• This educational activity is supported by independent educational grants from

• Neurocrine Biosciences and Teva Pharmaceuticals.

Faculty

Rakesh Jain, MD, MPH

Clinical Professor

Department of Psychiatry

Texas Tech Health Sciences Center

School of Medicine

Midland, Texas

Disclosures

• Dr. Rakesh Jain: Advisory Board—Alkermes, Janssen, Lilly, Lundbeck, Merck, Neos

Therapeutics, Neurocrine Biosciences, Otsuka, Pamlab, Pfizer, Shire, Sunovion, Supernus,

Takeda, Teva; Advisory Board (spouse)—Otsuka; Consultant—Acadia, Alfasigma USA, Inc.,

Allergan, Eisai, Evidera, Impel NeuroPharma, Janssen, Lilly, Lundbeck, Merck, Neos

Therapeutics, Neurocrine Biosciences, Osmotica Pharmaceuticals plc, Otsuka, Pamlab, Pfizer,

Shire, Sunovion, Supernus, Takeda, Teva; Consultant (spouse)—Lilly, Otsuka, Pamlab,

Sunovion; Grant/Research Support— Allergan, Lilly, Lundbeck, Otsuka, Pfizer, Shire, Takeda;

Speakers Bureau—Alkermes, Allergan, Ironshore Pharmaceuticals, Janssen, Lilly, Lundbeck,

Merck, Neos Therapeutics, Neurocrine, Otsuka, Pamlab, Pfizer, Shire, Sunovion, Takeda,

Teva, Tris Pharmaceuticals; Speakers Bureau (spouse)—Lilly.

Disclosure

• The faculty have been informed of their responsibility to disclose to the

audience if they will be discussing off-label or investigational use(s) of drugs,

products, and/or devices (any use not approved by the US Food and Drug

Administration).

– The off-label use of amantadine, clonazepam, botulinum toxin, deep brain

stimulation, Ginkgo biloba, and tetrabenazine for the treatment of tardive

dyskinesia will be discussed.

• Applicable CME staff have no relationships to disclose relating to the subject

matter of this activity.

• This activity has been independently reviewed for balance.

• Video clips of patients were obtained with permission.

Learning Objectives

• Outline the consequences of untreated tardive dyskinesia (TD) on quality of

life (QoL) in patients taking antipsychotic medications

• Describe the clinical indications for and clinical benefits of administering the

Abnormal Involuntary Movement Scale (AIMS) exam

• Incorporate currently available data on the long-term efficacy and safety of

vesicular monoamine transporter 2 (VMAT2) inhibitors for the treatment of TD

into clinical practice

Definition of Tardive Dyskinesia

A type of dyskinesia that typically emerges

after long-term use of antipsychotic drugs

(DRBAs)

Appearing or tending to appear late

Distortion or impairment of voluntary

movement

Socially stigmatizing, functionally impairing,

and probably irreversible medical condition

DSM Dx (highlights)

• Involuntary movements of the tongue, jaw, trunk, or

extremities have developed in association with the use of

neuroleptic medication

• The involuntary movements are present over a period of at

least 4 weeks and occurring any of the following patterns:

(1) choreiform movements (ie, rapid, jerky, nonrepetitive);

(2) athetoid movements (ie, slow, sinuous, continual);

(3) rhythmic movements (ie, stereotypies)

• Symptoms develop during exposure to a neuroleptic

medication or within 4 weeks of withdrawal from an oral

(or within 8 weeks of withdrawal from a depot) neuroleptic

medication

• There has been exposure to neuroleptic medication for at

least 3 months (1 month if age ≥ 60 years)

DRBA = dopamine receptor blocking agent.Lerner PP, et al. Psychiatry Clin Neurosci. 2015;69(6):321-334. Dorland’s Online Medical Dictionary. www.dorlands.com.

Tardive

Dyskinesia

Patient Perspectives on Living with Tardive Dyskinesia

TD Incidence Meta-Analysis

• 57 head-to-head RCTs, including 32 FGA and 86 SGA arms, were meta-analyzed,

yielding 32 FGA-SGA pairs and 35 SGA-SGA pairs

• The annualized TD incidence was

– FGAs: 6.5% (95% CI: 5.3-7.8%) vs.

– SGAs: 2.6% (95% CI: 2.0-3.1%)

• TD risk and annualized rates were lower with SGAs vs. FGAs

– Risk ratio = 0.47, 95% CI: 0.39-0.57, P<0.0001

– Rate ratio = 0.35, 95% CI: 0.28-0.45, P<0.0001, NNT = 20

• FGA-SGA TD rate ratios were significantly lower with olanzapine and aripiprazole vs.

other non-clozapine SGAs in exploratory pairwise comparisons

• SGA-SGA comparisons confirmed the olanzapine advantage vs. non-clozapine SGAs

(Rate ratio = 0.66, 95% CI: 0.49-0.88, P = 0.006, studies = 17, NNT = 100)

Carbon M, Kane JM, Leucht S, Correll CU. World Psychiatry. 2018;17(3):330-340.

