Advertisement

Journal of Autism and Developmental Disorders

, Volume 48, Issue 8, pp 2748–2757 | Cite as

An Exploratory Trial of Transdermal Nicotine for Aggression and Irritability in Adults with Autism Spectrum Disorder

  • Alan S. LewisEmail author
  • Gerrit Ian van Schalkwyk
  • Mayra Ortiz Lopez
  • Fred R. Volkmar
  • Marina R. Picciotto
  • Denis G. Sukhodolsky
Original Paper

Abstract

Nicotinic acetylcholine receptors (nAChRs), particularly the α7 nAChR, are implicated in the pathophysiology of both autism spectrum disorder (ASD) and aggressive behavior. We explored the feasibility, tolerability, and preliminary efficacy of targeting nAChRs using transdermal nicotine to reduce aggressive symptoms in adults with ASD. Eight subjects were randomized in a double-blind crossover trial of 7 mg transdermal nicotine or placebo, each for 1 week. All participants tolerated nicotine treatment well. Five subjects contributed data to the primary outcome, Aberrant Behavior Checklist-Irritability (ABC-I) subscale change from baseline, which was improved by nicotine compared to placebo. Sleep ratings were also improved by nicotine and correlated with ABC-I improvement. These findings support further investigation of nAChR agonists for aggression and sleep in ASD.

Keywords

Nicotine Nicotinic acetylcholine receptor Autism spectrum disorder Aggression Irritability Adult Sleep 

Notes

Acknowledgments

This work was supported by Autism Speaks grant #9699 (ASL), National Institutes of Health grants R01DA14241 and R01MH077681 (MRP), R25MH071584, T32MH019961, and T32MH14276 (ASL), and the Child Study Center Associates and the AACAP Pilot Award for General Psychiatry Residents (GIvS). We thank Lawrence Price, Roger Jou, Michael Bloch, and Philip Smith for constructive feedback on this study and Jeffrey Eilbott for technical assistance.

Author Contributions

ASL and GIvS conceived of the study, participated in its design, coordination, and data collection, and drafted the manuscript; MOL participated in the coordination of the study and performed data collection; FRV, MRP, and DGS participated in the design of the study and interpretation of the results. All authors read and approved the final manuscript.

Funding

This work was supported by Autism Speaks grant #9699, National Institutes of Health grants R01DA14241, R01MH077681, R25MH071584, T32MH019961, and T32MH14276, and the Yale Child Study Center Associates and the AACAP Pilot Award for General Psychiatry Residents.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflicts of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

