Tolerance to Stimulant Medication for Attention Deficit Hyperactivity Disorder: Literature Review and Case Report
2. Materials and Methods
3.1. Physiological Studies on Tolerance to Stimulant Medication
3.2. Clinical Research on Tolerance to Stimulant Medication
3.3. ADHD Treatment Guidelines and Tolerance
3.4. Case 1: Patient A
3.5. Case 2: Patient B
3.6. Case 3: Patient C
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; American Psychiatric Association: Washington, DC, USA, 2013; p. 59. [Google Scholar] [CrossRef]
- Thomas, R.; Sanders, S.; Doust, J.; Beller, E.; Glasziou, P. Prevalence of attention-deficit/hyperactivity disorder: A systematic review and meta-analysis. Pediatrics 2015, 135, e994–e1001. [Google Scholar] [CrossRef][Green Version]
- Song, P.; Zha, M.; Yang, Q.; Zhang, Y.; Li, X.; Rudan, I. The prevalence of adult attention-deficit hyperactivity disorder: A global systematic review and meta-analysis. J. Glob. Health 2021, 11, 04009. [Google Scholar] [CrossRef]
- Faraone, S.V.; Asherson, P.; Banaschewski, T.; Biederman, J.; Buitelaar, J.; Ramos-Quiroga, J.A.; Rohde, L.A.; Sonuga-Barke, E.; Tannock, R.; Franke, B. Attention-deficit/hyperactivity disorder. Nat. Rev. Dis. Primers 2015, 1, 15020. [Google Scholar] [CrossRef]
- CADDRA—Canadian ADHD Resource Alliance. Canadian ADHD Practice Guidelines, 4.1 Edition; CADDRA: Toronto, ON, Canada, 2020. [Google Scholar]
- Wolraich, M.L.; Hagan, J.F., Jr.; Allan, C.; Chan, E.; Davison, D.; Earls, M.; Evans, S.W.; Flinn, S.K.; Froehlich, T.; Frost, J.; et al. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics 2019, 144, e20192528. [Google Scholar] [CrossRef][Green Version]
- Kooij, J.J.S.; Bijlenga, D.; Salerno, L.; Jaeschke, R.; Bitter, I.; Balazs, J.; Thome, J.; Dom, G.; Kasper, S.; Filipe, C.N.; et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur. Psychiatry 2019, 56, 14–34. [Google Scholar] [CrossRef]
- Banaschewski, T.; Hohmann, S.; Millenet, S. Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) im Kindes-, Jugend- und Erwachsenenalter. In DGKJP, DGPPN and DGSPJ German Guidelines; Mannheim, Germany, 2018; Available online: https://www.awmf.org/fileadmin/user_upload/Leitlinien/028_D_G_f_Kinder-_und_Jugendpsychiatrie_und_-psychotherapie/028-045eng_S3_ADHS_2020-12.pdf (accessed on 29 May 2022).
- Ross, D.C.; Fischhoff, J.; Davenport, B. Treatment of ADHD when tolerance to methylphenidate develops. Psychiatr. Serv. 2002, 53, 102. [Google Scholar] [CrossRef]
- Bespalov, A.; Müller, R.; Relo, A.L.; Hudzik, T. Drug Tolerance: A Known Unknown in Translational Neuroscience. Trends Pharmacol. Sci. 2016, 37, 364–378. [Google Scholar] [CrossRef]
- Sproson, E.J.; Chantrey, J.; Hollis, C.; Marsden, C.A.; Fone, K.C.F. Effect of repeated methylphenidate administration on presynaptic dopamine and behaviour in young adult rats. J. Psychopharmacol. 2001, 15, 67–75. [Google Scholar] [CrossRef]
- Volkow, N.D.; Ding, Y.S.; Fowler, J.S.; Wang, G.J.; Logan, J.; Gatley, J.S.; Dewey, S.; Ashby, C.; Liebermann, J.; Hitzemann, R.; et al. Is Methylphenidate Like Cocaine? Studies on Their Pharmacokinetics and Distribution in the Human Brain. Arch. Gen. Psychiatry 1995, 52, 456–463. [Google Scholar] [CrossRef]
- Swanson, J.; Gupta, S.; Guinta, D.; Flynn, D.; Agler, D.; Lerner, M.; Williams, L.; Shoulson, I.; Wigal, S. Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. Clin. Pharmacol. Ther. 1999, 66, 295–305. [Google Scholar] [CrossRef]
- Wang, G.J.; Volkow, N.D.; Wigal, T.; Kollins, S.H.; Newcorn, J.H.; Telang, F.; Logan, J.; Jayne, M.; Wong, C.T.; Han, H.; et al. Long-Term Stimulant Treatment Affects Brain Dopamine Transporter Level in Patients with Attention Deficit Hyperactive Disorder. PLoS ONE 2013, 8, e63023. [Google Scholar] [CrossRef][Green Version]
- Castells, X.; Ramon, M.; Cunill, R.; Olivé, C.; Serrano, D. Relationship Between Treatment Duration and Efficacy of Pharmacological Treatment for ADHD: A Meta-Analysis and Meta-Regression of 87 Randomized Controlled Clinical Trials. J. Atten. Disord. 2021, 25, 1352–1361. [Google Scholar] [CrossRef]
