Trajectories of change in depression severity during treatment with antidepressants.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Medical Research Council Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, UK. rudolf.uher@iop.kcl.ac.uk
R
R
Uher
B
B
Muthén
D
D
Souery
O
O
Mors
J
J
Jaracz
A
A
Placentino
A
A
Petrovic
A
A
Zobel
N
N
Henigsberg
M
M
Rietschel
K J
KJ
Aitchison
A
A
Farmer
P
P
McGuffin
D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D015283:Citalopram / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009661:Nortriptyline / Q000627:therapeutic use; D010555:Personality Inventory / Q000706:statistics & numerical data; D010597:Pharmacogenetics; D011594:Psychometrics / Q000706:statistics & numerical data; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000235:genetics; D011985:Receptors, Serotonin / Q000187:drug effects / Q000235:genetics; D012008:Recurrence; D015203:Reproducibility of Results; D014894:Weights and Measures
D000928:Antidepressive Agents; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D015283:Citalopram; D009661:Nortriptyline