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

Primary outcomes

• Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score From Baseline to Week 8 [Baseline to Week 8]: 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.

Secondary outcomes

• Antidepressant Treatment Response Rate Based on Montgomery-Åsberg Depression Rating Scale (MADRS) at Week 8 [Baseline to Week 8]: 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.
• 17-item Hamilton Depression Rating Scale (HAMD-17)-Defined Treatment Response at Week 8 [Baseline to Week 8]: 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.
• Montgomery-Åsberg Depression Rating Scale (MADRS)-Defined Antidepressant Treatment Remission at Week 8 [Baseline to Week 8]: 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.
• 17-item Hamilton Depression Rating Scale (HAMD-17)-Defined Antidepressant Treatment Remission at Week 8 [Baseline to Week 8]: 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.
• Change in Hamilton Anxiety Rating Scale (HAMA) Score From Baseline to Week 8 [Baseline to Week 8]: 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).
• Change in Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) Score From Baseline to Week 8 [Baseline to Week 8]: 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).
• Change in Clinical Global Impression-Severity (CGI-S) Score From Baseline to Week 8 [Baseline to Week 8]: 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.
• Clinical Global Impression-Improvement (CGI-I) Score at Week 8 [Baseline to Week 8]: 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) From Baseline to Week 8 [Baseline to Week 8]: Number of participants with suicidal ideation or suicidal behavior assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)
• Change in Snaith-Hamilton Pleasure Scale (SHAPS) Score From Baseline to Week 8 [Baseline to Week 8]: 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.
• Change in Sheehan Disability Scale (SDS) Score From Baseline to Week 8 [Baseline to Week 8]: 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.
• Incidence of Depressive Relapse During 1-Year Follow-up [Baseline to 1 year]: 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.
• Longitudinal Trajectory of Montgomery-Åsberg Depression Rating Scale (MADRS) Score Over 1-Year Follow-up [Baseline, Week 2, Week 4, Week 8, Month 3, Month 6, and Year 1]: 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.
• Longitudinal Trajectory of Sheehan Disability Scale (SDS) Score Over 1-Year Follow-up [Baseline, Week 8, Month 6, and Year 1]: 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.

Other outcomes

• Area Under the Receiver Operating Characteristic Curve (AUROC) of Multi-Omics-Based Models for Discriminating Major Depressive Disorder From Healthy Controls [Baseline]: 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.
• Area Under the Receiver Operating Characteristic Curve (AUROC) of Multi-Omics-Based Models for Predicting MADRS-Defined Antidepressant Treatment Response at Week 8 [Baseline to Week 8 (baseline predictors and Week 8 treatment response assessment)]: 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.
• Area Under the Receiver Operating Characteristic Curve (AUROC) of Multi-Omics-Based Models Integrating Baseline Profiles and Week 4 Molecular Changes for Predicting MADRS-Defined Antidepressant Treatment Response at Week 8 [Baseline to Week 8]: 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.
• Number of Significantly Altered Multi-Omics Features From Baseline to Week 8 of Antidepressant Treatment [Baseline to Week 8]: 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.
• Predictive Performance of Multi-Omics-Based Models for Predicting One-Year Sheehan Disability Scale (SDS) Score [Baseline to Year 1]: 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.

Sex: All, ages: 14 Years to 45 Years, accepts healthy volunteers

Inclusion Criteria:

General criteria:

* Participants aged 14-45 years.
* Participants are able to understand the study procedures and provide written informed consent. For participants younger than 18 years, both the participant and their legal guardian must provide consent.

Major Depressive Disorder (MDD) cohort:

* Meet DSM-5 criteria for major depressive disorder (single or recurrent episode).
* Have a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥24 and 17-item Hamilton Depression Rating Scale (HAMD-17) score ≥18.

Healthy Control (HC) cohort:

\- Healthy participants without a current or lifetime diagnosis of major psychiatric disorders.

Exclusion Criteria:

For all participants:

\- Severe or unstable medical conditions, pregnancy or breastfeeding, or other conditions considered unsuitable for study participation.

For the MDD cohort:

* Current or lifetime diagnosis of other major psychiatric disorders, including schizophrenia spectrum disorders, schizoaffective disorder, or bipolar disorder.
* Substance use disorder within 12 months prior to screening.
* Depression secondary to medical or neurological conditions.
* Regular antidepressant treatment within 2 weeks prior to enrollment.
* Electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), or immunosuppressive therapy during the current depressive episode.
* Current active suicidal plan or recent suicidal behavior considered unsuitable for participation.

For the HC cohort:

* Current or lifetime diagnosis of any psychiatric disorder.
* Significant depressive, anxiety, manic, or psychotic symptoms.
* Previous treatment with antidepressants, antipsychotics, or mood stabilizers.
* Significant family history of major psychiatric disorders.

• Shen He, Principal investigator, Shanghai Mental Health Center