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Many double-blind, placebo-controlled, antidepressant clinical trials conducted in patients with major depressive disorder (MDD) fail to separate the candidate drug from placebo. Multiple factors can affect trial outcomes including the patient’s expectations and motivation, the clinician’s ratings competency and reliability, and the design of the trial itself. Two factors affecting treatment outcome associated with trial design are 1) the reliability of the baseline measure, and 2) an early, indiscriminate symptomatic response following randomization that can occur regardless of treatment assignment.
The motivation to participate in the trial itself can influence the baseline measurement as well as the early symptomatic response that follows the baseline. An unreliable baseline measure will affect all subsequent symptomatic assessments during the clinical trial and may affect the interpretation of results.
The baseline measure is usually the primary contingency variable used to evaluate treatment outcome in clinical trials and is typically a single point in time measurement obtained sometime on the baseline day. It is well known that the symptoms of MDD naturally fluctuate during the day (diurnal variation) and from day to day as well. Consequently, it is unrealistic to presume that a single point in time measurement can accurately and reliably capture the true symptom severity of all MDD patients at baseline.
Several MDD trials have revealed an early symptomatic response that occurs shortly after randomization regardless of treatment assignment. It has been shown that the early symptomatic response may be sustained throughout the trial, includes patients assigned to placebo, and may impede signal detection at the end of the study.
This review explores the importance of baseline reliability and the influence of early symptomatic response in some clinical trials of MDD patients and considers an alternative assessment method (ecological momentary assessment) as an innovative strategy to improve the reliability of the baseline measurement.
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2. Kessler RC, Demler O, Frank RG, Olfson M, Pincus HA, Walters EE, Wang P, Wells KB, Zaslavsky AM. Prevalence and Treatment of Mental Disorders, 1990 to 2003. N Engl J Med 2005, 352:2515-2523.
3. Patel V, Chisholm D, Parikh R, Charlson FJ, Degenhardt L, Dua T, Ferrari AJ, Hyman S, Laxminarayan R, Levin C, Lund C, Medina Mora ME, Petersen I, Scott, J, Shidhaye R, Vijayakumar L, Thornicroft G, Whiteford H and Group, DMA. Addressing the burden of mental, neurological, and substance use disorders: key messages from Disease Control Priorities, 3rd edition. Lancet 2016, 387: 1672-85.
4. Cipriani A, Furukawa T., Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe H G, Turner EH, Higgins, JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JPA, Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018, 391, 1357-1366.
5. Fava, M., Evins, A., Dorer, D., Schoenfeld, D. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother. Psychosom. 2003, 72 (3): 115-127.
6. Targum, S.D., Pollack, M.H., Fava, M., Re-defining affective disorders: relevance for drug development. CNS Neurosci. Ther. 2008, 14: 2-9.
7. Lambert MJ. Handbook of Psychotherapy Integration. Basic Books, New York,
1992, pp. 94e129.
8. Kirsch I, Deacon BJ, Huedo-Medina, TB, Scoboria A, Moore TJ, Johnson BT.
Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008, 5, e45. http://dx.doi.org/10.1371/journal.pmed.0050045.
9. Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, et al. Components of the placebo effect: a randomized controlled trial in irritable bowel syndrome. BMJ 2008, 336: 999–1003.
10. Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One 2010; 5(12):e15591. http://dx.doi.org/10.1371/journal.pone.0015591.
11. Kirsch I. Antidepressants and the Placebo Effect. Zeitschrift fur Psychologie
12. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960, 23:56-62.
13. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Brit J Psychiat., 1979, 134:382-389.
14. Faries DF, Heiligenstein JH, Tollefson GD, Potter WZ. The double blind variable placebo lead-in period: results from two antidepressant clinical trials. J. Clin. Psychopharmacol. 2001, 6: 561-568.
15. Evans KR, Sills T, Wunderlich GR, McDonald HP. Worsening of depressive symptoms prior to randomization in clinical trials: a possible screen for placebo responders?
J Psychiatric Res., 2004, 38:437–44.
16. Targum SD, Cameron BR, Ferreira L, MacDonald ID. Early score fluctuation and placebo response in a study of major depressive disorder. J Psychiatr. Res. 2020, 121: 118-125.
17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth edition, 2013. Arlington VA: American Psychiatric Press.
18. Peeters F, Berkhof J, Delespaul P, Rottenberg J, Nicolson NA. Diurnal mood variation in major depressive disorder. Emotion 2006, 6 (3): 383-391.
19. Morris DW, Rush AJ, Jain S, Fava M, Wisniewski SR, Balasubramani GK, Khan AY, Trivedi MH. Diurnal mood variation in outpatients with major depressive disorder: implications for DSM-V from an analysis of the Sequenced Treatment Alternatives to Relieve Depression Study data. J Clin Psychiatry 2007, 68 (9): 1339-1347.
20. Kobak KA, Kane JM, Thase, ME, Nierenberg AA. Why do clinical trials Fail? the problem of measurement error in clinical trials: time to test new paradigms? J. Clin. Psychopharmacol. 2007, 27 (1): 1-5.