Clinical Course of TD

Waln O, et al. Tremor Other Hyperkinet Mov. 2013;3:1-11. Bhidayasiri R, et al. Postgrad Med J. 2011;87(1024):132-141. Zutshi D, et al. Tremor Other Hyperkinet Mov. 2014;4:266.

TD can occur

after only 3 months

of exposure

Usually occurs

after 1 to 2 years

of therapy

Patient

begins DRBA

therapy

Can present

after

discontinuation

Dopamine Receptor Blocking Agent (DRBA)

Therapy Timeline

Severity

• Involuntary movements range from mild to severe and disabling

• Up to 10% of patients on long-term neuroleptic therapy may

experience considerable functional impairment

• Symptoms are chronic but may vary in severity over time

Persistence of Symptoms

• Following discontinuation of

neuroleptic therapy, symptoms of

TD continue in a majority of patients

(persistence rate estimates vary

from 67% to 89%)

Risk Factors for the Development of TD

• Age (HR = 1.04, P <.001)

• Diagnosis of schizophrenia (HR =

1.99, P<.001)

• Antipsychotic dosage (up to 100

mg/day chlorpromazine equivalent;

HR = 1.65, P<.01)

• Comorbid bipolar and related

disorders (HR = 1.39, P<.01)

• History of EPS (HR = 1.35)

• Parkinsonism (HR = 1.43)

• Bradykinesia (HR = 1.44)

• Tremors (HR = 2.12)

• Myoclonus (HR = 2.33)

EPS = extrapyramidal symptoms.Patterson-Lomba O, et al. BMC Neurol. 2019;19(1):174.

TD and Its Significant Impact on Functioning and Quality of Life

Consequences of TD on Functional Recovery, Clinical Outcomes, and Survival

TD Negatively Impacts Life No Matter theUnderlying Diagnosis (Schizophrenia, MDD, BD)

Impact on Mental Component Summary domain in BD: Cohen’s d=1.12; MDD: Cohen’s d=1.19; SZ: Cohen’s d=.74

BD = bipolar disorder; CGI = Clinical Global Impression; SW-ISMI = Social Withdrawal subscale of the Internalized Stigma of Mental Illness scale; MCS = mental component summary of the SF-12; MDD = major depressive disorder; PCS = physical component summary of the SF-12; PF = physical functioning of the SF-36v2; Q-LES-Q SF = Quality of Life Enjoyment and Satisfaction Questionnaire Short Form; SF-12 = SF-12v2 Health Survey; SZ = schizophrenia. McEvoy J, et al. Qual Life Res. 2019;28(12):3303-3312.

Non-TD Group

3.0

0

SW

-IS

MI S

co

re

2.5

2.0

P<.001

a

2.52.3

n=197n=219

0.6

0

Q-L

ES

-SF

Sc

ore

0.4

0.3

P<.001

c

0.460.53

n=196n=219

60

0

SF

-12

v2

Sc

ore

40

MCS

30

P=.04

b

36.438.4

n=197n=218

PCS

P<.001

44.648.8

n=197n=218

PF

P<.001

42.947.4

n=197n=218

0.550

TD Group

Social Withdrawal (↑ = Worse) Mental and Physical Functioning (↓ = Worse) Quality of Life (↓ = Worse)

Having TD Significantly ImpactsHow Employers See a Potential Hire

Ayyagari R, et al. An Experimental Study to Assess the Professional and Social Consequences of Mild-to-Moderate Tardive Dyskinesia. Presented at: 2019 Psych Congress; October 3-6, 2019; San Diego, California.

Randomized, digitally

administered survey

study used a one-time

data collection from a

sample of the general

population in the United

States

1200 watched patients

with TD and 1200

watched patients

without TD

I’d be interested in learning

more about this candidate

Without TD (%)

With TD (%)

I’d be willing to suggest that

others in my company should

interview this candidate

Without TD (%)

With TD (%)

This candidate was

dressed appropriately for

the interview

Without TD (%)

With TD (%)

I think the candidate

would be suitable for

client-facing jobs

Without TD (%)

With TD (%)

I think this candidate

would be suitable for

back-office jobs

Without TD (%)

With TD (%)

Strongly Disagree Disagree Neutral Agree Strongly Agree

22

20

53 50 20

42 54 21

21

22

3017 20 12

92 50 17

18

19

104 50 19

115 45 20

15

14

2212 37 14

66 56 18

19

20

228 38 12

103 50 17

Emerging Neurobiology and Modulation of Tardive Dyskinesia

Multiple Factors May ImpactTardive Dyskinesia

Multiple variables that may

impact TD

• Activity of VMAT2 at synaptic

vesicles

• How much this VMAT2 activity

modulates presynaptic

dopamine concentration

• The amount of dopamine at

supersensitive postsynaptic D2

receptors

• If the patient is also receiving a

D2-blocking antipsychotic drug

Stahl SM. CNS Spectr. 2018;23(4):239-247.

