Trajectories of Function and Symptom Change in Desvenlafaxine Clinical Trials: Toward Personalized Treatment for Depression

Sigal Zilcha-Mano, Xuemei Wang, Dalia B Wajsbrot, Matthieu Boucher, Stuart A Fine, Bret R Rutherford, Sigal Zilcha-Mano, Xuemei Wang, Dalia B Wajsbrot, Matthieu Boucher, Stuart A Fine, Bret R Rutherford

Abstract

Purpose/background: Heterogeneity has been documented in trajectories of symptom change during antidepressant treatment for major depressive disorder (MDD). It is unclear whether distinct trajectories of change exist for functioning during antidepressant treatment.

Methods/procedures: This analysis explored distinct trajectories of functioning in MDD and tested whether they corresponded to trajectories of symptom change. Data were from 4317 patients and were pooled from 9 randomized placebo-controlled trials. Growth mixture modeling was used to identify trajectories of Hamilton Rating Scale for Depression (HRSD) and Sheehan Disability Scale (SDS) for placebo- and desvenlafaxine-treated patients.

Findings/results: Three trajectories were identified for symptoms (HRSD) in patients receiving placebo (mean reduction baseline to week 8, -18.4 [most favorable] to -2.6 points [least favorable]). Four HRSD trajectories were identified for patients receiving desvenlafaxine (mean reduction from baseline to week 8, -17.2 [most favorable] to -2.6 points [least favorable]). Four trajectories were identified for functioning (SDS) in patients receiving placebo (mean reduction baseline to week 8, -13.6 [most favorable] to -0.8 points [least favorable]), and 3 for desvenlafaxine (-12.8 to -1.4 points, respectively). Percentages of agreement between most favorable HRSD and SDS trajectories were 75% (placebo) and 85% (desvenlafaxine), and for least favorable trajectories were 88% (placebo) and 80% (desvenlafaxine).

Implications/conclusions: Distinct trajectories of change based on symptoms and functioning were identified among patients with MDD receiving desvenlafaxine and among patients with MDD receiving placebo. Differentiating subpopulations of patients has the potential to provide a more personalized treatment of patients with MDD.ClinicalTrials.govIdentifiers: NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

FIGURE 1
FIGURE 1
Mean HRSD (top panels) and SDS (bottom panels) scores estimated from cubic trajectories for placebo- and desvenlafaxine-treated patients over 8 weeks of treatment.

