בשק תערפהב לופיט םיקיטו · Concerta® (methylphenidate HCl) extended-release tablets [package insert]. Mountain View, Calif: Alza Mountain View, Calif: Alza Corporation;

an

טיפול בהפרעת קשב

וטיקים

ר אריה אשכנזי"ד American Board of Psychiatry

and Neurology

נוירולוג ילדים סגן מנהלת המכון להתפתחות הילד

ש ספרא"ח לילדים ע"בי ח תל השומר"בי

טיפול בהפרעת קשב וטיקים דר אריה אשכנזי

נוירולוג ילדים

סגן מנהלת המכון להתפתחות הילד

מרכז רפואי עש שיבא–ח עש ספרא "בי

Faculty Disclosure Arie Ashkenasi MD

Janssen

Novartis

Medison

Pfizer

comorbidities

A.Language and Learning Disability (10-

15%)1.Usually less hyperactive and more

inattentive

B. Tourette's Syndrome (70% with tics

have ADHD)

C. Oppositional Defiant Disorder (35-65%

of ADHD patients)

D. Conduct Disorder (10-20% of ADHD

patients)

E. Major Depression (20% of ADHD

patients)

F. Anxiety Disorder (25% of ADHD

patients)

G. Substance Abuse (20-40% of ADHD

patients

What is a tic?

A “tic” is a sudden, rapid, recurrent, non-rhythmic,

stereotyped motor movement or vocalization

A tic may be simple (involving only a few muscles or

simple sounds) or complex (involving multiple groups of

muscles recruited in orchestrated bouts or words or

sentences)

TIC

Motor Tics (Simple)

Generally lasting less than several hundred milliseconds

Examples include:

eye blinking

nose wrinkling

neck jerking

shoulder shrugging

facial grimacing

abdominal tensing

Motor Tics (Complex)

Longer in duration than simple tics; usually lasting seconds or longer

Examples include: hand gestures

jumping, touching, pressing, or stomping

facial contortions

repeatedly smelling an object

squatting and/or deep knee bends

retracing steps and/or twirling when walking

assuming and holding unusual positions (including “dystonic” tics, such as holding the neck in a particular tensed position)

Copropraxia & Echopraxia

Both are considered complex motor tics

Copopraxia = a sudden, tic-like vulgar, sexual, or

obscene gesture

Echopraxia = a mirror phenomena, such as involuntary,

spontaneous imitation of someone else’s movements

Vocal Tics (Simple) Meaningless brief sounds

Examples include:

Throat clearing

Grunting

Sniffing

Snorting

Chirping

Vocal Tics (Simple) Meaningless brief sounds

Examples include:

Throat clearing

Grunting

Sniffing

Snorting

Chirping

Vocal Tics (Complex)

More clearly involve speech and language

Examples include:

sudden, spontaneous expression of single words or phrases

speech blocking

sudden and meaningless changes in pitch, emphasis, or

volume of speech;

The “Lalias”

All are considered complex vocal tics

Palilalia = repeating one’s own sounds or words

Echolalia = repeating the last heard sound, word,

or phrase

Coprolalia = the sudden, inappropriate expression

of a socially unacceptable word or phrase that may

include obscenities as well as specific ethnic,

racial, or religious slurs (found in fewer than 10%

of individuals with tic disorders)

Brain Stem

MESENCEPHALON

PONS

MEDULLARaphe nuclei(serotonin)

Substantia nigrategmentum(dopamine)

Locus ceruleus(norepinephrine)

to cerebellum

to cord

to diencephalon and

cerebrum

Basal ganglia

Nucleus

accumbens

Substantia

nigra

Ventral

tegmental area

Hypothalamus

Dopamine Pathways

Treatments: Psychosocial Education

Patient, family, and school

Counseling for family and patient

Relaxation therapy

Supportive therapy

Habit Reversal Therapy

Non Stimulants

Atomoxetine

Clonidine

Guanfacine

TCAs

Selective Norepinephrine Reuptake Inhibition:

Atomoxetine

• Potent inhibitor of presynaptic NEtransporter (reuptake pump)

• Minimal affinity for other noradrenergicreceptors or for other neurotransmittertransporters or receptors

Michelson et al. Pediatrics 2001;108:e83.

Biederman and Spencer. Biol Psychiatry 1999;46:1234.

Atomoxetine in ADHD

• Clinical effect similar to more NE-selective TCAs (eg, imipramine) withoutthe plethora of TCA-mediated adverseeffects

• Mechanism of action in ADHD is veryspecific to adrenergic system with nodirect effects on dopaminergic system

Michelson et al. Pediatrics 2001;108:e83.

Biederman and Spencer. Biol Psychiatry 1999;46:1234.

Clonidine, Guanfacine

• Efficacy of clonidine and guanfacine go along with theNE theory of deficit in ADHD

• Clonidine is an alpha 2 receptor agonist / guanfacinemore selective at alpha 2a

• Both presynaptic and postsynaptic receptors areinvolved– Stimulation of presynaptic receptors “dampens-down” the

locus ceruleus

– Stimulation of the alpha 2a receptors makes postsynapticneurons more responsive to specific inputs

Biederman and Spencer. Biol Psychiatry 1999;46:1234.

