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 Nov 21, 2023.

Clinical Overview

Use

Yi-gan san has been evaluated for use in treating borderline personality disorder, dementia, schizophrenia, tardive dyskinesia, and visual hallucinations. A yokukansan commercial product has been approved in Japan for the relief of symptoms of nervousness. However, clinical data are lacking to support the use of yi-gan san for any indication.

Dosing

According to the prescribing information for the Japanese commercial product (TJ-54), the usual adult yi-gan san dosage is 7.5 g/day of extract granules given orally in 2 or 3 divided doses for symptoms of nervousness. This dose has also been used in clinical studies evaluating use for the treatment of behavioral and psychological symptoms of dementia, tardive dyskinesia, aggressive dream-enacting behavior, and visual hallucinations. Yi-gan san dosages ranging from 2.5 to 7.5 g/day have been studied in females with borderline personality disorder.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Since 1555, yi-gan san has been used in breastfeeding 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 use in pregnancy 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 disorders of the GI tract, as adverse effects including anorexia, nausea, vomiting, diarrhea, and epigastric distress may occur.

Toxicology

No data.

Related/similar drugs

turmeric, Ginkgo Biloba

Scientific Family

• Compositae (sunflower)
• Leguminosae (legume)
• Polyporaceae (fungus)
• Rubiaceae (madder)
• Umbelliferae (celery, carrot, parsley)

Botany

Yi-gan san is an herbal formulation used in traditional East Asian medicine. Yi-gan san, in a ratio of 4:4:3:3:3:2:1.5, is composed of the following 7 dried medicinal herbs: Atractylodis Lanceae Rhizoma (rhizome of A. lancea De Candolle, Compositae), Poria (sclerotium 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).(Matsuda 2013, Matsumoto 2013)

In some yi-gan san formulations, Cnidium monnieri rootstock as well as Uncaria sinensis and Angelica sinensis root have been used in place of C. officinale and A. acutiloba, respectively.(Dos Santos-Neto 2006)

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.(Matsuda 2013, Muneoka 2015, Okamoto 2014, Uezono 2012, Yu 2014) 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 classified as "weak" and tenderness/discomfort in the hypochondrium on palpation and pulsation at the upper navel region (abdominal diagnosis).(Matsumoto 2013, Okamoto 2014)

In 1986, yokukansan (TJ-54) was approved in Japan by the Ministry of Health, Labor, and Welfare as a covered prescription under Japan's National Health Insurance. 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).(TJ-54 2014)

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.(Kanno 2014, Lerner 2015, Uezono 2012) 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.(Hiratsuka 2010, Matsumoto 2013)

Uses and Pharmacology

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, provide neuroprotective effects by crossing the blood-brain barrier and ameliorating astrocyte glutamate transporter dysfunction.(Yu 2014) Yi-gan san also protects dopaminergic neurons from methyl-phenylpyridine-methyl-phenyltetrahydropyridine (the Parkinson disease–inducing compound) toxicity.(Lerner 2015) Compounds contained only in U. rhynchophylla have been found to have affinity for serotonin receptors (ie, 5-HT_1A, 5-HT_2A, 5-HT_2C, and 5-HT₇). A corynanthean-type alkaloid, geissoschizine methyl ether, had high blood-brain barrier permeability, exhibiting 5-HT_1A receptor partial agonist activity and 5-HT_2A, 5-HT_2C, and 5-HT₇ receptor antagonist activity. Activation of the 5-HT_1A 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 D_2Long receptors with low intrinsic activity and partial activation.(Yu 2014)

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.(Uezono 2012)

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 alpha-2A adrenoceptor.(Nakagawa 2012)

Genomic studies in mice have revealed several mechanisms by which yokukansan affects cellular signaling pathways, including downregulation 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.(Kanno 2014, Shimizu 2015a, Shimizu 2015b, Wakabayashi 2014)

Apoptosis/Cellular stress

Experimental data

Pretreatment of rat pheochromocytoma cells (PC12) with a fraction of yokukansan, YGS40, prevented hydrogen peroxide–induced cytotoxicity and protected the cell line from hydrogen peroxide–triggered mitochondrial membrane potential loss and apoptosis.(Zhao 2015)

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.(Kanno 2014, Wakabayashi 2014)

