title: Improving study design for antidepressant effectiveness assessment.
abstract: Antidepressants effectiveness in major depressive disorder (MDD) is still questioned because the extrapolation of randomized controlled trial (RCT) results to "real life" settings is problematic. The application of the RCT paradigm in a disorder of this type, where global care plays a central role, raises questions regarding the internal and external validity of this type of study. Outcome measurement, attrition rates, the ability of the double-blind design to control for expectations, placebo response, the representativeness of trial participants and publication bias are major methodological pitfalls. This review discusses these issues. It is illustrated using original data and proposes some alternatives for assessing antidepressant effectiveness via different approaches. Some are easy to implement, such as ecological measures, qualitative approaches, improvement of analytical strategy and improvement of blinding procedures. Some are sophisticated, involving temporary deception to deal with the confounding effect of expectations, and they raise ethical issues. Others resort to external validity, this being the case in observational studies. But all are necessary to explore antidepressant effectiveness.
authors.affiliation: INSERM U669, Paris, France; Université de Rennes 1, EA-425 Unité Comportement et Noyaux Gris Centraux, Rennes, France; Centre d'Investigation Clinique CIC-P INSERM 0203, Hôpital de Pontchaillou, Centre Hospitalier Universitaire de Rennes & Université de Rennes 1, Rennes, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Naudet
authors.forename: Bruno
authors.initials: B
authors.lastname: Millet
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Reymann
authors.forename: Bruno
authors.initials: B
authors.lastname: Falissard
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D004311:Double-Blind Method; D006801:Humans; D064887:Observational Studies as Topic; D017063:Outcome Assessment, Health Care; D010552:Personality Assessment / Q000706:statistics & numerical data; D011594:Psychometrics / Q000706:statistics & numerical data; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000592:standards; D015203:Reproducibility of Results; D012107:Research Design; D011795:Surveys and Questionnaires
chemical_list: D000928:Antidepressive Agents
keywords: antidepressants; clinical trials; depression; effectiveness; methodology
references.citation: J Nerv Ment Dis. 1994 Sep;182(9):485-7
references.pmid: 8083675
references.citation: Psychiatry Res. 1986 Sep;19(1):75-86
references.pmid: 3538107
references.citation: Cochrane Database Syst Rev. 2004;(1):CD003012
references.pmid: 14974002
references.citation: Br J Psychiatry. 2000 Jul;177:47-51
references.pmid: 10945088
references.citation: BMC Fam Pract. 2011 Nov 15;12:127
references.pmid: 22085705
references.citation: J Clin Epidemiol. 2003 Jul;56(7):618-21
references.pmid: 12921929
references.citation: Arch Gen Psychiatry. 1961 Jun;4:561-71
references.pmid: 13688369
references.citation: Biol Psychiatry. 2000 Apr 15;47(8):733-5
references.pmid: 10773181
references.citation: Biol Psychiatry. 2006 Jun 1;59(11):1001-5
references.pmid: 16503329
references.citation: JAMA. 2010 Jan 6;303(1):47-53
references.pmid: 20051569
references.citation: N Engl J Med. 2008 Jan 17;358(3):252-60
references.pmid: 18199864
references.citation: Neuropsychopharmacology. 1992 Jan;6(1):39-48; discussion 49-63
references.pmid: 1571068
references.citation: PLoS One. 2011;6(6):e20811
references.pmid: 21687681
references.citation: Acta Psychiatr Scand. 1992 Jul;86(1):5-11
references.pmid: 1414401
references.citation: Am J Psychiatry. 2002 Mar;159(3):469-73
references.pmid: 11870014
