Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of the novel α4β2 neuronal nicotinic receptor partial agonist ABT-089 in adults with attention-deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled crossover study

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

Abstract

Rationale

α4β2 Neuronal nicotinic receptors (NNRs) are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD).

Objectives

This study examined the efficacy and safety of the α4β2 NNR partial agonist ABT-089 versus placebo in adults with ADHD.

Methods

In this multicenter, randomized, double-blind, placebo-controlled crossover study, subjects received placebo followed by ABT-089 (2 mg once daily [QD], 5 mg QD, 15 mg QD, 40 mg QD, or 40 mg twice daily [BID]), or vice versa, in a 2 × 2 crossover design. Each treatment period was 4 weeks, separated by a 2-week washout period. The primary efficacy endpoint was the Conners’ Adult ADHD Rating Scale–Investigator Rated (CAARS:Inv) total score at the end of each treatment period. Secondary outcomes based on clinician- and self-rated efficacy scales were evaluated.

Results

Of the 221 subjects enrolled, 171 met criteria for inclusion in the completers dataset for efficacy analyses. ABT-089 was superior to placebo on the CAARS:Inv total score at 40 mg QD and 40 mg BID (model-based least square mean difference from placebo: −4.33, P = 0.02; −3.02, P = 0.03, respectively). ABT-089 also demonstrated significant improvements on several secondary measures of efficacy. ABT-089 was generally safe and well tolerated. The most commonly reported adverse events (≥5%) for total ABT-089-treated subjects at rates higher than placebo were headache, upper respiratory tract infection, irritability, insomnia, and nasopharyngitis.

Conclusions

In this phase 2 crossover study, the NNR partial agonist ABT-089, at doses of 40 mg QD and 40 mg BID, was efficacious and generally well tolerated in treatment of adults with ADHD.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Adler L, Spencer T (2004). The Adult ADHD Clinical Diagnostic Scale (ACDS) V 1.2. New York: New York University School of Medicine

  • Adler LA, Spencer T, Faraone SV, Reimherr FW, Kelsey D, Michelson D, Biederman J (2005) Training raters to assess adult ADHD: reliability of ratings. J Atten Disord 8:121–126

    Article  PubMed  Google Scholar 

  • Adler LA, Goodman DW, Kollins SH, Weisler RH, Krishnan S, Zhang Y, Biederman J (2008) Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry 69:1364–1373

    Article  PubMed  CAS  Google Scholar 

  • Adler LA, Liebowitz M, Kronenberger W, Qiao M, Rubin R, Hollandbeck M, Deldar A, Schuh K, Durell T (2009a) Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder and comorbid social anxiety disorder. Depress Anxiety 26:212–221

    Article  PubMed  CAS  Google Scholar 

  • Adler LA, Spencer T, Brown TE, Holdnack J, Saylor K, Schuh K, Trzepacz PT, Williams DW, Kelsey D (2009b) Once-daily atomoxetine for adult attention-deficit/hyperactivity disorder: a 6-month, double-blind trial. J Clin Psychopharmacol 29:44–50

    Article  PubMed  CAS  Google Scholar 

  • Bain EE, Apostol G, Sangal RB, Robieson WZ, Abi-Saab WM, Saltarelli MD (2009) Safety and efficacy of ABT-089, a novel α4β2 neuronal nicotinic receptor partial agonist, in the treatment of adults with attention-deficit/hyperactivity disorder. Presented at the 56th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Oct. 27–Nov. 1, 2009; Honolulu, Hawaii

  • Biederman J, Wilens TE, Spencer TJ, Adler LA (2007) Diagnosis and treatment of adults with attention-deficit/hyperactivity disorder. CNS Spectr 12(4(Suppl 6)):1–14

    Google Scholar 

  • Brioni JD, Kim DJ, Brodie MS, Decker MW, Arneric SP (1995) ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity. Psychopharmacology (Berl) 119:368–375

    Article  CAS  Google Scholar 

  • Bush G, Frazier JA, Rauch SL, Seidman LJ, Whalen PJ, Jenike MA, Rosen BR, Biederman J (1999) Anterior cingulate cortex dysfunction in attention-deficit/hyperactivity disorder revealed by fMRI and the Counting Stroop. Biol Psychiatry 45:1542–1552

    Article  PubMed  CAS  Google Scholar 

  • Castellanos FX, Giedd JN, Eckburg P, Marsh WL, Vaituzis AC, Kaysen D, Hamburger SD, Rapoport JL (1994) Quantitative morphology of the caudate nucleus in attention deficit hyperactivity disorder. Am J Psychiatry 151:1791–1796

