Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with major depressive disorder--the EMC trial

André Tadić, Stanislav Gorbulev, Norbert Dahmen, Christoph Hiemke, Dieter F Braus, Joachim Röschke, Dietrich van Calker, Daniel Wachtlin, Kai Kronfeld, Thorsten Gorbauch, Monika Seibert-Grafe, Klaus Lieb, EMC Study Group, Klaus Lieb, André Tadić, Christoph Hiemke, Nadine Dreimüller, Omür Baskaya, Danuta Krannich, Sonja Lorenz, Annette Bernius, Tillmann Weichert, Markus Lorscheider, Stefanie Wagner, Isabella Helmreich, Karen Grüllich, Elnaz Ostad Haji, Yvonne Lober, Danuta Weichert, Konrad Schlicht, Stanislav Gorbulev, Daniel Wachtlin, Kai Kronfeld, Peter Friedrich-Mai, Anke Ehrlich, Anja Powaska, Thorsten Gorbauch, Monika Seibert-Grafe, Marija Tubic-Grozdanis, Carola Jekle, Irene Krämer, Norbert Dahmen, Marcel Gerbaulet, Daniela Sachsenheimer, Anja Rutschinski, Alice Engel, Karen Schwarz, Ulrike Gehrmann, Stefanie Bader, Birgit Schneider-Pohl, Manuela Justi, Hans-Christoph Thierolf, Joachim Röschke, Susanne Gabriel, Michael Kutzer, Anne-Pia Dorn, Frauke Schmidt, Sarah Porz, Isabella Sand, Joachim Röschke, Tatjana Prentice, Benjamin Hössl, Simin Seilheimer, Sophie Ott, Clarissa Frank, Dietrich van Calker, Sonja Gerber, Claus M Gross, Tobias Hornig, Rebecca Schneibel, Ritva Atmannsbacher, Dieter F Braus, Julia Reiff, Christoph Kindler, Svenja Davis, Tina Eyalil, Thorgerdur Reynisdottir, Claudia Ginap, Julia Kraus, Sabine Kaaden, Jelena Janzen, Nina Löffler, Caterina Topaloglu, André Tadić, Stanislav Gorbulev, Norbert Dahmen, Christoph Hiemke, Dieter F Braus, Joachim Röschke, Dietrich van Calker, Daniel Wachtlin, Kai Kronfeld, Thorsten Gorbauch, Monika Seibert-Grafe, Klaus Lieb, EMC Study Group, Klaus Lieb, André Tadić, Christoph Hiemke, Nadine Dreimüller, Omür Baskaya, Danuta Krannich, Sonja Lorenz, Annette Bernius, Tillmann Weichert, Markus Lorscheider, Stefanie Wagner, Isabella Helmreich, Karen Grüllich, Elnaz Ostad Haji, Yvonne Lober, Danuta Weichert, Konrad Schlicht, Stanislav Gorbulev, Daniel Wachtlin, Kai Kronfeld, Peter Friedrich-Mai, Anke Ehrlich, Anja Powaska, Thorsten Gorbauch, Monika Seibert-Grafe, Marija Tubic-Grozdanis, Carola Jekle, Irene Krämer, Norbert Dahmen, Marcel Gerbaulet, Daniela Sachsenheimer, Anja Rutschinski, Alice Engel, Karen Schwarz, Ulrike Gehrmann, Stefanie Bader, Birgit Schneider-Pohl, Manuela Justi, Hans-Christoph Thierolf, Joachim Röschke, Susanne Gabriel, Michael Kutzer, Anne-Pia Dorn, Frauke Schmidt, Sarah Porz, Isabella Sand, Joachim Röschke, Tatjana Prentice, Benjamin Hössl, Simin Seilheimer, Sophie Ott, Clarissa Frank, Dietrich van Calker, Sonja Gerber, Claus M Gross, Tobias Hornig, Rebecca Schneibel, Ritva Atmannsbacher, Dieter F Braus, Julia Reiff, Christoph Kindler, Svenja Davis, Tina Eyalil, Thorgerdur Reynisdottir, Claudia Ginap, Julia Kraus, Sabine Kaaden, Jelena Janzen, Nina Löffler, Caterina Topaloglu

Abstract

Background: In major depressive disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease >or=20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome.

Methods/design: The EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17 <or=7) on treatment day 56 compared to patients treated according to current guideline recommendation (treatment as usual; TAU). In level 1 of the EMC trial, non-improvers after 14 days of antidepressant treatment will be randomised to an EMC strategy or TAU. The EMC strategy for this study schedules a first medication change on day 15; in case of non-improvement between days 15-28, a second medication change will be performed. TAU schedules the first medication change after 28 days in case of non-response (HAMD-17 decrease <50%). Both interventions will last 42 days. In levels 2 and 3, EMC strategies will be compared with TAU strategies in improvers on day 14, who experience a stagnation of improvement during the course of treatment. The trial is supported by the German Federal Ministry of Education and Research (BMBF) and will be conducted in cooperation with the BMBF funded Interdisciplinary Centre Clinical Trials (IZKS) at the University Medical Centre Mainz and at six clinical trial sites in Germany.

