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Review

Efficacy of antidepressants: bias in randomized clinical trials and related issues

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Pages 15-25 | Received 02 Jul 2017, Accepted 05 Sep 2017, Published online: 14 Sep 2017

References

  • Every-Palmer S, Howick J. How evidence-based medicine is failing due to biased trials and selective publication. J Eval Clin Pract. 2014;20(6):908–914.
  • Ioannidis JP. Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials? Philos Ethics Humanit Med. 2008;3:14.
  • Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 2015;23(1):1–21.
  • Scott S. We Still Listen to Prozac? Peter D. Kramer Jumps Back Into the Antidepressant Debate. New York Times [Internet]. 2016 Jul 7 [cited 2017 Aug 19]; Book Review:[about 4 screens]. Available from: https://www.nytimes.com/2016/07/10/books/review/peter-d-kramer-ordinarily-well-about-antidepressants.html?mcubz=1.
  • Quitkin FM, Rabkin JG, Gerald J, et al. Validity of clinical trials of antidepressants. Am J Psychiatry. 2000;157(3):327–337.
  • Pacher P, Kecskemeti V. Trends in the development of new antidepressants. Is there a light at the end of the tunnel? Curr Med Chem. 2004;11(7):925–943.
  • Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015;95(2):81–97.
  • Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5(2):e45.
  • Spina E. Efficacy of antidepressants: issues related to bias in clinical trials. Clin Ther. 2016;38(10S):e2.
  • Mahableshwarkar AR, Jacobsen PL, Serenko M, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of 2 doses of vortioxetine in adults with major depressive disorder. J Clin Psychiatry. 2015;76(5):583–591.
  • Mathews M, Gommoll C, Chen D, et al. Efficacy and safety of vilazodone 20 and 40 mg in major depressive disorder: a randomized, double-blind, placebo-controlled trial. Int Clin Psychopharmacol. 2015;30(2):67–74.
  • Nutt D. Anxiety and depression: individual entities or two sides of the same coin? Int J Psychiatry Clin Pract. 2004;8(Suppl 1):19–24.
  • Wisniewski SR, Rush AJ, Nierenberg AA, et al. Can phase III trial results of antidepressant medications be generalized to clinical practice? A STAR*D report. Am J Psychiatry. 2009;166(5):599–607.
  • Schwartzbaum J, Ahlbom A, Feychting M. Berkson’s bias reviewed. Eur J Epidemiol. 2003;18(12):1109–1112.
  • Westreich D. Berkson’s bias, selection bias, and missing data. Epidemiology. 2012;23(1):159–164.
  • Sharpe N. Clinical trials and the real world: selection bias and generalisability of trial results. Cardiovasc Drugs Ther. 2002;16(1):75–77.
  • Subramaniam M, Abdin E, Vaingankar JA, et al. Comorbid diabetes and depression among older adults - prevalence, correlates, disability and healthcare utilisation. Ann Acad Med Singapore. 2017;46(3):91–101.
  • Scott NW, McPherson GC, Ramsay CR, et al. The method of minimization for allocation to clinical trials. a review. Control Clin Trials. 2002;23(6):662–674.
  • Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273(5):408–412.
  • Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303(1):47–53.
  • Juni P, Commentary: EM. Empirical evidence of attrition bias in clinical trials. Int J Epidemiol. 2005;34(1):87–88.
  • Tierney JF, Stewart LA. Investigating patient exclusion bias in meta-analysis. Int J Epidemiol. 2005;34(1):79–87.
  • Ellis AR, Dusetzina SB, Hansen RA, et al. Confounding control in a nonexperimental study of STAR*D data: logistic regression balanced covariates better than boosted CART. Ann Epidemiol. 2013;23(4):204–209.
  • VanderWeele TJ. On the distinction between interaction and effect modification. Epidemiology. 2009;20(6):863–871.
