Article | Published:

This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Increased risk of diseases of the basal ganglia and cerebellum in patients with a history of attention-deficit/hyperactivity disorder

Neuropsychopharmacology (2018) | Download Citation

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is marked by an ongoing pattern of inattention and/or hyperactivity and involves dysregulated dopaminergic pathways. Dopaminergic agents (i.e., amphetamine and methylphenidate) are thus prescribed to treat ADHD. As little is known regarding long-term consequences of either ADHD or its treatment, the objective of this study was to determine if either alters the risk of diseases of the basal ganglia and cerebellum, including Parkinson’s disease. Statewide medical records from 1996 to 2016 were retrieved from the Utah Population Database to conduct a retrospective cohort study. Participants included ADHD patients (International Classification of Diseases, 9th version (ICD-9) diagnosis codes 314.0–314.2, 314.8, 314.9) and 5:1 random sex-matched and age-matched subjects with no ADHD diagnosis history. Both patients and non-ADHD subjects met the following eligibility criteria: (1) no prior diagnosis of Parkinson’s disease, secondary parkinsonism, basal ganglia disease, or essential tremor (ICD-9 codes 332.0, 332.1, 333.0, 333.1), (2) born in 1950 or later and age ≥20 years at last follow-up, and (3) no history of substance abuse (illicit drugs or alcohol). Outcomes were measured as time to diagnosis of diseases of the basal ganglia and cerebellum, death, or study-end. A Cox model incorporating a competing risk of death was used to provide hazard ratio estimates. Patients with ADHD (N = 31,769) had a 2.4-fold increased risk of basal ganglia and cerebellum diseases (95% confidence interval (CI): 2.0–3.0; P < 0.0001) compared with 158,790 non-ADHD persons, after controlling for sex and age and adjusting for tobacco use and psychotic conditions. In 4960 ADHD patients prescribed psychostimulants, risk of basal ganglia and cerebellum diseases between ages 21 and 49 years was especially pronounced, at 8.6-fold (95% CI: 4.8–15.6; P < 0001). The association of ADHD patients prescribed psychostimulants with higher risk of diseases of the basal ganglia and cerebellum may reflect a more severe ADHD phenotype rather than a direct association between prescribed stimulant use and basal ganglia or cerebellum disorders. Future studies to assess and stratify patient risk so as to inform treatment are warranted.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Bonvicini C, Faraone SV, Scassellati C. Attention-deficit hyperactivity disorder in adults: a systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies. Mol Psychiatry. 2016;21:872–84.

  2. 2.

    Simon V, Czobor P, Balint S, Meszaros A, Bitter I. Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry. 2009;194:204–11.

  3. 3.

    Asherson P, Buitelaar J, Faraone SV, Rohde LA. Adult attention-deficit hyperactivity disorder: key conceptual issues. Lancet Psychiatry. 2016;3:568–78.

  4. 4.

    Visser SN, Danielson ML, Wolraich ML, Fox MH, Grosse SD, Valle LA, et al. Vital Signs: National and State-Specific Patterns of Attention Deficit/Hyperactivity Disorder Treatment Among Insured Children Aged 2–5 Years—United States, 2008–2014. MMWR Morb Mortal Wkly Rep. 2016;65:443–50.

  5. 5.

    Halpin LE, Collins SA, Yamamoto BK. Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine. Life Sci. 2014;97:37–44.

  6. 6.

    McCann UD, Kuwabara H, Kumar A, Palermo M, Abbey R, Brasic J, et al. Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users. Synapse. 2008;62:91–100.

  7. 7.

    McCann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA. Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428. J Neurosci. 1998;18:8417–22.

  8. 8.

    Sekine Y, Iyo M, Ouchi Y, Matsunaga T, Tsukada H, Okada H, et al. Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET. Am J Psychiatry. 2001;158:1206–14.

  9. 9.

    Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, et al. Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med. 1996;2:699–703.

  10. 10.

    Christine CW, Garwood ER, Schrock LE, Austin DE, McCulloch CE. Parkinsonism in patients with a history of amphetamine exposure. Mov Disord. 2010;25:228–31.

