Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents—meta-analysis and meta-regression analysis

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Objectives

The objective of this study was to evaluate the efficacy and safety of atomoxetine in children and adolescents.

Materials and methods

We searched for studies published between 1985 and 2006 through Medline, PubMed, PsychInfo and Cochrane Central Register of Controlled Trials (CENTRAL 2006 Issue 3) using keywords related to atomoxetine and attention-deficit/hyperactivity disorder (ADHD) and scanned though reference lists. We included nine randomized placebo-controlled trials (atomoxetine:placebo = 1,150:678).

Results

Atomoxetine was superior (p < 0.01) to placebo in reducing ADHD symptoms across different scales (Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Conners’ Parent and Teacher Rating Scales-Revised:Short Form, Clinical Global Impression-Severity) rated by different raters (parent, teacher, clinician). The number-needed-to-treat (NNTs) for treatment response and relapse prevention were 3.43 (95% CI, 2.79–4.45) and 10.30 (95% CI, 5.89–40.62), respectively. High baseline ADHD symptoms (p = 0.02) was associated with greater reduction in ADHD symptoms, whereas male gender (p = 0.02), comorbid oppositional defiant disorder (ODD) status (p = 0.01) and ADHD hyperactive/impulsive subtype (p = 0.01) were associated with smaller reductions. The commonest adverse events were gastrointestinal [appetite decrease, number-needed-to-harm (NNH) = 8.81; abdominal pain, NNH = 22.48; vomiting, NNH = 29.96; dyspepsia, NNH = 49.38] and sleep related (somnolence, NNH = 19.41). Young age (p = 0.03) and high baseline hyperactive/impulsive symptoms (p < 0.01) were associated with more adverse events, whereas ADHD inattentive subtype (p = 0.04) was associated with less adverse events. Quality of life using Child Health Questionnaire (CHQ) improved (p < 0.01) with atomoxetine treatment. Both ADHD and ODD symptoms (p < 0.01) were reduced in comorbid ADHD+ODD, and ODD status was not associated with more adverse events. Efficacy and side effects were not altered by comorbid general anxiety disorder or major depression.

Conclusions

Atomoxetine is efficacious in reducing ADHD symptoms. It may have a role in treating comorbid ODD or depression, and probably in comorbid anxiety.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Notes

  1. Drug name: Generic name (Trade name): Atomoxetine (Strattera)

Abbreviations

ADHD:

attention-deficit/hyperactivity disorder

OR:

odds ratio

NNH:

number-needed-to-harm

NNT:

number-needed-to-treat

References

  • Bagwell CL, Molina BS, Pelham WE et al (2001) Attention-deficit hyperactivity disorder and problems in peer relations: predictions from childhood to adolescence. J Am Acad Child Adolesc Psychiatry 40:1285–1292

    Article  PubMed  CAS  Google Scholar 

  • Banaschewski T, Coghill D, Santosh P, Zuddas A, Asherson P, Buitelaar J, Danckaerts M, Dopfner M, Faraone SV, Rothenberger A, Sergeant J, Steinhausen HC, Sonuga-Barke EJ, Taylor E (2006) Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline. Eur Child Adolesc Psychiatry 15(8):476–495

    Article  PubMed  Google Scholar 

  • Biederman J, Newcorn J, Sprich S (1991) Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 148:564–577

    PubMed  CAS  Google Scholar 

  • Biederman J, Baldessarini RJ, Wright V et al (1993) A double blind placebo controlled study of desipramine in the treatment of ADD, III: lack of impact of comorbidity and family history factors on clinical response. J Am Acad Child Adolesc Psychiatry 32:199–204

    Article  PubMed  CAS  Google Scholar 

  • Biederman J, Heiligenstein JH, Faries DE, Galil N, Dittmann R, Emslie GJ, Kratochvil CJ, Laws HF, Schuh KJ (2002) Atomoxetine ADHD study group. Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder. Pediatrics 110(6):e75

    Article  PubMed  Google Scholar 

  • Biederman J, Wigal SB, Spencer TJ, McGough JJ, Mays DA (2006) A post hoc subgroup analysis of an 18-day randomized controlled trial comparing the tolerability and efficacy of mixed amphetamine salts extended release and atomoxetine in school-age girls with attention-deficit/hyperactivity disorder. Clin Ther 28(2):280–293

    Article  PubMed  CAS  Google Scholar 

  • Biederman J, Spencer TJ, Newcorn JH, Gao H, Milton DR, Feldman PD, Witte MM (2007) Effect of comorbid symptoms of oppositional defiant disorder on responses to atomoxetine in children with ADHD: a meta-analysis of controlled clinical trial data. Psychopharmacology 190(1):31–41

