Symptom level analysis of recovery during antidepressant treatment

Proposal
5796

Title of Proposed Research

Lead Researcher

Markus Jokela

Affiliation

Department of Psychology and Logopedics, Medical Faculty, University of Helsinki, Helsinki, Finland

Funding Source

Potential Conflicts of Interest

Data Sharing Agreement Date

05 August 2019

Lay Summary

The purpose of the current project is to examine whether specific symptoms of depression respond differently to antidepressant treatment among individuals diagnosed with clinical depression. Antidepressant medication are known to decrease symptoms of depression in most, but not all, patients. This produces a heterogeneous treatment response in clinical trials, as the treatment works only on some patients. One potential reason for this heterogeneity in treatment response is the specific combination and profile of the person's depressive symptoms. Whereas depression symptoms have been traditionally considered as interchangeable indicators of the underlying disease, the symptoms can produce multiple variations of depression and there are hundreds of possible symptom combinations by which a diagnosis threshold of depression can be reached.The present project tests whether symptoms of depression are differently improved by treatment, and whether improvements in specific symptoms are more important than others in predicting improvements in other symptoms. We hypothesize that specific symptoms are differently influenced by treatment, and that the profile of specific symptoms, and not just the overall level of symptoms, can be used to predict a person's treatment response. Furthermore, we hypothesize that there are symptom cascades where a change in one symptom is required for a subsequent change in other symptoms to occur.A symptom-level understanding of antidepressant treatment may have clinical relevance in identifying symptom-level obstacles in treatment response and potential symptom-level obstacles among those with low response to antidepressant treatment. It would also help to better understand the psychological processes underlying antidepressant treatment, which has usually been assessed only at the level of depression sum scores instead of specific symptoms.

Study Data Provided

[{ "PostingID": 1623, "Title": "GSK-MY-1043/BRL-029060/115", "Description": "A multicenter, randomized, double-blind, placebo-controlled comparison of paroxetine and fluoxetine in the treatment of major depressive disorder." },{ "PostingID": 1633, "Title": "GSK-29060/448", "Description": "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" },{ "PostingID": 1634, "Title": "GSK-29060/449", "Description": "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" },{ "PostingID": 1639, "Title": "GSK-29060/874", "Description": "Assessment of Paxil CR, 12.5 and 25 mg/day in treating elderly patients with major depression" },{ "PostingID": 1646, "Title": "LILLY-F1J-MC-HMBC", "Description": "Duloxetine Versus Placebo in the Prevention of Relapse of Major Depressive Disorder" },{ "PostingID": 1955, "Title": "LILLY-F1J-MC-HMDI", "Description": "Duloxetine Versus Placebo in the Prevention of Recurrence of Major Depressive Disorder" },{ "PostingID": 2063, "Title": "GSK-AK130939", "Description": "A Multi-Centre, Randomised, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, Flexible Dose Study Evaluating the Efficacy, Safety and Tolerability of Extended-Release Bupropion Hydrochloride (150mg - 300mg once daily), Extended-Release Venlafaxine Hydrochloride (75mg - 150mg once daily) and Placebo in Subjects with Major Depressive Disorder." },{ "PostingID": 2064, "Title": "GSK-WXL101497", "Description": "A Multi-Centre, Randomised, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, Flexible Dose Study Evaluating the Efficacy, Safety and Tolerability of Extended-Release Bupropion Hydrochloride (150mg - 300mg once daily), Extended-Release Venlafaxine Hydrochloride (75mg - 150mg once daily) and Placebo in Subjects with Major Depressive Disorder." },{ "PostingID": 2127, "Title": "GSK-29060/057", "Description": "A Double-blind comparative multicentre study of paroxetine plus supportive psychotherapy and psychotherapy alone in the prevention of recurrent suicidal behavior and episodes of intermittent brief depression" },{ "PostingID": 2129, "Title": "GSK-29060/128", "Description": "A Multicenter, Randomized, Double-Blind, Placebo-Controlled Comparison of Paroxetine and Fluoxetine in the Treatment of Major Depressive Disorder" },{ "PostingID": 2137, "Title": "GSK-29060/487", "Description": "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" },{ "PostingID": 2138, "Title": "GSK-29060/625", "Description": "A double-blind, placebo-controlled multi-centre study to evaluate the efficacy and tolerability of Paroxetine in the treatment of post-stroke depression." },{ "PostingID": 2413, "Title": "LILLY-F1J-US-HMCB", "Description": "Duloxetine Once-Daily Dosing Versus Placebo in Patients With Major Depression and Pain" },{ "PostingID": 4238, "Title": "GSK-PCR112810", "Description": "A Randomized, Double-blind, Placebo Controlled Trial to Evaluate the Clinical Effects of Controlled Release Paroxetine in the Treatment of Major Depressive Disorder" }]

Statistical Analysis Plan

Our approach will follow that of Hieronymus et al. (2016 & 2015) . These studies focused on how anti-depressant treatment affected one of the items from the depression scales instead of the sum score of the scale. Our analysis will cover all the items and hence provide a more extensive overview on how antidepressant affect depression symptoms. Our analysis also follows that of Bringmann et al who studied how specific symptoms of Beck Depression Inventory changed in response to psychotherapy treatment. First, we use network analysis to examine how specific depression symptoms are related to each other (11) and whether these network structures are different before and after antidepressant treatment. Second, we use multilevel longitudinal analysis and time-lagged network analysis to examine whether improvements in some symptoms are particularly strong in predicting subsequent improvements in other symptoms (i.e., out-degree centrality) and whether some symptoms are particularly sensitive to earlier changes in other symptoms (i.e., in-degree centrality). Such within-individual analysis of symptom changes can be used to identify temporal cascades between depression symptoms, that is, whether the overall improvement associated with antidepressant treatment can be better described by systematic temporal associations between specific symptoms. The more follow-up measurements of depression the trials include the better we can estimate such temporal cascades.Crucially, the statistical analysis of specific versus non-specific symptoms is not based on simply assessing individual symptoms one by one in separate models because this would confound the specific and non-specific variance in the symptoms because of the correlations between symptoms. Instead, the current analysis is based on (a) separating the non-specific level of depression from unique variation in specific symptoms, as is done in the so-called bi- factor models, or (b) using partial correlation networks where residual scores are used to tease apart the unique variance in individual symptoms. In other words, all the analyses of the current project begin by separating the non-specific variation in depressive symptoms (i.e., shared variance across all symptoms) and the unique variation in individual symptoms (i.e., variance not shared with other symptoms).To get robust estimates for the depression symptom networks before and after anti-depressant treatment, we will use random-effect meta-analysis stratified by the anti-depressant used in each trial. Similarly, we will examine possible effect modification by age, sex, and socioeconomic status.

Publication Citation

Komulainen, K., Airaksinen, J., Savelieva, K. et al. Network dynamics of depressive symptoms in antidepressant medication treatment: secondary analysis of eight clinical trials. Mol Psychiatry (2020).
https://doi.org/10.1038/s41380-020-00884-3