Treating ADHD with agomelatine

Short Communicotion
Journal of Attention Disorders

r6(4) 34G348

Treating ADH D with Agomelatine

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DOI: I 0. I 177 I I 0970547 I I 4 17 400

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Osnce

Hetmut Niederhoferl

Abstract
Objective: Agomelatine is a relatively new antidepressant, with affìnities to MT I and MT2 (responsible for the circadian
rhythm) as well as to 5-HT2C receptors. Since antidepressants have demonstrated some benefìt in the treatment of ADH
and because of the fact" thatADHD is often associated with sleep disorders, we assumed, that ¡t might be a therapeutic
alternative also for ADHD. Method: We proved this assumption in ten ADHD pat¡ents in a placebo controlled manner.
Results: Agomelatine's effect was superior to that of placebo, but seems to be less than that of Methylphenidate or
placebo. Conclusion: lf ADHD therapy with Methylphenidate or Atomoxetine is not indicated e.g. because of adverse
side effects and if anADHD patient suffers from additional sleep disorders,Agomelatine might be a helpful therapeutic
alternarive. (J. of An- Dis. 201 2; I ó(4) 346-348)

Keywords
psychopharmacology, ADHD, neurobiology, agomelatine

Attention-deficit hyperactivity disorder (ADHD) is a common child psychiatric disorder with the following symptoms : distractibility, restlessness, and irritability. Diffrculty
with attention impairs leaming, whereas problems of restlessness and initability affect behavior. Associated prob-

of

lems

oppositionality, argumentativeness, and low

frushation tolerance often ADHD to the developmental
burden of these patients (Rapport, Denney, DuPaul, &
Gardner, 199 4).'Leaming disabilities and aggressive conduct disorder are significantly increased in this population,
leading to disruptions at home and at school (Rapport et al.,

1994). Depression and anxiety, irritability and explosiveness, substance abuse, and antisocial behavior also occur
with increased frequency (Biederman, Newcom, & Sprich,

l99l;

Faraone, Biederman, Keenan,

&

Tsuang,

l99l). In

approximately half the cases, the problem continues into
adolescence and adulthood, which is evident in persisting

disorganization and diminishing productivity. The psychostimulants such as methylphenidate (MPH) and atomòxetine are the major treatments for ADHD with and'ù/ithout
hyperactivity, but these medications have some significant
side effects and limitations. Although the psychostimulants
are the most effective medications for focusing attention,
they may be less potent at reducing extremely high levels
of activity and aggression. Side effects of decreased appe'tite, insomnia, the potential for increasing tics, and delaying
growth rate prompt investigation of alternative medications. Also, patient compliance with MPH is known to be

in spite of its beneficial clinical
Studies have documented the beneficial effects of

the o, noradrenergic agonist, clonidine, in the treatment of
highly active, oppositional, and aggressive patients with
ADHD when compared with placebo (Hunt, Minderaa, &
Cohen, 1985) and MPH (Hunt, 1987). Given in combination with MPH, clonidine reduces activity, aggression,
and oppositionality at a lower dose of MPH, thereby
reducing overall side effects (Hunt, 1988). However, the
usefulness of clonidine is clinically limited by side effects
of sedation, hypotension, and its relatively short half-life
(2.s hr).
In addition, antidepressants have been reported to have
some possible benefits in treating ADHD. Agomelatine has
afünities to MTI and MT2 (responsible for the circadian
rhythm) as well as to 5-HTr" receptoré; the latter are responsible for the antidepressive effect of agomelatine. Because of
the fact that ADHD patients often have problems with the
circadian rhythm and that antidepressants such as tricyclic
antidepressants (Gualtieri, Golden, & Fahs, 1983) or selective serotonin reuptake inhibitor (Quintana, Butterbaugh,
Purnell, & Layman, 2007) have been reported to be somewhat effective treating patients suffering from ADHD, we
hypothesized that agomelatine might improve some symptoms ofADHD. V/e didirot find any systematic study reporting a possible efficacy of agomelatine for ADHD.
lsachsisches

Krankenhaus, Rodewisch, Germany

Corresponding Authon
Helmut Niederhofer, Department of Child and Adolescent Psychiatry,

poor (Firestone, 1982)

Sachsisches Krankenhaus, D-08228, Rodewisch, Germany

effects.