Synaptic Dopamine

Concentration

VMAT2

ActivityPresynaptic Dopamine

Concentration

D2 Receptor Blocker

Affinity to D2 Receptor

D2 Receptor Blocker

Concentration

D2 Receptor

Number and Density

Signal

DAT = dopamine transporter; DOPA = dihydroxyphenylalanine; DOPAC = dihydroxyphenylacetic acid; DDC = dihydroxyphenylalaninedecarboxylase; MAO = monoamine oxidase; TH = tyrosine hydroxylase; Tyr = tyrosine; VMAT = vesicular monoamine transporter.Meyer AC, et al. J Neurochem. 2013;127(2):187-198.

DA

DA

VMAT2

DADA

DA DDC

MAO

DOPA

Tyr

THTH activity

DAT

DA

DADADA

DA

DOPAC

DOPAC

DOPAC DOPAC

DOPAC

DOPACDOPAC

Dopamine Depletion The Birth of a New Mechanism to Treat TD

VMAT1 is not

widely distributed in the

human brain

VMAT2 is extensively

distributed in the

human cortex, striatum,

and basal ganglia

It is found in

presynaptic neurons

VMAT2 Controls

Dopamine in

Presynaptic Vesicles

The AIMS

Identifying and Assessing Tardive Dyskinesia

The AIMS Examines 7 Body Regions

www.cqaimh.org/pdf/tool_aims.pdf. Accessed February 25, 2020.

Muscles of

facial expression

Lips and perioral region

Tongue

Jaw

Upper extremity

Lower extremity

Trunk –

neck, shoulders,

and hips

Ratings

The scale is rated from

0 (none)

1 (minimal)

2 (mild)

3 (moderate)

4 (severe)

Positive AIMS

• Score of 2 or more in TWO or more

• movements OR

• Score of 3 or 4 in a SINGLE movement

The AIMS Examination Preliminaries

• The chair to be used in the examination should be a hard, firm one without

arms

• Ask the patient whether there is anything in his or her mouth (such as gum or

candy) and, if so, to remove it

• Ask about the current condition of the patient’s teeth. Ask if he or she wears

dentures. Ask whether teeth or dentures bother the patient now

• Ask whether the patient notices any movements in his or her mouth, face,

hands, or feet. If yes, ask the patient to describe them and to indicate to what

extent they currently bother the patient or interfere with activities

Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised 1976. Rockville, MD: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs;1976:534-537.

The AIMS Exam

Watch this short video to see how to

perform the AIMS exam.

https://www.psychcongress.com/multim

edia/aims-exam-instructional-video

Telepsychiatry and TD: Challenging, Yet Doable

Current Challenges

• Telepsychiatry makes it

harder to complete a full

AIMS

• Video is a challenging

medium to do a full body

evaluation

• No specific guidelines

currently exist for TD

evaluation using

telepsychiatry

Potential Solutions

• A sub-optimal AIMS is better

than no AIMS

• Having a family

member/support system

present during telepsychiatry

visit vastly improves quality of

TD exam

• Most (thought not all) of the

TD exam can be conducted

via telepsychiatry

Other Motoric Disorders/Comorbidities

Diagnostic Barriers and Confounds

Relevant Terminology in the World ofAntipsychotic-Induced Movement Disorders

• Extrapyramidal symptoms: overarching term referring to involuntary movement disorders that may include

acute and tardive symptoms, including akathisia, bradykinesia, dyskinesia, dystonia, parkinsonism, and

tremor. When they are considered to be related to medication use, they are referred to as extrapyramidal side

effects.

• Akathisia: subjective complaints of restlessness that are often accompanied by excessive movements

(fidgeting of legs, rocking from foot to foot, inability to stand still) that can be observed.

• Bradykinesia: slowness / slowing of movement.

• Dystonia: abnormal, prolonged, contraction of the muscles of the eyes, head, neck, limbs, or trunk.

