AZD3480, a Novel Nicotinic Receptor Agonist, for the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults


      Laboratory studies have found that acute stimulation of nicotinic acetylcholine receptors improves cognition in adult attention-deficit/hyperactivity disorder (ADHD). Clinical trials of nicotinic agonists have been mixed, underscoring the need to understand the mechanisms for individual differences in clinical response. Using cognitive models within a clinical trial framework may provide insight into these differences.


      This was a within-subjects, randomized, placebo-controlled double-blind trial of the nicotinic agonist AZD3480 (also termed TC-1734) at doses of 5 mg and 50 mg and placebo in adults with ADHD. The order of the 2-week treatment periods was randomized, and a 3-week wash out separated each drug treatment period. Response inhibition (Stop Signal Task [SST]) and clinical efficacy (Investigator Rated Conners Adult ADHD Rating Scale [CAARS-INV]) were the a priori primary outcome measures of cognitive and clinical effects. We hypothesized that AZD3480 treatment would improve SST performance and clinical symptoms (CAARS-INV Total ADHD Symptoms Score).


      Thirty subjects were randomized, with 24 included in the intent-to-treat analyses. SST performance and total ADHD symptoms were significantly improved with 50 mg of AZD3480. CAARS-INV ratings of inattention, memory problems, and emotional lability/impulsivity were significantly improved with 50 mg of AZD3480.


      These results support previous work suggesting that nicotinic agonists are viable as treatments for adult ADHD. Measuring cognitive endophenotypes related to both the disorder and mechanism of treatment may help further rational drug development for dimensional features that cross-cut psychiatric disorders.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Barkley RA
        • Fischer M
        • Smallish L
        • Fletcher K
        The persistence of attention-deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder.
        J Abnorm Psychol. 2002; 111: 279-289
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision..
        American Psychiatric Association, Washington, DC2000
        • Biederman J.
        • Faraone S.V.
        • Spencer T.
        • Wilens T.
        • Norman D.
        • Lapey K.A.
        • et al.
        Patterns of psychiatric comorbidity, cognition, and psychosocial functioning in adults with attention deficit hyperactivity disorder.
        Am J Psychiatry. 1993; 150: 1792-1798
        • Faraone S.V.
        • Biederman J.
        • Spencer T.
        • Wilens T.
        • Seidman L.J.
        • Mick E.
        • et al.
        Attention-deficit/hyperactivity disorder in adults: an overview.
        Biol Psychiatry. 2000; 48: 9-20
        • Hervey A.S.
        • Epstein J.N.
        • Curry J.F.
        Neuropsychology of adults with attention-deficit/hyperactivity disorder: a meta-analytic review.
        Neuropsychology. 2004; 18: 485-503
        • Lieberman J.A.
        • Javitch J.A.
        • Moore H.
        Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry.
        Am J Psychiatry. 2008; 165: 931-936
        • Doyle A.E.
        • Faraone S.V.
        • Seidman L.J.
        • Willcutt E.G.
        • Nigg J.T.
        • Waldman I.D.
        • et al.
        Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD?.
        J Child Psychol Psychiatry. 2005; 46: 774-803
        • Durston S.
        • de Zeeuw P.
        • Staal W.G.
        Imaging genetics in ADHD: A focus on cognitive control.
        Neurosci Biobehav Rev. 2009; 33: 674-689
        • Nigg J.T.
        • Blaskey L.G.
        • Stawicki J.A.
        • Sachek J.
        Evaluating the endophenotype model of ADHD neuropsychological deficit: Results for parents and siblings of children with ADHD combined and inattentive subtypes.
        J Abnorm Psychol. 2004; 113: 614-625
        • Slaats-Willemse D.I.
        • Swaab-Barneveld H.
        • de Sonneville L.
        • van der Meulen E.
        • Buitelaar J.
        Deficient response inhibition as a cognitive endophenotype of ADHD.
        J Am Acad Child Adolesc Psychiatry. 2003; 42: 1242-1248
        • Willcutt E.G.
        • Doyle A.E.
        • Nigg J.T.
        • Faraone S.V.
        • Pennington B.F.
        Validity of the executive function theory of attention-deficit/hyperactivity disorder: A meta-analytic review.
        Biol Psychiatry. 2005; 57: 1336-1346
        • Seidman L.J.
        • Biederman J.
        • Faraone S.V.
        • Milberger S.
        • Norman D.
        • Seiverd K.
        • et al.
        Effects of family history and comorbidity on the neuropsychological performance of children with ADHD: Preliminary findings.
        J Am Acad Child Adolesc Psychiatry. 1995; 34: 1015-1024
        • Crosbie J.
        • Schachar R.
        Deficient inhibition as a marker for familial ADHD.
        Am J Psychiatry. 2001; 158: 1884-1890
        • Aron A.R.