  • Vetter TR, Mascha EJ. Bias, confounding, and interaction: lions and tigers, and bears, oh my! Anesth Analg. 2017;125(3):1042–1048.
  • Casilla-Lennon MM, Meltzer-Brody S, Steiner AZ. The effect of antidepressants on fertility. Am J Obstet Gynecol. 2016;215(3):314 e311–315.
  • Rief W, Bingel U, Schedlowski M, et al. Mechanisms involved in placebo and nocebo responses and implications for drug trials. Clin Pharmacol Ther. 2011;90(5):722–726.
  • DeSouza CM, Legedza AT, Sankoh AJ. An overview of practical approaches for handling missing data in clinical trials. J Biopharm Stat. 2009;19(6):1055–1073.
  • Bell ML, Kenward MG, Fairclough DL, et al. Differential dropout and bias in randomised controlled trials: when it matters and when it may not. Bmj. 2013;346:e8668.
  • Sedgwick P. Intention to treat analysis versus per protocol analysis of trial data. Bmj. 2015;350:h681.
  • Ranganathan P, Pramesh CS, Aggarwal R. Common pitfalls in statistical analysis: intention-to-treat versus per-protocol analysis. Perspect Clin Res. 2016;7(3):144–146.
  • Lachin JM. Statistical considerations in the intent-to-treat principle. Control Clin Trials. 2000;21(3):167–189.
  • Helms RW. Precise definitions of some terminology for longitudinal clinical trials: subjects, patient populations, analysis sets, intention to treat, and related terms. Pharm Stat. 2016;15(6):471–485.
  • Shrier I, Verhagen E, Stovitz SD. The intention-to-treat analysis is not always the conservative approach. Am J Med. 2017;130(7):867–871.
  • D’Agostino RB Sr., Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues - the encounters of academic consultants in statistics. Stat Med. 2003;22(2):169–186.
  • Streiner DL. Missing data and the trouble with LOCF. Evid Based Ment Health. 2008;11(1):3–5.
  • Liu G, Gould AL. Comparison of alternative strategies for analysis of longitudinal trials with dropouts. J Biopharm Stat. 2002;12(2):207–226.
  • Siddiqui O, Ali MW. A comparison of the random-effects pattern mixture model with last-observation-carried-forward (LOCF) analysis in longitudinal clinical trials with dropouts. J Biopharm Stat. 1998;8(4):545–563.
  • Woolley SB, Cardoni AA, Goethe JW. Last-observation-carried-forward imputation method in clinical efficacy trials: review of 352 antidepressant studies. Pharmacotherapy. 2009;29(12):1408–1416.
  • Prakash A, Risser RC, Mallinckrodt CH. The impact of analytic method on interpretation of outcomes in longitudinal clinical trials. Int J Clin Pract. 2008;62(8):1147–1158.
  • Siddiqui O, Hung HM, O’Neill R. MMRM vs. LOCF: a comprehensive comparison based on simulation study and 25 NDA datasets. J Biopharm Stat. 2009;19(2):227–246.
  • Lane P. Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches. Pharm Stat. 2008;7(2):93–106.
  • Baker CB, Johnsrud MT, Crismon ML, et al. Quantitative analysis of sponsorship bias in economic studies of antidepressants. Br J Psychiatry. 2003;183:498–506.
  • Cristea IA, Gentili C, Pietrini P, et al. Sponsorship bias in the comparative efficacy of psychotherapy and pharmacotherapy for adult depression: meta-analysis. Br J Psychiatry. 2017;210(1):16–23.
  • Sedgwick P. What is publication bias in a meta-analysis? Bmj. 2015;351:h4419.
  • Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358(3):252–260.
  • Smith R. Medical journals are an extension of the marketing arm of pharmaceutical companies. PLoS Med. 2005;2(5):e138.
  • Kyzas PA, Loizou KT, Ioannidis JP. Selective reporting biases in cancer prognostic factor studies. J Natl Cancer Inst. 2005;97(14):1043–1055.
