g/day with a lower dose of clonazepam (0.25 to 0.5 mg/day) was effective in treating sleep behavior disorders. Use of a benzodiazepine was considered clinically inappropriate in the third patient due to a diagnosis of diabetes mellitus and poor renal function; yi-gan san 2.5 g administered every evening resulted complete resolution of dream-enacting behavior without adverse effects.25

Tardive dyskinesia

Animal data

Research reveals no animal data regarding use of yi-gan san in tardive dyskinesia.

Clinical data

In an open-label study, 22 schizophrenic adults with neuroleptic-induced tardive dyskinesia were administered yi-gan san 7.5 g/day for 12 weeks. Patients had been on a stable psychotropic regimen (eg, risperidone, quetiapine, perphenazine) for at least 6 months, with an average dose equivalent to chlorpromazine of 839.3 mg/day; tardive dyskinesia had been stable for at least 3 months. Overall reduction in Abnormal Involuntary Movement Scale total scores was significant; mean severity score decreased 56% (P < 0.0001) and 81.8% of patients improved. Similarly, patient scores on all PANSS subscores improved significantly from baseline, with a mean decrease of 58% (P < 0.0001). In addition to improvement in symptomatology, a 4-point decrease in mean clinical global impression score (P < 0.0001) was observed. No serious adverse events were reported with yi-gan san; mild nausea and constipation were reported in 2 cases.26

American Academy of Neurology guidelines for the treatment of tardive syndromes, including tardive dyskinesia, conclude that data are insufficient to support or refute the use of yi-gan san in the treatment of tardive dyskinesia.27

Other uses

Chronic urticaria

A slight to marked improvement in treatment-resistant chronic urticaria was reported in 5 patients treated with yi-gan san. Patient age ranged from 20 to 65 years, and disease duration was 4 to 9 months. Within 2 weeks of therapy, disease activity scores improved from 6 to 0 (complete control) in 2 patients, from 6 to 1 in a third patient, from 6 to 3 in a fourth, and from 6 to 4 (modest improvement) in a fifth patient.28

Psychiatric symptoms of traumatic brain injury

Effective use of yokukansan to treat psychiatric symptoms (ie, impulsive and aggressive behavior) subsequent to traumatic brain injury was reported in an 85-year-old man who underwent surgery for hepatic portal cholangiocarcinoma; the patient subsequently experienced postsurgical delirium and sustained a traumatic brain injury after falling out of bed on day 5 postsurgery. Brain computed tomography scan revealed an acute subdural hematoma, traumatic subarachnoid hemorrhage, and a right temporal bone fracture. Over the next 104 days, several therapeutic attempts (eg, haloperidol, flunitrazepam, olanzapine, sodium valproate) failed to improve behavior and appetite and/or resulted in intolerable adverse effects. On day 109, yokukansan was initiated at 5 g/day. Within 12 days, the patient's appetite returned and his emotions stabilized. Persistence of evening excitability was managed with low-dose risperidone plus an increase of yokukansan to 7.5 g/day. The patient was transferred to a rehabilitation hospital on day 154 and continued on a regimen of yokukansan 7.5 g/day, mianserin 10 mg, and flunitrazepam 1 mg. The patient and discharged home 80 days later.29

Visual hallucinations

A 73-year-old woman with a 2-year history of complex visual hallucinations and ocular pathology with preserved cognitive status (Charles Bonnet syndrome), single-photon emission computed tomography (SPECT) revealed moderate hypoperfusion of regional blood flow of both occipital lobes. After 2 weeks of yi-gan san 7.5 g/day, hallucinations improved and eventually disappeared. After 1 year of yi-gan san therapy, SPECT scan showed recovered blood perfusion to the occipital lobe; clinical improvement was maintained, and no adverse events occurred.30 Yi-gan san also reduced the frequency and severity of hallucinations in an 81-year-old woman with Charles Bonnet syndrome. However, in addition to mild hypoperfusion in the medial occipital lobe, SPECT also showed mild generalized brain atrophy; years later the patient developed dementia with Lewy bodies.31 In a randomized controlled trial of 52 patients with dementia, a significant improvement in visual hallucinations, as measured by Neuropsychiatric Inventory subscale scores, was observed with yi-gan san 7.5 g/day administered for 4 weeks compared with control.32 In another study, resolution of cholinesterase inhibitor–resistant (ie, donepezil) visual hallucinations was observed after 2 weeks of yi-gan san treatment in 12 of 15 patients with dementia with Lewy bodies.33