    Article  PubMed  CAS  Google Scholar 

  • Buitelaar JK, Michelson D, Danckaerts M, Gillberg C, Spencer TJ, Zuddas A, Faries DE, Zhang S, Biederman J (2006) A randomized, double-blind study of continuation treatment for attention-deficit/hyperactivity disorder after 1 year. Biol Psychiatry 61(5):694–699

    Article  PubMed  CAS  Google Scholar 

  • Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27(5):699–711

    Article  PubMed  CAS  Google Scholar 

  • Conners CK (1997) Conners’ rating scales: revised technical manual. Multi-Health Systems, North Towanda, New York

    Google Scholar 

  • Diamond IR, Tannock R, Schachar RJ (1999) Response to methylphenidate in children with ADHD and comorbid anxiety. J Am Acad Child Adolesc Psychiatry 38(4):402–409

    Article  PubMed  CAS  Google Scholar 

  • DuPaul GJ, Power TJ, Anastopoulos AD, Reid R (1998) ADHD rating scale-IV: checklists, norms, and cinical interpretations. Guilford, New York

    Google Scholar 

  • Faraone SV, Biederman J, Monuteaux MC et al (2001) A psychometric measure of learning disability predicts educational failure four years later in boys with attention-deficit/hyperactivity disorder. J Atten Disord 4:220–230

    Article  Google Scholar 

  • Gammon GD, Brown TE (1993) Fluoxetine and methylphenidate in combination for treatment of attention deficit and comorbid depressive disorder. J Child Adolesc Psychopharmacol 3:1–10

    PubMed  CAS  Google Scholar 

  • Gaub M, Carlson CL (1997) Gender differences in ADHD: a meta-analysis and critical review. J Am Acad Child Adolesc Psychiatry 36:1036–1045

    Article  PubMed  CAS  Google Scholar 

  • Geddes J, Butler R (2002) Depressive disorders. Clin Evid 7:867–882

    PubMed  Google Scholar 

  • Goldman LS, Genel M, Bezman RJ, Slanetz PJ (1998) Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA 279:1100–1107

    Article  PubMed  CAS  Google Scholar 

  • Greene RW, Biederman J, Faraone SV et al (2001) Social impairment in girls with ADHD: patterns, gender comparisons, and correlates. J Am Acad Child Adolesc Psychiatry 40:704–710

    Article  PubMed  CAS  Google Scholar 

  • Guy W (1976) ECDEU assessment manual for psychopharmacology. US Department of Health, Education, and Welfare, Washington, DC

    Google Scholar 

  • Hazell P, Zhang S, Wolanczyk T, Barton J, Johnson M, Zuddas A, Danckaerts M, Ladikos A, Benn D, Yoran-Hegesh R, Zeiner P, Michelson D (2006) Comorbid oppositional defiant disorder and the risk of relapse during 9 months of atomoxetine treatment for attention-deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry 15(2):105–110

    Article  PubMed  Google Scholar 

  • Heiligenstein J, Wagner K, Casat C et al (2001) Efficacy of atomoxetine vs placebo in school-aged children of the inattentive type. Presented at the 154th annual meeting of the American Psychiatric Association, New Orleans, LA, November 5–10

  • Jensen PS, Hinshaw SP, Kraemer HC, Lenora N, Newcorn JH, Abikoff HB, March JS, Arnold LE, Cantwell DP, Conners CK, Elliott GR, Greenhill LL, Hechtman L, Hoza B, Pelham WE, Severe JB, Swanson JM, Wells KC, Wigal T, Vitiello B (2001) ADHD comorbidity findings from the MTA study: comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry 40:147–158

    Article  PubMed  CAS  Google Scholar 

  • Johnston C, Mash EJ (2001) Families of children with attention-deficit/hyperactivity disorder: review and recommendations for future research. Clin Child Fam Psychol Rev 4:183–207

    Article  PubMed  CAS  Google Scholar 

  • Kaplan S, Heiligenstein J, West S, Busner J, Harder D, Dittmann R, Casat C, Wernicke JF (2004) Efficacy and safety of atomoxetine in childhood attention-deficit/hyperactivity disorder with comorbid oppositional defiant disorder. J Atten Disord 8(2):45–52

    Article  PubMed  CAS  Google Scholar 

  • Kelsey DK, Sumner CR, Casat CD, Coury DL, Quintana H, Saylor KE, Sutton VK, Gonzales J, Malcolm SK, Schuh KJ, Allen AJ (2004) Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial. Pediatrics 114(1):e1–8