references.citation: Psychother Psychosom. 2012;81(4):226-34
references.pmid: 22584117
references.citation: Med Hypotheses. 2007;68(3):683-91
references.pmid: 17140747
references.citation: J Neurosci. 2005 Nov 9;25(45):10390-402
references.pmid: 16280578
references.citation: Am J Psychiatry. 1991 Aug;148(8):997-1008
references.pmid: 1853989
references.citation: Am J Psychiatry. 2009 May;166(5):599-607
references.pmid: 19339358
references.citation: Am J Geriatr Psychiatry. 2008 Jan;16(1):65-73
references.pmid: 17998306
references.citation: Lancet Neurol. 2004 Nov;3(11):679-84
references.pmid: 15488461
references.citation: Am J Psychiatry. 2006 Jan;163(1):148-50
references.pmid: 16390903
references.citation: Psychol Med. 1997 Sep;27(5):1051-63
references.pmid: 9300511
references.citation: BMJ. 1989 Jul 29;299(6694):313-5
references.pmid: 2504416
references.citation: Mol Interv. 2002 Apr;2(2):72-6
references.pmid: 14993352
references.citation: Lancet. 2001 Apr 14;357(9263):1191-4
references.pmid: 11323066
references.citation: Br J Psychiatry. 2006 Apr;188:303-4
references.pmid: 16582054
references.citation: Lancet. 2004 May 22;363(9422):1660-1
references.pmid: 15158623
references.citation: JAMA. 2002 Jan 9;287(2):203-9
references.pmid: 11779262
references.citation: JAMA. 2009 Sep 2;302(9):977-84
references.pmid: 19724045
references.citation: Neuropsychopharmacology. 2000 Jun;22(6):559-65
references.pmid: 10788756
references.citation: BMJ. 2009 Sep 10;339:b3496
references.pmid: 19744976
references.citation: Am J Psychiatry. 2010 Mar;167(3):250-2
references.pmid: 20194487
references.citation: Contemp Clin Trials. 2007 Jul;28(4):348-51
references.pmid: 17182286
references.citation: Psychol Med. 2010 May;40(5):781-8
references.pmid: 19732481
references.citation: J Clin Psychiatry. 2010 Nov;71(11):1425-33
references.pmid: 20816028
references.citation: World J Biol Psychiatry. 2011 Apr;12(3):188-200
references.pmid: 21375365
references.citation: BMC Med. 2012 Jul 02;10:67
references.pmid: 22747667
references.citation: Lancet. 2004 May 22;363(9422):1728-31
references.pmid: 15158638
references.citation: J Affect Disord. 1998 Sep;50(2-3):97-108
references.pmid: 9858069
references.citation: Ann Rheum Dis. 1999 Nov;58 Suppl 1:I82-5
references.pmid: 10577979
references.citation: J Clin Psychiatry. 2006 Sep;67(9):1428-34
references.pmid: 17017830
references.citation: Br J Psychiatry. 1979 Apr;134:382-9
references.pmid: 444788
references.citation: Eur Neuropsychopharmacol. 2009 Jan;19(1):34-40
references.pmid: 18823760
references.citation: J Clin Psychiatry. 2002;63 Suppl 2:8-13
references.pmid: 15453008
references.citation: PLoS Med. 2010 Mar 24;7(3):e1000251
references.pmid: 20352064
references.citation: Am J Psychiatry. 2004 Dec;161(12):2163-77
references.pmid: 15569884
references.citation: Clin Med (Lond). 2001 Nov-Dec;1(6):478-84
references.pmid: 11792089
references.citation: Lancet. 2002 Feb 16;359(9306):614-8
references.pmid: 11867132
references.citation: JAMA. 2002 Apr 10;287(14):1840-7
references.pmid: 11939870
references.citation: Psychother Psychosom. 1999;68(1):3-14
references.pmid: 9873236
references.citation: J Clin Psychiatry. 2010 Mar;71(3):270-9
references.pmid: 20122371
references.citation: BMJ. 1995 Aug 26;311(7004):551-3
references.pmid: 7663213
references.citation: Lancet. 2010 Feb 20;375(9715):686-95
references.pmid: 20171404
references.citation: BMC Health Serv Res. 2007 Apr 30;7:64
references.pmid: 17470280
references.citation: J Neurol Neurosurg Psychiatry. 1960 Feb;23:56-62
references.pmid: 14399272
references.citation: BMJ. 2010 Oct 12;341:c4737
references.pmid: 20940209
references.citation: Soc Sci Med. 2001 Apr;52(7):985-98
references.pmid: 11266056
references.citation: Cochrane Database Syst Rev. 2009 Jul 08;(3):CD007954