• Neuroleptic-induced parkinsonism: clinical syndrome categorized by Parkinsonian tremor, muscular

rigidity, akinesia (loss of or difficulty initiating movement), or bradykinesia occurring in association with

antipsychotic medication treatment. This term was used to describe both acute and more chronic

antipsychotic-induced movement disorders when these effects were first observed in the 1950s.

• Postural tremor: fine tremor occurring during attempts to maintain a posture.

• Tardive dyskinesia: involuntary athetoid or choreiform movements, generally involving the tongue, lower

face and jaw, and extremities, associated with the long-term use of antipsychotic medication.

Macaluso M, et al. J Psychiatr Pract. 2017;23(2):121-129.

Parkinsonian Symptoms are a Major Differential Diagnosis of TD

Truong DD, et al. Parkinsonism Relat Disord. 2019;59:146-150.

It is important to remember patients may have TD or Parkinsonian symptoms, or both

Distinguishing Features between DRBA-induced Parkinsonism, Tardive Parkinsonism, and Idiopathic Parkinson’s Disease

Parkinsonian symptoms present after DRBA exposure and improve after discontinuation of DRBA up to 1 year

No hyposmia

No autonomic dysfunction

DaT scan –

Path studies: Not performed

Persistent Parkinsonian symptoms in absence of DRBA exposure+ / - hyposmia

+ / - autonomic dysfunction

DaT scan +

Path studies: Reduction in SN pigmentation

Lewy bodies present

Alpha synuclein staining +

Parkinsonian symptoms present after DRBA exposure and persist after discontinuation of DRBA > 1 year

No hyposmia

No autonomic dysfunction

DaT scan not reported

Path studies: Reduction in SN pigmentation

Lewy bodies present

Alpha synuclein staining +

DRBA-induced Parkinsonism (DIP)

Idiopathic Parkinson’s DiseaseTardive Parkinsonism

Journal Club Review Article Discussion

Management of TD

A Treatment Paradigm for TD

GPi-DBS = globus pallidus interna deep brain stimulation.Bhidayasiri R, et al. J Neurol Sci. 2018;389:67-75.

Level A:

New generation

VMAT2 inhibitors

Level B:

Clonazepam or

Ginkgo Biloba

Level C:

Amantadine

Level C:

DBS

Determining lowesteffective dosage of

antipsychotics

Determining lowesteffective dosage of

antipsychotics

Review by specialistto identify

suitable alternatives

Close observationand regular follow-up

assessment

Close observationand regular follow-up

assessment

Level C:GPi DBS

Troublesomesymptoms

Non-troublesomesymptoms

Non-approved indications

Approvedindications*

Tardive dyskinesia

*Schizophrenia, psychotic disorders, bipolar

disorder, hyperactivity, severe behavioral

problems, generalized nonpsychotic anxiety,

and Tourette syndrome.

Level A:New generation VMAT2

inhibitors**

Level B:Clonazepam or Ginkgo biloba

Level C:Amantadine

Indications for antipsychotic use

Assessment of TD

Dosage evaluation

Consideration of

suppressive agents

Monitoring and

follow-up assessment

ImprovedNot improved and still troublesome

Not improved andstill troublesomeImproved

Improved

Improved

Not improved and still troublesome

Not improved and still troublesome

Improved

Improved**Consider

Tetrabenazine ONLY if

the new generation

VMAT2 inhibitors are

unavailable.

Canadian Treatment Guidelines for TD

• VMAT2 Inhibitors (deutetrabenazine and valbenazine): Recommendation (Grade A)

There is good evidence to support a favorable benefit–risk ratio for both as a treatment for TD. Both

should be considered a first-line treatment for TD.

• AMANTADINE: Recommendation (Grade B)

The evidence to support the use of amantadine for TD is extremely limited. Amantadine may be

considered for the treatment of TD if more established treatments are contraindicated or ineffective.

• BENZODIAZEPINES: Recommendation (Grade B)

Currently, there is little evidence to support the beneficial effects of benzodiazepines on reducing TD.

Recommendation (Grade C)

Clinicians may consider discontinuation of anticholinergic medications for the treatment of TD, keeping in

mind that there is very little evidence to support this course of action, and that drug-induced parkinsonism

may worsen.

• DEEP BRAIN STIMULATION: Recommendation (Grade C)

The current available evidence suggests that GPi-DBS could be considered in select cases where TD

symptoms are severe and distressing and not responsive to medical treatment, and where psychiatric

conditions are stabilized.

Ricciardi L, et al. Can J Psychiatry. 2019;64(6):388-399.

Benztropine May Be an Extra Significant Risk Factor for TD

Caroff SN, et al. J Clin Psychopharmacol. 2020;40(1):38-45.