  11. 11.

    Garwood ER, Bekele W, McCulloch CE, Christine CW. Amphetamine exposure is elevated in Parkinson’s disease. Neurotoxicology. 2006;27:1003–6.

  12. 12.

    Moratalla R, Khairnar A, Simola N, Granado N, Garcia-Montes JR, Porceddu PF, et al. Amphetamine-related drugs neurotoxicity in humans and in experimental animals: main mechanisms. Prog Neurobiol. 2017;155:149–70.

  13. 13.

    Curtin K, Fleckenstein AE, Robison RJ, Crookston MJ, Smith KR, Hanson GR. Methamphetamine/amphetamine abuse and risk of Parkinson’s disease in Utah: a population-based assessment. Drug Alcohol Depend. 2015;146:30–8.

  14. 14.

    Meszaros A, Czobor P, Balint S, Komlosi S, Simon V, Bitter I. Pharmacotherapy of adult attention deficit hyperactivity disorder (ADHD): a meta-analysis. Int J Neuropsychopharmacol. 2009;12:1137–47.

  15. 15.

    Visser SN, Danielson ML, Bitsko RH, Holbrook JR, Kogan MD, Ghandour RM, et al. Trends in the parent-report of health care provider-diagnosed and medicated attention-deficit/hyperactivity disorder: United States, 2003–2011. J Am Acad Child Adolesc Psychiatry. 2014;53:34–46 e32.

  16. 16.

    Post RE, Kurlansik SL. Diagnosis and management of adult attention-deficit/hyperactivity disorder. Am Fam Physician. 2012;85:890–6.

  17. 17.

    Benson K, Flory K, Humphreys KL, Lee SS. Misuse of stimulant medication among college students: a comprehensive review and meta-analysis. Clin Child Fam Psychol Rev. 2015;18:50–76.

  18. 18.

    Willis AW, Schootman M, Kung N, Racette BA. Epidemiology and neuropsychiatric manifestations of Young Onset Parkinson’s Disease in the United States. Park Relat Disord. 2013;19:202–6.

  19. 19.

    Tse W, Cersosimo MG, Gracies JM, Morgello S, Olanow CW, Koller W. Movement disorders and AIDS: a review. Park Relat Disord. 2004;10:323–34.

  20. 20.

    Callaghan RC, Cunningham JK, Sykes J, Kish SJ. Increased risk of Parkinson’s disease in individuals hospitalized with conditions related to the use of methamphetamine or other amphetamine-type drugs. Drug Alcohol Depend. 2012;120:35–40.

  21. 21.

    Brecht ML, Huang D, Evans E, Hser YI. Polydrug use and implications for longitudinal research: ten-year trajectories for heroin, cocaine, and methamphetamine users. Drug Alcohol Depend. 2008;96:193–201.

  22. 22.

    Bettiol SS, Rose TC, Hughes CJ, Smith LA. Alcohol consumption and Parkinson’s disease risk: a review of recent findings. J Park Dis. 2015;5:425–42.

  23. 23.

    Hernan MA, Chen H, Schwarzschild MA, Ascherio A. Alcohol consumption and the incidence of Parkinson’s disease. Ann Neurol. 2003;54:170–5.

  24. 24.

    Liu R, Guo X, Park Y, Wang J, Huang X, Hollenbeck A, et al. Alcohol consumption, types of alcohol, and Parkinson’s disease. PLoS ONE. 2013;8:e66452.

  25. 25.

    Schrag A, Schott JM. Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol. 2006;5:355–63.

  26. 26.

    Uc EY, Rodnitzky RL. Juvenile parkinsonism. Semin Pediatr Neurol. 2003;10:62–7.

  27. 27.

    Kleinbaum DGKM. Competing risks survival analysis. New York, NY: Springer; 2005. p. 391–461.

  28. 28.

    Dalsgaard S, Ostergaard SD, Leckman JF, Mortensen PB, Pedersen MG. Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet. 2015;385:2190–6.

  29. 29.