    PubMed  CAS  Google Scholar 

  • Conners CK, Levin ED, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J (1996) Nicotine and attention in adult attention deficit hyperactivity disorder (ADHD). Psychopharmacol Bull 32:67–73

    PubMed  CAS  Google Scholar 

  • Conners CK, Erhardt D, Sparrow E (1999) Conners’ Adults ADHD Rating Scales (CAARS). Multi-Health Systems, North Tonawanda, NY

    Google Scholar 

  • Faraone SV, Doyle AE, Mick E, Biederman J (2001) Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry 158:1052–1057

    Article  PubMed  CAS  Google Scholar 

  • Giedd JN, Castellanos FX, Casey BJ, Kozuch P, King AC, Hamburger SD, Rapoport JL (1994) Quantitative morphology of the corpus callosum in attention deficit hyperactivity disorder. Am J Psychiatry 151:665–669

    PubMed  CAS  Google Scholar 

  • Guy W (1976) ECDEU assessment manual for psychopharmacology. National Institutes of Mental Health (revised). National Institutes of Mental Health, Rockville, MD

    Google Scholar 

  • Hynd GW, Semrud-Clikeman M, Lorys AR, Novey ES, Eliopulos D (1990) Brain morphology in developmental dyslexia and attention deficit disorder/hyperactivity. Arch Neurol 47:919–926

    Article  PubMed  CAS  Google Scholar 

  • Hynd GW, Hern KL, Novey ES, Eliopulos D, Marshall R, Gonzalez JJ, Voeller KK (1993) Attention deficit-hyperactivity disorder and asymmetry of the caudate nucleus. J Child Neurol 8:339–347

    Article  PubMed  CAS  Google Scholar 

  • Kessler RC, Adler L, Ames M, Barkley RA, Birnbaum H, Greenberg P, Johnston JA, Spencer T, Ustun TB (2005) The prevalence and effects of adult attention deficit/hyperactivity disorder on work performance in a nationally representative sample of workers. J Occup Environ Med 47:565–572

    Article  PubMed  Google Scholar 

  • Lathyris DN, Trikalinos TA, Ioannidis JP (2007) Evidence from crossover trials: empirical evaluation and comparison against parallel arm trials. Int J Epidemiol 36:422–430

    Article  PubMed  Google Scholar 

  • Levin ED, Conners CK, Sparrow E, Hinton SC, Erhardt D, Meck WH, Rose JE, March J (1996) Nicotine effects on adults with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl) 123:55–63

    Article  CAS  Google Scholar 

  • Levin ED, Conners CK, Silva D, Hinton SC, Meck WH, March J, Rose JE (1998) Transdermal nicotine effects on attention. Psychopharmacology (Berl) 140:135–141

    Article  CAS  Google Scholar 

  • Levin ED, McClernon FJ, Rezvani AH (2006) Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl) 184:523–539

    Article  CAS  Google Scholar 

  • Medori R, Ramos-Quiroga JA, Casas M, Kooij JJ, Niemela A, Trott GE, Lee E, Buitelaar JK (2008) A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry 63:981–989

    Article  PubMed  CAS  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 53:112–120

    Article  PubMed  CAS  Google Scholar 

  • Parikh V, Man K, Decker MW, Sarter M (2008) Glutamatergic contributions to nicotinic acetylcholine receptor agonist-evoked cholinergic transients in the prefrontal cortex. J Neurosci 28:3769–3780

    Article  PubMed  CAS  Google Scholar 

  • Potter AS, Newhouse PA (2004) Effects of acute nicotine administration on behavioral inhibition in adolescents with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl) 176:182–194

    Article  CAS  Google Scholar 

  • Potter AS, Newhouse PA, Bucci DJ (2006) Central nicotinic cholinergic systems: a role in the cognitive dysfunction in attention-deficit/hyperactivity disorder? Behav Brain Res 175:201–211

    Article  PubMed  CAS  Google Scholar 

  • Prince J (2008) Catecholamine dysfunction in attention-deficit/hyperactivity disorder: an update. J Clin Psychopharmacol 28:S39–S45

    Article  PubMed  CAS  Google Scholar 

  • Rueter LE, Anderson DJ, Briggs CA, Donnelly-Roberts DL, Gintant GA, Gopalakrishnan M, Lin NH, Osinski MA, Reinhart GA, Buckley MJ, Martin RL, McDermott JS, Preusser LC, Seifert TR, Su Z, Cox BF, Decker MW, Sullivan JP (2004) ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders. CNS Drug Rev 10:167–182

    Article  PubMed  CAS  Google Scholar 

  • Spencer T, Adler L (2004) Diagnostic approaches to adult attention-deficit/hyperactivity disorder. Primary Psychiatry 11:49–53