  • Bruyere O, Kanis JA, Ibar-Abadie ME, et al. The need for a transparent, ethical, and successful relationship between academic scientists and the pharmaceutical industry: a view of the Group for the Respect of Ethics and Excellence in Science (GREES). Osteoporos Int. 2010;21(5):713–722.
  • McGoldrick RB, Hui K, Chang J. Bench to bedside: integrating advances in basic science into daily clinical practice. Hand Clin. 2014;30(3):305–317, vi.
  • Moher D, Fortin P, Jadad AR, et al. Completeness of reporting of trials published in languages other than English: implications for conduct and reporting of systematic reviews. Lancet. 1996;347(8998):363–366.
  • Egger M, Zellweger-Zahner T, Schneider M, et al. Language bias in randomised controlled trials published in English and German. Lancet. 1997;350(9074):326–329.
  • Middleton H, Shaw I, Hull S, et al. NICE guidelines for the management of depression. Bmj. 2005;330(7486):267–268.
  • Kirsch I. Antidepressants and the Placebo Effect. Z Psychol. 2014;222(3):128–134.
  • McCarney R, Warner J, Iliffe S, et al. The Hawthorne Effect: a randomised. Controlled Trial. BMC Med Res Methodol. 2007;7:30.
  • John MM. The “Pygmalion Effect” and Surgical Mentoring. Indian J Surg. 2016;78(1):79.
  • Barber C, Fraser JF, Mendez GG, et al. The Halo Effect: an Unintended Benefit of Care Pathways. J Knee Surg. 2017;30(3):264–268.
  • Davidson OB, Eden D. Remedial self-fulfilling prophecy: two field experiments to prevent Golem effects among disadvantaged women. J Appl Psychol. 2000;85(3):386–398.
  • Isacsson G, Adler M. Randomized clinical trials underestimate the efficacy of antidepressants in less severe depression. Acta Psychiatr Scand. 2012;125(6):453–459.
  • Bech P. Rating scales in depression: limitations and pitfalls. Dialogues Clin Neurosci. 2006;8(2):207–215.
  • Iannuzzo RW, Jaeger J, Goldberg JF, et al. Development and reliability of the HAM-D/MADRS interview: an integrated depression symptom rating scale. Psychiatry Res. 2006;145(1):21–37.
  • O’Sullivan RL, Fava M, Agustin C, et al. Sensitivity of the six-item Hamilton Depression Rating Scale. Acta Psychiatr Scand. 1997;95(5):379–384.
  • Boessen R, Groenwold RH, Knol MJ, et al. Comparing HAMD(17) and HAMD subscales on their ability to differentiate active treatment from placebo in randomized controlled trials. J Affect Disord. 2013;145(3):363–369.
  • Stewart-Williams S, Podd J. The placebo effect: dissolving the expectancy versus conditioning debate. Psychol Bull. 2004;130(2):324–340.
  • Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013;170(7):723–733.
  • Hicks M, D H, Wahbeh H. Expectancy effect in three mind-body clinical trials. J Evid Based Complementary Altern Med. 2016;21(4):NP103–109.
  • Rutherford BR, Wall MM, Glass A, et al. The role of patient expectancy in placebo and nocebo effects in antidepressant trials. J Clin Psychiatry. 2014;75(10):1040–1046.
  • Mojtabai R, Olfson M. National patterns in antidepressant treatment by psychiatrists and general medical providers: results from the national comorbidity survey replication. J Clin Psychiatry. 2008;69(7):1064–1074.
  • Stettin GD, Yao J, Verbrugge RR, et al. Frequency of follow-up care for adult and pediatric patients during initiation of antidepressant therapy. Am J Manag Care. 2006;12(8):453–461.
  • Vieta E, Carne X. The use of placebo in clinical trials on bipolar disorder: a new approach for an old debate. Psychother Psychosom. 2005;74(1):10–16.