21. Quitkin FM, Rabkin JG, McGrath PJ, Stewart JW, Harrison W, Ross DC, et al. Heterogeneity of clinical response during placebo treatment. Am J Psychiatry 1991, 148:193–196.
22. Khan A, Cohen S, Dager S, Avery, DH, Dunner DL. Onset of response in relation to outcome in depressed outpatients with placebo and imipramine. J. Affect. Disord. 1989, 17 (1): 33-38.
23. Khan A, Detke M, Khan SR, Mallinckrodt C. Placebo response and antidepressant clinical trial outcome. J. Nerv. Ment. Dis. 2003, 191: 211-218.
24. Cusin C, Fava M, Amsterdam JD, Quitkin FM, Reimherr FW, Beasley Jr CM, Rosenbaum JF, Perlis RH, Early symptomatic worsening during treatment with fluoxetine in major depressive disorder: prevalence and implications.
J. Clin. Psychiatry 2007, 68 (1): 52-57.
25. Katz, MM, Meyers AL., Prakash A, Gaynor PJ, Houston JP. Early symptom change: prediction of remission in depression treatment. Psychopharmacol.
Bull. 2009, 42: 94-107.
26. Szegedi, A., Jansen, W.T., van Willigenburg, A.P., van der Meulen, E., Stassen, H.H.,
Thase, M.E., Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J. Clin. Psychiatry 2009, 70 (3): 344–353.
27. Thase ME, Larsen KG, Kennedy SH. Assessing the ‘true’ effect of active antidepressant therapy v. placebo in major depressive disorder. Br. J. Psychiatry 2011, 199: 501-507.
28. Targum, S.D., Early symptomatic improvement affects treatment outcome in a study of major depressive disorder. J. Psychiatr. Res. 2017, 95: 276–281.
29. Targum, S.D., Catania, C.J., Early treatment response affects signal detection in a placebo-controlled depression study. Pers. Med. Psychiatry 2017, 4–6: 19–24.
30. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression variable, substantial, and growing. JAMA 2002, 287 (14): 1840-1847.
31. Khan A, Leventhal RM, Khan, SR, Brown, WA. Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J. Clin. Psychopharmacol. 2002, 22 (1): 40–45.
32. Iovieno N, Papakostas GI. Correlation between different levels of placebo response rate and clinical trial outcome in major depressive disorder: a meta-analysis. J. Clin. Psychiatry 2012, 73 (10), 1300–1306.
33. Targum SD, Wedel PC, Bleicher LS, Busner J, Daniel DS, Robinson J, Rauh P, Barlow C. A comparative analysis of centralized, site-based, and patient ratings in a clinical trial of Major Depressive Disorder. J. Psychiatr. Res. 2013, 47: 944-954.
34. Wirz-Justice A. Diurnal variation of depressive symptoms. Dialogues in Clin Neuroscience 2008, 10 (3): 337-353.
35. Ben-Zeev D, Young MA, Madsen JW. Retrospective recall of affect in clinically depressed individuals and controls. Cognition and Emotion 2009, 23: 1021-1040.
36. Armey MF, Schatten HT, Haradhvala N, Miller IW. Ecological momentary assessment (EMA) of depression-related phenomena. Current Opin Psychol. 2015, 1 (4): 21-25.
37. Ebner-Priemer UW, Trull TJ. Ecological momentary assessment of mood disorders and mood dysregulation. Psychol Assess. 2009, 21 (4): 463-475.
38. Aan het Rot M, Hogenelst K, Schoevers RA. Mood disorders in everyday life: a systematic review of experience sampling and ecological momentary assessment studies. Clin Psychol. Review. 2012, 32 (6): 510-523.
39. Bech P. Rating scales in depression: limitations and pitfalls. Dialogues in Clin Neuroscience 2006, 8 (2): 207-215.
40. Targum SD, Sauder C, Evan M, Saber JN, Harvey PD. Ecological momentary assessment as a measurement tool in depression trials. Submitted for publication.
41. Targum SD, Leventer S, Hughes TE, Owen JR, Vlasuk GP. NV-5138 a Novel, Direct Activator of the Mechanistic Target of Rapamycin Complex 1 (mTORC1): A Phase 1b Randomized, Double-Blind, Placebo-Controlled Single Oral Dose Study in Subjects with Treatment-Resistant Depression (TRD). 2019: December 9; Presented at ACNP, Orlando Florida.
42. Altin M, Harada E, Schacht A, Berggren L, Walker D, Dueñas H. Does early improvement in anxiety symptoms in patients with major depressive disorder affect remission rates? a post-hoc analysis of pooled duloxetine clinic trials. Open J Depression 2014, 3:112–23.
43. Trivedi M, Rush J. Does a placebo run-in or a placebo treatment cell affect the efficacy of antidepressant medications? Neuropsychopharmacology 1995, 11: 33-43.