Nocebo Response in Attention Deficit Hyperactivity Disorder: Meta-Analysis and Meta-Regression of 105 Randomized Clinical Trials

Abstract

Objective:

To determine nocebo response in ADHD, identify covariates modifying nocebo response, and study the relationship between nocebo response and drug safety.

Method:

Systematic review of randomized, double-blind, placebo-controlled clinical trials (RCT) investigating the efficacy and safety of pharmacological interventions for ADHD patients. The influence of covariates was studied using meta-regression.

Results:

A total of 105 studies with 8,743 patients in placebo arms were included. Slightly over half (55.5%) of the patients experienced adverse events (AE) while receiving placebo. Nocebo response was associated positively with age, treatment length and method for collecting AEs. Studies with the largest nocebo response showcased the greatest drug response and the best outcome for drug safety.

Conclusion:

Nocebo response in ADHD RCTs is remarkable, showing a positive relationship with drug response, and a negative relationship with drug safety.

Keywords

ADHD meta-analysis meta-regression nocebo response

Get full access to this article

View all access options for this article.

References

Alam

J. M.

Hadjivassiliou

Zis

(2019). Nocebo in cerebellar ataxia: A systematic review and meta-analysis of placebo-controlled clinical trials. Journal of Neurological Sciences, 401(March), 112–117. https://doi.org/10.1016/j.jns.2019.04.039

Allen

E. N.

Chandler

C. I.

Mandimika

Leisegang

Barnes

(2018). Eliciting adverse effects data from participants in clinical trials. Cochrane Database of Systematic Reviews, 1, MR000039. https://doi.org/10.1002/14651858.MR000039.pub2

Azur

M. J.

Stuart

E. A.

Frangakis

Leaf

P. J.

(2011). Multiple imputation by chained equations: What is it and how does it work? International Journal of Methods in Psychiatric Research, 20(1), 40–49. https://doi.org/10.1002/mpr.329

Barsky

A. J.

Saintfort

Rogers

M. P.

Borus

J. F.

(2002). Nonspecific medication side effects and the Nocebo phenomenon. The Journal of the American Medical Association, 287(5), 622–627. https://doi.org/10.1001/jama.287.5.622

Benedetti

Frisaldi

Piedimonte

(2019). The need to investigate nocebo effects in more detail. World Psychiatry, 18(2), 227–228. https://doi.org/10.1002/wps.20627

Benedetti

Lanotte

Lopiano

Colloca

(2007). When words are painful: Unraveling the mechanisms of the nocebo effect. Neuroscience, 147(2), 260–271. https://doi.org/10.1016/j.neuroscience.2007.02.020

Borenstein

Higgins

J. P.

(2013). Meta-Analysis and subgroups. Prevention Science, 14(2), 134–143. https://doi.org/10.1007/s11121-013-0377-7

Buitelaar

J. K.

Sobanski

Stieglitz

R. D.

Dejonckheere

Waechter

Schäuble

(2012). Predictors of placebo response in adults with attention-deficit/hyperactivity disorder: Data from 2 randomized trials of osmotic-release oral system methylphenidate. Journal of Clinical Psychiatry, 73(8), 1097–1102. https://doi.org/10.4088/JCP.11m07528

Castells

Baykova

Mayoral

Cunill

Serrano

(2020a). P.054 gender bias in randomized, controlled trials of pharmacological interventions for attention deficit hyperactivity disorder. European Neuropsychopharmacology, 40(Supplement 1), S36–S37. https://doi.org/10.1016/j.euroneuro.2020.09.052

10.

Castells

Ramon

Cunill

Olivé

Serrano

(2020b). Relationship between treatment duration and efficacy of pharmacological treatment for ADHD: A meta-analysis and meta-regression of 87 randomized controlled clinical trials. Journal of Attention Disorders, 25, 1352–1361. https://doi.org/10.1177/1087054720903372

11.

Castells

Saez

Barcheni

Cunill

Serrano

López

van Lissa

C. J.

(2021a). Placebo response and its predictors in attention deficit hyperactivity disorder: A meta-analysis and comparison of meta-regression and MetaForest. The International Journal of Neuropsychopharmacology, 25, 26–35. https://doi.org/10.1093/ijnp/pyab054

12.

