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Trajectories of change in depression severity during treatment with antidepressants

  • R. Uher (a1), B. Muthén (a2), D. Souery (a3), O. Mors (a4), J. Jaracz (a5), A. Placentino (a6), A. Petrovic (a7), A. Zobel (a8), N. Henigsberg (a9), M. Rietschel (a10), K. J. Aitchison (a1), A. Farmer (a1) and P. McGuffin (a1)...

Response and remission defined by cut-off values on the last observed depression severity score are commonly used as outcome criteria in clinical trials, but ignore the time course of symptomatic change and may lead to inefficient analyses. We explore alternative categorization of outcome by naturally occurring trajectories of symptom change.


Growth mixture models were applied to repeated measurements of depression severity in 807 participants with major depression treated for 12 weeks with escitalopram or nortriptyline in the part-randomized Genome-based Therapeutic Drugs for Depression study. Latent trajectory classes were validated as outcomes in drug efficacy comparison and pharmacogenetic analyses.


The final two-piece growth mixture model categorized participants into a majority (75%) following a gradual improvement trajectory and the remainder following a trajectory with rapid initial improvement. The rapid improvement trajectory was over-represented among nortriptyline-treated participants and showed an antidepressant-specific pattern of pharmacogenetic associations. In contrast, conventional response and remission favoured escitalopram and produced chance results in pharmacogenetic analyses. Controlling for drop-out reduced drug differences on response and remission but did not affect latent trajectory results.


Latent trajectory mixture models capture heterogeneity in the development of clinical response after the initiation of antidepressants and provide an outcome that is distinct from traditional endpoint measures. It differentiates between antidepressants with different modes of action and is robust against bias due to differential discontinuation.