- Safer, D.J.; Allen, R.P. Absence of tolerance to the behavioral effects of methylphenidate in hyperactive and inattentive children. J. Pediatrics 1989, 115, 1003–1008. [Google Scholar] [CrossRef]
- Kupietz, S.S.; Winsberg, B.G.; Richardson, E.; Maitinsky, S.; Mendell, N. Effects of methylphenidate dosage in hyperactive reading-disabled children: I. Behavior and cognitive performance effects. J. Am. Acad. Child Adolesc. Psychiatry 1988, 27, 70–77. [Google Scholar] [CrossRef]
- Cunill, R.; Castells, X.; Tobias, A.; Capellà, D. Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: A meta-analysis and meta-regression in over 9000 patients. Psychopharmacology 2016, 233, 187–197. [Google Scholar] [CrossRef]
- Coghill, D.R.; Banaschewski, T.; Lecendreux, M.; Johnson, M.; Zuddas, A.; Anderson, C.S.; Civil, R.; Dauphin, M.; Higgins, N.; Lyne, A.; et al. Maintenance of Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Randomized-Withdrawal Study Design. J. Am. Acad. Child Adolesc. Psychiatry 2014, 53, 647–657.e1. [Google Scholar] [CrossRef]
- Matthijssen, A.F.M.; Dietrich, A.; Bierens, M.; Kleine Deters, R.; van de Loo-Neus, G.H.; van den Hoofdakker, B.J.; Buitelaar, J.K.; Hoekstra, P.J. Continued Benefits of Methylphenidate in ADHD After 2 Years in Clinical Practice: A Randomized Placebo-Controlled Discontinuation Study. AJP 2019, 176, 754–762. [Google Scholar] [CrossRef]
- Swanson, J.M.; Hinshaw, S.P.; Arnold, L.E.; Gibbons, R.D.; Marcus, S.U.E.; Hur, K.; Jensen, P.S.; Vitiello, B.; Abikoff, H.B.; Greenhill, L.L.; et al. Secondary Evaluations of MTA 36-Month Outcomes: Propensity Score and Growth Mixture Model Analyses. J. Am. Acad. Child Adolesc. Psychiatry 2007, 46, 1003–1014. [Google Scholar] [CrossRef]
- Hinshaw, S.P.; Arnold, L.E. ADHD, Multimodal Treatment, and Longitudinal Outcome: Evidence, Paradox, and Challenge. Wiley Interdiscip. Rev. Cogn. Sci. 2015, 6, 39–52. [Google Scholar] [CrossRef][Green Version]
- Sibley, M.H.; Arnold, L.E.; Swanson, J.M.; Hechtman, L.T.; Kennedy, T.M.; Owens, E.; Molina, B.S.; Jensen, P.S.; Hinshaw, S.P.; Roy, A.; et al. Variable Patterns of Remission from ADHD in the Multimodal Treatment Study of ADHD. AJP 2022, 179, 142–151. [Google Scholar] [CrossRef]
- Ibrahim, K.; Donyai, P. Drug Holidays from ADHD Medication: International Experience Over the Past Four Decades. J. Atten. Disord. 2015, 19, 551–568. [Google Scholar] [CrossRef]
- Cortese, S.; Newcorn, J.H.; Coghill, D. A Practical, Evidence-informed Approach to Managing Stimulant-Refractory Attention Deficit Hyperactivity Disorder (ADHD). CNS Drugs 2021, 35, 1035–1051. [Google Scholar] [CrossRef]
- Piper, B.J.; Ogden, C.L.; Simoyan, O.M.; Chung, D.Y.; Caggiano, J.F.; Nichols, S.D.; McCall, K.L. Trends in use of prescription stimulants in the United States and Territories, 2006 to 2016. PLoS ONE 2018, 13, e0206100. [Google Scholar] [CrossRef]
- Post, R.M. Acquired lithium resistance revisited: Discontinuation-induced refractoriness versus tolerance. J. Affect. Disord. 2012, 140, 6–13. [Google Scholar] [CrossRef]
- Fornaro, M.; Anastasia, A.; Novello, S.; Fusco, A.; Pariano, R.; De Berardis, D.; Solmi, M.; Veronese, N.; Stubbs, B.; Vieta, E.; et al. The emergence of loss of efficacy during antidepressant drug treatment for major depressive disorder: An integrative review of evidence, mechanisms, and clinical implications. Pharmacol. Res. 2019, 139, 494–502. [Google Scholar] [CrossRef][Green Version]
|Ross et al. 2002 ||Treatment of ADHD when tolerance to methylphenidate develops||Retrospective chart review, n = 166||-24.7% of patients developed tolerance—some within days and some after one year of treatment|
-predictor of tolerance was needing higher/off label dosage of MPH
-switched classes of stimulant medicine to treat tolerance