Retrospective study of

7985 Veterans taking

antipsychotics

Benztropine use was

associated with the

highest risk of TD

(OR, 2.25: 95% CI

1.73-2.91; P<.0001)

Tre

atm

en

t

1.00 0.5 2.0

Odds Ratio

3.01.5 2.5

Major Depression

Tobacco Use

Edentulousness

Drug Use

Diabetes

Alcohol Use

Schizophrenia

Bipolar Disorder

PTSD

Black (Race)

Age

Male

Other (Race)

Antidepressant

Anticonvulsant

Antipsychotic

Benztropine

Lithium

Co

mo

rbid

itie

sD

em

og

rap

hic

s

1.54

1.64

1.52

2.25

1.22

1.40

1.05

0.78

0.92

1.06

1.11

0.93

0.82

0.75

0.38

1.16

1.16

1.04

DA

DA

VMAT2

DADA

DA DDC

MAO

DOPA

Tyr

THTH activity

DAT

DA

DADADA

DA

DOPAC

DOPAC

DOPAC DOPAC

DOPAC

DOPACDOPAC

Dopamine Depletion The Birth of a New Mechanism to Treat TD

DAT = dopamine transporter; DOPA = dihydroxyphenylalanine; DOPAC = dihydroxyphenylacetic acid; DDC = dihydroxyphenylalaninedecarboxylase; MAO = monoamine oxidase; TH = tyrosine hydroxylase; Tyr = tyrosine; VMAT = vesicular monoamine transporter.

Meyer AC, et al. J Neurochem. 2013;127(2):187-198.

VMAT1 is not widely

distributed in the human

brain

VMAT2 is extensively

distributed in the human

cortex, striatum, and

basal ganglia

It is found in presynaptic

neurons

VMAT2 Controls

Dopamine in

Presynaptic Vesicles

Receptor Pharmacology Comparison ofValbenazine and Deutetrabenazine

Stahl SM. CNS Spectr. 2018;23(4):239-247.

“At therapeutic doses, net occupancy of VMAT2 by the

active metabolites of both compounds is comparable”

Deutetrabenazine

20

100

Recep

tor

Occu

pan

cy (

%)

60

40

0

80

6 mg 9 mg 12 mg 15 mg 18 mg 24 mg 30 mg 33 mg 36 mg 42 mg 48 mg 40 mg 80 mg

Valbenazine

2

16

Ste

ad

y S

tate

Pla

sm

a

Co

ncen

trati

on

(n

g/m

L)

8

4

0

12

40 mg 80 mg 6 mg 9 mg 12 mg 15 mg 18 mg 24 mg

10

90

50

30

70

14

6

10

DeutetrabenazineValbenazine

Deuterium (D) is a

naturally-occurring,

stable, non-radioactive,

non-toxic isotope of

hydrogen

Deutetrabenazine

NO

CH3

O

CH3

O

H

D3

Deuteration AttenuatesMetabolic Breakdown of Active Metabolites

US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/index.cfm.Meyer JM. CNS Spectr. 2016;21(S1):13-24. Tung RD. Innovations in Pharmaceutical Technology. 2010;32:1-4. Chen JJ, et al. Clin Ther. 2012;34(7):1487-504.

Deuterium attenuates metabolic breakdown of active metabolites → BID dosing

Orally-administered Drug

Hepatic carbonyl

reductase

Tetrabenazine

CYP2D6

Hepatic carbonyl

reductase CYP2D6

Deutetrabenazine

NO

CH3

O

CH3

O

H

NO

C

O

C

O

H

α- and β-dihydrodeutetrabenazine

Active Metabolites

α- and β-dihydrotetrabenazine

NO

CH3

O

CH3

OH

H

NO

CD3

O

CD3

OH

H

O-desmethyl dihydrodeutetrabenazine

Inactive Metabolites

O-desmethyl dihydrotetrabenazine

NO

CH3

HO

OH

H

NO

CD3

HO

OH

H

D3

Valbenazine

Valbenazine and Tetrabenazine Metabolism

Primary metabolites derived from TBZ and VBZ. TBZ is metabolized into 4 independent isomers: R,R,R-HTBZ (NBI-98782); S,R,R HTBZ(NBI-98795); S,S,S-HTBZ (NBI-98771); and R,S,S-HTBZ (NBI-98772). VBZ is metabolized into 2 primary metabolites: R,R,R-HTBZ and NBI-136110. R,R,R-HTBZ is the only HTBZ stereoisomer common as a metabolite for both TBZ and VBZ.Grigoriadis DE, et al. J Pharmacol Exp Ther. 2017;361(3):454-461.

