HIDETO SHINNO

Traditional Medicine-2015Birmingham, UK

August 03 – 05, 2015

Traditional Traditional

MedicineMedicine

20152015

Herbal Medicine for Sleep Disturbances in the Elderly

Hideto SHINNOKagawa University School of Medicine

Japan

The 3rd International Conference and Exhibition onTraditional & Alternative MedicineAugust 3, 2015 Birmingham, UK

Sleep Disturbances in the Elderly

1. Characteristics of sleep in the elderly

2. Treatment of sleep disturbances

in the elderly

Herbal prescription

for sleep disturbances

Sleep Disturbances in the Elderly

1. Characteristics of sleep in the elderly

2. Treatment of sleep disturbances

in the elderly

Herbal prescription

for sleep disturbances

PolysomnographySubjects in the Elderly

WREM

IIIIIIIV

sleep stages

PolysomnographySubjects in the Elderly

WREM

IIIIIIIV

sleep stages

PolysomnographySubjects in the Elderly

WREM

IIIIIIIV

sleep stages

PolysomnographySubjects in the Elderly

WREM

IIIIIIIV

sleep stages

non-REM sleep

PolysomnographySubjects in the Elderly

WREM

IIIIIIIV

sleep stages

PolysomnographySubjects in the Elderly

WREM

IIIIIIIV

sleep stages

A prolonged sleep latency

PolysomnographySubjects in the Elderly

WREM

IIIIIIIV

sleep stages

Decrease in slow wave sleep (stages III +IV)

PolysomnographySubjects in the Elderly

WREM

IIIIIIIV

sleep stages

frequent arousals

PolysomnographySubjects in the Elderly

WREM

IIIIIIIV

sleep stages

Decrease in REM sleep

Sleep in the ElderlyPolysomnography

A shortened total sleep timeA shortened total sleep time A shortened REM sleep timeA shortened REM sleep time

Relatively increased stage IRelatively increased stage I A decrease in slow wave sleep A decrease in slow wave sleep

Increase in PLMsIncrease in PLMs

Periodic limb movements during sleep

Increase in apnea-

hypopneaindex

Increase in apnea-

hypopneaindex

Sleep fragmentation

(frequent arousals)

Sleep fragmentation

(frequent arousals)

IncreasedWake time

after sleep onset

IncreasedWake time

after sleep onset

Periodic Limb Movement during Sleep (PLMs)

Repetitive, stereotyped movements

of the lower extremities in sleep

Rhythmic extensions of the big toe

and dorsiflexions of the ankle

Periodic Limb Movement during Sleep (PLMs)

Repetitive, stereotyped movements

of the lower extremities in sleep

Rhythmic extensions of the big toe

and dorsiflexions of the ankle

Followed by Accelerated heart

rates

Followed by Accelerated heart

rates

Periodic Limb Movement during Sleep (PLMs)

Repetitive, stereotyped movements

of the lower extremities in sleep

Rhythmic extensions of the big toe

and dorsiflexions of the ankle

frequent arousals

sleep disruption

Increase in PLMs

Followed by Accelerated heart

rates

Followed by Accelerated heart

rates

Periodic Limb Movement during Sleep (PLMs)

Repetitive, stereotyped movements

of the lower extremities in sleep

Rhythmic extensions of the big toe

and dorsiflexions of the ankle

frequent arousals

sleep disruption

Increase in PLMs

PLM DisorderPLMs > 15 / hourAmerican Academy of Sleep Medicine (2005)

Periodic Limb Movement during Sleep (PLMs)

Repetitive, stereotyped movements

of the lower extremities in sleep

Rhythmic extensions of the big toe

and dorsiflexions of the ankle

frequent arousals

sleep disruption

Increase in PLMs

After awakenings

PLMs disappears

Periodic Limb Movement during Sleep (PLMs)

Repetitive, stereotyped movements

of the lower extremities in sleep

Rhythmic extensions of the big toe

and dorsiflexions of the ankle

frequent arousals

sleep disruption

Increase in PLMs

After awakenings

PLMs disappears

Patients are usually unaware of PLMs.

Patients are usually unaware of PLMs.