Email:


Niederhoỵr

347

Table l. Agomelatine's Effects on ADHD
Item
Fidgety

Subscales

Placebo Agomelatine t
t.82

Restlessness

t.s4

0.64
0.87

Disruptive Sounds
Frustration

t.88

0.45

Anxiety
Excessive Energy
Finish Projeca

Disattention
Rejection
Lack of Cooperation
Rigidity

Headaches and stomach

2.t6

l.t2

t.08
t.24

0.34
t.27
t.47
t.36
0.72

2.22
2.48
1.34

0.93

o.7

t.il

0.14

t

Þ

3.24 .03
2.| .U
3.56 .03
3.67 .04
3.98 .U
3.24 .05
3. t6
.03

2.37 .04
3.57 .03
1.39 .04
2.12 .04

We studied a possible benefit of agomelatine in l0 participants ranging in age from 17 to 19 yeaß (M = l7.l

years); 8 were male, and2 were female. All participants met
Diagnostic and Statistical Manual of Mental Disorders (3rd
ed., revised; DSM-III-R;American psychiatric Association,
1987) criteria for ADHD. The participants were derived

from our clinic. This was a population of middle-class,
motivated, and cooperative participants of socioeconomic
status Levels II through IV. Participants gave informed consent verbally and in writing after reviewing the potential
benefits, side effects, and investigational nature of the use
of this available medication.

Participants were evaluated using ratings of ADHDspcctrum behaviors developed by Ward, Wender, and
Reimhen (1993). Follow-up measures using the same ratings were administered approximately I month after treatment. In addition tq the preexisting medication with MpH
or atomoxetine, respectively, four male and one female
patient received agomelatine for 4 weeks (dosage = 25 mE,
administered once a day by oral administration of tablets)
and four male and one female patient received placebo. The
patients did not receive any other medication.

Dependent measures consisted

of the ADHD

factor

scores. We wanted to clarify the most specific pattems of
change induced by this new treatment. Statistical analysis
used paired-sample / tests.
Patients reported a significant improvement in function-

ing, evident in the overall average score on the 60-item
Wender-Utah Questionnaire (items, asking about disattention and hyperactivity, have to be answered with 3 = /es or
0 = no). The mean score before medication was l.16 compared with the mean score of 0.84 on agomelatine
ỵlacebo:
l.22before medication and 1.07 under medication), indicating that patients had significantly fewer ADÍ{D symptoms
during treatment.
The scores on the individual behavioral items demonstrated agomelatine's specific effects (Table l). Participants
did not experience any clinically significant changes in blood
pressure. None were consequently dropped from treatment.

the frrst 2 weeks and th
who had mild episodes.
and continue treatrnent.
tional focus and behavioral control stemming from MpH in
patients who are severely overactive and distractible.
This observation indicates that agomelatine is a benefi_

cial and useful treatment of ADHD. The major beneficial
effects of agomelatine are in behaviors reflecting high lev_
els of arousal and activity and in cognitive aspects of inhibi_

tion and

selective attention. Agomelatine reduces

hyperactivity and enhances frushation tolerance and affect
modulation. It appears to facilitate voluntary selective pro_
cesses essential to willful cognition and discriminant atten_
tion. These patients appear to benefit from agomelatine by
exhibiting decreased irritability and enhanced affect regula_
tion. A remarkable finding from this open trial of agomela_
tine was the scarcity of side effects observed in the patients

after treatment. The predominant behavioral effects of
calming and improved frustration tolerance occurring at the
expense of only slight sedation appear most beneficial in
highly aroused, irritable, hyperactive patients. In particular,
a wide spectrum of ADHD patients with associated oppositional defiant behavior may respond preferentially to
agomelatine. Studies in process will determine the age as
well as diagnostic and personality profiles of patients with
optimal response to agomelatine relative to MpH and clonidine. Compared with clonidine, agomelatine appears less
sedating and longer acting. Compared with MpH, agomelatine may be more effective on activity, low frustration tolerance, and high arxiety. Also, ADHD patients may respond
better to a combination of agomelatine and MpH than to
either medication alone.
Mechanistic sh¡dies should be undertaken in ADHD patients
and in nonhuman prirrntes to further clarify the neural
mechanisms underlying the effects of agomelatine. Given
the large number of individual patients and adults affected
by ADHD and related problems, there appears to be substantial potential benefit from using agomelatine in the treatment of ADHD-spectrum disorders.

