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Proposal 1575

Title of the Proposed Research

Early improvement in individual symptoms and response to antidepressants in patients with major depressive disorder

Lead Researcher

Ymkje Anna de Vries

Affiliation

Interdisciplinary Center Psychopathology and Emotion regulation, University Center of Psychiatry, University Medical Center Groningen, the Netherlands

Funding Source

No specific funding will be used for the proposed project. All researchers are employed by and receive a salary from either the University Medical Center Groningen or the University of Groningen.

Potential Conflicts of Interest

None

Data Sharing Agreement Date

11 October 2016

Lay Summary

Major depressive disorder (MDD) affects around 7% of the population yearly and has been estimated to be the third leading cause of disease burden worldwide. Although effective treatments are available, many patients fail to respond to the first treatment that is tried. In clinical trials, only around half of all patients respond to 6 to 12 weeks of antidepressant treatment. Given these high failure rates, the ability to predict as early as possible whether a patient is (un)likely to respond would be of great value, as it would enable physicians to change treatment strategies faster. Early improvement, usually defined as an improvement in depressive symptoms of at least 20% by the end of two weeks of treatment, has consistently been found to be a strong predictor of later response. However, misclassification is still quite common, with perhaps a third of those who do not show early improvement going on to respond.

Conversely, a substantial proportion of those who do show early improvement do not go on to respond. One possibility for improving the predictive power of early improvement is to examine individual symptoms, rather than the total score on a depression rating scale. Some items, for example, could reflect antidepressant side effects (e.g. gastrointestinal symptoms) and may not be very predictive. In the STAR*D study, of citalopram, remission was associated with early improvement in five particular symptoms: sad mood, negative self-view, feeling slowed down, low energy, and restlessness. In another study, of mirtazapine, remission was predicted by early improvements in late insomnia (i.e., waking up too early), general somatic symptoms, and illness insight. In the proposed project, we aim to examine the relationship between early improvement in individual symptoms and response to antidepressants in a very large patient sample. This large sample size will enable us to use more rigorous methods than previous studies, such as the use of cross-validation to confirm our findings. It will also allow us to examine a large set of predictors, including possible interactions among early-improving symptoms and between symptoms and demographic factors like age and gender. We will also examine the added value of individual symptoms over and above using the total symptom score alone and possible differences between different antidepressant classes. We will use penalized (lasso) regression, which is well-suited to analyzing data with a large number of (potentially highly correlated) predictors. Lasso regression selects a subset of predictors, yielding models that have higher predictive accuracy and are easier to interpret. In our primary analysis, we will predict response after 6 weeks of treatment. In secondary analyses, we will also predict remission at week 6 and response and remission at week 12. Our findings will be communicated through conference presentations and publication in a peer-reviewed medical journal.

Study Data Provided

GSK-MY-1043/BRL-029060/115: A multicenter, randomized, double-blind, placebo-controlled comparison of paroxetine and fluoxetine in the treatment of major depressive disorder.
GSK-29060/448: A Double-Blind, Placebo Controlled Trial to Evaluate the Clinical Effects of Immediate Release Paroxetine and Modified Release Paroxetine in the Treatment of Major Depression
GSK-29060/449: A Double-Blind, Placebo Controlled Trial to Evaluate the Clinical Effects of Immediate Release Paroxetine and Modified Release Paroxetine in the Treatment of Major Depression
GSK-29060/810: A double-blind, placebo-controlled, 3-arm, fixed-dose study of 12.5 mg/day and 25mg/day Paroxetine CR in the treatment of Major Depression.
GSK-29060/874: Assessment of Paxil CR, 12.5 and 25 mg/day in treating elderly patients with major depression
GSK-NKF100096: A Randomised, Double-Blind, Double-Dummy, Parallel-Group, Placebo-Controlled, Forced Dose Titration Study Evaluating the Efficacy and Safety of GW679769 and Paroxetine in Subjects with Major depressive Disorder (MDD)
GSK-29060/01/001: A Phase II, Placebo-Controlled, Double-Blind Study of Paroxetine in Depressed Outpatients
GSK-29060/02/001: A Double-Blind, Imipramine- and Placebo-Controlled Study of Paroxetine in Depressed Outpatients
GSK-29060/03/001: A Double-Blind, Imipramine- and Placebo-Controlled Study of Paroxetine in Depressed Outpatients
GSK-29060/07/001: A Double-Blind Comparison of Paroxetine, Amitriptyline, and Placebo in Inpatients with Major Depressive Disorder with Melancholia
GSK-29060/009: A Multicenter, Double-blind, Placebo-controlled Fixed-dose Evaluation of Four Doses of Paroxetine
GSK-29060/128: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Comparison of Paroxetine and Fluoxetine in the Treatment of Major Depressive Disorder
GSK-29060/276: A double-blind study to investigate the efficacy, safety and tolerability of Paroxetine in the treatment of depression in comparison with placebo
GSK-29060/012_3: A Study to Assess the Effectiveness and Tolerance of Paroxetine by Double-Blind Comparison with Placebo and Mianserin
GSK-29060/487: A Double-Blind, Placebo Controlled Trial to Evaluate the Clinical Effects of Immediate Release Paroxetine and Controlled Release Paroxetine in the Treatment of Major Depression in Elderly Patients
GSK-NKD20006: An 8-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Fixed-Dose Study Comparing the Efficacy and Safety of GW597599B or Paroxetine to Placebo in Moderately to Severely Depressed Patients with Major Depressive Disorder
LILLY-F1J-US-HMFA: Duloxetine Versus Placebo in the Long-Term Treatment of Patients With Late-Life Major Depression
LILLY-F1J-MC-HMAQ(A): Duloxetine Versus Placebo in the Treatment of Major Depression
LILLY-F1J-MC-HMAQ(B): Duloxetine Versus Placebo in the Treatment of Major Depression
LILLY-F1J-MC-HMAT(A): Duloxetine Versus Placebo and Paroxetine in the Acute Treatment of Major Depression
LILLY-F1J-MC-HMAT(B): Duloxetine Versus Placebo and Paroxetine in the Acute Treatment of Major Depression
LILLY-F1J-US-HMFS: Duloxetine Versus Placebo in Patients With Major Depressive Disorder (MDD): Assessment of Energy and Vitality in MDD
LILLY-F1J-AA-HMCV: Duloxetine Versus Paroxetine in the Acute Treatment of Major Depression
LILLY-F1J-MC-HMAY(A): Duloxetine Versus Placebo and Paroxetine in the Treatment of Major Depression
LILLY-F1J-MC-HMAY(B): Duloxetine Versus Placebo and Paroxetine in the Treatment of Major Depression
LILLY-F1J-MC-HMBH(A): Duloxetine Once-Daily Dosing Versus Placebo in the Acute Treatment of Major Depression
LILLY-F1J-MC-HMBH(B): Duloxetine Once-Daily Dosing Versus Placebo in the Acute Treatment of Major Depression
LILLY-F1J-MC-HMBU: Duloxetine Versus Venlafaxine Extended Release in the Treatment of Major Depressive Disorder
LILLY-F1J-MC-HMCQ Duloxetine Versus Venlafaxine Extended Release in the Treatment of Major2007 Depressive Disorder
LILLY-F1J-US-HMCR: Duloxetine Versus Escitalopram and Placebo in the Treatment of Patients With Major Depression
LILLY-F1J-MC-HMBV: Duloxetine Versus Placebo in the Treatment of Elderly Patients With Major Depressive Disorder

Statistical Analysis Plan

Publication Citation

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Summary Results

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