Discussion: If the EMC strategies lead to significantly more remitters, changes of clinical practice, guidelines for the treatment of MDD as well as research settings can be expected.

Trial registration: Clincaltrials.gov Identifier: NCT00974155; EudraCT: 2008-008280-96.

Figures

Figure 1
Figure 1
Design of The EMC Trial. Abbreviations: d = study day; ESC = Escitalopram; LI = Lithium; t = time point; VEN = Venlafaxine; EMC = early medication change group; TAU = treatment as usual group; IML2 = improver group level 2; IML3 = improver group level 3. Definitions: improvement = reduction of HAMD17 sum score ≥20% in a specified time span, e.g. between time point (t) 0 and t1; non-improvement = reduction of HAMD17 sum score <20%; response = reduction of HAMD17 sum score ≥50%; non-response = reduction of HAMD17 sum score <20%. Grey boxes indicate randomized groups (non-improver t0-t1; non-improver 2/t2-t3; non-improver 3/t2-t3).
Figure 2
Figure 2
Schedule of The EMC Trial. § in case of existing pre-medication to assure complete wash-out; §§ in case of lithium treatment; Abbreviations: BL (baseline visit); CIRS: Cumulative illness Rating Scale; CPL (plasma concentration); HAMD17 (17-item Hamilton-Depression-Rating-Scale); IDS-C30 (30-item Inventory of Depressive Symptomatology); SC (screening visit); M.I.N.I. (Mini International Neuropsychiatric Interview); SCID-II (Structured Clinical Interview for DSM-IV Axis II Disorders); SF-12 (12-item Short Form Health Survey); UKU (Udvalg for Kliniske Undersogelser).