References

    1. Rush AJ Trivedi MH Wisniewski SR, et al. . Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–1917.
    1. Zilcha-Mano S Roose SP Brown PJ, et al. . Early symptom trajectories as predictors of treatment outcome for citalopram versus placebo. Am J Geriatr Psychiatry. 2017;25:654–661.
    1. Gueorguieva R, Mallinckrodt C, Krystal JH. Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses. Arch Gen Psychiatry. 2011;68:1227–1237.
    1. DeRubeis RJ Cohen ZD Forand NR, et al. . The Personalized Advantage Index: translating research on prediction into individualized treatment recommendations. a demonstration. PLoS One. 2014;9:e83875.
    1. Thase ME, Larsen KG, Kennedy SH. Assessing the ‘true’ effect of active antidepressant therapy v. placebo in major depressive disorder: use of a mixture model. Br J Psychiatry. 2011;199:501–507.
    1. Greer TL, Kurian BT, Trivedi MH. Defining and measuring functional recovery from depression. CNS Drugs. 2010;24:267–284.
    1. Katzman MA Nierenberg AA Wajsbrot DB, et al. . Speed of improvement in symptoms of depression with desvenlafaxine 50 mg and 100 mg compared with placebo in patients with major depressive disorder. J Clin Psychopharmacol. 2017;37:555–561.
    1. Larsen KG Kennedy SH Reines EH, et al. . Patient response trajectories in major depressive disorder. Psychopharmacol Bull. 2020;50:8–28.
    1. Katzman MA Wang X Wajsbrot DB, et al. . Effects of desvenlafaxine versus placebo on MDD symptom clusters: a pooled analysis. J Psychopharmacol. 2020;34:280–292.
    1. Novick D Montgomery W Vorstenbosch E, et al. . Recovery in patients with major depressive disorder (MDD): results of a 6-month, multinational, observational study. Patient Prefer Adherence. 2017;11:1859–1868.
    1. Sheehan DV Harnett-Sheehan K Spann ME, et al. . Assessing remission in major depressive disorder and generalized anxiety disorder clinical trials with the discan metric of the Sheehan disability scale. Int Clin Psychopharmacol. 2011;26:75–83.
    1. DeMartinis NA Yeung PP Entsuah R, et al. . A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder. J Clin Psychiatry. 2007;68:677–688.
    1. Liebowitz MR Tourian KA Hwang E, et al. . A double-blind, randomized, placebo-controlled study assessing the efficacy and tolerability of desvenlafaxine 10 and 50 mg/day in adult outpatients with major depressive disorder. BMC Psychiatry. 2013;13:94.
    1. Liebowitz MR Manley AL Padmanabhan SK, et al. . Efficacy, safety, and tolerability of desvenlafaxine 50 mg/day and 100 mg/day in outpatients with major depressive disorder. Curr Med Res Opin. 2008;24:1877–1890.
    1. Boyer P Montgomery S Lepola U, et al. . Efficacy, safety, and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/day for major depressive disorder in a placebo-controlled trial. Int Clin Psychopharmacol. 2008;23:243–253.
    1. Tourian KA Padmanabhan SK Groark J, et al. . Desvenlafaxine 50 and 100 mg/d in the treatment of major depressive disorder: an 8-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial and a post hoc pooled analysis of three studies. Clin Ther. 2009;31(Pt 1):1405–1423.
    1. Iwata N Tourian KA Hwang E, et al. . Efficacy and safety of desvenlafaxine 25 and 50 mg/day in a randomized, placebo-controlled study of depressed outpatients. J Psychiatr Pract. 2013;19:5–14.
    1. Clayton AH Kornstein SG Dunlop BW, et al. . Efficacy and safety of desvenlafaxine 50 mg/d in a randomized, placebo-controlled study of perimenopausal and postmenopausal women with major depressive disorder. J Clin Psychiatry. 2013;74:1010–1017.
    1. Dunlop BW Reddy S Yang L, et al. . Symptomatic and functional improvement in employed depressed patients: a double-blind clinical trial of desvenlafaxine versus placebo. J Clin Psychopharmacol. 2011;31:569–576.
    1. Clayton AH Tourian KA Focht K, et al. . Desvenlafaxine 50 and 100 mg/d versus placebo for the treatment of major depressive disorder: a phase 4, randomized controlled trial. J Clin Psychiatry. 2015;76:562–569.
    1. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.
    1. Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol. 1996;11(suppl 3):89–95.
    1. Verbeke G, Lesaffre E. A linear mixed-effects model with heterogeneity in the random-effects population. JSTOR. 1996;91:217–221.
    1. Muthén B, Shedden K. Finite mixture modeling with mixture outcomes using the EM algorithm. Biometrics. 1999;55:463–469.
    1. Proust C, Jacqmin-Gadda H. Estimation of linear mixed models with a mixture of distribution for the random effects. Comput Methods Prog Biomed. 2005;78:165–173.
    1. Proust-Lima C, Philipps V, Liquet B. Estimation of extended mixed models using latent classes and latent processes: the R package lcmm. J Stat Softw. 2017;78:56.
    1. Quitkin FM Rabkin JG Ross D, et al. . Identification of true drug response to antidepressants. Use of pattern analysis. Arch Gen Psychiatry. 1984;41:782–786.
    1. Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci. 2015;16:403–418.
    1. Kobak KA Kane JM Thase ME, et al. . Why do clinical trials fail? The problem of measurement error in clinical trials: time to test new paradigms? J Clin Psychopharmacol. 2007;27:1–5.
    1. Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013;170:723–733.
    1. Evans VC Alamian G McLeod J, et al. . The effects of newer antidepressants on occupational impairment in major depressive disorder: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs. 2016;30:405–417.
    1. Salanti G Chaimani A Furukawa TA, et al. . Impact of placebo arms on outcomes in antidepressant trials: systematic review and meta-regression analysis. Int J Epidemiol. 2018;47:1454–1464.
    1. Landin R DeBrota DJ DeVries TA, et al. . The impact of restrictive entry criterion during the placebo lead-in period. Biometrics. 2000;56:271–278.

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