ADHD AND NICOTINE:
IMPLICATIONS FOR
TREATMENT
Hervé CACI, MD, PhD
Pôle Enfants-Adolescents
CHU de Nice (France)
EPA Lisbon - January 24-28, 2009
ADHD: a piece of history
• ADHD-like symptoms have been
described for more than 300 years.
• Clinical trials in adults are conducted
for 30 years only.
1976: Paul Wender
1904: Emil Kraepelin
1902: George Still
1880: Désiré-Magloire Bourneville
1798: Sir Alexander Crichton
1653: Molière (The Blunderer)
Pathophysiology of ADHD is
not fully understood

Psychostimulants:
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increase both dopamine and norepinephrine
neurotransmission
have greater effects on overt behavioral features
than on cognitive domains measured in laboratory
the reduction of motor activity follows a different
dose-reponse curve than the effects on cognition
are overall effective for 70% of the patients
Non-catecholaminergic neurotransmitter
systems may be involved in the cognitive
symptoms of ADHD
Stimulants limitations

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Response to stimulants varies in different age
groups and with certain comorbidities1.
Stimulants may increase smoking behavior
by increasing the relative reinforcing effects of
cigarette smoking2.
Are there long-lasting effects of stimulants
related to changes in dopaminergic
systems3?
1Biederman
et al. (2004) The International Journal of Neuropsychopharmacology;7:77-97
et al. (2000) Psychopharmacology;153:85-92
3Volkow & Insel (2003) Biological Psychiatry;54:1307-1309
2Tidey
Recent pharmacological
treatments for ADHD

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Although stimulants still domine the market
There is a growing choice of treatment
options:
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In 2002, atomoxetine (Strattera®) was launched as
the first non-stimulant drug
In 2007, the FDA approved guanfacine (Intuniv®),
a central a2-agonist, as a second-line treatment
And, for the last twenty years, an alternative
"nicotinergic hypothesis" has been
developed.
ACh/Nicotine "direct" effects

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Nuclei from the Basal Forebrain Cholinergic
System (BFCS) provide the major innervation
of the cortex and the hippocampus.
The components of the BFCS are critically
involved in sustained attention, selective
attention and the ability to increase and
decrease attention to stimuli1.
The cortical cholinergic input system
generally acts to optimize the processing of
signals in attention-demanding contexts2.
1Beane
2Sarter
& Marrocco (2004) Progress in Neurobiology;74:167-181
et al. (2005) Brain Research Reviews;48:98-111
Cholinergic system
and cognition in ADHD (1)

Behavioral inhibition:

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Nicotine reduces SSRT1,2 in the Stop Signal Task3
Nicotine but not MPH improves the Stroop Task
Sustained attention

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Nicotine improves accuracy (d’) on the Continuous
Performance Task4
Nicotine reduces the number of omissions and the
variability of response times5
1Potter
& Newhouse (2004) Psychopharmacology;176:182-194
& Newhouse (2005) Biological Psychiatry;57:69S
3Willcutt et al. (2005) Biological Psychiatry;57:1336-1346
4Shytle et al. (2002) World Journal of Biological Psychiatry;3:150-155
5Levin et al. (1996) Psychopharmacology;123:55-63
2Potter
Cholinergic system
and cognition in ADHD (2)

Delay aversion:

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Nicotine improves the Two-choice Delay Task
(more larger-later reward choices)
Working memory