Castells

Barshini

Cunill

(2021b). P.0635 influence of age on placebo response in children and adolescents with ADHD: A meta-regression analysis of 58 studies. European Neuropsychopharmacology, 53, S467–S468.

13.

Chen

Y.-F.

Wang

S.-J.

Khin

N. A.

Hung

H. M.

Laughren

T. P.

(2010). Trial design issues and treatment effect modeling in multi-regional schizophrenia trials. Pharmaceutical Statistics, 9(3), 217–229. https://doi.org/10.1002/pst.439

14.

Craig

S. G.

Davies

Schibuk

Weiss

M. D.

Hechtman

(2015). Long-Term effects of stimulant treatment for ADHD: What Can we tell our patients? Current Developmental Disorders Reports, 2(1), 1–9. https://doi.org/10.1007/s40474-015-0039-5

15.

DerSimonian

Laird

(1986). Meta-analysis in clinical trials. Controlled Clinical Trials, 7(3), 177–188. https://doi.org/10.1016/0197-2456(86)90046-2

16.

Dodd

Dean

O. M.

Vian

Berk

(2017). A review of the theoretical and biological understanding of the nocebo and placebo phenomena. Clinical Therapeutics, 39(3), 469–476. https://doi.org/10.1016/j.clinthera.2017.01.010

17.

Dodd

Walker

A. J.

Brnabic

A. J. M.

Hong

Burns

Berk

(2019). Incidence and characteristics of the nocebo response from meta-analyses of the placebo arms of clinical trials of olanzapine for bipolar disorder. Bipolar Disorders, 21(2), 142–150. https://doi.org/10.1111/bdi.12662

18.

Doove

L. L.

Van Buuren

Dusseldorp

(2014). Recursive partitioning for missing data imputation in the presence of interaction effects. Computational Statistics & Data Analysis, 72, 92–104. https://doi.org/10.1016/j.csda.2013.10.025

19.

Egger

Davey Smith

Schneider

Minder

(1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315(7109), 629–634. https://doi.org/10.1136/bmj.315.7109.629

20.

Enck

Benedetti

Schedlowski

(2008). New insights into the placebo and nocebo responses. Neuron, 59(2), 195–206. https://doi.org/10.1016/j.neuron.2008.06.030

21.

Faraone

S. V.

Newcorn

J. H.

Cipriani

Brandeis

Kaiser

Hohmann

Haege

Cortese

(2021). Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: A systematic review and meta-analysis. Molecular Psychiatry. Advance online publication. https://doi.org/10.1038/s41380-021-01134-w

22.

Fox

Monette

(1992). Generalized collinearity diagnostics. Journal of the American Statistical Association, 87(417), 178–183. https://doi.org/10.1080/01621459.1992.10475190

23.

Gklinos

Papadopoulos

Mitsikostas

D. D.

(2019). Nocebo in multiple sclerosis trials: A meta-analysis on oral and newer injectable disease-modifying treatments. Multiple Sclerosis and Related Disorders, 36(July), 101389. https://doi.org/10.1016/j.msard.2019.101389

24.

Greenland

Morgenstern

(1989). Ecological bias, confounding, and effect modification. International Journal of Epidemiology, 18(1), 269–274. https://doi.org/10.1093/ije/18.1.269

25.

Hauser

Bartram

Bartram-Wunn

Tolle

(2014). Adverse events attributable to Nocebo in randomized controlled drug trials in fibromyalgia syndrome and painful diabetic peripheral neuropathy. Clinical Journal of Pain, 30(3), 278. https://doi.org/10.1097/ajp.0000000000000073

26.

Higgins

J. P. T.

Altman

D. G.

Sterne

J. A. C.

(Eds.). (2011). Chapter 8: Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions. Retrieved January 2, 2021, from https://handbook-5-1.cochrane.org/chapter_8/8_assessing_risk_of_bias_in_included_studies.htm

27.

Higgins

J. P. T.

Thompson

S. G.

(2002). Quantifying heterogeneity in a meta-analysis. Statistics in Medicine, 21(11), 1539–1558. https://doi.org/10.1002/sim.1186

28.