    Article  PubMed  Google Scholar 

  • Kemner JE, Starr HL, Ciccone PE, Hooper-Wood CG, Crockett RS (2005) Outcomes of OROS methylphenidate compared with atomoxetine in children with ADHD: a multicenter, randomized prospective study. Adv Ther 22(5):498–512

    PubMed  CAS  Google Scholar 

  • Kratochvil CJ, Bohac D, Harrington M, Baker N, May D, Burke WJ (2001) An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 11(2):167–170

    Article  PubMed  CAS  Google Scholar 

  • Kratochvil CJ, Newcorn JH, Arnold LE, Duesenberg D, Emslie GJ, Quintana H, Sarkis EH, Wagner KD, Gao H, Michelson D, Biederman J (2005) Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms. J Am Acad Child Adolesc Psychiatry 44(9):915–924

    Article  PubMed  Google Scholar 

  • Kratochvil CJ, Wilens TE, Greenhill LL, Gao H, Baker KD, Feldman PD, Gelowitz DL (2006) Effects of long-term atomoxetine treatment for young children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 45(8):919–927

    Article  PubMed  Google Scholar 

  • Landgraf JM, Abetz L, Ware JE (1996) The CHQ user’s manual, 1st edn. The Health Institute, New England Medical Center, Boston

    Google Scholar 

  • Leucht S, Pitschel-Walz G, Abraham D, Kissling W (1999) Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res 35:51–68

    Article  PubMed  CAS  Google Scholar 

  • Lim JR, Faught PR, Chalasani NP, Molleston JP (2006) Severe liver injury after initiating therapy with atomoxetine in two children. J Pediatr 148(6):831–834

    Article  PubMed  Google Scholar 

  • Livingstone RL, Dykman RA, Ackerman PT (1990) Psychiatric comorbidity and response to two doses of methylphenidate in children with attention deficit disorder. J Child Adolesc Psychopharmacol 2:115–122

    Article  Google Scholar 

  • Maedgen JW, Carlson CL (2000) Social functioning and emotional regulation in the attention-deficit hyperactivity disorder subtypes. J Clin Child Psychol 29:30–42

    Article  PubMed  CAS  Google Scholar 

  • Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, Spencer T (2001) Atomoxetine ADHD Study Group. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose–response study. Pediatrics 108(5):E83

    Article  PubMed  CAS  Google Scholar 

  • Michelson D, Allen AJ, Busner J, Casat C, Dunn D, Kratochvil C, Newcorn J, Sallee FR, Sangal RB, Saylor K, West S, Kelsey D, Wernicke J, Trapp NJ, Harder D (2002) Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 159(11):1896–1901

    Article  PubMed  Google Scholar 

  • Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, Kelsey D, Wernicke J, Dietrich A, Milton D (2003) Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry 53(2):112–120

    Google Scholar 

  • Michelson D, Buitelaar JK, Danckaerts M, Gillberg C, Spencer TJ, Zuddas A, Faries DE, Zhang S, Biederman J (2004) Relapse prevention in pediatric patients with ADHD treated with atomoxetine: a randomized, double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 43(7):896–904

    Article  PubMed  Google Scholar 

  • Newcorn JH, Spencer TJ, Biederman J, Milton DR, Michelson D (2005) Atomoxetine treatment in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry 44(3):240–248

    Article  PubMed  Google Scholar 

  • Pataki CS, Carlson GA, Kelly KL et al (1993) Side effects of methylphenidate and desipramine alone and in combination in children. J Am Acad Child Adolesc Psychiatry 32:1065–1072

    Article  PubMed  CAS  Google Scholar 

  • Perneger TV (1998) What’s wrong with Bonferroni adjustments. BMJ 316:1236–1238

    PubMed  CAS  Google Scholar 

  • Perwien AR, Faries DE, Kratochvil CJ, Sumner CR, Kelsey DK, Allen AJ (2004) Improvement in health-related quality of life in children with ADHD: an analysis of placebo controlled studies of atomoxetine. J Dev Behav Pediatr 25(4):264–271

    Article  PubMed  Google Scholar 

  • Pliszka SR (1989) Effect of anxiety on cognition, behavior and stimulant response in ADHD. J Am Acad Child Adolesc Psychiatry 28:882–887

    Article  PubMed  CAS  Google Scholar 

  • Pliszka SR (1998) Comorbidity of attention-deficit/hyperactivity disorder with psychiatric disorder: an overview. J Clin Psychiatry 59(Suppl 7):50–58