Dosing

The commercial product (TJ-54) is a mixed extract in packages of 2.5 g per unit and is usually taken 2 to 3 times daily before meals.5

Dementia

In a meta-analysis of 4 randomized controlled trials, elderly Japanese patients with varying etiologies of dementia including Alzheimer disease, dementia with Lewy bodies, and vascular dementia, the usual dose was 7.5 g/day for 4 or 12 weeks.1 A mean dose of 7.02 g/day was documented in an 8-week single-blind randomized comparator trial.17

Borderline personality disorder

A dose of yi-gan san 2.5 to 7.5 g/day for 12 weeks was administered in 22 female adult patients in an open-label pilot study; the average dose by the end of the study was 6.4 g/day.18

Psychiatric symptoms of traumatic brain injury

Addition of yokukansan 7.5 g/day to a regimen consisting of mianserin 10 mg and flunitrazepam 1 mg effectively managed psychiatric symptoms (ie, impulsive and aggressive behavior) subsequent to traumatic brain injury in an 85-year-old man.29

Schizophrenia

In a review of clinical trials of yokukansan for treatment of schizophrenia average doses were 5.2 to 6.7 g/day for 4 weeks and 7.5 g/day for 2 or 12 weeks.5

As an adjunct to regular antipsychotic treatment, yi-gan san 2.5 g 3 times daily for 4 weeks effectively managed treatment-resistant schizophrenia in a double-blind, placebo-controlled trial.21

Sleep disorders

Adjunctive use of yi-gan san 2.5 g twice daily (in the evening and at bedtime) with pramipexole (approximately 0.5 mg/day) in 2 patients and clonazepam (1 mg/day) in a third patient resolved unpleasant leg sensations and sleep disturbances.23

In an elderly Japanese man with nocturnal eating/drinking syndrome and RLS suspected to be induced by aripiprazole, which was part of his psychotropic regimen that also included quazepam, brotizolam, ramelteon, and trazodone, aripiprazole was replaced with paliperidone, and 10 days after adding yi-gan san 2.5 g at bedtime to the patient's regimen, his sleep and leg pain/discomfort improved. Additionally, the patient's abnormal night eating behavior resolved.24

Improvements in aggressive dream-enacting behavior were observed in 3 elderly patients with the addition of yi-gan san 7.5 g/day to a low dose of clonazepam (0.25 to 0.5 mg/day); in a diabetic patient, yi-gan san was administered at 2.5 g every evening.25

Tardive dyskinesia

In an open-label study of 22 schizophrenic adults, neuroleptic-induced tardive dyskinesia improved with administration of yi-gan san 7.5 g/day for 12 weeks.26

Visual hallucinations

Yi-gan san 7.5 g/day reduced visual hallucinations within 2 to 4 weeks in elderly Japanese patients with a history of Charles Bonnet syndrome as well as dementia. In one case, SPECT scan showed recovered blood perfusion to the occipital lobes after 1 year of therapy.30, 31, 32

Pregnancy / Lactation

Use of yokukansan in breast-feeding infants, children, and mothers (referred to as MICA) during China's Ming dynasty period (circa 1555) has been described.4

Information regarding safety and efficacy in pregnancy and lactation is lacking. According to Japanese product labeling, the safety of yi-gan san has not been established. Use should be considered only if the expected benefit outweighs possible risks.8

Interactions

Coadministration of glycyrrhiza-, glycyrrhizinic acid-, or glycyrrhizinate-containing preparations may lead to pseudoaldosteronism, hypokalemia, and myopathy.8

Adverse Reactions

Use caution in patients with extremely weak GI tracts, as adverse effects including anorexia, nausea, vomiting, diarrhea, epigastric distress may occur.

Reversible adverse effects including sedation, nausea, vomiting, diarrhea, epigastric discomfort, hypokalemia, and leg edema have been reported with yokukansan administration; no metabolic adverse effects have been documented. However, suppression of lipid synthesis and reduction of fat accumulation in adipocytes was observed via modulation of transcription factors without affecting glucose uptake.5, 34 A case of yokukansan-induced pneumonitis was reported in a 74-year-old man.35

Clinically important adverse reactions described in TJ-54 prescribing information include interstitial pneumonia, pseudoaldosteronism, heart failure, myopathy or rhabdomyolysis, hepatic dysfunction and jaundice, and skin hypersensitivity (ie, rash, redness, pruritus). Monitor patients closely and discontinue use if any of these adverse events occur.8

Toxicology

No data are available.