|Castells et al., 2021 ||Relationship Between Treatment Duration and Efficacy of Pharmacological Treatment for ADHD: A Meta-Analysis and Meta-Regression of 87 Randomized Controlled Clinical Trials||Meta-Analysis and Meta-Regression of 87 randomized controlled trials; treatment duration was 3–28 weeks; 9 weeks on average; included children, teens and adults||-This study did not find tolerance to medication treatment in studies with the treatment range of 3–28 weeks.|
-Excluded studies shorter than 3 weeks
|Safer et al., 1989 ||Absence of tolerance to the behavioral effects of methylphenidate in hyperactive and inattentive children||Retrospective chart review, n = 108; tracking stimulant treatment of ADHD for 3–10 years||-the dose of methylphenidate, when adjusted for growth, did not change significantly during the 3 to 10 years of treatment;|
-Only 2.7% of patients lost the therapeutic benefit from medicine without an evident explanation other than the possibility of tolerance
-the dose calculations that minimized the effects of growth with age were milligrams per kilogram to the 0.7th power and milligrams per square meter of estimated body surface area
|Kupietz et al., 1988 ||Effects of Methylphenidate Dosage in Hyperactive Reading-disabled Children: II. Reading Achievement||Prospective Study, n = 47; children with hyperactivity and reading disorder, treated for 6 months with methylphenidate immediate release twice daily||-Results showed positive effects of methylphenidate on reading that were mediated through behavioral control especially during the first 3 months of treatment.|
-The teachers noted an increase in hyperactivity during the last three months of treatment, and this was not explained by MPH plasma levels.
-The cause of this change was suspected to be tolerance, though the authors acknowledge that it could possibly relate to situational issues, particularly because there was a (smaller) worsening in the placebo group as well in the last three months of the study
|Cunill et al., 2016 ||Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients||Systematic Review, meta-Analysis and Meta-Regression of 44 studies with 9952 adult ADHD patients; the duration of the studies was 4–26 weeks||-The analysis showed that the longer the study duration, the smaller the efficacy of the pharmacological treatment for reducing ADHD symptoms.|
-This may suggest chronic tolerance to the medication in adults treated with stimulant medication for up to 26 weeks.
|Coghill et al., 2014 ||Maintenance of Efficacy of Lisdexamfetamine Dimesylate in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: Randomized-Withdrawal Study Design||Randomized Withdrawal Period (RWP) Study; n = 157 children and adolescents treated with lisdexamfetamine for 26 weeks underwent a 6 week randomized withdrawal period||-During the RWP, significantly fewer LDX patients met failure criteria than placebo|
-demonstrates the maintenace of efficacy of LDX in the treatment of children and adolescents with ADHD, and the rapid return of symptoms upon discontinuing LDX
-the study demonstrate that for the majority of patients, stimulant medication is still effective after 6 months, and stopping medication generally worsens ADHD symptoms.
|Matthijssen et al., 2019 ||Continued Benefits of Methylphenidate in ADHD After 2 Years in Clinical Practice: A Randomized Placebo-Controlled Discontinuation Study||Randomized Withdrawal Period (RWP); n = 94 children and adolescents who had been treated with methylphenidate for 2 years; assigned to double blind continuation or withdrawal of treatment over 7 weeks||-On average, the ADHD scores deteriorated significantly more in the discontinuation group than the continuation group.|
-The researchers found that MPH treatment was still effective at 2 years, and discontinuing treatment led to worsened symptom ratings by both investigator and teacher rated ADHD symptom ratings.