Tetrabenazine

NBI-98785

NO

O

O

H

H2N

O

NO

O

O

H

NO

O

O

H

Valbenazine

NBI-98854

NO

O

OH

H

NO

O

OH

H

NO

O

OH

H

NO

O

OH

H

NO

O

O

H

H2N

O

OH

Hydrolysis Mono-oxidation

Carbonyl Reductase

R,S,S-DHTBZNBI-98772

S,S,S-DHTBZNBI-98771

S,R,R-DHTBZNBI-98795

R,R,R-DHTBZNBI-98782 NBI-136110

Recent Clinical Trials of VMAT2 Inhibitors for Treatment of

Tardive Dyskinesia

0

Deutetrabenazine (AIM-TD): Fixed-DoseStudy Design, Mean Change in AIMS Score

Anderson KE, et al. Lancet Psychiatry. 2017;4(8):595-604.

Week

Mean

Ch

an

ge i

n A

IMS

Sco

re

0

-4

-3

-1

-2

0

-4LS

Me

an

Ch

an

ge

in

AIM

S S

co

re a

t W

ee

k 1

2

-3

-1

24 mg/day12 mg/dayPlacebo

-2

36 mg/day

Deutetrabenazine

-3.2-2.1-1.4 -3.3

P=.003

P=.001

6 1242 108

Placebo

Deutetrabenazine 12 mg/day

Deutetrabenazine 24 mg/day

Deutetrabenazine 36 mg/day

Deutetrabenazine Safety and TolerabilityProfile in Placebo-Controlled TD Studies

Fernandez HH, et al. Neurology. 2017;88(21):2003-2010. Anderson KE, et al. Lancet Psychiatry. 2017;4(8):595-604.

Adverse ReactionDeutetrabenazine

(n=279) (%)

Placebo

(n=131) (%)

Headache 5 8

Somnolence 4 7

Diarrhea 4 4

Nasopharyngitis 4 2

Fatigue 4 5

Insomnia 4 1

Anxiety 4 5

Upper respiratory tract infection 3 4

Dry mouth 3 5

Nausea 2 7

Weight increased 2 3

Urinary tract infection 2 2

Depression/dysthymic disorder 2 1

Akathisia / Agitation / Restlessness 2 1

4% of patients

required dose

reduction of

deutetrabenazine

due to AEs vs

2% of patients

taking placebo

Placebo-Controlled TD Studies: Adverse Reactions

Reported in ≥2% of Patients Treated with Deutetrabenazine

-0.1

-1.9

-0.3

Valbenazine (KINECT 3): Fixed-Dose Study Design,AIMS Change from Baseline by Study Visit

Intent-to-Treat Population: Included all randomized participants who had at least one post-randomization AIMS value.*P<.05. **P<.01. ***P≤.001 for valbenazine vs placebo. aDose that was statistically significantly different from placebo after adjusting for multiplicity. Hauser RA, et al. Am J Psychiatry. 2017;174(5):476-484.

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

***

***

* *

**

***

Placebo

Valbenazine 40 mg

Valbenazine 80 mg

LS

Mean

Ch

an

ge (

SE

M)

-0.1

-1.4-1.4

-1.9

-2.7

-3.2

WeeksBaseline 2 4 6

a

Placebo (n)

Valbenazine 40 mg (n)

Valbenazine 80 mg (n)

76

70

79

76

70

77

73

64

73

69

63

70

Adverse Reactions in 3 Placebo-Controlled Studies of Valbenazine6-Week Treatment Duration Reported at ≥2% and >Placebo

aWithin each adverse reaction category, the observed adverse reactions are listed in order of decreasing frequency.US Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. www.accessdata.fda.gov/scripts/cder/daf/index.cfm.

Adverse Reactiona Valbenazine

(n=262) (%)

Placebo

(n=183) (%)

General Disorders

Somnolence (somnolence, fatigue, sedation) 10.9 4.2

Nervous System Disorders

Anticholinergic effects (dry mouth, constipation,

disturbance in attention, vision blurred, urinary retention)5.4 4.9

Balance disorders/fall (fall, gait disturbance, dizziness,

balance disorder)4.1 2.2

Headache 3.4 2.7

Akathisia (akathisia, restlessness) 2.7 0.5

Gastrointestinal Disorders

Vomiting 2.6 0.6

Nausea 2.3 2.1

Musculoskeletal Disorders

Arthralgia 2.3 0.5

Deutetrabenazine

Valbenazine

VMAT2 Therapy –Long-Term Data

DeutetrabenazineLong-Term Data is Reassuring

CGIC = Clinical Global Impression of Change; PGIC = Patient Global Impression of Change. Hauser RA, et al. Long-Term Treatment With Deutetrabenazine Is Associated With Continued Improvement in Tardive Dyskinesia (TD): Results From an Open-Label Extension Study. Presented at: 70th Annual Meeting of the American Academy of Neurology; April 21–27, 2018; Los Angeles, CA. Fernandez HH, et al.J Neurol Neurosurg Psychiatry. 2019;90(12):1317-1323.