Kemp

A. S.

Schooler

N. R.

Kalali

A. H.

Alphs

Anand

Awad

Davidson

Dubé

Ereshefsky

Gharabawi

Leon

A. C.

Lepine

J. P.

Potkin

S. G.

Vermeulen

(2010). What is causing the reduced drug-placebo difference in recent schizophrenia clinical trials and what can be done about it? Schizophrenia Bulletin, 36(3), 504–509. https://doi.org/10.1093/schbul/sbn110

29.

Khan

Fahl Mar

Brown

W. A.

(2017a). Does the increasing placebo response impact outcomes of adult and pediatric ADHD clinical trials? Data from the US food and drug administration 2000–2009. Journal of Psychiatric Research, 94, 202–207. https://doi.org/10.1016/j.jpsychires.2017.07.018

30.

Khan

Fahl Mar

Faucett

Khan Schilling

Brown

W. A.

(2017b). Has the rising placebo response impacted antidepressant clinical trial outcome? Data from the US food and drug administration 1987–2013. World Psychiatry, 16(2), 181–192. https://doi.org/10.1002/wps.20421

31.

Kong

Gollub

R. L.

Polich

Kirsch

LaViolette

Vangel

Rosen

Kaptchuk

T. J.

(2008). A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect. Journal of Neuroscience, 28(49), 13354–13362. https://doi.org/10.1523/jneurosci.2944-08.2008

32.

Leal Rato

Duarte

G. S.

Ferreira

A. N.

Alves

Mainoli

Teodoro

Mestre

T. A.

Costa

Ferreira

J. J

. (2019). Nocebo response in Parkinson’s disease: A systematic review and meta-analysis. Parkinsonism & Related Disorders, 65(April), 13–19. https://doi.org/10.1016/j.parkreldis.2019.04.015

33.

Leucht

Chaimani

Mavridis

Leucht

Huhn

Helfer

Samara

Cipriani

Geddes

J. R.

Davis

J. M.

(2019). Disconnection of drug-response and placebo-response in acute-phase antipsychotic drug trials on schizophrenia? Meta-regression analysis. Neuropsychopharmacology, 44(11), 1955–1966. https://doi.org/10.1038/s41386-019-0440-6

34.

Meister

Jansen

Härter

Nestoriuc

Kriston

(2017). Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder. A meta-regression analysis. Journal of Affective Disorders, 215, 288–298. https://doi.org/10.1016/j.jad.2017.03.024

35.

Minerva Database. (2021, December 13). Minerva database. https://www.minervadatabase.org/en/

36.

Mitsikostas

D. D.

Mantonakis

Chalarakis

(2014). Nocebo in clinical trials for depression: A meta-analysis. Psychiatry Research, 215(1), 82–86. https://doi.org/10.1016/j.psychres.2013.10.019

37.

Mitsikostas

D. D.

Mantonakis

L. I.

Chalarakis

N. G.

(2011). Nocebo is the enemy, not placebo. A meta-analysis of reported side effects after placebo treatment in headaches. Cephalalgia, 31(5), 550–561. https://doi.org/10.1177/0333102410391485

38.

Newcorn

J. H.

Sutton

V. K.

Zhang

Wilens

Kratochvil

Emslie

G. J.

D’souza

D. N.

Schuh

L. M.

Allen

A. J.

(2009). Characteristics of placebo responders in pediatric clinical trials of attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 48(12), 1165–1172. https://doi.org/10.1097/CHI.0b013e3181bc730d

39.

Palermo

Giovannelli

Bartoli

Amanzio

(2019). Are patients with schizophrenia spectrum disorders more prone to manifest nocebo-like-effects? A meta-analysis of adverse events in placebo groups of double-blind antipsychotic trials. Frontiers in Pharmacology, 10, 502. https://doi.org/10.3389/fphar.2019.00502

40.

Papadopoulos

Mitsikostas

D. D.

(2012). A meta-analytic approach to estimating nocebo effects in neuropathic pain trials. Journal of Neurology, 259(3), 436–447. https://doi.org/10.1007/s00415-011-6197-4

41.

