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.
AlamJ. M.HadjivassiliouM.ZisP. (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
2.
AllenE. N.ChandlerC. I.MandimikaN.LeisegangC.BarnesK. (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
3.
AzurM. J.StuartE. A.FrangakisC.LeafP. 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
4.
BarskyA. J.SaintfortR.RogersM. P.BorusJ. 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
5.
BenedettiF.FrisaldiE.PiedimonteA. (2019). The need to investigate nocebo effects in more detail. World Psychiatry, 18(2), 227–228. https://doi.org/10.1002/wps.20627
6.
BenedettiF.LanotteM.LopianoL.CollocaL. (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
BuitelaarJ. K.SobanskiE.StieglitzR. D.DejonckheereJ.WaechterS.SchäubleB. (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
9.
CastellsX.BaykovaE.MayoralS.CunillR.SerranoD. (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.
CastellsX.RamonM.CunillR.OlivéC.SerranoD. (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.
CastellsX.SaezM.BarcheniM.CunillR.SerranoD.LópezB.van LissaC. 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.
CastellsX.BarshiniM.CunillR. (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.
ChenY.-F.WangS.-J.KhinN. A.HungH. M.LaughrenT. 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.
CraigS. G.DaviesG.SchibukL.WeissM. D.HechtmanL. (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
DoddS.DeanO. M.VianJ.BerkM. (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.
DoddS.WalkerA. J.BrnabicA. J. M.HongN.BurnsA.BerkM. (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.
DooveL. L.Van BuurenS.DusseldorpE. (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.
EggerM.Davey SmithG.SchneiderM.MinderC. (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
FaraoneS. V.NewcornJ. H.CiprianiA.BrandeisD.KaiserA.HohmannS.HaegeA.CorteseS. (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
GklinosP.PapadopoulosD.MitsikostasD. 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.
GreenlandS.MorgensternH. (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.
HauserW.BartramC.Bartram-WunnE.TolleT. (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
HigginsJ. P. T.ThompsonS. G. (2002). Quantifying heterogeneity in a meta-analysis. Statistics in Medicine, 21(11), 1539–1558. https://doi.org/10.1002/sim.1186
28.
KempA. S.SchoolerN. R.KalaliA. H.AlphsL.AnandR.AwadG.DavidsonM.DubéS.EreshefskyL.GharabawiG.LeonA. C.LepineJ. P.PotkinS. G.VermeulenA. (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.
KhanA.Fahl MarK.BrownW. 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.
KhanA.Fahl MarK.FaucettJ.Khan SchillingS.BrownW. 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.
KongJ.GollubR. L.PolichG.KirschI.LaVioletteP.VangelM.RosenB.KaptchukT. 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 RatoM.DuarteG. S.FerreiraA. N.AlvesM.MainoliB.TeodoroT.MestreT. A.CostaJ.FerreiraJ. 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.
LeuchtS.ChaimaniA.MavridisD.LeuchtC.HuhnM.HelferB.SamaraM.CiprianiA.GeddesJ. R.DavisJ. 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.
MeisterR.JansenA.HärterM.NestoriucY.KristonL. (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
MitsikostasD. D.MantonakisL.ChalarakisN. (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.
MitsikostasD. D.MantonakisL. I.ChalarakisN. 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.
NewcornJ. H.SuttonV. K.ZhangS.WilensT.KratochvilC.EmslieG. J.D’souzaD. N.SchuhL. M.AllenA. 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.
PalermoS.GiovannelliF.BartoliM.AmanzioM. (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.
PapadopoulosD.MitsikostasD. 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-MirquezJ. C.Rodriguez-ZuñigaM. J.Bonilla-EscobarF. J.Garcia-PerdomoH. A.PetkovM.BecerraL.BorsookD.LinnmanC. (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.
ShafiqF.MitsikostasD. D.ZisP. (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.
ShahA. D.BartlettJ. W.CarpenterJ.NicholasO.HemingwayH. (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.
SharpS. J. (2001). Analysing the relationship between treatment benefit and underlying risk: Precautions and recommendations. In EggerM.SmithG. D.AltmanD. G. (Eds.), Systematic reviews in health care (pp. 176–188). BMJ Publishing Group.
45.
SilvaM. A.DuarteG. S.CamaraR.RodriguesF. B.FernandesR. M.AbreuD.MestreT.CostaJ.TrenkwalderC.FerreiraJ. 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.
SyskoR.WalshB. 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.
VarmaA.ZisP. (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.
WernickeJ. F.FariesD.MiltonD.WeyrauchK. (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.
YildizA.VietaE.TohenM.BaldessariniR. 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.
ZaccaraG.GiovannelliF.FrancoV.CincottaM.TramacereL.VerrottiA. (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.
ZisP.HadjivassiliouM.SarrigiannisP. G.JenkinsT. M.MitsikostasD. 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.
ZisP.MitsikostasD. 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.
ZisP.MitsikostasD. 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
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