    Howes OD, Murray RM. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet. 2014;383:1677–87.

  30. 30.

    Hernan MA, Takkouche B, Caamano-Isorna F, Gestal-Otero JJ. A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson’s disease. Ann Neurol. 2002;52:276–84.

  31. 31.

    Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol. 2011;26:S1–58.

  32. 32.

    Ritz B, Lee PC, Lassen CF, Arah OA. Parkinson disease and smoking revisited: ease of quitting is an early sign of the disease. Neurology. 2014;83:1396–402.

  33. 33.

    Shin HW, Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8:15–21.

  34. 34.

    Sandoval V, Riddle EL, Hanson GR, Fleckenstein AE. Methylphenidate alters vesicular monoamine transport and prevents methamphetamine-induced dopaminergic deficits. J Pharmacol Exp Ther. 2003;304:1181–7.

  35. 35.

    Merrill RM, Hilton SC, Daniels M. Impact of the LDS church’s health doctrine on deaths from diseases and conditions associated with cigarette smoking. Ann Epidemiol. 2003;13:704–11.

  36. 36.

    Brichta L, Greengard P. Molecular determinants of selective dopaminergic vulnerability in Parkinson’s disease: an update. Front Neuroanat. 2014;8:152.

  37. 37.

    Swanson JM, Kinsbourne M, Nigg J, Lanphear B, Stefanatos GA, Volkow N, et al. Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol Rev. 2007;17:39–59.

  38. 38.

    Krauel K, Feldhaus HC, Simon A, Rehe C, Glaser M, Flechtner HH, et al. Increased echogenicity of the substantia nigra in children and adolescents with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2010;68:352–8.

  39. 39.

    Romanos M, Weise D, Schliesser M, Schecklmann M, Loffler J, Warnke A, et al. Structural abnormality of the substantia nigra in children with attention-deficit hyperactivity disorder. J Psychiatry Neurosci. 2010;35:55–58.

  40. 40.

    Zhuang X, Oosting RS, Jones SR, Gainetdinov RR, Miller GW, Caron MG, et al. Hyperactivity and impaired response habituation in hyperdopaminergic mice. Proc Natl Acad Sci USA. 2001;98:1982–7.

  41. 41.

    Subramaniam M, Althof D, Gispert S, Schwenk J, Auburger G, Kulik A, et al. Mutant alpha-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels. J Neurosci. 2014;34:13586–99.

  42. 42.

    Wile DJ, Agarwal PA, Schulzer M, Mak E, Dinelle K, Shahinfard E, et al. Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol. 2017;16:351–9.

  43. 43.

    Geissler JM, International Parkinson Disease Genomics Consortium, Romanos M, Gerlach M, Berg D, Schulte C. No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease in nine ADHD candidate SNPs. Atten Defic Hyperact Disord. 2017;9:121–7.

  44. 44.

    Bjorklund G, Stejskal V, Urbina MA, Dadar M, Chirumbolo S, Mutter J. Metals and Parkinson’s disease: mechanisms and biochemical processes. Curr Med Chem. 2017;29 (Epub ahead of print).

  45. 45.

    Camacho-Soto A, Warden MN, Searles Nielsen S, Salter A, Brody DL, Prather H, et al. Traumatic brain injury in the prodromal period of Parkinson’s disease: a large epidemiological study using medicare data. Ann Neurol. 2017;82:744–54.

  46. 46.

    Volkow ND. Long-term safety of stimulant use for ADHD: findings from nonhuman primates. Neuropsychopharmacology. 2012;37:2551–52.

  47. 47.

    Yuan J, McCann U, Ricaurte G. Methylphenidate and brain dopamine neurotoxicity. Brain Res. 1997;767:172–5.

  48. 48.

    Wang GJ, Volkow ND, Wigal T, Kollins SH, Newcorn JH, Telang F, et al. Long-term stimulant treatment affects brain dopamine transporter level in patients with attention deficit hyperactive disorder. PLoS ONE. 2013;8:e63023.

  49. 49.

    Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ. Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS ONE. 2012;7:e33693.