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.(Hiratsuka 2010)

Autism spectrum disorder

Animal data

The effect of yokukansan on behavior and brain metabolism during the nursing period was investigated in an animal model of neurodevelopmental disorders induced prenatally by 5-bromo-2ꞌdeoxyruidine. 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.(Muneoka 2015)

Borderline personality disorder

Clinical data

An open-label, pilot study evaluated the efficacy and tolerability of yi-gan san in 22 adult female 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 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 and nausea (n=2) and tiredness (n=1) were reported.(Miyaoka 2008b)

Chronic migraine

Clinical data

The efficacy of traditional Japanese Kampo medicines, including yokukansan, for headache has been reported. In a study of a 39-year-old woman with a diagnosis of migraine without aura (17-year history), administration of yokukansan 7.5 g/day was observed to drastically reduce frequency and severity of chronic migraine and tension headache episodes that had become resistant to multiple pharmaceutical and traditional Japanese Kampo medicines in previous years.(Akiyama 2019)

Chronic urticaria

Clinical data

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.(Kato 2010)

Dementia

Clinical data

A meta-analysis of randomized controlled trials assessing the effect of yi-gan san for treatment of patients with behavioral and psychological symptoms of dementia (BPSD) identified 4 eligible studies (N=236) published up to July 2012. Mean participant age 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 effective than usual care 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 had 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.(Matsuda 2013) The 2016 updated meta-analysis included 1 additional randomized controlled trial, for a total of 5 trials evaluating 381 patients with BPSD. In contrast to the original analysis, yokukansan resulted in a significant improvement in BPSD total scores only in the subgroup of patients with mixed dementia (P=0.001 vs controls) but not in the subgroup of patients with Alzheimer disease.(Matsunaga 2016)

In a multicenter, double-blind, randomized, placebo-controlled trial in older Japanese patients with Alzheimer disease (N=145; mean age, 78 years), treatment with yokukansan 2.5 g 3 times daily for 4 weeks resulted in no significant overall differences in BPSD compared with placebo; both groups exhibited significant improvements from baseline in Neuropsychiatric Inventory-Questionnaire (NPI-Q) total scores. Similarly, after an additional 8 weeks during which yokukansan was administered to all patients (non–double-blind period), no significant differences in NPI-Q or MMSE total scores were observed between the groups. In a subgroup of patients scoring below 20 points on the MMSE at baseline, a significantly greater decrease in the agitation/aggression subscore was observed with yokukansan compared with placebo (P=0.007); greater improvements were also observed with yokukansan in patients who presented with hallucinations at baseline. Throughout the study, patients were allowed to continue receiving stable doses of their previous medications, excluding typical or atypical neuroleptics, tri- or tetracyclic antidepressants, or other Kampo medicine, which could not be used during or within 4 weeks of starting the trial. No patients required rescue drugs during the trial. Hypokalemia was a suspected treatment-related adverse effect that occurred in 3 patients receiving yokukansan.(Furukawa 2017)

An 8-week, single-blind, randomized comparator trial assessed the efficacy and tolerability of yokukusan, fluvoxamine, and risperidone for the treatment of BPSD in older Japanese inpatients with dementia (N=82; mean age, approximately 82 years). Patients had diagnoses of Alzheimer disease, vascular dementia, or dementia with Lewy bodies; total MMSE score was less than 19. 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 doses at study end were 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-treated patients (fracture, head injury, fall with contusion), 3 fluvoxamine-treated patients (hallucination and delusion, refusal to eat, fall with contusion), and 5 risperidone-treated patients (fall with contusion, oversedation, swallowing difficulty, stridor, sudden death). Muscle rigidity occurred in more than 19% of risperidone patients compared with 0% of yokukansan-treated patients.(Teranishi 2013)

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 statement that alternative agents, including yi-gan san, are not generally recommended because of uncertain efficacy and safety.(APA [Rabins 2014])

Opioid tolerance and physical dependence

Animal and in vitro data

Prolonged oral administration of yokukansan inhibited morphine tolerance and physical dependence in mice. 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. A yokukansan dose of 1 g/kg, but not 0.5 g/kg, reduced development of morphine tolerance and naloxone-precipitated withdrawal signs (jumps and weight loss), without affecting the analgesic effects of morphine. The inhibitory effects of yokukansan 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 the alpha-2a adrenoreceptor. Of the 7 herbs that comprise yokukansan, only Glycyrrhiza radix and Uncaria hook bind 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.(Nakagawa 2012)