        • Poldrack R.A.
        The cognitive neuroscience of response inhibition: Relevance for genetic research in attention-deficit/hyperactivity disorder.
        Biol Psychiatry. 2005; 57: 1285-1292
        • Jorgensen J.T.
        Are we approaching the post-blockbuster era? Pharmacodiagnostics and rational drug development.
        Exp Rev Mol Diagn. 2008; 8: 689-695
        • Greenhill L.L.
        • Perel J.M.
        • Rudolph G.
        • Feldman B.
        • Curran S.
        • Puig-Antich J.
        • et al.
        Correlations between motor persistence and plasma levels in methylphenidate-treated boys with ADHD.
        Int J Neuropsychopharmacol. 2001; 4: 207-215
        • Swanson J.M.
        • Wigal S.
        • Greenhill L.L.
        • Browne R.
        • Waslik B.
        • Lerner M.
        • et al.
        Analog classroom assessment of Adderall in children with ADHD.
        J Am Acad Child Adolesc Psychiatry. 1998; 37: 519-526
        • Fischer M.
        • Barkley R.A.
        • Edelbrock C.S.
        • Smallish L.
        The adolescent outcome of hyperactive children diagnosed by research criteria: II. Academic, attentional, and neuropsychological status.
        J Consult Clin Psychol. 1990; 58: 580-588
        • Durston S.
        A review of the biological bases of ADHD: What have we learned from imaging studies?.
        Ment Retard Dev Disabil Res Rev. 2003; 9: 184-195
        • Potter A.S.
        • Newhouse P.A.
        • Bucci D.J.
        Central nicotinic cholinergic systems: A role in the cognitive dysfunction in attention-deficit/hyperactivity disorder?.
        Behav Brain Res. 2006; 175: 201-211
        • Pomerleau O.F.
        • Downey K.K.
        • Stelson F.W.
        • Pomerleau C.S.
        Cigarette smoking in adult patients diagnosed with attention deficit hyperactivity disorder.
        J Subst Abuse. 1995; 7: 373-378
        • Milberger S.
        • Biederman J.
        • Faraone S.V.
        • Chen L.
        • Jones J.
        ADHD is associated with early initiation of cigarette smoking in children and adolescents.
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 37-44
        • Lambert N.M.
        • Hartsough C.S.
        Prospective study of tobacco smoking and substance dependencies among samples of ADHD and non-ADHD participants [see comment].
        J Learning Disabil. 1998; 31: 533-544
        • Lerman C.
        • Audrain J.
        • Tercyak K.
        • Hawk Jr, L.W.
        • Bush A.
        • Crystal-Mansour S.
        • et al.
        Attention-deficit hyperactivity disorder (ADHD) symptoms and smoking patterns among participants in a smoking-cessation program.
        Nicotine Tob Res. 2001; 3: 353-359
        • Wilens T.E.
        • Vitulano M.
        • Upadhyaya H.
        • Adamson J.
        • Sawtelle R.
        • Utzinger L.
        • et al.
        Cigarette smoking associated with attention deficit hyperactivity disorder.
        J Pediatr. 2008; 153: 414-419
        • Kollins S.H.
        • McClernon F.J.
        • Fuemmeler B.F.
        Association between smoking and attention-deficit/hyperactivity disorder symptoms in a population-based sample of young adults.
        Arch Gen Psychiatry. 2005; 62: 1142-1147
        • Levin E.D.
        • Rezvani A.H.
        Nicotinic treatment for cognitive dysfunction.
        Curr Drug Targets CNS Neurol Disord. 2002; 1: 423-431
        • Newhouse P.A.
        • Potter A.
        • Singh A.
        Effects of nicotinic stimulation on cognitive performance.
        Curr Opin Pharmacol. 2004; 4: 36-46
        • Sacco K.A.
        • Bannon K.L.
        • George T.P.
        Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders.
        J Psychopharmacol. 2004; 18: 457-474
        • Levin E.D.
        • McClernon F.J.
        • Rezvani A.H.
        Nicotinic effects on cognitive function: Behavioral characterization, pharmacological specification, and anatomic localization.
        Psychopharmacology. 2006; 184: 523-539
        • Levin E.D.
        • Conners C.K.
        • Sparrow E.
        • Hinton S.C.
        • Erhardt D.
        • Meck W.H.
        • et al.
        Nicotine effects on adults with attention-deficit/hyperactivity disorder.
        Psychopharmacology (Berl). 1996; 123: 55-63
        • Singh A.
        • Potter A.
        • Newhouse P.
        Nicotinic acetylcholine receptor system and neuropsychiatric disorders.
        IDrugs. 2004; 7: 1096-1103
        • Wilens T.E.
        • Spencer T.J.
        • Biederman J.
        A review of the pharmacotherapy of adults with attention-deficit/hyperactivity disorder.