Declaration of Conflicting lnterests
The author(s) declared no potential conflicts ofinterest with respect
to the research, authorship, and/or publication

ofthis article.

Funding
The author(s) received no financial support for the research,
authorship, and,/or publication of this article.

References
American Psychiatric Association. (1987). Diagnostic and statistícal manual of mental dßorders (3rd ed., revised). Washington,
DC: Author.
Biederman, J., Newcorn, J., & Sprich, S. (1991). Comorbidity of
attention dehcit hyperactivity disorder with conduct, depressive,


of Anention Disorders I

r48,su-s77.
Faraone, S. V., Biederman, J., Keenan, K., & Tsuang, M. T.
(1991). Separation of DSMJII attention deficit disorder and

conduct disorder: Evidence from a family-genetic study of
American child psychiatric patients. Psychological Medicine,

21,109-121.
Firestone, P. (1982). Factors associated with patients' adherence
to stimulant medication. American Journal of Orthopsychia-

try, 52,447-457.
Gualtieri, C. T., Golden, R. N., & Fahs, J. J. (1983). New developments in pediahic psychopharmacology. Journal of Developmenlal and Behavioral Pediatrics, 4, 202-209.
Hunt, R. D. (1987). Treatment effects of oral and transdermal

clonidine in relation to metỵlphenidate: An open pilot study
in õDD-H. Psychopharmacologt Bulletớn, I 2 3, ll l-114.
Hunt, R. D. (1988). Attention deficit disorder: Diagnosis, assessment and treatment. ln C. Kestenbaum & D. Williams (Eds.),
Handbook of clinical assessment of patients and adolescents :
A biopsychosocial approach (Vol. II, pp. 519-561). New York,

NY: New York University Press.
Hunt, R. D., Minderaa, R. 8., & Cohen, D. J. (1985). Clonidine
benefits patients with attention deficit disorder and hyperactivity: Report of a double-blind placebo-controlled crossover
stludy. Journal of the Amerícan Academy of Chíld Psychiatry,

24,617-629.

Quintana, H., Butterbaugh, G. J., Pumell, V/., & Layman, A. K.
(2007). Fluoexitine monotherapy in attention-dehcit/hyperactivity disorder and comorbid non-bipolar mood disorders in
children and adolescents. Child Psychiatry and Human Development, 37,241-253.
Rapport, M. D., Denney, C., DuPaul, G. J., & Gardner, M. J. (1994).

Attention deficit disorder and methylphenidate: Normalization rates, clinical effectiveness, and response prediction in 76
patienls. Journal of the American Academy of Child Psychiatry,
-t3, 882-893.

Ward, M. F., Wender, P. H., & Reimherr, F. rW. (1993). The
Wender Utah Rating Scale: Än aid in tbe retrospective diagnosis of childhood attention deficit hyperactivity disorder.
American Journal of Psychiatry, 150,885-890.

Bio
Helmut Niederhofer, MD, PhD, was born in the year 1966 in
Vienna, Austria. He finished his high school in Vienna and then
studied medicine and psychology at Vienna University Medical

School from 1984 to 1990. He specialized in general medicine
(1991-1993), neurology and psychiatry (199+-2000), and child
and adolescent psychiatry (2001-2006) from Innsbruck
(Austria), Bolzano (Italy), and Munich University Medical
School (Germany), respectively. He is the director of the Depart-

ment

of Child and Adolescent

Psychiatry

at

Sachsisches

Krankenhaus.

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anxiety, and other disorders. American Journal of Psychiatry,