references.pmid: 19588448
references.citation: J Psychiatr Res. 2006 Apr;40(3):243-6
references.pmid: 15979643
references.citation: Am J Psychiatry. 2002 Feb;159(2):191-200
references.pmid: 11823258
references.citation: Br J Psychiatry. 2007 Apr;190:287-92
references.pmid: 17401033
references.citation: Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003974
references.pmid: 20091554
references.citation: BMJ. 2005 Feb 19;330(7488):396
references.pmid: 15718539
references.citation: Br J Psychiatry. 1997 Nov;171:427-33
references.pmid: 9463600
references.citation: BMJ. 2001 Mar 31;322(7289):772-5
references.pmid: 11282864
references.citation: J Neuropsychiatr. 1963 Oct;4:65-70
references.pmid: 14089795
references.citation: Arch Gen Psychiatry. 2011 Mar;68(3):253-62
references.pmid: 21383263
references.citation: Br J Psychiatry. 2002 Mar;180:193-4
references.pmid: 11872507
references.citation: Int J Methods Psychiatr Res. 2011 Mar;20(1):1-9
references.pmid: 21574206
references.citation: Lancet. 2004 Aug 28-Sep 3;364(9436):755
references.pmid: 15337394
references.citation: Stat Med. 2009 Nov 30;28(27):3363-85
references.pmid: 19731223
references.citation: J Affect Disord. 2008 Jun;108(3):195-8
references.pmid: 18280581
references.citation: BMJ. 2003 May 31;326(7400):1167-70
references.pmid: 12775614
references.citation: Int J Law Psychiatry. 2008 Dec;31(6):453-62
references.pmid: 18954907
references.citation: Am J Psychiatry. 1982 Nov;139(11):1487-9
references.pmid: 6753613
references.citation: BMC Psychiatry. 2007 Feb 06;7:7
references.pmid: 17284321
references.citation: Perspect Biol Med. 2009 Spring;52(2):252-63
references.pmid: 19395823
references.citation: J Clin Psychiatry. 2004 Sep;65(9):1174-9
references.pmid: 15367043
references.citation: Curr Med Res Opin. 2008 May;24(5):1329-35
references.pmid: 18377706
references.citation: J Clin Psychiatry. 2010 Mar;71(3):235-8
references.pmid: 20122368
references.citation: Philos Ethics Humanit Med. 2008 May 27;3:14
references.pmid: 18505564
references.citation: PLoS Med. 2005 Dec;2(12):e392
references.pmid: 16268734
references.citation: J Clin Psychopharmacol. 2002 Feb;22(1):40-5
references.pmid: 11799341
references.citation: Lancet. 1993 Aug 14;342(8868):418-21
references.pmid: 8101908
references.citation: BMJ. 2006 Apr 22;332(7547):969-71
references.pmid: 16627519
references.citation: J Psychiatr Res. 1964 Jun;2:101-22
references.pmid: 14177088
references.citation: Arch Intern Med. 2004 Mar 22;164(6):597-600
references.pmid: 15037487
references.citation: Psychother Psychosom. 2009;78(3):172-81
references.pmid: 19321970
references.citation: Account Res. 2006 Jul-Sep;13(3):259-75
references.pmid: 17124761
references.citation: Homeopathy. 2005 Jul;94(3):145-52
references.pmid: 16060200
references.citation: Am J Psychiatry. 2005 Jul;162(7):1370-2
references.pmid: 15994721
references.citation: Lancet. 2005 Aug 27-Sep 2;366(9487):726-32
references.pmid: 16125589
references.citation: Arch Gen Psychiatry. 2000 Apr;57(4):311-7
references.pmid: 10768687
references.citation: Psychother Psychosom. 2005;74(1):17-25
references.pmid: 15627852
references.citation: Arch Gen Psychiatry. 2012 Jun;69(6):572-9
references.pmid: 22393205
references.citation: J Nerv Ment Dis. 2006 May;194(5):324-9
references.pmid: 16699380
references.citation: Science. 1999 Apr 9;284(5412):238-40
references.pmid: 10232967
references.citation: Homeopathy. 2005 Jul;94(3):153-63
references.pmid: 16060201
references.citation: J Nerv Ment Dis. 2000 Dec;188(12):799-804
references.pmid: 11191579
references.citation: PLoS Med. 2008 Feb;5(2):e45
references.pmid: 18303940
references.citation: Eur Neuropsychopharmacol. 2010 Aug;20(8):562-7
references.pmid: 20219330