Perioperative psychiatric effects

Clinical data

A retrospective chart review of 19 patients who underwent colorectal tumor resection and received yokukansan for preoperative anxiety noted a significant decrease in patient-reported anxiety scores compared with baseline (P=0.028) but not in physician-assessed scores. Postoperative delirium was also assessed; however, confounders prevented useful interpretation of the data.(Wada 2017)

Psychiatric symptoms of traumatic brain injury

Clinical data

Efficacy of yokukansan in treating psychiatric symptoms (ie, impulsive and aggressive behavior) subsequent to traumatic brain injury was reported in an 85-year-old man who 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 was discharged 80 days later.(Saito 2010)

Schizophrenia

Animal data

In rat models of schizophrenia, yokukansan suppressed microglial activation and promoted neurogenesis in the hippocampal dentate gyrus, and the active constituent 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.(Furuya 2013, Morita 2014)

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, including 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; however, the excitement/hostility subscale score of the PANSS was significantly improved with adjunctive yi-gan san therapy compared with placebo. Yi-gan san was well tolerated.(Miyaoka 2015) A review of 5 clinical trials by the same author (published between 2008 and 2013) stated that yokukansan has evident therapeutic effect for neuropsychiatric disorders; documented average yi-gan san dosages were 5.2 to 6.7 g/day for 4 weeks and 7.5 g/day for 2 or 12 weeks in patients with schizophrenia.(Yu 2014)

Sleep disorders

Clinical data

Several case reports have documented successful use of yi-gan san in the treatment and/or management of sleep disorders in older 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 in 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 per hour to 28 per hour).(Shinno 2007)

Three case reports describe adjunctive use of yi-gan san 2.5 g twice daily (in the evening and at bedtime) with pramipexole or clonazepam in patients (age range, 62 to 80 years) with various diagnoses (eg, uterine carcinoma and anemia, colon polyposis with anemia, and renal failure and anemia) experiencing restless legs syndrome (RLS). 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 the unpleasant leg sensations and sleep disturbances associated with RLS, and was well tolerated.(Shinno 2010) A case report describes a 50-year-old man with a 16-year history of schizophrenia and 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 regimen, the patient's sleep and leg pain/discomfort improved; at 1 month, the patient's Pittsburgh Sleep Quality Index score improved from 10/21 to 7/21 and total sleeping time increased from 6 to 9 hours per night. Additionally, abnormal night eating behavior resolved. Yi-gan san was well tolerated, with no adverse effects reported.(Kawabe 2012)

Improvements in dream-enacting behaviors were observed with yi-gan san therapy in 3 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 the patients, clonazepam (first-line agent for sleep behavior disorder) was only partially effective, and higher doses (0.5 mg/day or greater) led to intolerable adverse effects. 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 disorder. In the third patient who was unable to take a benzodiazepine, yi-gan san 2.5 g administered every evening resulted in complete resolution of dream-enacting behavior without adverse effects.(Shinno 2008) In a retrospective chart review of 36 older patients (mean age, 69 years) with idiopathic REM sleep behavior disorder who had received yokukansan either as monotherapy or adjunctive therapy, significantly lower mean physician-assessed illness severity scores were reported in the monotherapy group (n=17) compared with the adjunctive group (n=19) (2.3 vs 3.5, respectively; P<0.01). The majority of patients (n=30) received yokukansan 2.5 g/day, whereas the remaining 6 received 5 g/day; the mean duration of treatment was 24.8 months (range, 1 to 77 months). Responder rate was 70.6% of monotherapy-treated patients and 21.1% of patients who received yokukansan adjunctively. Of the 8 patients who received yokukansan as an adjunct to clonazepam, none showed significant improvement. Mild gastric distress was reported in 1 patient receiving yokukansan 2.5 g/day.(Matsui 2019)