Sleep in the ElderlyPolysomnography

A shortened total sleep timeA shortened total sleep time A shortened REM sleep timeA shortened REM sleep time

Relatively increased stage IRelatively increased stage I A decrease in slow wave sleep A decrease in slow wave sleep

Increase in PLMsIncrease in PLMs

Periodic limb movements during sleep

Increase in apnea-

hypopneaindex

Increase in apnea-

hypopneaindex

Sleep fragmentation

(frequent arousals)

Sleep fragmentation

(frequent arousals)

IncreasedWake time

after sleep onset

IncreasedWake time

after sleep onset

Sleep Disturbances in the Elderly

1. Characteristics of sleep in the elderly

2.Treatment of sleep disturbances

in the elderly

Herbal prescription

for sleep disturbances

Prescriptions for sleep disturbances

Prescriptions for sleep disturbances

Benzodiazepines

Prescriptions for sleep disturbances

Benzodiazepines

hangover effects

prolongation of the hypnotic effect

Prescriptions for sleep disturbances

Benzodiazepines

hangover effects

prolongation of the hypnotic effect

amnesia, delirium

Prescriptions for sleep disturbances

Benzodiazepines

hangover effects

prolongation of the hypnotic effect

amnesia, delirium

Contraindications

sleep apnea syndrome

Prescriptions for sleep disturbances

Benzodiazepines

hangover effects

prolongation of the hypnotic effect

amnesia, delirium

Contraindications

sleep apnea syndrome

Insufficient efficacy

periodic limb movement (PLM)-assocoated arousals

Prescriptions for PLM

Clonazepam

Dopaminergic agentsL-dopaHening W, et al. (1999) Sleep 22: 970-99Brodeur C, et al. (1988) Neurolgy 38: 1845-8

PramipexoleJama L, et al. (2009) Sleep Med 10: 630-6Manconi M, et al. (2007) Sleep Med 8: 491-7

Saletu M, et al (2001) Eur Neuropsychopharmacol 11: 153-61Milter MM, et al. (1986) Sleep 9: 385-92Boghen D, et al (1986) Can J Neurol Sci 13: 245-7

GABA

dopamine

Sleep Disturbances in the Elderly

The effect of Herbal prescription

TJ-54 on sleep disturbances

Yokukansan (YKS)Yokukansan (YKS)The herbal prescription

Yokukansan, TJ-54Yi-Gan SanPulvis deressionis efficientiae

Introduction

Yokukansan (YKS)

The herbal prescription

Introduction

Yokukansan (YKS)

The herbal prescription

YKS was originally developed as a remedy for restlessness and agitation in children.

Introduction

Yokukansan (YKS)

The herbal prescription

YKS was originally developed as a remedy for restlessness and agitation in children.

In Japan, YKS has been approved for neurosis, insomnia, and night time crying in children.

Introduction

Yokukansan (YKS)

The herbal prescription

YKS was originally developed as a remedy for restlessness and agitation in children.

In Japan, YKS has been approved for neurosis, insomnia, and night time crying in children.

Recently YKS is prescribed for psychiatric symptoms in dementia.

Atractylodis

Lanceae Rhizoma

Glycyrrhizae Radix

AngelicaeRadi

x

Cnidii Rhizom

a

Bupleuri

Radix

Hoelen

Uncarie Uncis Cum

Ramulus

　 The Ingredients of YKS

　 The Ingredients of YKS7 herbs

Yokukansan (YKS)Yokukansan (YKS)Extract Granules for Ethical Use

The effect of YKS on sleep disturbancesin patients with Dementia

Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.

Polysomnography

YKS administration (7.5 g/day)

YKS treatment days (week)mean age: 81±7 years oldAlzheimer’s disease: 4 casesDementia with Lewy bodies: 4 cases

The effect of YKS on sleep disturbances

Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.

time (min)

The effect of YKS on sleep disturbances

Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.Significant increase

in Total Sleep Timeand WASO

Significant increase in Total Sleep Time

and WASO

time (min)WASO; wake time after sleep onset

The effect of YKS on sleep disturbances

Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.Significant

increase in Stage II Sleep

Significant increase in

Stage II Sleep

time (min)

Number of awakenings at night

After YKS treatment, number of awakenings significantly decreased.

Shinno H, et al. (2008) Prog Neuro-Psychopharm Biol Psychiat

No. ofarousals

*P<0.0 ５

*

The effect of YKS on PLM during sleep

Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.