No new safety signals or concerns emerged

in this long-term study

Patients “much improved” or “very much improved” on

CGI and PGI over the long-term treatment period

2-year (Week 106) open-label response rates are reported in this interim analysis. Of 343 patients enrolled

in the extension study, 232 previously received deutetrabenazine and 111 previously received placebo.

0

Week

Me

an

Ch

an

ge

fro

m

Ba

se

lin

ein

AIM

S S

co

re

0

-10

-6

-2

-8

50 1103010 9080

-4

Prior Placebo

Prior Deutetrabenazine

All Patients

Week 0 2 4 6 15 28 41 54 67 80 93 106

Prior Placebo (n) 111 111 108 104 101 83 65 50 34 27 10 2

Prior Deutetrabenazine (n) 232 230 229 223 208 168 137 96 69 39 13 6

All Patients (n) 343 341 337 327 309 251 202 146 103 66 23 8

40 10020 7060

Week

25

100

Pa

tie

nts

(%

)

50

0

75

4 6 15 28 41 54 67 80 93 106

75 75

87

74

706868

61

67

62

67 66

59 5860

5456

54

45 44

CGIC PGIC

Valbenazine 40 mg

Valbenazine 80 mg

After Washout

After Washout

Valbenazine 40 mg

Valbenazine 80 mg

After Washout

After Washout

ValbenazineLong-Term Data is Reassuring

Factor SA, et al. Effects of Long-Term Valbenazine on Tardive Dyskinesia and Patient-Reported Outcomes: Results from the KINECT 4 Study. Presented at: 70th Annual Meeting of the American Academy of Neurology; April 21–27, 2018; Los Angeles, CA. Marder SR, et al. J Clin Psychopharmacol. 2019;39(6):620-627.

Of the 163 participants included in the analyses,149 completed the Week 8 visit and 103 completed Week 48

No new safety signals or concerns emerged in this long-term study

Sustained improvements were found in adults with TD

who received once-daily valbenazine for up to 48 weeks,

based on clinician- and patient-rated measures

40 mg (n) 45 33 30 25 20 20 20

80 mg (n) 107 105 97 87 79 74 74

Week

AIM

S M

ean

Sco

re C

han

ge

fro

m B

aselin

e (

±S

EM

)

0

-12

-8

-2

-6

-10

-4

BL 36248 5212 48

(n) 33 105 30 97 25 87 20 79 20 74 20 74 (n) 33 105 30 97 25 87 19 79 20 74 20 74

Week

Part

icip

an

ts w

ith

Resp

on

se (

%) 100

0

20

80

40

60

36248 5212 48

PGIC Score ≤ 2(“Very Much Improved” or “Much Improved”)

69.7

49.5

80.0

63.9

92.0

80.5

89.5 89.9 90.0 89.2

65.062.2

Week

Part

icip

an

ts w

ith

Resp

on

se (

%) 100

0

20

80

40

60

36248 5212 48

CGI-TD Score ≤ 2(“Very Much Improved” or “Much Improved”)

57.6

42.9

70.0

56.7

72.0

85.1 85.0

94.9

90.0

95.9

35.0

43.2

Potential Challenges with VMAT2 Therapy &Potential Solutions

Sleepiness and Sedation

• Both VMAT2 therapies

can lead to sedation

• It can complicate

adherence

• It can lead to medication

discontinuation

• Rates are relatively low for both options, most cases are

mild-to-moderate, and in most it is time limited

• Caution patient before starting therapy

• Reduce dose – don’t increase until sedation disappears or

is manageable

• Change dose to evening time dosing with valbenazine

• If needed, off-label recommendation is to offer valbenazine

40 mg every other day until sedation is improved. Later

challenge with approved doses

• If needed, off-label recommendation is to offer

deutetrabenazine nighttime dose only. Temporarily skip AM

dosing until sedation is manageable. Later challenge with

approved doses

Akathisia / EPS

• Both VMAT2 therapies

can lead to akathisia /

EPS

• It can complicate

adherence

• It can lead to medication

discontinuation

• Rates are relatively low for both options, most cases are

mild-to-moderate, and in most it is time limited

• Caution patient before starting therapy

• Reduce dose of either VMAT2 therapy – don’t increase

until akathisia or EPS disappear or are manageable

• If EPS presents, ask yourself, “Did I uncover Parkinson’s

disease?”

• If needed, off-label recommendation is to offer valbenazine

40 mg every other day until akathisia or EPS is improved.