References

1. Matsuda Y, Kishi T, Shibayama H, Iwata N. Yokukansan in the treatment of behavioral and psychological symptoms of dementia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol. 2013;28(1):80-86.23359469
2. Matsumoto K, Zhao Q, Niu Y, et al. Kampo formulations, chotosan, and yokukansan, for dementia therapy: existing clinical and preclinical evidence. J Pharmacol Sci. 2013;122(4):257-269.23883485
3. Dos Santos-Neto LL, de Vilhena Toledo MA, Medeiros-Souza P, de Souza GA. The use of herbal medicine in Alzheimer's disease-a systematic review. Evid Based Complement Alternat Med. 2006;3(4):441-445.17173107
4. Muneoka K, Kuwagata M, Ogawa T, Shioda S. Mother/offspring co-administration of the traditional herbal remedy yokukansan during the nursing period influences grooming and cerebellar serotonin levels in a rat model of neurodevelopmental disorders. Cerebellum. 2015;14(2):86-96.25315739
5. Yu CH, Ishii R, Yu SC, Takeda M. Yokukansan and its ingredients as possible treatment options for schizophrenia. Neuropsychiatr Dis Treat. 2014;10:1629-1634.25210456
6. Okamoto H, Iyo M, Ueda K, Han C, Hirasaki Y, Namiki T. Yokukan-san: a review of the evidence for use of this Kampo herbal formula in dementia and psychiatric conditions. Neuropsychiatr Dis Treat. 2014;10:1727-1742.25246794
7. Uezono Y, Miyano K, Sudo Y, Suzuki M, Shiraishi S, Terawaki K. A review of traditional Japanese medicines and their potential mechanism of action. Curr Pharm Des. 2012;18(31):4839-4853.22632864
8. Tsumura Yokukansan extract granules for ethical use [prescribing information]. Akasaka, Minato-ku, Tokyo, Japan: Tsumura & Co; 2014.
9. Lerner PP, Miodownik C, Lerner V. Tardive dyskinesia (syndrome): Current concept and modern approaches to its management. Psychiatry Clin Neurosci. 2015;69(6):321-334.25556809
10. Kanno H, Kawakami Z, Mizoguchi K, Ikarashi Y, Kase Y. Yokukansan, a kampo medicine, protects PC12 cells from glutamate-induced death by augmenting gene expression of cystine/glutamate antiporter system Xc-. PLoS One. 2014;9(12):e116275.25551766
11. Hiratsuka T, Matsuzaki S, Miyata S, et al. Yokukansan inhibits neuronal death during ER stress by regulating the unfolded protein response. PLoS One. 2010;5(10):e13280.20967273
12. Nakagawa T, Nagayasu K, Nishitani N, et al. Yokukansan inhibits morphine tolerance and physical dependence in mice: the role of α2A-adrenoceptor. Neuroscience. 2012;227:336-349.23069764
13. Shimizu S, Tanaka T, Takeda T, Tohyama M, Miyata S. The Kampo medicine yokukansan decreases microRNA-18 expression and recovers glucocorticoid receptors protein expression in the hypothalamus of stressed mice. Biomed Res Int. 2015;2015:797280.26106615
14. Shimizu S, Tanaka T, Tohyama M, Miyata S. Yokukansan normalizes glucocorticoid receptor protein expression in oligodendrocytes of the corpus callosum by regulating microRNA-124a expression after stress exposure. Brain Res Bull. 2015;114:49-55.25857947
15. Zhao YR, Qu W, Liu WY, et al. YGS40, an active fraction of Yi-Gan San, reduces hydrogen peroxide-induced apoptosis in PC12 cells. Chin J Nat Med. 2015;13(6):438-444.26073340
16. Wakabayashi M, Hasegawa T, Yamaguchi T, et al. Yokukansan, a traditional Japanese medicine, adjusts glutamate signaling in cultured keratinocytes. Biomed Res Int. 2014;2014:364092.25313361
17. Teranishi M, Kurita M, Nishino S, et al. Efficacy and tolerability of risperidone, yokukansan, and fluvoxamine for the treatment of behavioral and psychological symptoms of dementia: a blinded, randomized trial. J Clin Psychopharmacol. 2013;33(5):600-607.23948783
18. Miyaoka T, Furuya M, Yasuda H, Hayashia M, Inagaki T, Horiguchi J. Yi-gan san for the treatment of borderline personality disorder: an open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):150-154.17765378
