Short Communicotion Journal of Attention Disorders r6(4) 34G348 Treating ADH D with Agomelatine @ 2012 SAGE Publiedons Reprints and permission: sagepub.com/iournalsPermissions.nav DOI: I I 177 I I 0970547 I I 17 400 hapJ/jad,sgepub.com 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: helmut.niederhofer@skhro.sms.sachsen.de 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 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); 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 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 = /es or = 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 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 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 View publication stats anxiety, and other disorders American Journal of Psychiatry, ... 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... disattention and hyperactivity, have to be answered with = /es or = no) The mean score before medication was l.16 compared with the mean score of 0.84 on agomelatine ỵlacebo: l.22before medication and... 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_