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ADHS Attentional deficit Hyperactivity Syndrome. Frequency/prevalence. 4 – 6 % of school children more boys than girls About 75 % are affected in adulthood Fixation of a limit is controversial. Symptoms. Attention deficit: distractable, problems to

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ADHS

Attentional deficit

Hyperactivity Syndrome


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Frequency/prevalence

4 – 6 % of school children

more boys than girls

About 75 % are affected in adulthood

Fixation of a limit is controversial


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Symptoms

Attention deficit: distractable, problems to

concentrate, to finish a task

Hyperactivity: inability to remain seated

talking too much

Impuslivity: interrupts other spakers

can‘t wait for anything

antisocial behaviour

No insight into the own disease-state


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Cause

There is a strong genetic component

Speculative:

Polymorphism of the D4 gene ???

of the DA-transporter Gene ???

Environmental factors alone can not explain

the disease


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Psychostimulants in ADHD

Amphetamines: Amphetamine (Adderall®))

Methamphetamine (Adderall ®)

Methylphenidate (Ritalin ®)

Non Amphetamines: Pemoline (Cylert ®)

Atomoxetine (Strattera®)

Modafinil

Under Ivestigation:

ABT-418 (N-ACH-R-Ago)

S-Citalopram (Escitalopram®, Lexapro®)

Histamine H3 receptor antagonists (Komater et al. 2002)



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Amphetamin

Methamphetamin



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Amphetamines:

Methylphenidate: Ritalin ®, Medikinet®, Equasym®,

Concerta ®

Methadate ®

D-Amphetamine (D- / S-isomer)

Dexedrine ®=Dexamphetamine ®=go-pills

for those who do not respond to Ritalin

Adderall ®

is an amphetamine coctail


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  • Behavioural pharmacology of amphetamine

  • Self-administered

  • Dopamine-dependent, mediated by the brain reward system

  • Dose dependent increase in:

  • -All behaviours resulting in fragmentation of behaviour

  • -swichtching – finally stereotypy

  • Dopamin-dependent, mediated by striatum and N.accumbens

  • Amphetamine acts rate dependently:

  • It icreases the response rate of low-rate responder

  • It decreases the response rate of high-rate responder

  • („the rate dependency principle“)


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Amphetamines in ADHD

Rate dependency hypothesis:

Children with ADHD are high-rate responders

And amphetamines reduce response rates

Adults are low rate responders and amphetamines enhance

response rates

Teicher et al. J Child Adolesc Psychopharmacol 2003, 13: 41-51:

„We provide preliminary evidence that methylphenidate exerts

rate-dependent behavioural effects (attentiveness) in children with

ADHD…..“

„These findings illustrate a clear inverse association between

symptom severity and degree of therapeutic response….“


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The Yerkes-Dodson-Law

Erregungs-

Niveau

Response-rate


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Effect of amphetamine on low-rate responders

…….on high-rate responders


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Further evidence for

the rate dependency principle

Children with severe cognitive impairment

(IQ less than 45, developmental age less than 4.5 years)

react to methylphenidate with increased stimulation/excitation

or did not profit from medication.

(Handen et al. 1991)

Hypothesis:

The paradoxical sedating effects of

methylphenidate occurs only in high rate responders.


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Atomoxetine (Strattera®)

Approved in USA and UK for ADHD in children,

adolescents and adults.

In Germany: March 2005

No psychostimulant drug/ not controlled by BtMG

Contraindication: MAO inhibitors

Metabolism:

P450 pathway: 7 % white 2% black

Are poor metabolizers (not dangerous)


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Atomoxetine: Mechanism of action

Selective noradrenaline reuptake inhibition

SNARI

Some selectivity for the prefrontal cortex

Reboxetine


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  • Atomoxetine effects in humans

  • Mood brightening, but

  • no psychostimulant-like high

  • Neuropharmacology

  • Enhancement of noradrenaline tone

  • Facilitates neuronal differentiation during developent

  • Facilitates neuronal plasticity

  • protects against various neurotoxins

  • Behavioural pharmacology

  • Alerting effects


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Atomoxetine in ADHD

1.2 – 1.8 mg /kg /day effective

(comparable to methylphenidate)

Administration: once daily

Approved in the USA for all ages

Advantages: see list

Disadvantages: see list


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Modafinil (Vigil, Provigil, Vigicier, Alertec®)

Approved for treatment of narcolepsy

Excessive solomnescense

Obstructive sleeping-apnoe

Controlled by BTM


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Modafinil

Mechanisms of action

α-agonist (prazosin antagonizes some effects)

Facilitates Glu-transmission

Reduces GABA-transmission

Modafinil activates Orexin producing neurons

Orexine is a peptide transmitter

exclusively originating in the lateral hypothalamus

Wakefulness promoting/sleep supressing

Orexine deficit is the cause of narcolepsy

(Orexine k.o…as a model)


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  • Modafinil effects in humans

  • Prescribed for narcolepsy, unusual fatigue,

  • for Parkinsonian patients

  • Increases vigilance (enhancement in sports)

  • in US-military, esp. Air Force dexedrine (go-pills) will be replaced by Modafinil

  • Stimulant, mood brightening

  • Enhances willingness to work

  • Meomory enhancing

  • Compared to amphetamines: Less jitteriness, anxiety, agitation,

  • no hypersolomescent rebound effect

  • less peripheral efects

  • Minimal abuse potential (Rush. et al. 2002, Behav. Pharm. 13:105-115)


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Modafinil in ADHD

…may be a useful treatment…. When anorexia

limits use of stimulants.

(Rugino et al. Ped Neurol 2003, 29: 136-142)

No rebound upon abrupt discontinuation

Improvement in car driving performance

Side effects: insomnia


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Histamine H3-antagonists in ADHD

The H3 receptor is a presynaptic auto- and

heteroreceptor

It inhibits histamine and

Catecholamine release

H3-antagonists enhance catecholamine

release


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Nicotine-R agonists in ADHD

Nicotinic ACH-Receptors are located

Presynaptically as heteroreceptors on

Catecholaminergic terminals

Nicotine-R-agonists enhance catecholamine

release


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Animal models for ADHD

Neonatal 6-OH-Dopamine lesion leads to hyperactivity

in adulthood (Davids et al. 2002, JPET:301: 1097-1102)

Reduced dopamine and metabolite concentration

in the striatum (for ex. 90 %)

Hyperinnervation due to sprouting by 5-HT neurons

Originating in the medial Raphe (for ex. 80%)


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  • Neonatal NMDA-R-anatgonists, cause hyperactivity,

  • inattention, impulsivity (Fredriksson and Archer 2004)

  • DAT k.o.

  • Irrespective of the target addressed:

  • Many knock-out or knock-in mice exhibit increased

  • hyperactivity, irritability, impulsivity, aggressivity.

  • ??? do different neonatal disturbances and compensation processes lead to hyperactivity ???


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ADHD in adulthood

Untreated ADHD persists in about 66% to

Adulthood and results in:

adverse/inappropriate/antisocial behaviour

addiction.


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Stimulant treatment and addiction

„Pharmacotherapy of ADHD reduces risk for substance

use disorder“ (Biederman et al. 1999)

Animal studies

Early methylphenidate treatment reduces cocaine brain

Reward and stimulation in adulthood ( Mague et al. 2005,

Carlezon et al. 2003)

Problem: young, but not hyperactive animals have been used


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Misuse of ADHD drugs as enhancers

For combating sleep

For enhacement of motivation for work

For mood brightening

For cognition enhancement (learning, memory, communication)