iMORE+ Study: A Multi-Omics Cohort Study of Major Depressive Disorder

The primary outcome is the change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to Week 8 after antidepressant treatment. The MADRS is a clinician-rated scale assessing depressive symptom severity. The total score ranges from 0 to 60, with higher scores indicating greater depressive symptom severity (worse outcome). Change in MADRS total score from baseline to Week 8 will be assessed as the primary clinical endpoint.

Treatment response is defined as a ≥50% reduction from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 8. The MADRS score ranges from 0 to 60, with higher scores indicating greater depressive symptom severity (worse outcome). The outcome measure is the percentage of participants achieving treatment response.

Treatment response is defined as a ≥50% reduction from baseline in 17-item Hamilton Depression Rating Scale (HAMD-17) total score at Week 8. The HAMD-17 total score ranges from 0 to 52, with higher scores indicating greater depressive symptom severity (worse outcome). The outcome measure is the percentage of participants achieving treatment response.

Remission is defined as a total score ≤10 on the Montgomery-Åsberg Depression Rating Scale (MADRS) at Week 8. The MADRS score ranges from 0 to 60, with higher scores indicating greater depressive symptom severity (worse outcome). The outcome measure is the percentage of participants achieving remission.

Remission is defined as a total score ≤7 on the 17-item Hamilton Depression Rating Scale (HAMD-17) at Week 8. The HAMD-17 score ranges from 0 to 52, with higher scores indicating greater depressive symptom severity (worse outcome). The outcome measure is the percentage of participants achieving remission.

The Hamilton Anxiety Rating Scale (HAMA) is a clinician-rated scale assessing anxiety symptom severity. The total score ranges from 0 to 56, with higher scores indicating greater anxiety severity (worse outcome).

The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) assesses biological rhythm disruption. The total score range from 18 to 72, with higher scores indicating greater circadian rhythm disturbance (worse outcome).

The Clinical Global Impression-Severity (CGI-S) scale assesses overall illness severity as rated by the clinician. Scores range from 1 to 7, with higher scores indicating greater illness severity (worse outcome). Change in CGI-S score from baseline to Week 8 will be assessed.

The Clinical Global Impression-Improvement (CGI-I) scale assesses overall clinical improvement after treatment. Scores range from 1 to 7, with lower scores indicating greater improvement (better outcome).

Number of participants with suicidal ideation or suicidal behavior assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)

The Snaith-Hamilton Pleasure Scale (SHAPS) is a self-reported scale assessing anhedonia. The total score ranges from 0 to 14, with higher scores indicating greater anhedonia severity (worse outcome). Change in SHAPS score from baseline to Week 8 will be assessed.

The Sheehan Disability Scale (SDS) is a self-reported scale assessing functional impairment in work/school, social life, and family life. The total score ranges from 0 to 30, with higher scores indicating greater functional impairment (worse outcome). Change in SDS score from baseline to Week 8 will be assessed.

Depressive relapse during 1-year follow-up will be assessed according to DSM-5 criteria and clinically relevant clinical events. The number and percentage of participants experiencing relapse will be reported.

The Montgomery-Åsberg Depression Rating Scale (MADRS) assesses depressive symptom severity. Total scores range from 0 to 60, with higher scores indicating greater depressive symptom severity (worse outcome). Longitudinal changes in MADRS scores from baseline will be assessed at predefined assessment time points (Baseline, Week 2, Week 4, Week 8, Month 3, Month 6, and Year 1) to characterize trajectories of depressive symptom change over the 1-year follow-up period.

The Sheehan Disability Scale (SDS) assesses functional impairment in work/school, social life, and family life. The total score ranges from 0 to 30, with higher scores indicating greater functional impairment (worse outcome). Changes in SDS scores from baseline will be assessed at Week 8, Month 6, and Year 1 to characterize trajectories of functional recovery over the 1-year follow-up period.

A multivariable model integrating clinical characteristics and multi-omics data, including immune profiling (CyTOF and cytokine profiling), genomics, epigenomics, bulk transcriptomics, single-cell transcriptomics, proteomics, metabolomics, and microbiome profiling, will be developed to discriminate participants with major depressive disorder from healthy controls. Model discrimination performance will be primarily assessed by the area under the receiver operating characteristic curve (AUROC). Sensitivity, specificity, and predictive accuracy will be reported as supportive metrics.

A multivariable model integrating baseline clinical characteristics and multi-omics data, including immune profiling (CyTOF and cytokine profiling), genomics, epigenomics, bulk transcriptomics, single-cell transcriptomics, proteomics, metabolomics, and microbiome profiling, will be developed to predict antidepressant treatment response at Week 8. Treatment response will be defined as a ≥50% reduction from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 8. Model predictive performance will be primarily assessed by the area under the receiver operating characteristic curve (AUROC), with internal validation performed using bootstrap resampling. Calibration, sensitivity, specificity, and predictive accuracy will be reported as supportive metrics.

A longitudinal multivariable model integrating baseline clinical characteristics, baseline multi-omics profiles, and multi-omics changes from baseline to Week 4 will be developed to predict MADRS-defined antidepressant treatment response at Week 8. Treatment response will be defined as a ≥50% reduction from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 8. Multi-omics data will include immune profiling (CyTOF and cytokine profiling), genomics, epigenomics, bulk transcriptomics, single-cell transcriptomics, proteomics, metabolomics, and microbiome profiling. Model predictive performance will be primarily assessed by the area under the receiver operating characteristic curve (AUROC), with internal validation performed using bootstrap resampling. Calibration, sensitivity, specificity, and predictive accuracy will be reported as supportive metrics.

Longitudinal changes in multi-omics profiles from baseline to Week 8 will be analyzed to identify molecular features significantly altered following antidepressant treatment. Multi-omics analyses will include immune profiling (CyTOF and cytokine profiling), genomics, epigenomics, bulk transcriptomics, single-cell transcriptomics, proteomics, metabolomics, and microbiome profiling. Statistically significant features will be identified based on predefined statistical thresholds, and the number of significantly altered features will be reported.

A multivariable model integrating baseline clinical characteristics and multi-omics data will be developed to predict the Sheehan Disability Scale (SDS) total score at 1-year follow-up. The SDS is a self-reported scale assessing functional impairment. The SDS total score ranges from 0 to 30, with higher scores indicating greater functional impairment (worse outcome). Model predictive performance will be assessed using predefined regression metrics, including coefficient of determination (R²), root mean square error (RMSE), and mean absolute error (MAE). Internal validation will be performed using bootstrap resampling.