Excitatory signal

a2A receptor

NE

Ion channel

Reuptake transporter

Postsynaptic neuron

NE presynaptic terminal

Wang M, et al. Cell. 2007;129:397-410.

Transmission of Neuronal Signal

is Modulated by the a2A Receptor

TCAs

• Therapeutic effect mediated by 5HT and

NE reuptake blockade

– Desipramine, imipramine (used in ADHD)

more selective for NE reuptake blockade

• Adverse effects mediated by histamine,

muscarinic cholinergic, and alpha-

adrenergic receptor actions

Biederman and Spencer. Biol Psychiatry 1999;46:1234.

Antipsychotic Treatment Historically high potency first generation antipsychotics

Pimozide (Orap) best studied

Haloperidol

Severe side effects has led to search for alternative 2nd

generation antipsychotics

Risperidone- Aripiperazole

ADHD

Stimulant Medications

Of pharmacologic options available for

ADHD, stimulant medications are the:

Most studied

Most commonly used

Most effective

First-line agents for treatment

Spencer T et al. J Am Acad Child Adolesc Psychiatry. 1996;35:409-432; Dulcan M et al, for the Work Group on Quality Issues of the American

Academy of Child and Adolescent Psychiatry.

J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S; Greenhill LL et al, for the Work Group on Quality Issues of the American Academy of

Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry. 2002;41:26S-49S.

Stimulants Found to

Improve ADHD

Inattention

Impulsivity

Hyperactivity

Compliance

Impulsive aggression

Social interactions

Academic efficiency

Academic accuracy

AND

Spencer T et al. J Am Acad Child Adolesc Psychiatry. 1996;35:409-432; Dulcan M et al, for the Work Group on Quality Issues of the

American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S;

Greenhill LL et al, for the Work Group on Quality Issues of the American Academy of Child and Adolescent Psychiatry. J Am Acad Child

Adolesc Psychiatry. 2002;41:26S-49S; Zametkin AJ, Ernst M. N Engl J Med. 1999;340:40-46.

Core Symptoms

Stimulant dosing

No parameter predicts optimal stimulant dose or timing.

Not weight

Not age

Not gender

Not severity of illness

Each person must have the dose titrated to their

individual needs and duration of dose.

The best dose is that which leads to optimal effects

minimal side effects.

American Academy of Pediatrics clinical practice guideline. Pediatrics 2001:108:1033

v v Storage

vesicle

DA Transporter

Cytoplasmic DA

Methylphenidate

Presynaptic Neuron

Synapse

Probable Mechanism of Action

of Methylphenidate

Wilens T, Spencer TJ. Handbook of Substance Abuse: Neurobehavioral Pharmacology. 1998;501-513.

STIMULANTS:

METHYLYPHENIDATE

SHORT ACTING: Ritalin, Focalin (Dexmethlyphenidate)

INTERMEDIATE ACTING:, Ritalin LA

LONG ACTING: Concerta. Focalin XR. Daytrana

AMPHETAMINE

SHORT ACTING:,, Adderall (Mixed Salt)’Attent

LONG ACTING: Adderall XR .Vyvanse

AACAP Clinical Practice Guidelines. J Am Acad Child Adolesc Psychiatry. 1997;36(suppl):85S-121S.

Controversies: growth deficits, tic exacerbation, seizures, abuse

(Effects occurring in >5% of patients and >placebo)

Stimulants: Potential Side Effects

Appetite loss,

abdominal pain

Insomnia

Nervousness

Before Operation During Operation

Water

Water Push

Compartment

Drug

Compartment #2

Drug

Compartment #1

Orifice/Exit Port

Drug

Overcoat

Rate-

Controlled

Membrane

Methylphenidate HCI (Concerta®) Extended-Release

Tablets: Trilayer

Capsule-Shaped Tablets

Concerta® (methylphenidate HCl) extended-release tablets [package insert]. Mountain View, Calif: Alza

Corporation; 2006; Greenhill LL et al, for the Work Group on Quality Issues of the American Academy of

Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry. 2002;41:26S-49S;

Ritalin® LA: Extended-release Delivery via

SODAS™ Technology

SODAS™ is a trademark of Elan Corporation, PLC

H

N

H

H

Ph CH3OOC

2’

2

D (+) Methylphenidate

Dexmethylphenidate

H

H

H

Ph COOCH3

2’

2

l (-) Methylphenidate

N

Focalin: A Refined Form of Ritalin®

Chemical Structure of Vyvanse

Vyvanse is a prodrug that is therapeutically inactive until it

is converted to active d-amphetamine in the body

l-lysine

H N 2

O

OH

NH 2

+

d-amphetamine

(active)

H N 2

CH 3

Lisdexamfetamine

(Prodrug)

H N 2

O

N H

NH 2

CH 3

Site of cleavage

Rate-limited

Hydrolysis