References

  1. Allen, M. H., Debanne, M., Lazignac, C., Adam, E., Dickinson, L. M., & Damsa, C. (2011). Effect of nicotine replacement therapy on agitation in smokers with schizophrenia: A double-blind, randomized, placebo-controlled study. American Journal of Psychiatry, 168, 395–399.  https://doi.org/10.1176/appi.ajp.2010.10040569.CrossRefPubMedGoogle Scholar
  2. Aman, M. G., Singh, N. N., Stewart, A. W., & Field, C. J. (1985). The aberrant behavior checklist: A behavior rating scale for the assessment of treatment effects. American Journal of Mental Deficiency, 89, 485–491.PubMedGoogle Scholar
  3. Arnold, L. E., Aman, M. G., Hollway, J., Hurt, E., Bates, B., Li, X., et al. (2012). Placebo-controlled pilot trial of mecamylamine for treatment of autism spectrum disorders. Journal of child and Adolescent Psychopharmacology, 22, 198–205.  https://doi.org/10.1089/cap.2011.0056.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Baddick, C. G., & Marks, M. J. (2011). An autoradiographic survey of mouse brain nicotinic acetylcholine receptors defined by null mutants. Biochemical Pharmacology, 82, 828–841.  https://doi.org/10.1016/j.bcp.2011.04.019.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bagai, K., & Malow, B. A. (2010). A novel approach to treating morning sleep inertia in narcolepsy. Journal of Clinical Sleep Medicine, 6, 77–78.PubMedPubMedCentralGoogle Scholar
  6. Carmel, H., & Sheitman, B. B. (2007). Adjunctive transdermal nicotine reduced behavioral agitation in severe dementia. The American Journal of Geriatric Psychiatry, 15, 449.  https://doi.org/10.1097/01.JGP.0000235688.05709.e2.CrossRefPubMedGoogle Scholar
  7. Chen, C., Shen, Y. D., Xun, G. L., Cai, W. X., Shi, L. J., Xiao, L., et al. (2017). Aggressive behaviors and treatable risk factors of preschool children with autism spectrum disorder. Autism Research, 10, 1155–1162.  https://doi.org/10.1002/aur.1751.CrossRefPubMedGoogle Scholar
  8. Constantino, J. N., & Gruber, C. P. (2012). Social responsiveness scale: SRS-2 (2nd ed.). Torrance: Western Psychological Services.Google Scholar
  9. Cubells, J. F., DeOreo, E. H., Harvey, P. D., Garlow, S. J., Garber, K., Adam, M. P., et al. (2011). Pharmaco-genetically guided treatment of recurrent rage outbursts in an adult male with 15q13.3 deletion syndrome. American Journal of Medical Genetics Part A, 155A, 805–810.  https://doi.org/10.1002/ajmg.a.33917.CrossRefPubMedGoogle Scholar
  10. Erickson, C. A., Veenstra-Vanderweele, J. M., Melmed, R. D., McCracken, J. T., Ginsberg, L. D., Sikich, L., et al. (2014). STX209 (arbaclofen) for autism spectrum disorders: An 8-week open-label study. Journal of Autism and Developmental Disorders, 44, 958–964.  https://doi.org/10.1007/s10803-013-1963-z.CrossRefPubMedGoogle Scholar
  11. Fankhauser, M. P., Karumanchi, V. C., German, M. L., Yates, A., & Karumanchi, S. D. (1992). A double-blind, placebo-controlled study of the efficacy of transdermal clonidine in autism. The Journal of Clinical Psychiatry, 53, 77–82.PubMedGoogle Scholar
  12. Freedman, R. (2014). alpha7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia. Annual Review of Medicine, 65, 245–261.  https://doi.org/10.1146/annurev-med-092112-142937.CrossRefPubMedGoogle Scholar
  13. Geerts, H. (2012). alpha7 Nicotinic receptor modulators for cognitive deficits in schizophrenia and Alzheimer’s disease. Expert Opinion on Investigational Drugs, 21, 59–65.  https://doi.org/10.1517/13543784.2012.633510.CrossRefPubMedGoogle Scholar
  14. Gillentine, M. A., & Schaaf, C. P. (2015). The human clinical phenotypes of altered CHRNA7 copy number. Biochemical Pharmacology, 97, 352–362.  https://doi.org/10.1016/j.bcp.2015.06.012.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Gillentine, M. A., White, J. J., Grochowski, C. M., Lupski, J. R., Schaaf, C. P., & Calarge, C. A. (2017). CHRNA7 deletions are enriched in risperidone-treated children and adolescents. Journal of Child and Adolescent Psychopharmacology.  https://doi.org/10.1089/cap.2017.0068.PubMedGoogle Scholar
  16. Hill, A. P., Zuckerman, K. E., Hagen, A. D., Kriz, D. J., Duvall, S. W., Van Santen, J., et al. (2014). Aggressive behavior problems in children with autism spectrum disorders: Prevalence and correlates in a large clinical sample. Research in Autism Spectrum Disorders, 8, 1121–1133.  https://doi.org/10.1016/j.rasd.2014.05.006.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hoppman-Chaney, N., Wain, K., Seger, P. R., Superneau, D. W., & Hodge, J. C. (2013). Identification of single gene deletions at 15q13.3: Further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype. Clinical Genetics, 83, 345–351.  https://doi.org/10.1111/j.1399-0004.2012.01925.x.CrossRefPubMedGoogle Scholar
  18. Ji, N., & Findling, R. L. (2015). An update on pharmacotherapy for autism spectrum disorder in children and adolescents. Current Opinion in Psychiatry, 28, 91–101.  https://doi.org/10.1097/YCO.0000000000000132.PubMedGoogle Scholar