        J Atten Disord. 2002; 5: 189-202
        • Conners C.K.
        • Levin E.D.
        • Sparrow E.
        • Hinton S.C.
        • Erhardt D.
        • Meck W.H.
        • et al.
        Nicotine and attention in adult attention deficit hyperactivity disorder (ADHD).
        Psychopharmacol Bull. 1996; 32: 67-73
        • Gehricke J.G.
        • Hong N.
        • Whalen C.K.
        • Steinhoff K.
        • Wigal T.L.
        Effects of transdermal nicotine on symptoms, moods, and cardiovascular activity in the everyday lives of smokers and nonsmokers with attention-deficit/hyperactivity disorder.
        Psychol Addict Behav. 2009; 23: 644-655
        • Poltavski D.V.
        • Petros T.
        Effects of transdermal nicotine on attention in adult non-smokers with and without attentional deficits.
        Physiol Behav. 2006; 87: 614-624
        • Potter A.S.
        • Newhouse P.A.
        Acute nicotine improves cognitive deficits in young adults with attention-deficit/hyperactivity disorder.
        Pharmacol Biochem Behav. 2008; 88: 407-417
        • Potter A.S.
        • Newhouse P.A.
        Effects of acute nicotine administration on behavioral inhibition in adolescents with attention-deficit/hyperactivity disorder.
        Psychopharmacology (Berl). 2004; 176: 182-194
        • Shytle R.D.
        • Silver A.A.
        • Wilkinson B.J.
        • Sanberg P.R.
        A pilot controlled trial of transdermal nicotine in the treatment of attention deficit hyperactivity disorder.
        World J Biol Psychiatry. 2002; 3: 150-155
        • Wilens T.E.
        • Decker M.W.
        Neuronal nicotinic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: Focus on cognition.
        Biochem Pharmacol. 2007; 74: 1212-1223
        • Wilens T.E.
        • Biederman J.
        • Spencer T.J.
        • Bostic J.
        • Prince J.
        • Monuteaux M.C.
        • et al.
        A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder.
        Am J Psychiatry. 1999; 156: 1931-1937
        • Wilens T.E.
        • Verlinden M.H.
        • Adler L.A.
        • Wozniak P.J.
        • West S.A.
        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. 2006; 59: 1065-1070
        • Wilens T.E.
        • Biederman J.
        • Wong J.
        • Spencer T.J.
        • Prince J.B.
        Adjunctive donepezil in attention deficit hyperactivity disorder youth: Case series.
        J Child Adolesc Psychopharmacol. 2000; 10: 217-222
        • Biederman J.
        • Mick E.
        • Faraone S.
        • Hammerness P.
        • Surman C.
        • Harpold T.
        • et al.
        A double-blind comparison of galantamine hydrogen bromide and placebo in adults with attention-deficit/hyperactivity disorder: A pilot study.
        J Clin Psychopharmacol. 2006; 26: 163-166
        • Wilens T.E.
        • Waxmonsky J.
        • Scott M.
        • Swezey A.
        • Kwon A.
        • Spencer T.J.
        • et al.
        An open trial of adjunctive donepezil in attention-deficit/hyperactivity disorder.
        J Child Adolesc Psychopharmacol. 2005; 15: 947-955
        • Joober R.
        On the simple and the complex in psychiatry, with reference to DSM 5 and Research Domain Criteria.
        J Psychiatry Neurosci. 2013; 38: 148-151
        • Crosbie J.
        • Arnold P.
        • Paterson A.
        • Swanson J.
        • Dupuis A.
        • Li X.
        • et al.
        Response inhibition and ADHD traits: Correlates and heritability in a community sample.
        J Abnorm Child Psychol. 2013; 31: 497-507
        • Campbell S.B.
        • von Stauffenberg C.
        Delay and inhibition as early predictors of ADHD symptoms in third grade.
        J Abnorm Child Psychol. 2009; 37: 1-15
        • Verte S.
        • Geurts H.M.
        • Roeyers H.
        • Oosterlaan J.
        • Sergeant J.A.
        The relationship of working memory, inhibition, and response variability in child psychopathology.
        J Neurosci Methods. 2006; 151: 5-14
        • Wodushek T.R.
        • Neumann C.S.
        Inhibitory capacity in adults with symptoms of attention deficit/hyperactivity disorder (ADHD).
        Arch Clin Neuropsychol. 2003; 18: 317-330
        • Potter A.S.
        • Bucci D.J.
        • Newhouse P.A.
        Manipulation of nicotinic acetylcholine receptors differentially affects behavioral inhibition in human subjects with and without disordered baseline impulsivity.
        Psychopharmacology (Berl). 2012; 220: 331-340
        • Dunbar G.
        • Boeijinga P.H.
        • Demazieres A.
        • Cisterni C.
        • Kuchibhatla R.
        • Wesnes K.