References

    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Washington DC: American Psychiatric Association; 1994.
    1. Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS, Bryson H, de Girolamo G, Graaf R, Demyttenaere K, Gasquet I, Haro JM, Katz SJ, Kessler RC, Kovess V, Lépine JP, Ormel J, Polidori G, Russo LJ, Vilagut G, Almansa J, Arbabzadeh-Bouchez S, Autonell J, Bernal M, Buist-Bouwman MA, Codony M, Domingo-Salvany A, Ferrer M, Joo SS, Martínez-Alonso M, Matschinger H, Mazzi F, Morgan Z, Morosini P, Palacín C, Romera B, Taub N, Vollebergh WA. ESEMeD/MHEDEA 2000 Investigators, European Study of the Epidemiology of Mental Disorders (ESEMeD) Project. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatrica Scandinavica Supplement. 2004;420:21–27.
    1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS. National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R) The Journal of the American Medical Association. 2003;289:3095–3105. doi: 10.1001/jama.289.23.3095.
    1. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. Public Library of Science Medicine. 2006;3:e442.
    1. Sobocki P, Jönsson B, Angst J, Rehnberg C. Cost of depression in Europe. Journal of Mental Health and Policy and Economics. 2006;9:87–98.
    1. Greenberg PE, Kessler RC, Birnbaum HG, Leong SA, Lowe SW, Berglund PA, Corey-Lisle PK. The economic burden of depression in the United States: how did it change between 1990 and 2000? Journal of Clinical Psychiatry. 2003;64:1465–1475.
    1. 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. Public Library of Science Medicine Medicine. 2008;5:e45.
    1. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. New England Journal of Medicine. 2008;358:252–260. doi: 10.1056/NEJMsa065779.
    1. Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results: a comprehensive review of findings. Current Psychiatry Reports. 2007;9:449–459. doi: 10.1007/s11920-007-0061-3.
    1. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746–758. doi: 10.1016/S0140-6736(09)60046-5.
    1. Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Annals of Internal Medicine. 2005;143:415–426.
    1. Quitkin FM, Rabkin JG, Ross D, Stewart JW. Identification of true drug response to antidepressants. Use of pattern analysis. Archives of General Psychiatry. 1984;41:782–786.
    1. Quitkin FM, Rabkin JD, Markowitz JM, Stewart JW, McGrath PJ, Harrison W. Use of pattern analysis to identify true drug response. A replication. Archives of General Psychiatry. 1987;44:259–264.
    1. Bauer M, Bschor T, Pfennig A, Whybrow PC, Angst J, Versiani M, Möller HJ. WFSBP Task Force on Unipolar Depressive Disorders: World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. World Journal of Biological Psychiatry. 2007. pp. 67–104.
    1. Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ) Berlin. 2 2006. Empfehlungen zur Therapie der Depression.
    1. Nationale Versorgungsleitline Depression.
    1. Deutsche Gesellschaft für Psychiatrie Psychotherapie und Nervenheilkunde. Behandlungsleitlinie Affektive Erkrankungen. Heidelberg: Springer; 2000.
    1. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision) American Journal of Psychiatry. 2000;157(suppl 4):1–45.
    1. Nierenberg AA, Farabaugh AH, Alpert JE, Gordon J, Worthington JJ, Rosenbaum JF, Fava M. Timing of onset of antidepressant response with fluoxetine treatment. American Journal of Psychiatry. 2000;157:1423–1428. doi: 10.1176/appi.ajp.157.9.1423.
    1. Katz MM, Tekell JL, Bowden CL, Brannan S, Houston JP, Berman N, Frazer A. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology. 2004;29:566–579. doi: 10.1038/sj.npp.1300341.
    1. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. The Journal of Clinical Psychiatry. 2005;66:148–158. doi: 10.4088/JCP.v66n0201.
    1. Papakostas GI, Perlis RH, Scalia MJ, Petersen TJ, Fava M. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. Journal of Clinical Psychopharmacology. 2006;26:56–60. doi: 10.1097/01.jcp.0000195042.62724.76.
    1. Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Archives of General Psychiatry. 2006;63:1217–1223. doi: 10.1001/archpsyc.63.11.1217.
    1. Stassen HH, Angst J, Hell D, Scharfetter C, Szegedi A. Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2848 patients. The Journal of Clinical Psychiatry. 2007;68:1195–1205. doi: 10.4088/JCP.v68n0805.
    1. Szegedi A, Müller MJ, Anghelescu I, Klawe C, Kohnen R, Benkert O. Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression. The Journal of Clinical Psychiatry. 2003;64:413–420.
    1. Szegedi A, Jansen WT, van Willigenburg AP, Meulen E van der, Stassen HH, Thase ME. Early improvement as a predictor of treatment outcome in patients with major depressive disorder: Why the first 2 weeks really matter-evidence from 6,562 patients. The Journal of Clinical Psychiatry. 2009;70:344–353. doi: 10.4088/JCP.07m03780.
    1. Tadić A, Helmreich I, Mergl R, Hautzinger M, Kohnen R, Henkel V, Hegerl U. Early improvement is a predictor of treatment outcome in patients with mild major minor or subsyndromal depression. Journal of Affective Disorders. 2010;120:86–93. doi: 10.1016/j.jad.2009.04.014.
    1. Hamilton M. Development of a rating scale for primary depressive illness. The British Journal of Social and Clinical Psychology. 1967;6:278–296.
    1. Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, Rush AJ, Weissman MM. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse and recurrence. Archives of General Psychiatry. 1991;48:851–855.
    1. Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatrica Scandinavica. 1987. pp. 1–100.
    1. Bielski RJ, Ventura D, Chang CC. A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder. The Journal of Clinical Psychiatry. 2004;65:1190–1196.
    1. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. The Journal of Clinical Psychiatry. 2002;63:331–336.
    1. Montgomery SA, Baldwin DS, Blier P, Fineberg NA, Kasper S, Lader M, Lam RW, Lépine JP, Möller HJ, Nutt DJ, Rouillon F, Schatzberg AF, Thase ME. Which antidepressants have demonstrated superior efficacy? A review of the evidence. International Clinical Psychopharmacolology. 2007;22:323–329. doi: 10.1097/YIC.0b013e3282eff7e0.
    1. Ruhé HG, Huyser J, Swinkels JA, Schene AH. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. The Journal of Clinical Psychiatry. 2006;67:1836–1855. doi: 10.4088/JCP.v67n1203.
    1. Adli M, Baethge C, Heinz A, Langlitz N, Bauer M. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. European Archives of Psychiatry and Clinical Neuroscience. 2005;255:387–400. doi: 10.1007/s00406-005-0579-5.
    1. Crossley NA, Bauer M. Accelaration and Augmentation of Antidepressants with lithium for depressive disoders: 2 meta-analyses of randomized, placebo-controlled trials. The Journal of Clinical Psychiatry. 2007;68:935–940. doi: 10.4088/JCP.v68n0617.
    1. Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Rao ML, Riederer P, Zernig G. Arbeitsgemeinschaft für Neuropsychopharmakologie und -pharmakopsychiatrie. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry. 2004;37:243–265. doi: 10.1055/s-2004-832687.
    1. Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M. STAR*D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. The New England Journal of Medicine. 2006;354:1231–1242. doi: 10.1056/NEJMoa052963.
    1. Adli M, Berghöfer A, Linden M, Helmchen H, Müller-Oerlinghausen B, Mackert A, Stamm T, Bauer M. Effectiveness and feasibility of a standardized stepwise drug treatment regimen algorithm for inpatients with depressive disorders: results of a 2-year observational algorithm study. The Journal of Clinical Psychiatry. 2002;63:782–790.
    1. Leucht S, Busch R, Kissling W, Kane JM. Early prediction of antipsychotic nonresponse among patients with schizophrenia. The Journal of Clinical Psychiatry. 2007;68:352–360. doi: 10.4088/JCP.v68n0301.
    1. Leucht S, Shamsi SA, Busch R, Kissling W, Kane JM. Predicting antipsychotic drug response - replication and extension to six weeks in an international olanzapine study. Schizophrenia Research. 2008;101:312–319. doi: 10.1016/j.schres.2008.01.018.
    1. Pollack MH, Kornstein SG, Spann ME, Crits-Christoph P, Raskin J, Russell JM. Early improvement during duloxetine treatment of generalized anxiety disorder predicts response and remission at endpoint. Journal of Psychiatric Research. 2008;42:1176–1184. doi: 10.1016/j.jpsychires.2008.02.002.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe