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Placebo and Nocebo Responses in Randomized, Controlled Trials of Medications for ADHD: A Systematic Review and Meta-Analysis

24 Pages Posted: 20 Oct 2020

See all articles by Stephen V. Faraone

Stephen V. Faraone

State University of New York (SUNY) - Department of Psychiatry

Jeffrey H. Newcorn

Mount Sinai Icahn School of Medicine - Departments of Psychiatry and Pediatrics

Andrea Cipriani

University of Oxford - Department of Psychiatry

Daniel Brandeis

University of Zurich - Neuroscience Center Zurich

Anna Kaiser

Heidelberg University - Central Institute of Mental Health

Sarah Hohmann

Heidelberg University - Central Institute of Mental Health

Alexander Haege

Heidelberg University - Department of Child and Adolescent Psychiatry and Psychotherapy

Samuele Cortese

University of Southampton - Centre for Innovation in Mental Health; University of Nottingham - Division of Psychiatry and Applied Psychology

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Abstract

Background: The nature and magnitude of placebo and nocebo responses to ADHD medications is unclear. The extent to which response to active medications and placebo are inter-correlated has not been explored.

Methods: We searched scientific literature until June 26, 2019 for published/unpublished double-blind, randomised placebo-controlled trials (RCTs) of ADHD medications in children, adolescents and adults. Authors and drug manufacturers were contacted for additional information. We assessed placebo effects on efficacy and nocebo effects on tolerability outcomes using aggregate data from trials and random-effects meta-analysis. We assessed the association of study design and patient features with placebo/nocebo response.

Findings: We analysed 128 RCTs and found significant and heterogenous placebo effects for all efficacy outcomes, with no publication bias. We found nocebo effects on some tolerability outcomes. Apart from self-ratings, efficacy outcomes from other raters showed significant positive correlations between the baseline to endpoint placebo effects and the baseline to endpoint drug effects, suggesting that response to placebo and ADHD medications are influenced by similar non-specific factors. Baseline severity and type of rating scale influenced the magnitude of placebo response.

Interpretation: Placebo effects are highly significant and response to placebo and ADHD medications are correlated, suggesting that 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, and future studies should explore how such effects influence response to medication treatment.

Funding Statement: This was not a funded study.

Declaration of Interests: In the past year, Dr. Faraone received income, potential income, travel expenses continuing education support and/or research support from Takeda, OnDosis, Tris, Otsuka, Arbor, Ironshore, Rhodes, Akili Interactive Labs, Enzymotec, Sunovion, Supernus and Genomind. 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, Dr. Newcorn is/has been an advisor and/or consultant for Adlon Therapeutics, Arbor, Eisai, NLS, OnDosis, Rhodes, Shire/Takeda, and Supernus. He was a DSMB member for Pfizer and Sunovion, and received research funds from Otsuka, 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.

Dr. Cipriani has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma.

Dr. Brandeis serves as an unpaid scientific consultant for an EUfunded neurofeedback trial.

Anna Kaiser reports has no financial disclosures.

Sarah Hohmann has no financial disclosures.

Dr. Häge 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.

Dr. Cortese 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.

Keywords: Placebo response, medication response, nocebo effects, ADHD

Suggested Citation

Faraone, Stephen V. and Newcorn, Jeffrey H. and Cipriani, Andrea and Brandeis, Daniel and Kaiser, Anna and Hohmann, Sarah and Haege, Alexander and Cortese, Samuele, Placebo and Nocebo Responses in Randomized, Controlled Trials of Medications for ADHD: A Systematic Review and Meta-Analysis. Available at SSRN: https://ssrn.com/abstract=3687364 or http://dx.doi.org/10.2139/ssrn.3687364

Stephen V. Faraone (Contact Author)

State University of New York (SUNY) - Department of Psychiatry ( email )

Syracuse, NY
United States

Jeffrey H. Newcorn

Mount Sinai Icahn School of Medicine - Departments of Psychiatry and Pediatrics ( email )

New York, NY 10025
United States

Andrea Cipriani

University of Oxford - Department of Psychiatry ( email )

Warneford Hospital
Warneford Ln
Oxford, OX3 7JX
United Kingdom

Daniel Brandeis

University of Zurich - Neuroscience Center Zurich

Rämistrasse 71
Zürich, CH-8006
Switzerland

Anna Kaiser

Heidelberg University - Central Institute of Mental Health

Mannheim, 68159
Germany

Sarah Hohmann

Heidelberg University - Central Institute of Mental Health

Grabengasse 1
Heidelberg, 69117
Germany

Alexander Haege

Heidelberg University - Department of Child and Adolescent Psychiatry and Psychotherapy ( email )

Mannheim, 68159
Germany

Samuele Cortese

University of Southampton - Centre for Innovation in Mental Health

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

University of Nottingham - Division of Psychiatry and Applied Psychology

University Park
Nottingham, NG7 2RD
United Kingdom

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