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Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis

Molecular Psychiatry volume 27, pages 212–219 (2022)Cite this article

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Abstract

The nature and magnitude of placebo and nocebo responses to ADHD medications and the extent to which response to active medications and placebo are inter-correlated is unclear. To assess the magnitude of placebo and nocebo responses to ADHD and their association with active treatment response. We searched literature until June 26, 2019, for published/unpublished double-blind, randomised placebo-controlled trials (RCTs) of ADHD medication. Authors were contacted for additional data. We assessed placebo effects on efficacy and nocebo effects on tolerability using random effects meta-analysis. We assessed the association of study design and patient features with placebo/nocebo response. We analysed 128 RCTs (10,578 children/adolescents and 9175 adults) and found significant and heterogenous placebo effects for all efficacy outcomes, with no publication bias. The placebo effect was greatest for clinician compared with other raters. We found nocebo effects on tolerability outcomes. Efficacy outcomes from most raters showed significant positive correlations between the baseline to endpoint placebo effects and the baseline to endpoint drug effects. Placebo and nocebo effects did not differ among drugs. Baseline severity and type of rating scale influenced the findings. Shared non-specific factors influence response to both placebo and active medication. Although ADHD medications are superior to placebo, and placebo treatment in clinical practice is not feasible, clinicians should attempt to incorporate factors associated with placebo effects into clinical care. Future studies should explore how such effects influence response to medication treatment. Upon publication, data will be available in Mendeley Data: PROSPERO (CRD42019130292).

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Fig. 1: Percent of patients in Drug and Placebo Groups improved or Very Much Improved at Endpoint on the Clinical Global Impressions Scale.
Fig. 2

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Data availability

In the spirit of Open science, the full dataset will be available online (Mendeley Data) following the publication of this paper.

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Acknowledgements

We thank the European ADHD Guidelines group (EAGG) for creating the publicly available data used in this manuscript. Dr. Faraone is supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667302 and 965381; NIMH grants U01MH109536-01, U01AR076092-01A1, R0MH116037 and 5R01AG06495502. Dr Cipriani is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017–08-ST2–006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215–20005). The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health.

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Authors and Affiliations

  1. Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA

    Stephen V. Faraone

  2. Departments of Psychiatry and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jeffrey H. Newcorn

  3. Department of Psychiatry, University of Oxford and Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK

    Andrea Cipriani

  4. Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zürich, and Neuroscience Center Zurich, University of Zürich and ETH Zürich, Zürich, Switzerland

    Daniel Brandeis

  5. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany

    Daniel Brandeis, Anna Kaiser, Sarah Hohmann & Alexander Haege

  6. Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life sciences & Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK

    Samuele Cortese

  7. Solent NHS Trust, Southampton, UK

    Samuele Cortese

  8. Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK

    Samuele Cortese

  9. Hassenfeld Children’s Hospital at NYU Langone, New York University Child Study Center, New York, NY, USA

    Samuele Cortese

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  1. Stephen V. Faraone
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  7. Alexander Haege
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  8. Samuele Cortese
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Contributions

SVF, JHN, AC and SC designed the study protocol. SVF ran the analyses and wrote the first draft. All authors provided critical comments on multiple drafts of the manuscript. SC designed the search strategy and data extraction protocol and addressed data management issues. SH, AK and AH completed the literature search and extracted data under the supervision of SC.

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Correspondence to Stephen V. Faraone.

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Conflict of interest

In the past year, SVF received income, potential income, travel expenses continuing education support and/or research support from Arbor, Genomind, Ironshore, KemPharm/Corium, Ondosis, Otsuka, Rhodes, Shire/Takeda, Supernus, and Tris. With his institution, he has US patent US20130217707 A1 for the use of sodium–hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.adhdinadults.com. In the past year, JHN is/has been an advisor and/or consultant for Adlon Therapeutics, Arbor, Cingulate Therapeutics, Corium, Eisai, Lundbeck, Medice, Myriad Neuroscience, NLS, OnDosis, Rhodes, Shire/Takeda, and Supernus. He has received research support from the National Institute on Drug Abuse (NIDA), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Adlon, Shire and Supernus. He also has received speaker fees from Shire/Takeda for disease-state presentations, and served as a consultant for the US National Football League. AC has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma. DB serves as an unpaid scientific consultant for an EU-funded neurofeedback trial. AK reports no financial disclosures. SH has no financial disclosures. AH received conference support, speaker’s fee and/or served in an advisory role for Shire/Takeda and Lily. He was involved as investigator in clinical trials by Shire, Janssen-Cilag, Otsuka, Sunovion, Servier, Lundbeck, Takeda, Nuvelution, Gedeon Richter, and Emalex. The present work is unrelated to the above relationships. SC declares reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, Canadian ADHD Resource Alliance (CADDRA), British Association of Psychopharmacology (BAP), and from Healthcare Convention for educational activity on ADHD.

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Faraone, S.V., Newcorn, J.H., Cipriani, A. et al. Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis. Mol Psychiatry 27, 212–219 (2022). https://doi.org/10.1038/s41380-021-01134-w

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