-There were some participants who were able to stop the medication and did not experience worsened symptoms.
-The study demonstrate that for the majority of patients, stimulant medication is still effective after 24 months, and stopping medication generally worsens ADHD symptoms.
|Swanson et al., 2007 ||Secondary Evaluations of MTA 36-Month Outcomes: Propensity Score and Growth Mixture Model Analyses||Naturalistic follow-up of the NIMH Multimodal Treatment Study (MTA) at 36 months||-At the 36 month follow-up evaluation of the patients, growth mixture modeling found 3 latent classes.|
-In class 1, which comprised 34% of the children in the study, they had the smallest initial benefit to medication in the study, but their medication effects increased over time and were significant at the 36 month assessment.
-In classes 2 and 3, the medication benefits were larger than class 1 at 14 months; however, by the 36 month assessment, the medication benefits were not significant.
-For the majority of children treated with medication (66%), beyond the 24 month assessment point in the MTA protocol, the overall effect of medication treatment was not beneficial for the reduction of ADHD symptoms.
-This suggests the possibility of waning benefit for continued medicine beyond 2 years for children with combined type ADHD
|Sibley et al., 2022 ||Variable Patterns of Remission From ADHD in the Multimodal Treatment Study of ADHD||Analysis of the 16 year naturalistic follow-up of the NIMH Multimodal Treatment Study (MTA), reviewing the ADHD assessments from years 2–16||-Approximately 30% of children with ADHD experienced full remission at some point during the follow-up period; but a majority of them (60%) experienced recurrence of ADHD after the initial period of remission.|
-Most participants with ADHD (63.8%) had fluctuating periods of remission and recurrence over time; According to our review, theoretically, the natural course of ADHD may impact clinician’s ability to assess medication response during longer term follow up of ADHD medication treatment
|Ibrahim et al., 2015 ||Drug Holidays From ADHD Medication:|
International Experience Over the Past
|Review of literature||-Drug holidays are prevalent in 25% to 70% of families with children/teens taking stimulant medication and are more likely to be exercised during school holidays.|
-They test whether medication is still needed and are also considered for managing medication side effects and drug tolerance.
-One of the reviewed studies documented that doctors used breaks from medication to reset tolerance to the medicine
|Cortese et al., 2021 ||Evidence-informed Approach to Managing Stimulant-Refractory Attention Deficit Hyperactivity Disorder (ADHD)||Review of literature, review of clinical guidelines, knowledge of expert practice in the field||-Refractory ADHD is defined as a failure to remit, minimal improvement, partial response with persistence of impairments, or no benefit at all to medication.|
-They note that to deal with refractory ADHD, it is important to:
-Optimize stimulants for ADHD core symptoms;
-Try alternative monotherapies for ADHD core symptoms;
-Try non-stimulants for ADHD;
-Use combination pharmacotherapy; use off-label medications with evidence that they help ADHD;
-Treat comorbid conditions with ADHD.
-Some patients may develop tolerance to stimulant medication, but the extent and frequency of this is not understood.
-Raising the dose of stimulant may provide a temporary solution, but a short drug holiday may help with tolerance
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Handelman, K.; Sumiya, F. Tolerance to Stimulant Medication for Attention Deficit Hyperactivity Disorder: Literature Review and Case Report. Brain Sci. 2022, 12, 959. https://doi.org/10.3390/brainsci12080959
Handelman K, Sumiya F. Tolerance to Stimulant Medication for Attention Deficit Hyperactivity Disorder: Literature Review and Case Report. Brain Sciences. 2022; 12(8):959. https://doi.org/10.3390/brainsci12080959Chicago/Turabian Style
Handelman, Kenneth, and Fernando Sumiya. 2022. "Tolerance to Stimulant Medication for Attention Deficit Hyperactivity Disorder: Literature Review and Case Report" Brain Sciences 12, no. 8: 959. https://doi.org/10.3390/brainsci12080959