Rojas-Mirquez

J. C.

Rodriguez-Zuñiga

M. J.

Bonilla-Escobar

F. J.

Garcia-Perdomo

H. A.

Petkov

Becerra

Borsook

Linnman

(2014). Nocebo effect in randomized clinical trials of antidepressants in children and adolescents: Systematic review and meta-analysis. Frontiers in Behavioral Neuroscience, 8, 375. https://doi.org/10.3389/fnbeh.2014.00375

42.

Shafiq

Mitsikostas

D. D.

Zis

(2017). Nocebo in motor neuron disease: Systematic review and meta-analysis of placebo-controlled clinical trials. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 18(7–8), 576–582. https://doi.org/10.1080/21678421.2017.1335325

43.

Shah

A. D.

Bartlett

J. W.

Carpenter

Nicholas

Hemingway

(2014). Comparison of random forest and parametric imputation models for imputing missing data using MICE: A CALIBER study. American Journal of Epidemiology, 179(6), 764–774. https://doi.org/10.1093/aje/kwt312

44.

Sharp

S. J.

(2001). Analysing the relationship between treatment benefit and underlying risk: Precautions and recommendations. In Egger

Smith

G. D.

Altman

D. G.

(Eds.), Systematic reviews in health care (pp. 176–188). BMJ Publishing Group.

45.

Silva

M. A.

Duarte

G. S.

Camara

Rodrigues

F. B.

Fernandes

R. M.

Abreu

Mestre

Costa

Trenkwalder

Ferreira

J. J.

(2017). Placebo and nocebo responses in restless legs syndrome: A systematic review and meta-analysis. Neurology, 88(23), 2216–2224. https://doi.org/10.1212/WNL.0000000000004004

46.

Sysko

Walsh

B. T.

(2007). A systematic review of placebo response in studies of bipolar mania. Journal of Clinical Psychiatry, 68(8), 1213–1217. https://doi.org/10.4088/JCP.V68N0807

47.

Varma

Zis

(2019). Nocebo effect in myasthenia gravis: Systematic review and meta-analysis of placebo-controlled clinical trials. Acta Neurologica Belgica, 119, 257–264. https://doi.org/10.1007/s13760-019-01143-1

48.

Wernicke

J. F.

Faries

Milton

Weyrauch

(2005). Detecting treatment emergent adverse events in clinical trials : A comparison of spontaneously reported and solicited collection methods. Drug Safety, 28(11), 1057–1063. https://doi.org/10.2165/00002018-200528110-00006

49.

Yildiz

Vieta

Tohen

Baldessarini

R. J.

(2011). Factors modifying drug and placebo responses in randomized trials for bipolar mania. The International Journal of Neuropsychopharmacology, 14(07), 863–875. https://doi.org/10.1017/s1461145710001641

50.

Zaccara

Giovannelli

Franco

Cincotta

Tramacere

Verrotti

(2014). Adverse events, placebo and nocebo effects in placebo-treated paediatric patients with refractory focal epilepsies. Analysis of double-blind studies. Epilepsy Research, 108(10), 1685–1693. https://doi.org/10.1016/j.eplepsyres.2014.09.015

51.

Zis

Hadjivassiliou

Sarrigiannis

P. G.

Jenkins

T. M.

Mitsikostas

D. D.

(2018). Nocebo in chronic inflammatory demyelinating polyneuropathy; a systematic review and meta-analysis of placebo-controlled clinical trials. Journal of Neurological Sciences, 388, 79–83. https://doi.org/10.1016/j.jns.2018.03.009

52.

Zis

Mitsikostas

D. D.

(2015). Nocebo in Alzheimer’s disease: Meta-analysis of placebo-controlled clinical trials. Journal of Neurological Sciences, 355(1–2), 94–100. https://doi.org/10.1016/j.jns.2015.05.029

53.

Zis

Mitsikostas

D. D.

(2018). Nocebo responses in brain diseases: A systematic review of the current literature. International Review of Neurobiology, 139, 443–462. https://doi.org/10.1016/bs.irn.2018.07.025

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.01 MB

0.03 MB

0.06 MB

0.02 MB

0.17 MB

0.23 MB

0.02 MB