    PubMed  Google Scholar 

  • Quintana H, Butterbaugh GJ, Purnell W, Layman AK (2007) Fluoxetine monotherapy in attention-deficit/hyperactivity disorder and comorbid non-bipolar mood disorders in children and adolescents. Child Psychiatry Hum Dev 37(3):241–253

    Article  PubMed  Google Scholar 

  • Rapport MD, Carlson GA, Kelly KL et al (1993) Methylphenidate and desipramine in hospitalized children, I: separate and combined effects on cognitive function. J Am Acad Child Adolesc Psychiatry 32:333–342

    Article  PubMed  CAS  Google Scholar 

  • Soomro GM (2002) Obsessive–compulsive disorder. Clin Evid 7:896–905

    PubMed  Google Scholar 

  • Spencer T, Biederman J, Wilens T, Prince J, Hatch M, Jones J, Harding M, Faraone SV, Seidman L (1998) Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 155(5):693–695

    PubMed  CAS  Google Scholar 

  • Spencer T, Biederman J, Heiligenstein J, Wilens T, Faries D, Prince J, Faraone SV, Rea J, Witcher J, Zervas S (2001) An open-label, dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 11(3):251–265

    Article  PubMed  CAS  Google Scholar 

  • Spencer T, Heiligenstein JH, Biederman J, Faries DE, Kratochvil CJ, Conners CK, Potter WZ (2002) Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry 63(12):1140–1147

    PubMed  CAS  Google Scholar 

  • Starr HL, Kemner J (2005) Multicenter, randomized, open-label study of OROS methylphenidate versus atomoxetine: treatment outcomes in African-American children with ADHD. J Natl Med Assoc 97(10 Suppl):11S–16S

    PubMed  Google Scholar 

  • Stojanovski SD, Casavant MJ, Mousa HM, Baker P, Nahata MC (2007) Atomoxetine-induced hepatitis in a child. Clin Toxicol 45(1):51–55

    Article  CAS  Google Scholar 

  • Swanson J, Gupta S, Guinta D et al (1999) Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. Clin Pharmacol Ther 66:295–305

    Article  PubMed  CAS  Google Scholar 

  • Tannock R, Schachar R (1992) Is ADHD with comorbid overanxious disorder different from ADHD? In: Comorbidity of ADHD: discriminating features and methodologic problems, Newcorn J (chair). Symposium conducted at the 39th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Washington, DC

  • Tannock R, Ickowicz A, Schachar R (1995) Differential effects of methylphenidate on working memory in ADHD children with and without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 34:886–896

    Article  PubMed  CAS  Google Scholar 

  • Taylor E, Schachar R, Thorley G, Wieselberg HM, Everitt B, Rutter M (1987) Which boys respond to stimulant medication? A controlled trial of MPH in boys with disruptive behavior. Psychol Med 17:121–143

    Article  PubMed  CAS  Google Scholar 

  • The MTA Cooperative Group (1999) Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the Multimodal Treatment Study of children with Attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 56(12):1088–1096

    Article  Google Scholar 

  • Todd RD, Sitdhiraksa N, Reich W et al (2002) Discrimination of DSM-IV and latent class attention-deficit/hyperactivity disorder subtypes by educational and cognitive performance in a population-based sample of child and adolescent twins. J Am Acad Child Adolesc Psychiatry 41:820–828

    Article  PubMed  Google Scholar 

  • Weiss M, Tannock R, Kratochvil C, Dunn D, Velez-Borras J, Thomason C, Tamura R, Kelsey D, Stevens L, Allen AJ (2005) A randomized, placebo-controlled study of once-daily atomoxetine in the school setting in children with ADHD. J Am Acad Child Adolesc Psychiatry 44(7):647–655

    Article  PubMed  Google Scholar 

  • Wilens TE, Newcorn JH, Kratochvil CJ, Gao H, Thomason CK, Rogers AK, Feldman PD, Levine LR (2006) Long-term atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder. J Pediatr 149(1):112–119

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank Dr. TP Ho for his comments on this manuscript.

Declaration of competing interests

All authors: None declared.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong

    Jackie Y. W. Cheng, Ronald Y. L. Chen, John S. N. Ko & Emil M. L. Ng

  2. Department of Psychiatry, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, SAR, Hong Kong

    Jackie Y. W. Cheng

Authors
  1. Jackie Y. W. Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronald Y. L. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John S. N. Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emil M. L. Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jackie Y. W. Cheng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, J.Y.W., Chen, R.Y.L., Ko, J.S.N. et al. Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents—meta-analysis and meta-regression analysis. Psychopharmacology 194, 197–209 (2007). https://doi.org/10.1007/s00213-007-0840-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0840-x

Keywords

Search

Navigation