Later challenge with approved doses

• If needed, off-label recommendation is to offer

deutetrabenazine nighttime dose only. Temporality skip AM

dosing until akathisia or EPS is manageable. Later

challenge with approved doses

Lack of Insight

• Lack of self-awareness,

and/or lack of insight, are

both prevalent in some

patients with TD

• We should appreciate many psychiatric disorders,

particularly psychotic disorders, are often

accompanied by lack of awareness and lack of

insight

• Sometimes, a patient is so afraid we clinicians will

“change their medications and screw things up” they

will purposefully deny TD or hide impairments

resulting from it

• Assuring such patients, addition of a VMAT2 therapy

does not mean you have to reduce or change other

current medications automatically. This often

reassures the patient and they are more open to

discussing TD in an open and honest dialogue

Critical Issues to Remember with Both VMAT2 Therapies

• There is no need to discontinue, reduce, or change antipsychotic therapy

• There is no need to change … antidepressant or mood stabilizer therapy

• Both VMAT2 medications are effective in TD no matter what the underlying

disorder may be – schizophrenia or a mood disorder

New Modified Delphi Guidelines on TD

Breaking News New Modified Delphi Guidelines on TD

• A steering committee of 11 TD

experts met in nominal group format

to prioritize questions to be

addressed and identify core

bibliographic materials and criteria

for survey panelists

• Of 60 invited experts, 29 (23

psychiatrists and 6 neurologists)

agreed to participate

• Average experience = 29 years;

academic, private, and community

practices all had representationCaroff SN, et al. J Clin Psychiatry. 2020;81(2):e1-e11.

New Modified Delphi Guidelines on TDFocus on Screening

Screening Assessments

• AIMS is the standard structured assessment for screening and monitoring for severity

of TD

• Semi-structured assessments should be utilized in clinical practice to screen for TD

• A semi-structured assessment should include

– Patient recognition of current/recent abnormal movements as part of a review of side effects

at time of assessment

– Visual observation of psychomotor abnormalities on mental status examination

– Caregiver report of recent/current abnormal movements

– Patient report of history of movement/psychomotor changes

– Patient complaints about changes in movement being distressful or interfering with functioning

or QoL

AIMS = Abnormal Involuntary Movement Scale.Caroff SN, et al. J Clin Psychiatry. 2020;81(2):e1-e11.

New Modified Delphi Guidelines on TDTreatment Approach

The following strategies should be considered as part of your

treatment approach

– Discussion of treatment options with patients and caregivers

– Review and consider modifying antipsychotic regimen

– Treatment of TD with VMAT2 inhibitor

Caroff SN, et al. J Clin Psychiatry. 2020;81(2):e1-e11.

New Modified Delphi Guidelines on TDTreatment Approach

The following are important considerations when choosing treatments

– Severity of TD symptoms

– Severity of underlying psychiatric disorder

– Phenomenology of TD symptoms (eg, dystonia)

– Psychiatric stability on current treatment regimen

– Current antipsychotic medication

– Current acute extrapyramidal side effects

– Patient psychiatric history (eg, suicide attempts, hospitalizations, severe

psychosis, etc.)

– Patient-reported subjective awareness, distress, and impact of movements

on functioning and QoL

– Current anticholinergic medication Caroff SN, et al. J Clin Psychiatry. 2020;81(2):e1-e11.

Caroff SN, et al. J Clin Psychiatry. 2020;81(2):e1-e11.

New Modified Delphi Guidelines onTD VMAT2 Inhibitors and TD

• The following should be considered in the prescription of VMAT2 inhibitors

as part of TD management

– As part of an overall and integrated, pharmacologic treatment plan

– Depends on a patient’s condition and needs

– If a patient and caregiver request, prefer, or agree to this treatment option

– After the response to antipsychotic maintenance or modifications is determined

• The following patient- or drug-specific factors impact selection of a specific

VMAT2 inhibitor

– Tolerability, Safety, Efficacy, Ease of use

• If a VMAT2 inhibitor is ineffective, not tolerated, or declined by a patient, the

next step is to switch to another VMAT2 inhibitor before using other less

evidence-based agents

Conclusion

In ConclusionWhat have we learned together today?

• Screening proactively, routinely, and systematically for TD in

patients on atypical and typical antipsychotics is a mandate for all

clinicians

• Innovative alterations of tetrabenazine (such

as deutetrabenazine and valbenazine) are expected to better

serve patients’ needs

• Significant, promising research is occurring including activity on

control of TD symptoms with multiple VMAT2 inhibitors. It

behooves us clinicians to keep abreast of important new

developments in this field

• Improving functionality in TD patients is a major goal of treatment