PLMs index(No. / hour)

PLMs index=No. of PLMs / sleep time (hour)

The effect of YKS on sleep disturbances

Shinno H, et al (2008) Prog Neuropsychopharmacol Biol Psychiatry 32: 881-885.

PLMs index(No. / hour)

** **p<0.01

YKS reduced PLMs.YKS reduced PLMs.

Pittsburgh Sleep Quality Index (PSQI)

YKS treatment improved subjective sleep quality.

developed by Buysse et al. (1989)

PSQI score

Shinno H, et al. (2008) Prog Neuro-Psychopharm Biol Psychiat

baseline YKS-treated

*

*P<0.05

Effect of YKS on Insomnia in the (non-demented) Elderly

Effect of YKS on Insomnia in the (non-demented) Elderly

Subjects: 10 patients with neurotic disorders 4 males and 6 femalesmean age 73.3±4.4 years old

Methods:Polysomnography was carried out

at adaptation night, baselineafter treated with YKS for 4 weeks

Sleep architectures and PLMs index were compared.

Adaptation night

-1d

baseline After treatmentYKS5g/d (evening and bedtime)For 4 weeks

Effect of YKS on Insomnia in the (non-demented) Elderly

Time (min)

Effect of YKS on Insomnia in the (non-demented) Elderly

Time (min)Improved Daytime

sleepiness

Improved Daytime

sleepiness

NOT affectedApnea-IndexNOT affectedApnea-Index

Effect of YKS on Insomnia in the (non-demented) Elderly

**

**p<0.01

Effect of YKS onRestless Legs Syndrome (RLS)

Restless legs syndrome (RLS)Four essential criteria

I) An urge to move the legsOften associated with discomfort sensations

I) An urge to move the legsOften associated with discomfort sensations

The International RLS Study Group (2005)

Paraesthesia/ dysesthesia

II) Begin or worsenDuring periods of REST or Inactivity

II) Begin or worsenDuring periods of REST or Inactivity

Lying down or sitting

III) Be partially or totally relieved by movement

III) Be partially or totally relieved by movement

IV) Occur predominantly in the evening or night

IV) Occur predominantly in the evening or night

Walking or stretching Few occur in the daytime

Restless legs syndrome (RLS)Four essential criteria

I) An urge to move the legsOften associated with discomfort sensations

I) An urge to move the legsOften associated with discomfort sensations

The International RLS Study Group (2005)

Paraesthesia/ dysesthesia

II) Begin or worsenDuring periods of REST or Inactivity

II) Begin or worsenDuring periods of REST or Inactivity

Lying down or sitting

III) Be partially or totally relieved by movement

III) Be partially or totally relieved by movement

IV) Occur predominantly in the evening or night

IV) Occur predominantly in the evening or night

Walking or stretching Few occur in the daytime

Sleep disturbancesSleep disturbances

Pathophysiology of Restless legs syndrome (RLS)

Iron deficiency Renal failureParkinson’s diseaseneuropathy

HypothalamusA11 dopaminergic

system

HypothalamusA11 dopaminergic

systemRLSRLS

DA decrease

Treatment of Restless legs syndrome (RLS)

RLSRLSDopaminergic agents

PramipexoleRopiniroleRotigotine

improvementimprovement

Adverse EffectsAdverse Effects

Nausea(visual) hallucinationsAugmentationMorning rebound

YKS for patients with RLS who had complained of side effect against previous treatment

Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-

YKS for patients with RLS who had complained of side effect against previous treatment

Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-

RLS severity

IRLS score

Side effectsSide effects

YKS 5g/dayYKS 5g/day

Previous treatments Smaller doses of PPX

0 2 4 6

YKS treatment days (weeks)

YKS for patients with RLS who had complained of side effect against previous treatment

Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-

RLS severity

IRLS score

Side effectsSide effects

YKS 5g/dayYKS 5g/day

Previous treatments Smaller doses of PPX

0 2 4 6

YKS treatment days (weeks)

Severe RLS

Extra-severe:IRLS>31

YKS for patients with RLS who had complained of side effect against previous treatment

Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-

RLS severity

IRLS score

Side effectsSide effects

YKS 5g/dayYKS 5g/day

Previous treatments Smaller doses of PPX

0 2 4 6

YKS treatment days (weeks)

moderate RLS

YKS for patients with RLS who had complained of side effect against previous treatment

Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-

RLS severity

IRLS score

Side effectsSide effects

YKS 5g/dayYKS 5g/day

Previous treatments Smaller doses of PPX

0 2 4 6

YKS treatment days (weeks)

mild RLS

YKS for patients with RLS who had complained of side effect against previous treatment

Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-

RLS severity

IRLS score

Side effectsSide effects

Previous treatments

0 2 4 6

YKS treatment days (weeks)

Before visiting to my Dept.Before visiting to my Dept.

