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Improving Methylphenidate Titration in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): A Randomized Controlled Trial Using Placebo-Controlled Titration Implemented in Clinical Practice

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Abstract

Background and Objectives

Concerns exist regarding the rising use of methylphenidate. A double-blind, placebo-controlled methylphenidate titration (PCT) for children with attention-deficit/hyperactivity disorder (ADHD) has shown potential to improve titration (i.e., detection of placebo responders and larger ADHD symptom improvement) in experimental settings. This study aims to determine if these advantages can be transferred to clinical settings.

Method

Children (aged 5–13 years) with an ADHD diagnosis and an indication to start methylphenidate (MPH) treatment were recruited. Participants were randomized to PCT or care as usual (CAU) in a 1:1 ratio followed by a 7-week randomized controlled trial (T1) and 6-month, naturalistic, open-label follow-up (T2). Parents, teachers, and physicians rated ADHD symptoms, ADHD medication use, MPH dosing, and treatment satisfaction using questionnaires.

Results

A total of 100 children were enrolled and randomized to PCT (n = 49) or CAU (n = 51). In the PCT group, we found 8.2% placebo responders, 16.3% non-responders, and 65.3% responders to MPH. With PCT compared with CAU, a significantly larger number of children discontinued MPH (T1: 24.5 vs 5.9%, p = 0.009; T2: 41.7 vs 10.4%, p < 0.001) and refrained from using other pharmacological treatment (T1: 20.4 vs 3.9%, p = 0.013; T2: 20.83 vs 6.25%, p = 0.002). At both timepoints, there were no significant differences between the groups in the average dose of MPH, ADHD symptoms, or treatment satisfaction.

Conclusions

PCT can be used to improve detection of children who do not benefit from MPH, and may therefore potentially reduce overtreatment of ADHD with MPH.

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Acknowledgements

We would like to thank all participating children, parents, teachers, and physicians for their participation in the study. We thank all research interns for their valuable support in data collection. We are grateful to all participating centers for their help in the study.

Author information

Authors and Affiliations

  1. Vrije Universiteit Amsterdam, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands

    Karen Vertessen, Marjolein Luman & Jaap Oosterlaan

  2. University Psychiatric Centre, Katholieke Universiteit Leuven, Leuven, Belgium

    Karen Vertessen

  3. Levvel Specialists in Youth and Family Care, Amsterdam, The Netherlands

    Marjolein Luman & Reino Stoffelsen

  4. Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC, VU Medical Center, Amsterdam, The Netherlands

    Pierre Bet

  5. Institute of Education and Child Studies, Leiden University, Leiden, The Netherlands

    Catharina E. Bergwerff

  6. Child Study Center Accare, UMC Groningen, Groningen, The Netherlands

    Marco Bottelier

  7. Department of Pediatrics, University of California, Irvine, USA

    James M. Swanson

  8. Youz, Center for Youth Mental Healthcare, Velsen-Noord, The Netherlands

    Annemiek Wisse

  9. Department of Epidemiology and Biostatistics, VU Medical Center, Amsterdam, Amsterdam, The Netherlands

    Jos Twisk

  10. Department of Pediatrics, Emma Children’s Hospital, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands

    Jaap Oosterlaan

  11. Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands

    Jaap Oosterlaan

Authors
  1. Karen Vertessen
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Corresponding author

Correspondence to Karen Vertessen.

Ethics declarations

Funding

This study is part of the project ‘Reduce and optimize methylphenidate use in children and adolescents with ADHD’ (Grant p3119), funded by Innovation Fund of Health Insurances (Innovatiefonds Zorgverzekeraars). The funder/sponsor did not participate in the work.

Conflict of interest

Karen Vertessen has been involved in a clinical trial sponsored by Takeda. The other authors have no conflicts of interest relevant to this article to disclose.

Ethics approval

The local ethics committee approved the study (METC Amsterdam UMC, 2016.594) and the study was registered prospectively in the Dutch trial register (NL8121).

Consent to participate

Parents and children older than 11 years provided signed informed consent.

Availability of data and material

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

The code used to analyze the data in the current study are available from the corresponding author on reasonable request.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by MB, RS, KV and AW. Professor JT was the statistical expert for this study. The first draft of the manuscript was written by KV and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript and agree to be accountable for the work.

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Vertessen, K., Luman, M., Bet, P. et al. Improving Methylphenidate Titration in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): A Randomized Controlled Trial Using Placebo-Controlled Titration Implemented in Clinical Practice. Pediatr Drugs (2024). https://doi.org/10.1007/s40272-023-00604-8

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