  19. Kanne, S. M., & Mazurek, M. O. (2011). Aggression in children and adolescents with ASD: Prevalence and risk factors. Journal of Autism and Developmental Disorders, 41, 926–937.  https://doi.org/10.1007/s10803-010-1118-4.CrossRefPubMedGoogle Scholar
  20. Lewis, A. S., Mineur, Y. S., Smith, P. H., Cahuzac, E. L., & Picciotto, M. R. (2015). Modulation of aggressive behavior in mice by nicotinic receptor subtypes. Biochemical Pharmacology, 97, 488–497.  https://doi.org/10.1016/j.bcp.2015.07.019.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lewis, A. S., Pittenger, S. T., Mineur, Y. S., Stout, D., Smith, P. H., & Picciotto, M. R. (2017). Bidirectional regulation of aggression in mice by hippocampal alpha-7 nicotinic acetylcholine receptors. Neuropsychopharmacology.  https://doi.org/10.1038/npp.2017.276.Google Scholar
  22. Masurel-Paulet, A., Andrieux, J., Callier, P., Cuisset, J. M., Le Caignec, C., Holder, M., et al. (2010). Delineation of 15q13.3 microdeletions. Clinical Genetics, 78, 149–161.  https://doi.org/10.1111/j.1399-0004.2010.01374.x.CrossRefPubMedGoogle Scholar
  23. Matson, J. (2009). Aggression and tantrums in children with autism: A review of behavioral treatments and maintaining variables. Journal of Mental Health Research in Intellectual Disabilities, 2, 169–187.  https://doi.org/10.1080/19315860902725875.CrossRefGoogle Scholar
  24. Mazurek, M. O., & Sohl, K. (2016). Sleep and behavioral problems in children with autism spectrum disorder. Journal of Autism and Developmental Disorders, 46, 1906–1915.  https://doi.org/10.1007/s10803-016-2723-7.CrossRefPubMedGoogle Scholar
  25. McCracken, J. T., McGough, J., Shah, B., Cronin, P., Hong, D., Aman, M. G., et al. (2002). Risperidone in children with autism and serious behavioral problems. New England Journal of Medicine, 347, 314–321.  https://doi.org/10.1056/NEJMoa013171.CrossRefPubMedGoogle Scholar
  26. McDougle, C. J., Scahill, L., Aman, M. G., McCracken, J. T., Tierney, E., Davies, M., et al. (2005). Risperidone for the core symptom domains of autism: Results from the study by the autism network of the research units on pediatric psychopharmacology. American Journal of Psychiatry, 162, 1142–1148.  https://doi.org/10.1176/appi.ajp.162.6.1142.CrossRefPubMedGoogle Scholar
  27. Mikhail, F. M., Lose, E. J., Robin, N. H., Descartes, M. D., Rutledge, K. D., Rutledge, S. L., et al. (2011). Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders. American Journal of Medical Genetics Part A, 155A, 2386–2396.  https://doi.org/10.1002/ajmg.a.34177.CrossRefPubMedGoogle Scholar
  28. Morgan, P. T., Pace-Schott, E., Pittman, B., Stickgold, R., & Malison, R. T. (2010). Normalizing effects of modafinil on sleep in chronic cocaine users. American Journal of Psychiatry, 167, 331–340.  https://doi.org/10.1176/appi.ajp.2009.09050613.CrossRefPubMedGoogle Scholar
  29. Newhouse, P., Kellar, K., Aisen, P., White, H., Wesnes, K., Coderre, E., et al. (2012). Nicotine treatment of mild cognitive impairment: A 6-month double-blind pilot clinical trial. Neurology, 78, 91–101.  https://doi.org/10.1212/WNL.0b013e31823efcbb.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Oginsky, M. F., Cui, N., Zhong, W., Johnson, C. M., & Jiang, C. (2014). Alterations in the cholinergic system of brain stem neurons in a mouse model of Rett syndrome. American Journal of Physiology-Cell Physiology, 307, C508-20.  https://doi.org/10.1152/ajpcell.00035.2014.CrossRefPubMedGoogle Scholar
  31. Olincy, A., Blakeley-Smith, A., Johnson, L., Kem, W. R., & Freedman, R. (2016). Brief report: Initial trial of alpha7-nicotinic receptor stimulation in two adult patients with autism spectrum disorder. Journal of Autism and Developmental Disorders, 46, 3812–3817.  https://doi.org/10.1007/s10803-016-2890-6.CrossRefPubMedGoogle Scholar
  32. Picciotto, M. R., Addy, N. A., Mineur, Y. S., & Brunzell, D. H. (2008). It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Progress in Neurobiology, 84, 329–342.  https://doi.org/10.1016/j.pneurobio.2007.12.005.CrossRefPubMedGoogle Scholar
  33. Picciotto, M. R., Lewis, A. S., van Schalkwyk, G. I., & Mineur, Y. S. (2015). Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states. Neuropharmacology.  https://doi.org/10.1016/j.neuropharm.2014.12.028.PubMedPubMedCentralGoogle Scholar
  34. Potenza, M. N., Holmes, J. P., Kanes, S. J., & McDougle, C. J. (1999). Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: An open-label pilot study. Journal of Clinical Psychopharmacology, 19, 37–44.CrossRefPubMedGoogle Scholar
  35. Ray, M. A., Graham, A. J., Lee, M., Perry, R. H., Court, J. A., & Perry, E. K. (2005). Neuronal nicotinic acetylcholine receptor subunits in autism: An immunohistochemical investigation in the thalamus. Neurobiology of Disease, 19, 366–377.  https://doi.org/10.1016/j.nbd.2005.01.017.CrossRefPubMedGoogle Scholar