    Google Scholar 

  • Sullivan JP, Donnelly-Roberts D, Briggs CA, Anderson DJ, Gopalakrishnan M, Xue IC, Piattoni-Kaplan M, Molinari E, Campbell JE, McKenna DG, Gunn DE, Lin NH, Ryther KB, He Y, Holladay MW, Wonnacott S, Williams M, Arneric SP (1997) ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. a potent and selective cholinergic channel modulator with neuroprotective properties. J Pharmacol Exp Ther 283:235–246

    PubMed  CAS  Google Scholar 

  • Targacept (2009) Targacept announces positive top-line results from phase II study of AZD3480 in adult ADHD. http://www.targacept.com/wt/page/pr_1242008964. Accessed 26 October 2010

  • Targacept (2010) Targacept announces top-line results of phase 2 trial of AZD1446 in adults with ADHD and provides update on status of AZD1446 Development Program. http://www.targacept.com/wt/page/pr_1286400140. Accessed October 26, 2010

  • Wang N, Orr-Urtreger A, Korczyn AD (2002) The role of neuronal nicotinic acetylcholine receptor subunits in autonomic ganglia: lessons from knockout mice. Prog Neurobiol 68:341–360

    Article  PubMed  CAS  Google Scholar 

  • Wilens TE, Decker MW (2007) Neuronal nicotinic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: focus on cognition. Biochem Pharmacol 74:1212–1223

    Article  PubMed  CAS  Google Scholar 

  • Wilens TE, Biederman J, Spencer TJ, Bostic J, Prince J, Monuteaux MC, Soriano J, Fine C, Abrams A, Rater M, Polisner D (1999a) A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder. Am J Psychiatry 156:1931–1937

    PubMed  CAS  Google Scholar 

  • Wilens TE, Biederman J, Spencer TJ, Frazier J, Prince J, Bostic J, Rater M, Soriano J, Hatch M, Sienna M, Millstein RB, Abrantes A (1999b) Controlled trial of high doses of pemoline for adults with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol 19:257–264

    Article  PubMed  CAS  Google Scholar 

  • Wilens TE, Verlinden MH, Adler LA, Wozniak PJ, West SA (2006) ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study. Biol Psychiatry 59:1065–1070

    Article  PubMed  CAS  Google Scholar 

  • Wilens TE, Biederman J, Faraone SV, Martelon M, Westerberg D, Spencer TJ (2009) Presenting ADHD symptoms, subtypes, and comorbid disorders in clinically referred adults with ADHD. J Clin Psychiatry 70:1557–1562

    Article  PubMed  Google Scholar 

  • Wilens TE, Gault LM, Childress A, Kratochvil CJ, Bensman L, Hall CM, Olson E, Robieson WZ, Garimella TS, Abi-Saab WM, Apostol G, Saltarelli MD (2011) Safety and efficacy of ABT-089 in pediatric attention-deficit/hyperactivity disorder: results from two randomized placebo-controlled clinical trials. J Am Acad Child Adolesc Psychiatry 50(73–84):e71

    Google Scholar 

  • Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Rumsey J, Hamburger S, Cohen RM (1990) Cerebral glucose metabolism in adults with hyperactivity of childhood onset. N Engl J Med 323:1361–1366

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was funded by Abbott, Abbott Park, IL (NCT 00391729; URL: http://clinicaltrials.gov/ct2/show/NCT00391729?term=M06-855&rank=1). Abbott was involved in original concepts and systematic review of existing trial evidence, the design, the choice of investigators, the control of the allocation schedule, the conduct of the trial, the collection and monitoring of data, the analysis and interpretation, and the writing and approval of this report. The authors have had full control of all primary data and agree to allow the journal to review the data if requested. The authors wish to acknowledge the following investigators for their contributions to this study: Valerie K. Arnold, M.D. (Clinical Neuroscience Solutions, Inc., Memphis, TN); Charles Dean Casat, M.D. (Carolina NeuroSolutions, LLC, Charleston, SC); Jeffrey A. Danziger, M.D. (CORE Research, Inc., Maitland, FL); Mark V. DiBuono, M.D. (Richmond Behavioral Associates, Staten Island, NY); Judith C. Fallon, M.D. (NeuroScience, Inc., Herndon, VA); C. Thomas Gualtieri, M.D. (North Carolina Neuropsychiatry, PA, Chapel Hill, NC); Cynthia Huffman, M.D. (Meridien Research, Tampa, FL); Rakesh Jain, M.D., M.P.H. (R/D Clinical Research, Inc., Lake Jackson, TX); John Mark Joyce, M.D. (Clinical Neuroscience Solutions, Inc., Jacksonville, FL); Vernon L. Kliewer, M.D. (Cientifica, Inc. At Prairie View, Inc., Newton, KS); Jerry C. Steiert, M.D. (Summit Research Network (Seattle), LLC, Seattle, WA); Leslie vH. Taylor, M.D. (Dean Foundation of Health, Research and Education, Middleton, WI); Kathleen Toups, M.D. (Bay Area Research Institute, Lafayette, CA). The authors wish to thank Timothy E. Wilens, M.D., for assistance with study design, rater training, and critical review of the study data and manuscript. The authors also wish to thank the following, all of Abbott, for their contributions to this study: Jennifer Barrett, Dawnelle L. McNeill, and Peter J. Schmitz, M.S. Regula E. Egli, Ph.D., of Abbott, provided technical assistance, copyediting and writing support in the preparation of this manuscript. All experiments reported in this manuscript complied with the current laws of the country in which they were performed.