19. Morita S, Tatsumi K, Makinodan M, Okuda H, Kishimoto T, Wanaka A. Geissoschizine methyl ether, an alkaloid from the Uncaria hook, improves remyelination after cuprizone-induced demyelination in medial prefrontal cortex of adult mice. Neurochem Res. 2014;39(1):59-67.24190599
20. Furuya M, Miyaoka T, Tsumori T, et al. Yokukansan promotes hippocampal neurogenesis associated with the suppression of activated microglia in Gunn rat. J Neuroinflammation. 2013;10:145.24305622
21. Miyaoka T, Furuya M, Horiguchi J, et al. Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled trial (a Positive and Negative Syndrome Scale, five-factor analysis). Psychopharmacology (Berl). 2015;232(1):155-164.24923986
22. Shinno H, Utani E, Okazaki S, et al. Successful treatment with Yi-Gan San for psychosis and sleep disturbance in a patient with dementia with Lewy bodies. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(7):1543-1545.17688986
23. Shinno H, Yamanaka M, Ishikawa I, et al. Successful treatment of restless legs syndrome with the herbal prescription Yokukansan. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(1):252-253.19913591
24. Kawabe K, Ueno S, Hosoda Y, Horiguchi J. Nocturnal eating/drinking syndrome with restless legs syndrome caused by neuroleptics improved by Yi-Gan San add-on treatment: a case report. Clin Neuropharmacol. 2012;35(6):290-291.23151467
25. Shinno H, Kamei M, Nakamura Y, Inami Y, Horiguchi J. Successful treatment with Yi-Gan San for rapid eye movement sleep behavior disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(7):1749-1751.18656519
26. Miyaoka T, Furuya M, Yasuda H, et al. Yi-gan san for the treatment of neuroleptic-induced tardive dyskinesia: an open-label study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(3):761-764.18201810
27. Bhidayasiri R, Fahn S, Weiner WJ, Gronseth GS, Sullivan KL, Zesiewicz TA; American Academy of Neurology. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology [published correction appears in Neurology. 2013;81(22):1968]. Neurology. 2013;81(5):463-469.23897874
28. Kato S, Kato TA, Nishie H, et al. Successful treatment of chronic urticaria with a Japanese herbal medicine, yokukansan. J Dermatol. 2010;37(12):1066-1067.21083714
29. Saito S, Kobayashi T, Osawa T, Kato S. Effectiveness of Japanese herbal medicine yokukansan for alleviating psychiatric symptoms after traumatic brain injury. Psychogeriatrics. 2010;10(1):45-48.20594286
30. Miyaoka T, Nagahama M, Tsuchie K, et al. Charles Bonnet syndrome: successful treatment of visual hallucinations due to vision loss with Yi-gan san. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(2):382-383.19141308
31. Hanyu H, Takasaki A, Sato T, Akai T, Iwamoto T. Is Charles Bonnet syndrome an early stage of dementia with Lewy bodies? J Am Geriatr Soc. 2008;56(9):1763-1764.19166452
32. Iwasaki K, Satoh-Nakagawa T, Maruyama M, et al. 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. J Clin Psychiatry. 2005;66(2):248-252.15705012
33. Iwasaki K, Maruyama M, Tomita N, et al. Effects of the traditional Chinese herbal medicine Yi-Gan San for cholinesterase inhibitor-resistant visual hallucinations and neuropsychiatric symptoms in patients with dementia with Lewy bodies. J Clin Psychiatry. 2005;66(12):1612-1613.16401166
34. Nishiyama N, Takeshita M, Tanaka K, Miyao M, Mizuno Y. A case of severe hypokalemia caused by a Chinese herbal remedy (Yokukansan) in an 81-year-old woman with dementia [in Japanese]. Nihon Ronen Igakkai Zasshi. 2011;48(5):553-557.22323035
35. Nakamura K, Shimizu T, Mitsuhata H. Case of pneumonitis caused by Yokukansan [in Japanese]. Masui. 2012;61(2):214-216.22413451
36. Rabins PV, Rovner BW, Rummans T, Schneider LS, Tariot PN. Guideline watch (October 2014): practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/alzheimerwatch.pdf. Accessed July 22, 2017.

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