YKS for patients with RLS who had complained of side effect against previous treatment

Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-

RLS severity

IRLS score

Side effectsSide effects

YKS 5g/dayYKS 5g/day

Previous treatments Smaller doses of PPX

0 2 4 6

YKS treatment days (weeks)

YKS for patients with RLS who had complained of side effect against previous treatment

Self-report total sleep time

YKS treatment days (weeks)

Self-report sleep latency time

YKS for patients with RLS who had complained of side effect against previous treatment

Shinno H et al (2010) Prog Neuro-Psychopharm Biol Psychiat 34(1); 252-

EpworthSleepinessScale score Side effectsSide effects

YKS 5g/dayYKS 5g/day

Previous treatments Smaller doses of PPX

0 2 4 6

Daytime somnolence improvedDaytime somnolence improved

YKS treatment days (weeks)

YKS may be effective for sleep disturbances in the elderly.

What pharmacological properties are beneficial ?

In the elderly, functions of dopamine (DA) and serotonin (5-HT)

are declined.

YKS increases 5-HT and DA levels in the aged rats

Mizoguchi K, et al. (2010) J Ethnopharmacol 127: 70-76.

Effect of YKS on 5-HT and DA systemAt prefrontal cortex in aged and young rats

YKS increases 5-HT and DA levels in the aged rats

Mizoguchi K, et al. (2010) J Ethnopharmacol 127: 70-76.

In aged rats, Decreases in

•Basal 5-HT and DA levels•KCl-induced 5-HT release and DA release

Effect of YKS on 5-HT and DA systemAt prefrontal cortex in aged and young rats

YKS increases 5-HT and DA levels in the aged rats

Mizoguchi K, et al. (2010) J Ethnopharmacol 127: 70-76.

YKS administarationYKS administaration

In aged rats, Decreases in

•Basal 5-HT and DA levels•KCl-induced 5-HT release and DA release

Increased5-HT and DA

releases

Increased5-HT and DA

releases

Effect of YKS on 5-HT and DA systemAt prefrontal cortex in aged and young rats

The Effect of YKS

on the on the serotonin (5-HT) systemserotonin (5-HT) system on the on the serotonin (5-HT) systemserotonin (5-HT) system

Repeated administration of YKS modulatesan altered function of 5-HT2A receptors.

Egashira,N ． et al. (2008) Prog Neuro-Psychopharmacol Biol Psychiatry 32: 1516-20 ．

Repeated administration of YKS inhibits DOI-induced head-twitch response

100 300 0

YKS (p.o.)

DOI 5mg/kg (i.p.)

20

15

10

5

0

hea

d-tw

itche

s /

5min

(repeated) 13days YKS +

YKS (p.o.)DOI (i.p.) head-twitch

DOI ： 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane

mg/kg

＊

DOI induces head-twitch via 5-HT2A receptor.

Egashira,N ． et al. (2008) Prog Neuro-Psychopharmacol Biol Psychiatry 32: 1516-20 ．

Repeated administration of YKS inhibits DOI-induced head-twitch response

100 300 0

YKS (p.o.)

DOI 5mg/kg (i.p.)

20

15

10

5

0

hea

d-tw

itche

s /

5min

(repeated) 13days YKS +

YKS (p.o.)DOI (i.p.) head-twitch

DOI ： 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane

mg/kg

＊

DOI induces head-twitch via 5-HT2A receptor.

Egashira,N ． et al. (2008) Prog Neuro-Psychopharmacol Biol Psychiatry 32: 1516-20 ．

Repeated administration of YKS inhibits DOI-induced head-twitch response

100 300 0

YKS (p.o.)

DOI 5mg/kg (i.p.)