Tardive dyskinesia

Clinical data

An open-label study evaluated effects of yi-gan san on 22 adults with schizophrenia and neuroleptic-induced tardive dyskinesia who had been receiving a stable psychotropic regimen (eg, risperidone, quetiapine, perphenazine) for at least 6 months, with an average dose equivalent to chlorpromazine 839.3 mg/day; tardive dyskinesia had been stable for at least 3 months. Yi-gan san 7.5 g/day was administered for 12 weeks; doses of all psychotropic medications were kept unchanged throughout the study. Overall reduction in Abnormal Involuntary Movement Scale total scores was significant; mean severity score decreased 56% from baseline (P<0.0001), and 81.8% of patients improved. Similarly, patient scores on all PANSS subscales 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 patients.(Miyaoka 2008a)

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.(AAN [Bhidayasiri 2013])

Visual hallucinations

Clinical data

In 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.(Miyaoka 2009) In another report of an 81-year-old woman with Charles Bonnet syndrome, yi-gan san also reduced the frequency and severity of hallucinations. 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.(Hanyu 2008)

In a randomized controlled trial in patients with dementia (N=52), an improvement in visual hallucinations, as measured by NPI subscale scores, was observed with yi-gan san 7.5 g/day administered for 4 weeks compared with control.(Iwasaki 2005a) 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.(Iwasaki 2005b)

Dosing

The commercial yokukansan product approved in Japan (TJ-54) is a mixed extract in packages of 2.5 g per unit. For symptoms of nervousness, 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.(TJ-54 2014, Yu 2014)

Borderline personality disorder

Yi-gan san dosages ranging from 2.5 to 7.5 g/day for 12 weeks as monotherapy were evaluated in female outpatients with borderline personality disorder; average dose by the end of the study was 6.4 g/day.(Miyaoka 2008b)

Dementia

Yokukansan 7.5 g/day for 4 or 12 weeks was administered in a trial of older Japanese patients with varying etiologies of dementia, including Alzheimer disease, dementia with Lewy bodies, and vascular dementia.(Matsuda 2013) A mean dose of 7.02 g/day for 8 weeks has also been documented in a trial of patients with behavioral and psychological symptoms of dementia.(Teranishi 2013)

Schizophrenia

Average yokukansan dosages of 5.2 g/day or 6.7 g/day for 4 weeks and 7.5 g/day for 2 or 12 weeks were reported for treatment of schizophrenia.(Yu 2014)

As an adjunct to regular antipsychotic treatment, yi-gan san 2.5 g 3 times daily for 4 weeks was evaluated for management of treatment-resistant schizophrenia.(Miyaoka 2015)

Tardive dyskinesia

Yi-gan san 7.5 g/day (ie, 2.5 g of yi-gan san powder 3 times a day before meals) for 12 weeks was evaluated for use in neuroleptic-induced tardive dyskinesia.(Miyaoka 2008a)

Visual hallucinations

Yi-gan san 7.5 g/day for 2 to 4 weeks was used to reduce visual hallucinations in older Japanese patients with a history of Charles Bonnet syndrome as well as dementia.(Iwasaki 2005a, Miyaoka 2009)

Pregnancy / Lactation

Use of yokukansan in breastfeeding infants, children, and mothers (MICA treatment approach) during China's Ming dynasty period (circa 1555) has been described.(Muneoka 2015)

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.(TJ-54 2014)

Interactions

Coadministration of glycyrrhiza-, glycyrrhizinic acid–, or glycyrrhizinate-containing preparations with yokukansan may lead to pseudoaldosteronism, hypokalemia, and myopathy.(TJ-54 2014)

Results of animal and in vitro assays suggest no pharmacokinetic or pharmacologic drug interaction between yokukansan and memantine.(Matsumoto 2018)

Adverse Reactions

Use caution in patients with disorders of the GI tract, as adverse effects including anorexia, nausea, vomiting, diarrhea, and 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 were observed via modulation of transcription factors without affecting glucose uptake.(Nishiyama 2011, Yu 2014) A case of yokukansan-induced pneumonitis was reported in a 74-year-old man.(Nakamura 2012)

Clinically important adverse reactions described in the TJ-54 prescribing information include interstitial pneumonia, pseudoaldosteronism, heart failure, myopathy or rhabdomyolysis, hepatic dysfunction and jaundice, and skin hypersensitivity (ie, rash, redness, pruritus). The Japanese product labeling recommends close monitoring and discontinuation of use if any of these adverse events occur.(TJ-54 2014)

Toxicology

No data.

References

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