Disclosures

Drs. Apostol, Abi-Saab, and Saltarelli were employees of Abbott at the time of this study. Dr. Abi-Saab is currently a full-time employee of Novartis Pharma AG, Basel, Switzerland, owns equity in both Abbott and Novartis, and is an inventor on patents from Abbott. Dr. Apostol is currently a full-time employee of and owns equity in Novartis Pharma AG, Basel, Switzerland. Dr. Saltarelli is currently a full-time employee of Shire Pharmaceuticals, Wayne, PA, owns equity in Abbott and Shire, and is an inventor on Abbott and Pfizer patents.

Dr. Kratochvil is supported by National Institute of Mental Health (NIMH) Grant 5K23MH06612701A1; receives grant support from Eli Lilly, Abbott, and Somerset; is a consultant for Eli Lilly, AstraZeneca, Abbott and Pfizer; is Editor of the Brown University Child & Adolescent Psychopharmacology Update and member of the REACH Institute Primary Pediatric Psychopharmacology Steering Committee; receives study drug for an NIMH-funded study from Eli Lilly and Abbott.

Dr. Adler has received grant/research support from Shire, Eli Lilly, National Institute of Drug Abuse, and Chelsea Therapeutics; has served on Advisory Boards and as a consultant for AstraZeneca, Eli Lilly, Major League Baseball, Otsuka, and Shire; as a consultant for i3 Research, INC Research, Epi-Q, and United Biosource Corporation. Dr. Adler has received royalty payments (as inventor) from New York University for license of adult ADHD scales and training materials since 2004.

Dr. Feifel has received speaking/consulting fees and/or research grants from Abbott, Alexza, Addrenex, Astra Zeneca, Bristol Myers Squibb, Danipon-Sumitomo, Eli Lilly, Forest, Janssen, Sanofi, Shire, and Wyeth.

Drs. Robieson, Gault, Pritchett, and Collins are employees of Abbott, and hold equity in and receive salary, stock, stock options and other compensation from Abbott.

Author information

Author notes

  1. George Apostol & Walid Abi-Saab

    Present address: Novartis Pharma AG, Basel, Switzerland

  2. Mario D. Saltarelli

    Present address: Shire Pharmaceuticals, Wayne, PA, USA

Authors and Affiliations

  1. Abbott, 100 Abbott Park Road, Abbott Park, IL, 60064, USA

    George Apostol, Walid Abi-Saab, Weining Z. Robieson, Laura M. Gault, Yili L. Pritchett, Michelle A. Collins & Mario D. Saltarelli

  2. University of Nebraska Medical Center, Omaha, NE, USA

    Christopher J. Kratochvil

  3. New York University School of Medicine and New York VA Harbor Healthcare System, New York, NY, USA

    Lenard A. Adler

  4. University of California, San Diego Medical Center, San Diego, CA, USA

    David Feifel

Authors
  1. George Apostol
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Walid Abi-Saab
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher J. Kratochvil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lenard A. Adler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weining Z. Robieson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laura M. Gault
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yili L. Pritchett
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David Feifel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michelle A. Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mario D. Saltarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura M. Gault.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 72.0 kb)

ESM 2

(DOC 63.5 kb)

ESM 3

(DOC 26.5 kb)

ESM 4

(DOC 51.5 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Apostol, G., Abi-Saab, W., Kratochvil, C.J. et al. Efficacy and safety of the novel α4β2 neuronal nicotinic receptor partial agonist ABT-089 in adults with attention-deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled crossover study. Psychopharmacology 219, 715–725 (2012). https://doi.org/10.1007/s00213-011-2393-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2393-2

Keywords

Search

Navigation