  • Rutherford BR, Sneed JR, Tandler JM, et al. Deconstructing pediatric depression trials: an analysis of the effects of expectancy and therapeutic contact. J Am Acad Child Adolesc Psychiatry. 2011;50(8):782–795.
  • Nierenberg AA, Ostergaard SD, Iovieno N, et al. Predictors of placebo response in bipolar depression. Int Clin Psychopharmacol. 2015;30(2):59–66.
  • Bass MJ, Buck C, Turner L, et al. The physician’s actions and the outcome of illness in family practice. J Fam Pract. 1986;23(1):43–47.
  • Barnett AG, Van der Pols JC, Dobson AJ. Regression to the mean: what it is and how to deal with it. Int J Epidemiol. 2005;34(1):215–220.
  • Streiner DL. Regression toward the mean: its etiology, diagnosis, and treatment. Can J Psychiatry. 2001;46(1):72–76.
  • Streiner DL. Statistics commentary series: commentary #16-regression toward the mean. J Clin Psychopharmacol. 2016;36(5):416–418.
  • Rutherford BR, Mori S, Sneed JR, et al. Contribution of spontaneous improvement to placebo response in depression: a meta-analytic review. J Psychiatr Res. 2012;46(6):697–702.
  • Kisely S, Scott A, Denney J, et al. Duration of untreated symptoms in common mental disorders: association with outcomes: international study. Br J Psychiatry. 2006;189:79–80.
  • Gelenberg AJ. A review of current guidelines for depression treatment. J Clin Psychiatry. 2010;71(7):e15.
  • Godwin M, Ruhland L, Casson I, et al. Pragmatic controlled clinical trials in primary care: the struggle between external and internal validity. BMC Med Res Methodol. 2003;3:28.
  • Bschor T, Kilarski LL. Are antidepressants effective? A debate on their efficacy for the treatment of major depression in adults. Expert Rev Neurother. 2016;16(4):367–374.
  • Doucet M, Sismondo S. Evaluating solutions to sponsorship bias. J Med Ethics. 2008;34(8):627–630.
  • Tagore A. Drug promotion tactics-yet another pharma deception? Int J Clin Pract. 2014;68(6):662–665.
  • Nutt D, Goodwin G. ECNP summit on the future of CNS drug research in Europe 2011: report prepared for ECNP by David Nutt and Guy Goodwin. Eur Neuropsychopharmacol. 2011;21(7):495–499.
  • Hendrie CA. The funding crisis in psychopharmacology: an historical perspective. J Psychopharmacol. 2010;24(3):439–440.
  • Gartlehner G, Hansen RA, Nissman D, et al. Criteria for distinguishing effectiveness from efficacy trials in systematic reviews. Rockville (MD):Agency for Healthcare Research and Quality (US); 2006.
  • ICH.org [Internet]. Geneva Switzerland:  ICH Topic E10: Choice of control groups in clinical trials [cited 2017 Aug 13]. Available from: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E10/Step4/E10_Guideline.pdf.
  • Friedman JH. Randomized, double-blind, placebo-controlled trials: the gold standard? Med Health R I. 2004;87(9):262–263.
  • Gispen-De Wied C, Stoyanova V, Yu Y, et al. The placebo arm in clinical studies for treatment of psychiatric disorders: a regulatory dilemma. Eur Neuropsychopharmacol. 2012;22(11):804–811.
  • Simon R, Blumenthal GM, Rothenberg ML, et al. The role of nonrandomized trials in the evaluation of oncology drugs. Clin Pharmacol Ther. 2015;97(5):502–507.
  • Eichler HG, Bloechl-Daum B, Bauer P, et al. “Threshold-crossing”: a useful way to establish the counterfactual in clinical trials? Clin Pharmacol Ther. 2016;100(6):699–712.
  • Kirsch I. The use of placebos in clinical trials and clinical practice. Can J Psychiatry. 2011;56(4):191–192.

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