  50. 50.

    Noyes K, Liu H, Holloway R, Dick AW. Accuracy of Medicare claims data in identifying Parkinsonism cases: comparison with the Medicare current beneficiary survey. Mov Disord. 2007;22:509–14.

  51. 51.

    Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003;157:1015–22.

  52. 52.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth edition: DSM-5. Washington, DC: American Psychiatric Association; 2013.

  53. 53.

    Centers for Disease Control and Prevention (CDC). Attention-Deficit/Hyperactivity Disorder (ADHD) Data & Statistics. Available at: https://www.cdc.gov/ncbddd/adhd/data.html. Accessed 1 Mar 2018.

  54. 54.

    Centers for Disease Control and Prevention (CDC). Smoking & Tobacco Use, State Highlights 2010, Utah. Available at: http://www.cdc.gov/tobacco/data_statistics/state_data/state_highlights/2010/states/utah/index.htm. Accessed 10 Oct 2016.

  55. 55.

    Governor’s Office of Planning and Budget. Census brief: race and ethnicity in Utah. Third in a Series of 2010 Census Analyses; April 2012. p. 3–4.

  56. 56.

    Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Treatment Episode Data Set (TEDS): 2002-2012. National Admissions to Substance Abuse Treatment Services. BHSIS Series S-71, HHS Publication No. (SMA) 14-4850. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014.

  57. 57.

    The University of Utah Pedigree and Population Resource: Utah Population Database. Available at: http://healthcare.utah.edu/huntsmancancerinstitute/research/updb/. Accessed on 25 July 2017.

Download references

Acknowledgements

We gratefully acknowledge the thoughtful insights and suggestions of Dr. Kathleen Ries Merikangas, Ph.D., and Senior Investigator and Chief, Genetic Epidemiology Research Branch with the National Institute of Mental Health Intramural Research Program in the preparation of this manuscript. We thank the Pedigree and Population Resource, Huntsman Cancer Institute, at the University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the UPDB. We acknowledge the University of Utah’s Information Technology Services and Biomedical Informatics Core for establishing the Master Subject Index between the UPDB, University of Utah Health Care, and Intermountain Healthcare; without their institutional support, this study would not be possible. Supported by DA031833, DA039145 and the Huntsman Cancer Foundation. The UPDB is partially supported by P30-CA042014, the University of Utah’s Program in Personalized Health and Center for Clinical and Translational Science, and NCRR R01-RR021746. The support for this study was provided by National Institute on Drug Abuse grants DA031833 (to G.R.H.) and DA039145 (to A.E.F.). Partial support for the UPDB was provided by: National Cancer Institute P30 CA2014; the University of Utah’s Program in Personalized Health and Center for Clinical and Translational Science (funded by NIH Clinical and Translational Science Awards); and a National Center for Research Resources grant, “Sharing Statewide Health Data for Genetic Research” (RR021746 to G. Mineau) with additional support from the Utah State Department of Health.

Author information

Affiliations

  1. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

    • Karen Curtin
  2. University of Utah School of Dentistry, Salt Lake City, UT, USA

    • Annette E. Fleckenstein
    •  & Glen R. Hanson
  3. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

    • Brooks R. Keeshin
  4. Department of Pediatric Psychiatry, Intermountain Healthcare Primary Children’s Hospital, Salt Lake City, UT, USA

    • Brooks R. Keeshin
  5. Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA

    • Deborah A. Yurgelun-Todd
    •  & Perry F. Renshaw
  6. Human Development and Family Studies, University of Utah, Salt Lake City, UT, USA

    • Ken R. Smith

Authors

  1. Search for Karen Curtin in:

  2. Search for Annette E. Fleckenstein in:

  3. Search for Brooks R. Keeshin in:

  4. Search for Deborah A. Yurgelun-Todd in:

  5. Search for Perry F. Renshaw in:

  6. Search for Ken R. Smith in:

  7. Search for Glen R. Hanson in:

Competing interest

The authors declare no competing interest.

Corresponding author

Correspondence to Glen R. Hanson.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41386-018-0207-5