        • et al.
        Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers.
        Psychopharmacology (Berl). 2007; 191: 919-929
        • Dunbar G.C.
        • Inglis F.
        • Kuchibhatla R.
        • Sharma T.
        • Tomlinson M.
        • Wamsley J.
        Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI).
        J Psychopharmacol. 2007; 21: 171-178
        • Dunbar G.
        • Demazieres A.
        • Monreal A.
        • Cisterni C.
        • Metzger D.
        • Kuchibhatla R.
        • et al.
        Pharmacokinetics and safety profile of ispronicline (TC-1734), a new brain nicotinic receptor partial agonist, in young healthy male volunteers.
        J Clin Pharmacol. 2006; 46: 715-726
        • First M.B.
        • Spitzer R.L.
        • Gibbon M.
        • Williams J.
        Structured Clinical Interview for DSM-IV Axis I DisordersPatient Edition, Version 2.0. New York State Psychiatric Institute, New York1996
        • Kaufman J.
        • Birmaher B.
        • Brent D.
        • Rao U.
        • Flynn C.
        • Moreci P.
        • et al.
        Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL): initial reliability and validity data [see comment].
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 980-988
        • Guy W.
        Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology.
        National Institute of Mental Health, Early Clinical Drug Evaluation, Psychopharmacology Research Branch, Rockville, MD1976: 217-222
        • Conners C.K.
        Clinical use of rating scales in diagnosis and treatment of attention-deficit/hyperactivity disorder.
        Pediatr Clin North Am. 1999; 46 (vi): 857-870
        • Wechsler D.
        Wechsler Abbreviated Scales of Intelligence.
        The Psychological Corporation, San Antonio, TX1999
        • Logan G.D.
        On the ability to inhibit thought and action: A users guide to the stop signal paradigm.
        in: Dagenbach D. Carr T.H. Inhibitory Processes in Attention, Memory and Language. Academic Press, San Diego, CA1994
        • Apostol G.
        • Abi-Saab W.
        • Kratochvil C.J.
        • Adler L.A.
        • Robieson W.Z.
        • Gault L.M.
        • et al.
        Efficacy and safety of the novel alpha(4)beta(2) neuronal nicotinic receptor partial agonist ABT-089 in adults with attention-deficit/hyperactivity disorder: A randomized, double-blind, placebo-controlled crossover study.
        Psychopharmacology (Berl). 2012; 219: 715-725
        • Benjamini Y.
        • Yekutieli D.
        The control of the false discovery rate in multiple testing under dependency.
        Ann Stat. 2001; 29: 1165-1188
        • Perkins K.A.
        Baseline-dependency of nicotine effects: A review.
        Behav Pharmacol. 1999; 10: 597-615
        • Faraone S.V.
        • Glatt S.J.
        A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes.
        J Clin Psychiatry. 2010; 71: 754-763
        • Freedman R.
        • Olincy A.
        • Buchanan R.W.
        • Harris J.G.
        • Gold J.M.
        • Johnson L.
        • et al.
        Initial phase 2 trial of a nicotinic agonist in schizophrenia.
        Am J Psychiatry. 2008; 165: 1040-1047
        • Knott V.
        • Mohr E.
        • Mahoney C.
        • Engeland C.
        • Ilivitsky V.
        Effects of acute nicotine administration on cognitive event-related potentials in tacrine-treated and non-treated patients with Alzheimer’s disease.
        Neuropsychobiology. 2002; 45: 156-160
        • Potter A.S.
        • Ryan K.K.
        • Newhouse P.A.
        Effects of acute ultra-low dose mecamylamine on cognition in adult attention-deficit/hyperactivity disorder (ADHD).
        Hum Psychopharmacol. 2009; 24: 309-317
        • Sarter M.
        • Hasselmo M.E.
        • Bruno J.P.
        • Givens B.
        Unraveling the attentional functions of cortical cholinergic inputs: Interactions between signal-driven and cognitive modulation of signal detection.
        Brain Res Rev. 2005; 48: 98-111
        • Solanto M.V.
        • Abikoff H.
        • Sonuga-Barke E.
        • Schachar R.
        • Logan G.D.
        • Wigal T.
        • et al.
        The ecological validity of delay aversion and response inhibition as measures of impulsivity in AD/HD: A supplement to the NIMH multimodal treatment study of AD/HD.
        J Abnorm Child Psychol. 2001; 29: 215-228
        • Sarter M.
        • Parikh V.
        • Howe W.M.
        nAChR agonist-induced cognition enhancement: Integration of cognitive and neuronal mechanisms.
        Biochem Pharmacol. 2009; 78: 658-667
        • Sarter M.
        • Parikh V.
        • Howe W.M.
        Phasic acetylcholine release and the volume transmission hypothesis: Time to move on.
        Nat Rev Neurosci. 2009; 10: 383-390