Advertisement

CNS Drugs

, Volume 33, Issue 10, pp 971–980 | Cite as

Meta-Analysis of Placebo Response in Adult Antidepressant Trials

  • Fenghua Li
  • Madeeha Nasir
  • Baris Olten
  • Michael H. BlochEmail author
Systematic Review

Abstract

Background

Roughly 80% of the symptom improvement experienced on antidepressants in clinical trials is also observed in the placebo comparison group. Understanding the correlates of placebo improvement and response is important to designing efficient and successful trials of future antidepressants.

Objective

The objective of this meta-analysis was to investigate the magnitude of placebo symptom improvement and placebo response rates in second-generation antidepressant trials of depression, anxiety, and obsessive-compulsive disorder.

Methods

We searched PubMed on 10 June, 2016, with no date or language limits, to identify randomized placebo-controlled trials of second-generation antidepressants in adults with depression, anxiety, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the magnitude of placebo symptom improvement using standardized mean difference and placebo response rate. Stratified subgroup analysis and meta-regression were utilized to examine the effect of diagnostic indication and correlates of placebo symptom improvement.

Results

The meta-analysis included 164 trials involving 19,591 participants. Magnitude of placebo improvement and placebo response rates varied significantly between diagnostic indications. The magnitude of placebo improvement was much lower in obsessive-compulsive disorder (standardized mean difference = 0.58, 95% confidence interval 0.36–0.79) than in depression (standardized mean difference = 1.22, 95% confidence interval 1.12–1.32) or anxiety (standardized mean difference = 1.01, 95% confidence interval 0.90–1.12) trials. There was a large amount of heterogeneity in placebo improvement between studies (Q = 899, df = 110, p < 0.001, I2 = 88%). A greater number of study sites and a later publication year were associated with a greater magnitude of placebo improvement and response rate. Presence of a placebo lead-in and absence of non-US sites were associated with a reduced magnitude of placebo improvement. Trial duration was positively associated with the magnitude of placebo improvement in depression trials but negatively associated with the magnitude of placebo improvement in anxiety and obsessive-compulsive disorder trials.

Conclusions

Magnitude of placebo symptom improvement differed significantly based on diagnostic indication with improvement being significantly less in obsessive-compulsive disorder than anxiety and depression. Some trial characteristics were associated with a greater magnitude of placebo improvement in trials across disorders but others were disorder specific.

Notes

Acknowledgements

The authors are grateful to Chad Beyer and Kiley Cappetta for their assistance in the study selection and data extraction.

Compliance with Ethical Standards

Funding

No sources of funding were received for the preparation of this article.

Conflict of interest

Michael H. Bloch receives research support from Therapix Biosciences, Neurocrine Biosciences, Janssen Pharmacueticals, and Biohaven Pharmaceuticals. He also gratefully acknowledges additional research support from NIH, NARSAD, and the Patterson Foundation. Fenghua Li, Madeeha Nasir, and Baris Olten have no conflicts of interest that are directly relevant to the content of this article. This article was completed in compliance with the recommendations for the Conduct, Reporting, Editing and Publication of Scholarly work in Medical Journals’ issued by the International Committee for Medical Journal Editors.

Supplementary material

40263_2019_662_MOESM1_ESM.docx (218 kb)
Supplementary material 1 (DOCX 218 kb)