  36. Reitstetter, R., Lukas, R. J., & Gruener, R. (1999). Dependence of nicotinic acetylcholine receptor recovery from desensitization on the duration of agonist exposure. Journal of Pharmacology and Experimental Therapeutics, 289, 656–660.PubMedGoogle Scholar
  37. Research Units on Pediatric Psychopharmacology Autism, N. (2005). Risperidone treatment of autistic disorder: Longer-term benefits and blinded discontinuation after 6 months. American Journal of Psychiatry, 162, 1361–1369.  https://doi.org/10.1176/appi.ajp.162.7.1361.CrossRefGoogle Scholar
  38. Rosin, R. A., Levine, M. D., & Peskind, E. (2001). Transdermal nicotine for agitation in dementia. The American Journal of Geriatric Psychiatry, 9, 443–444.  https://doi.org/10.1097/00019442-200111000-00014.CrossRefPubMedGoogle Scholar
  39. Rubboli, F., Court, J. A., Sala, C., Morris, C., Chini, B., Perry, E., et al. (1994). Distribution of nicotinic receptors in the human hippocampus and thalamus. European Journal of Neuroscience, 6, 1596–1604.CrossRefPubMedGoogle Scholar
  40. Sharp, A. J., Mefford, H. C., Li, K., Baker, C., Skinner, C., Stevenson, R. E., et al. (2008). A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nature Genetics, 40, 322–328.  https://doi.org/10.1038/ng.93.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Shinawi, M., Schaaf, C. P., Bhatt, S. S., Xia, Z., Patel, A., Cheung, S. W., et al. (2009). A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nature Genetics, 41, 1269–1271.  https://doi.org/10.1038/ng.481.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Spielberger, C. D. (1999). The state-trait anger expression inventory-2 (STAXI-2): Professional manual. Odessa, FL: Psychological Assessment Resources, Inc.Google Scholar
  43. Spielberger, C. D., Gorsuch, R. L., Lushene, R., Vagg, P. R., & Jacobs, G. A. (1983). Manual for the state-trait anxiety inventory. Palo Alto, CA: Consulting Psychologists Press.Google Scholar
  44. Sukhodolsky, D. G., Wyk, B. C. V., Eilbott, J. A., McCauley, S. A., Ibrahim, K., Crowley, M. J., et al. (2016). Neural mechanisms of cognitive-behavioral therapy for aggression in children and adolescents: Design of a randomized controlled trial within the national institute for mental health research domain criteria construct of frustrative non-reward. Journal of child and Adolescent Psychopharmacology, 26, 38–48.  https://doi.org/10.1089/cap.2015.0164.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Suzuki, K., Miyamoto, M., Miyamoto, T., & Hirata, K. (2015). Parkinson’s disease and sleep/wake disturbances. Current Neurology and Neuroscience Reports, 15, 8.  https://doi.org/10.1007/s11910-015-0525-5.CrossRefPubMedGoogle Scholar
  46. Tsakanikos, E., Costello, H., Holt, G., Sturmey, P., & Bouras, N. (2007). Behaviour management problems as predictors of psychotropic medication and use of psychiatric services in adults with autism. Journal of Autism and Developmental Disorders, 37, 1080–1085.  https://doi.org/10.1007/s10803-006-0248-1.CrossRefPubMedGoogle Scholar
  47. van Schalkwyk, G. I., Lewis, A. S., Beyer, C., Johnson, J., van Rensburg, S., & Bloch, M. H. (2017). Efficacy of antipsychotics for irritability and aggression in children: A meta-analysis. Expert Review of Neurotherapeutics, 17, 1045–1053.  https://doi.org/10.1080/14737175.2017.1371012.CrossRefPubMedGoogle Scholar
  48. Van Schalkwyk, G. I., Lewis, A. S., Qayyum, Z., Koslosky, K., Picciotto, M. R., & Volkmar, F. R. (2015a). Reduction of aggressive episodes after repeated transdermal nicotine administration in a hospitalized adolescent with autism spectrum disorder. Journal of Autism and Developmental Disorders, 45, 3061–3066.  https://doi.org/10.1007/s10803-015-2471-0.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Van Schalkwyk, G. I., Peluso, F., Qayyum, Z., McPartland, J. C., & Volkmar, F. R. (2015b). Varieties of misdiagnosis in ASD: An illustrative case series. Journal of Autism and Developmental Disorders, 45, 911–918.  https://doi.org/10.1007/s10803-014-2239-y.CrossRefPubMedGoogle Scholar
  50. White, H. K., & Levin, E. D. (1999). Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer’s disease. Psychopharmacology (Berlin), 143, 158–165.CrossRefGoogle Scholar
  51. White, H. K., & Levin, E. D. (2004). Chronic transdermal nicotine patch treatment effects on cognitive performance in age-associated memory impairment. Psychopharmacology (Berlin), 171, 465–471.  https://doi.org/10.1007/s00213-003-1614-8.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PsychiatryYale University School of MedicineNew HavenUSA
  2. 2.Child Study CenterYale University School of MedicineNew HavenUSA
  3. 3.Butler HospitalProvidenceUSA
  4. 4.Department of PsychiatryYale University School of MedicineNew HavenUSA

Personalised recommendations