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With laboratory animals, a4b2 and a7 nicotinic
agonists improve and antagonists disrupt working
memory1.
In rats and monkeys, nicotine improves working
memory by reducing distractibility2,3,4.
1Levin
ED (2002) Journal of Neurobiology;53:633-640
et al. (1997) Psychopharmacology;130:276-284
3Prendergast et al. (1998) Psychopharmacology;136:50-58
4Terry et al. (2002) J Pharmacology and Exp Ther;301:284-292
2Prendergast
Cigarette smoking
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ADHD subjects:
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report earlier initiation of smoking
are more likely to progress from initiation to regular smoking
smoke at higher rates than controls:
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for adults: 41-42% vs. 26%
for adolescents: 19-46% vs. 10-24%
adults report more difficulty quitting than individuals in the
general population
ADHD is an independent risk factor for tobacco use
even after controlling for Conduct Disorder
Additionally, the risk for smoking is more strongly
associated with the number of reported inattention
symptoms than by the diagnosis of ADHD itself
Maternal smoking during
pregnancy is a risk factor
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Prenatal nicotine exposure modifies the
behavior of mice through early development1
Maternal smoking during pregnancy is
associated with low birth weight2, preterm
delivery, and stillbirth
In two case-controlled studies, the odds-ratio
was up to 4:1, similar to the risk accounted
for by maternal ADHD status3,4
Most of 18 cohort studies showed an
& Ahmad (1998) Pharmacological Biochemisty and Behavior;59:313-318
association5 Ajarem
Kallen et al. (2001) European Journal of Public Health; 11:329-333
1
2
3Milberget
et al. (1998) Journal of Clinical Child Psychology; 27:352-358
et al. (2002) J Am Acad Child Adolesc Psychiatry; 41:378-385
5Linnet et al. (2003) American Journal of Psychiatry; 160:1028-1040
4Mick
Supports for the
"Nicotinic Hypothesis"

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Neuro-anatomical data
Pharmacological data
Epidemiological data:
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Increased risk for ADHD in the offspring
when mother smoked during pregnancy
Earlier and heavier cigarette smoking in
ADHD adolescents and adults
Transdermal nicotine patches

In non-smoking adults with ADHD, 7 mg patches
improved:
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In smoking adults with ADHD, 21 mg patches
improved
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CGI Improvement and Therapic Effect scores (N=11)1
POMS*-Vigor (N=11)1,
Cognitive performance (Stop Signal Task, N=12)2.
POMS*-Concentration (N=6)1.
CPT: Decreased RT and smaller SE change in RT (N=6)1.
Adverse effects: nausea, dizziness, itching, and
headache
1Levin
*Profile of Mood States
ED et al. (1996) Psychopharmacology, 123:55-63
& Newhouse (2008) Pharmacology, Biochemistry and Behavior, 88:407-417
2Potter
Anticholinesterases

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Both Donezepil (Aricept®) and Galantamine
(Reminyl®) have been reported to be helpful
as an adjunctive treatment in limited series1.
There are obstacles to the use of these
medications in ADHD:
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Possible alterations to ovarian functions
Relatively narrow therapeutic index
Limited tolerability, particularly in children
1Wilens
(2000) Journal of Child and Adolescent Psychopharmacology;10:217-22
Neural Nicotinic Receptors
(NNR) targeted molecules

University of Florida & Taiho & CoMentis:
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Targacept:
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GTS-21 for schizophrenia, AD and ADHD
More than 10 molecules under development
In phase 2: AZD3480 (TC-1734) for cognitive
impairment, including AD, schizophrenia, and
ADHD
Abbott maintains three molecules in phase 2:
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1999: ABT-418
2006: ABT-089
2008: ABT-894 (with NeuroSearch) for ADHD and
neuropathic pain
Pilots studies with ABT-418
and ABT-089 (a4b2 agonists)

ABT-4181 (N=32):
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Double-blind, placebocontrolled, cross-over trial
(3-week periods separated
by 1-week washout) with
75mg of ABT-418
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Transdermal patch

Well tolerated

Preferential improvement in
adults with the inattentive
symptom cluster, as well as
those with less severe
ADHD symptoms.
1Wilens
2Wilens
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ABT-0892 (N=11):

Double-blind, placebocontrolled, cross-over trial
(2-week periods) with three
doses of ABT-089 (2, 4 and
20 mg b.i.d)

Per os

Well tolerated

Clinical improvements were
seen at lower two doses.

At all doses, both clusters of
symptoms were decreased
after only 2 weeks of
treatment compared with
placebo.
et al. (1999) The American Journal of Psychiatry;156:1931-1937
et al. (2006) Biological Psychiatry; 59:1065-1070
CONCLUSION
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Nicotine plays a critical role in cognition
Nicotinergic agents under development are a
promising new treatment for cognitive
dysfunction including ADHD
The magnitude of effects is not clearly stated
in comparison with stimulants
They may lower the risk of initiation of
cigarette smoking in adolescents
To date, it cannot be concluded whether
these nicotinergic agents would be used
primarily or secondarily