References

  1. 1.
    Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382(9904):1575–86.CrossRefPubMedGoogle Scholar
  2. 2.
    Bose A, Korotzer A, Gommoll C, Li D. Randomized placebo-controlled trial of escitalopram and venlafaxine XR in the treatment of generalized anxiety disorder. Depress Anxiety. 2008;25(10):854–61.CrossRefPubMedGoogle Scholar
  3. 3.
    Coric V, Feldman HH, Oren DA, Shekhar A, Pultz J, Dockens RC, et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress Anxiety. 2010;27(5):417–25.CrossRefPubMedGoogle Scholar
  4. 4.
    Lepola UM, Loft H, Reines EH. Escitalopram (10–20 mg/day) is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol. 2003;18(4):211–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Stein DJ, Wreford Andersen E, Tonnoir B, Fineberg N. Escitalopram in obsessive-compulsive disorder: a randomized, placebo-controlled, paroxetine-referenced, fixed-dose, 24-week study. Curr Med Res Opin. 2007;23(4):701–11.CrossRefPubMedGoogle Scholar
  6. 6.
    Khin NA, Chen Y-F, Yang Y, Yang P, Laughren TP. Exploratory analyses of efficacy data from major depressive disorder trials submitted to the US Food and Drug Administration in support of new drug applications. J Clin Psychiatry. 2011;72(4):464–72.CrossRefPubMedGoogle Scholar
  7. 7.
    Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013;170(7):723–33.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kirsch I. Antidepressants and the placebo effect. Z Psychol. 2014;222(3):128–34.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Khan A, Detke M, Khan SR, Mallinckrodt C. Placebo response and antidepressant clinical trial outcome. J Nerv Ment Dis. 2003;191(4):211–8.PubMedGoogle Scholar
  10. 10.
    Weimer K, Colloca L, Enck P. Placebo effects in psychiatry: mediators and moderators. Lancet Psychiatry. 2015;2(3):246–57.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Furukawa TA, Cipriani A, Atkinson LZ, Leucht S, Ogawa Y, Takeshima N, et al. Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies. Lancet Psychiatry. 2016;3(11):1059–66.CrossRefPubMedGoogle Scholar
  12. 12.
    Meister R, Jansen A, Härter M, Nestoriuc Y, Kriston L. Placebo and nocebo reactions in randomized trials of pharmacological treatments for persistent depressive disorder: a meta-regression analysis. J Affect Disord. 2017;215:288–98.CrossRefPubMedGoogle Scholar
  13. 13.
    Stein DJ, Baldwin DS, Dolberg OT, Despiegel N, Bandelow B. Which factors predict placebo response in anxiety disorders and major depression? An analysis of placebo-controlled studies of escitalopram. J Clin Psychiatry. 2006;67(11):1741–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Huppert JD, Schultz LT, Foa EB, Barlow DH, Davidson JR, Gorman JM, et al. Differential response to placebo among patients with social phobia, panic disorder, and obsessive-compulsive disorder. Am J Psychiatry. 2004;161(8):1485–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Keck PE Jr, Welge JA, McElroy SL, Arnold LM, Strakowski SM. Placebo effect in randomized, controlled studies of acute bipolar mania and depression. Biol Psychiatry. 2000;47(8):748–55.CrossRefPubMedGoogle Scholar
  16. 16.
    Reyes MM, Panza KE, Martin A, Bloch MH. Time-lag bias in trials of pediatric antidepressants: a systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2011;50(1):63–72.CrossRefPubMedGoogle Scholar
  17. 17.
    Rutherford BR, Pott E, Tandler JM, Wall MM, Roose SP, Lieberman JA. Placebo response in antipsychotic clinical trials: a meta-analysis. JAMA Psychiatry. 2014;71(12):1409–21.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Nutt D. Anxiety and depression: individual entities or two sides of the same coin? Int J Psychiatry Clin Pract. 2004;8(Suppl.):19–24.CrossRefPubMedGoogle Scholar
  19. 19.
    Fava M, Rush AJ, Alpert JE, Balasubramani G, Wisniewski SR, Carmin CN, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342–51.CrossRefPubMedGoogle Scholar
  20. 20.
    Blier P, de Montigny C. Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology. 1999;21(2):91S–8S.CrossRefPubMedGoogle Scholar
  21. 21.
    Greenberg RP, Fisher S, Riter JA. Placebo washout is not a meaningful part of antidepressant drug trials. Percept Mot Skills. 1995;81(2):688–90.CrossRefPubMedGoogle Scholar
  22. 22.
    Geers AL, Helfer SG, Kosbab K, Weiland PE, Landry SJ. Reconsidering the role of personality in placebo effects: dispositional optimism, situational expectations, and the placebo response. J Psychosom Res. 2005;58(2):121–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Locher C, Koechlin H, Zion SR, Werner C, Pine DS, Kirsch I, et al. Efficacy and safety of selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74(10):1011–20.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rief W, Nestoriuc Y, Weiss S, Welzel E, Barsky AJ, Hofmann SG. Meta-analysis of the placebo response in antidepressant trials. J Affect Disord. 2009;118(1–3):1–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Yale Child Study Center, Yale University School of MedicineNew HavenUSA
  2. 2.Key Lab of Mental HealthInstitute of Psychology, Chinese Academy of SciencesBeijingPeople’s Republic of China
  3. 3.Yale Department of Psychiatry, Yale University School of MedicineNew HavenUSA

Personalised recommendations