Corresponding author
*Address for correspondence: Dr R. Uher, Medical Research Council (MRC) Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, UK (Email:
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Bandelow B, Baldwin DS, Dolberg OT, Andersen HF, Stein DJ (2006). What is the threshold for symptomatic response and remission for major depressive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder? Journal of Clinical Psychiatry 67, 14281434.
Bech P, Allerup P, Reisby N, Gram LF (1984). Assessment of symptom change from improvement curves on the Hamilton depression scale in trials with antidepressants. Psychopharmacology (Berlin) 84, 276281.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961). An inventory for measuring depression. Archives of General Psychiatry 4, 561571.
Beunckens C, Molenberghs G, Verbeke G, Mallinckrodt C (2008). A latent-class mixture model for incomplete longitudinal Gaussian data. Biometrics 64, 96105.
Carmody TJ, Rush AJ, Bernstein I, Warden D, Brannan S, Burnham D, Woo A, Trivedi MH (2006). The Montgomery Asberg and the Hamilton ratings of depression: a comparison of measures. European Neuropsychopharmacology 16, 601611.
Cohen J (1960). A coefficient of agreement for nominal scales. Educational and Psychological Measurement 20, 3746.
Fahndrich E (1984). The arbitrariness of response definition in clinical trials with antidepressants. Pharmacopsychiatry 17, 107108.
Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, Rush AJ, Weissman MM (1991). Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Archives of General Psychiatry 48, 851855.
Gueorguieva R, Krystal JH (2004). Move over ANOVA: progress in analyzing repeated-measures data and its reflection in papers published in the Archives of General Psychiatry. Archives of General Psychiatry 61, 310317.
Hamilton M (1967). Development of a rating scale for primary depressive illness. British Journal of Clinical Psychology 6, 278296.
Joyce PR, Mulder RT, Luty SE, Sullivan PF, McKenzie JM, Abbott RM, Stevens IF (2002). Patterns and predictors of remission, response and recovery in major depression treated with fluoxetine or nortriptyline. Australian and New Zealand Journal of Psychiatry 36, 384391.
Lane P (2008). Handling drop-out in longitudinal clinical trials: a comparison of the LOCF and MMRM approaches. Pharmaceutical Statistics 7, 93106.
Leucht S, Heres S, Hamann J, Kane JM (2008). Methodological issues in current antipsychotic drug trials. Schizophrenia Bulletin 34, 275285.
Mallinckrodt CH, Clark WS, David SR (2001). Accounting for dropout bias using mixed-effects models. Journal of Biopharmaceutical Statistics 11, 921.
Montgomery SA (1994). Clinically relevant effect sizes in depression. European Neuropsychopharmacology 4, 283284.
Montgomery SA, Asberg M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382389.
Mulder RT, Joyce PR, Frampton C (2003). Relationships among measures of treatment outcome in depressed patients. Journal of Affective Disorders 76, 127135.
Muthén B, Asparouhov T (2008). Growth mixture modeling: Analysis with non-Gaussian random effects. In Longitudinal Data Analysis (ed. Fitzmaurice G., Davidian M., Verbeke G. and Molenberghs G.), pp. 143165. Chapman, all/CRC Press: Boca Raton.
Muthén B, Brown H, Leuchter A, Hunter A (2008). General approaches to analysis of course: Applying growth mixture modeling to randomized trials of depression medication. In Causality and Psychopathology: Finding the Determinants of Disorders and their Cures (ed. Shrout P. E.). American Psychiatric Publishing: Washington, DC.
Muthén B, Muthén L. (2008). Mplus User's Guide. Muthén, Muthén: Los Angeles, CA.
Papakostas GI, Crawford CM, Scalia MJ, Fava M (2007). Timing of clinical improvement and symptom resolution in the treatment of major depressive disorder. A replication of findings with the use of a double-blind, placebo-controlled trial of Hypericum perforatum versus fluoxetine. Neuropsychobiology 56, 132137.
Parker G (2009). Antidepressants on trial: how valid is the evidence? British Journal of Psychiatry 194, 13.
Prien RF, Carpenter LL, Kupfer DJ (1991). The definition and operational criteria for treatment outcome of major depressive disorder. A review of the current research literature. Archives of General Psychiatry 48, 796800.
Quitkin FM, Rabkin JG, Ross D, Stewart JW (1984). Identification of true drug response to antidepressants. Use of pattern analysis. Archives of General Psychiatry 41, 782786.
Rietschel M, Kennedy JL, Macciardi F, Meltzer HY (1999). Application of pharmacogenetics to psychotic disorders: the first consensus conference. The Consensus Group for Outcome Measures in Psychoses for Pharmacological Studies. Schizophrenia Research 37, 191196.
Royston P, Altman DG, Sauerbrei W (2006). Dichotomizing continuous predictors in multiple regression: a bad idea. Statistics in Medicine 25, 127141.
Stassen HH, Angst J, Hell D, Scharfetter C, Szegedi A (2007). Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2848 patients. Journal of Clinical Psychiatry 68, 11951205.
StataCorp (2007). Stata statistical software: release 10. Stata Corp LP: College Station, TX.
Streiner DL (2002). Breaking up is hard to do: the heartbreak of dichotomizing continuous data. Canadian Journal of Psychiatry 47, 262266.
Szegedi A, Jansen WT, Willigenburg AP Pv, van der ME, Stassen HH, Thase ME (2009). 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. Journal of Clinical Psychiatry 70, 344353.
Szegedi A, Muller MJ, Anghelescu I, Klawe C, Kohnen R, Benkert O (2003). Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression. Journal of Clinical Psychiatry 64, 413420.
Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z (2006). Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Archives of General Psychiatry 63, 12171223.
Uher R (2008). The implications of gene-environment interactions in depression: will cause inform cure? Molecular Psychiatry 13, 10701078.
Uher R, Farmer A, Maier W, Rietschel M, Hauser J, Marusic A, Mors O, Elkin A, Williamson RJ, Schmael C, Henigsberg N, Perez J, Mendlewicz J, Janzing JG, Zobel A, Skibinska M, Kozel D, Stamp AS, Bajs M, Placentino A, Barreto M, McGuffin P, Aitchison KJ (2008). Measuring depression: comparison and integration of three scales in the GENDEP study. Psychological Medicine 38, 289300.
Uher R, Huezo-Diaz P, Perroud N, Smith R, Rietschel M, Mors O, Hauser J, Maier W, Kozel D, Henigsberg N, Barreto M, Placentino A, Dernovsek MZ, Schulze T, Kalember P, Zobel A, Czerski P, Larsen ER, Souery D, Govannini C, Gray JM, Lewis CM, Farmer A, Aitchison KJ, McGuffin P, Craig I (2009 a). Genetic predictors of antidepressant response in the GENDEP project. Pharmacogenomics Journal 9, 225233.
Uher R, Maier W, Hauser J, Marusic A, Schmael C, Mors O, Henigsberg N, Souery D, Placentino A, Rietschel M, Zobel A, Dmitrzak-Weglarz M, Petrovic A, Jorgensen L, Kalember P, Govannini C, Barreto M, Elkin A, Landau S, Farmer A, Aitchison KJ, McGuffin P (2009 b). Differential efficacy of escitalopram and nortriptyline on dimensional measures of depression in the GENDEP project. British Journal of Psychiatry 194, 252259.
Vandenbroucke JP (2008). Observational research, randomised trials, and two views of medical science. PLoS Medicine 5, e67.
Wing JK, Sartorius N, Ustin TB (1998). Diagnosis and Clinical Measurement in Psychiatry. A Reference Manual for SCAN. World Health Organization: Geneva.
Zimmerman M, Posternak MA, Chelminski I (2004). Derivation of a definition of remission on the Montgomery-Asberg depression rating scale corresponding to the definition of remission on the Hamilton rating scale for depression. Journal of Psychiatric Research 38, 577582.
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Psychological Medicine
  • ISSN: 0033-2917
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