20

15

10

5

0

hea

d-tw

itche

s /

5min

(repeated) 13days YKS +

YKS (p.o.)DOI (i.p.) head-twitch

mg/kg

＊

Over-activated5-HT2A receptors

Over-activated5-HT2A receptors

restoredrestoredYKS

The Effect of YKS

on the on the GABA systemGABA system

γ-aminobutyric acid

The effect of YKS on the GABA system

Aim: To elucidate the mechanism of the anxiolytic-like effects in mice

YKS increased the number of head-dipping behavior, an indicator of anxiolytic effect.

Pretreatment with Flumazenil, GABA-BZP receptor antagonist

Behavioral study with the hole-board test

The effect of YKS was inhibited.

Kamei J (2009) Prog Neuropsychopharmacol Biol Psychiatry 33: 1431-7

The effect of YKS on the GABA system

Aim: To elucidate the mechanism of the anxiolytic-like effects in mice

YKS increased the number of head-dipping behavior, an indicator of anxiolytic effect.

Pretreatment with Flumazenil, GABA-BZP receptor antagonist

Behavioral study with the hole-board test

The effect of YKS was inhibited.

Kamei J (2009) Prog Neuropsychopharmacol Biol Psychiatry 33: 1431-7

The effect of YKS on the GABA system

Aim: To elucidate the mechanism of the anxiolytic-like effects in mice

YKS increased the number of head-dipping behavior, an indicator of anxiolytic effect.

Pretreatment with Flumazenil, GABA-BZP receptor antagonist

Behavioral study with the hole-board test

The effect of YKS was inhibited.

Kamei J (2009) Prog Neuropsychopharmacol Biol Psychiatry 33: 1431-7

The effect of YKS on Sleep DisturbancesHypothesis on the mechanism

The effect of YKS on Sleep DisturbancesHypothesis on the mechanism

Improve Sleep Continuity(Decrease in awakenings at night )

Improve Sleep Continuity(Decrease in awakenings at night )

Restore ofSleep architecture

Restore ofSleep architecture

Decrease inPLMs

Decrease inPLMs

Increase intotal sleep time

Increase intotal sleep time

The effect of YKS on Sleep DisturbancesHypothesis on the mechanism

DopamineDopamine

YKS

Improve Sleep Continuity(Decrease in awakenings at night )

Improve Sleep Continuity(Decrease in awakenings at night )

Restore ofSleep architecture

Restore ofSleep architecture

Decrease inPLMs

Decrease inPLMs

Increase intotal sleep time

Increase intotal sleep time

The effect of YKS on Sleep DisturbancesHypothesis on the mechanism

DopamineDopamine

YKS

Improve Sleep Continuity(Decrease in awakenings at night )

Improve Sleep Continuity(Decrease in awakenings at night )

GABAGABA

Restore ofSleep architecture

Restore ofSleep architecture

Decrease inPLMs

Decrease inPLMs

Increase intotal sleep time

Increase intotal sleep time

The effect of YKS on Sleep DisturbancesHypothesis on the mechanism

DopamineDopamine5-HT5-HT

YKS

Improve Sleep Continuity(Decrease in awakenings at night )

Improve Sleep Continuity(Decrease in awakenings at night )

GABAGABA

Restore ofSleep architecture

Restore ofSleep architecture

Decrease inPLMs

Decrease inPLMs

Increase intotal sleep time

Increase intotal sleep time

Atractylodis

Lanceae Rhizoma

Glycyrrhizae Radix

AngelicaeRadi

x

Cnidii Rhizom

a

Bupleuri

Radix

Hoelen

Uncarie Uncis Cum

Ramulus

　 　 The Ingredients of YKS　 　 The Ingredients of YKS

Atractylodis

Lanceae Rhizoma

Glycyrrhizae Radix

AngelicaeRadi

x

Cnidii Rhizom

a

Bupleuri

Radix

Hoelen

Uncarie Uncis Cum

Ramulus

　 　 The Ingredients of YKS　 　 The Ingredients of YKS

5-HTGABA5-HT

GABA

5-HTGABA5-HT

GABA

dopamineGABA

dopamineGABA

YKS

Summary

★ effective for sleep disturbances in the elderly

★ few adverse events

extrapyramidal signs

hang-over effects

symptoms associated with anti-cholinergic effect

dopaminedopamine serotoninserotonin GABAGABA

Caution: lowering serum K+Caution: lowering serum K+

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