Biomarkers and Pharmacogenomics for Precision Depression Therapy

Study on Multidimensional Biomarkers of Depression and Individualized Therapy Based on Pharmacogenomic Technology

Background: The clinical management of major depressive disorder (MDD) is hampered by the lack of objective biomarkers and high inter-individual variability in drug response, with conventional antidepressants achieving only a 50% response rate.

Objective and Design: This prospective, randomized, parallel-controlled trial aims to enroll 220 MDD patients, who will be allocated 1:1 to either a pharmacogenomics (PGx)-guided therapy group (treatment selection based on genetic testing) or a conventional treatment group (treatment as usual per guidelines), with a 12-week follow-up. Additionally, a matched healthy control cohort will be included for cross-sectional biomarker comparisons.

Intervention and Outcomes: Patients in the PGx group undergo buccal swab testing for key genetic polymorphisms (e.g., CYP2D6, CYP2C19) to inform antidepressant type and dosage. The primary outcome is the 12-week response rate (≥50% reduction in HAMD-17 score from baseline). Secondary outcomes include remission rate, incidence of adverse drug reactions, and medication adjustment frequency.

Exploratory Aims: Multidimensional baseline data-including resting-state fMRI (VMHC), peripheral blood biomarkers (inflammatory cytokines, thyroid function, BDNF), urinary metabolites, and gut microbiome-will be integrated to construct a predictive model for treatment efficacy and to identify novel MDD biomarkers.

Scientific Significance: This study seeks to validate the clinical utility of PGx-guided prescribing and to advance the shift from symptom-based diagnosis towards a biological-characteristic-based precision medicine framework for depression.

Study Overview

• Status: Not yet recruiting
• Conditions: Depression / Major Depressive Disorder
• Intervention / Treatment: Diagnostic test: Pharmacogenomic Testing; Drug: Antidepressant Agents

Detailed Description

1. Study Design and Overall Framework This is a prospective, randomized, parallel-controlled, single-center clinical trial, conducted in accordance with the Declaration of Helsinki and Chinese ethical regulations. A total of 220 patients diagnosed with major depressive disorder (MDD) per DSM-5 criteria will be enrolled, along with 80-100 age-, sex-, and education-matched healthy controls (retrospective data from an anonymized health check-up database). Patient participants will be randomized 1:1 via block randomization (block size 4-6) into: (1) Pharmacogenomics (PGx)-guided therapy group; (2) Conventional treatment group (guideline- and experience-based). The follow-up duration is 12 weeks, with assessments scheduled at baseline, Week 4, Week 8, and Week 12 (endpoint). Healthy controls provide only cross-sectional baseline data.
2. Participant Eligibility and Screening Inclusion criteria for patients: (1) MDD diagnosis confirmed by two senior psychiatrists; (2) HAMD-17 total score ≥17 at baseline; (3) aged 14-60 years; (4) at least junior high school education. Exclusion criteria include: other psychiatric disorders, organic CNS diseases, severe physical illnesses, substance abuse history, physical therapy within the past year, pregnancy/lactation, or significant abnormalities in ECG, routine blood tests, liver/kidney/thyroid function. Written informed consent is obtained from all patients (and legal guardians for minors or cognitively impaired individuals).
3. Interventions and Procedures (1) PGx-guided group: Buccal swab samples are collected at baseline for targeted genotyping (chip or sequencing) of key polymorphisms in drug-metabolizing enzymes, transporters, and targets, including CYP2D6, CYP2C19, CYP3A4/5, CYP1A2, CYP2B6, CYP2C9, HTR2A, and SLC6A4. The report classifies patients into ultrarapid, normal, intermediate, or poor metabolizer phenotypes and provides prescribing recommendations for SSRIs (escitalopram, sertraline, fluoxetine, paroxetine, fluvoxamine, citalopram), SNRIs (venlafaxine, duloxetine, milnacipran), NaSSAs (mirtazapine), and others (bupropion). Clinicians prioritize drugs predicted to offer better efficacy and lower risk, adjusting starting doses based on metabolic type.

(2) Conventional group: Buccal swabs are collected but not analyzed (sham procedure to maintain blinding balance). Clinicians prescribe antidepressants following Chinese depression treatment guidelines, based on symptom profiles, prior medication history, and clinical judgment. Both groups allow dose adjustments during follow-up, with all changes documented.

4. Data Acquisition and Multi-Dimensional Biomarker Assessment All participants (including healthy controls) undergo baseline assessments: (1) Demographics and clinical history; (2) Peripheral blood for inflammatory markers (CRP, IL-6), endocrine function (thyroid panel: TSH, FT3, FT4), neurotrophic factor (BDNF), and routine biochemistry (liver/kidney function, glucose, lipids); (3) Urine and stool samples for future metabolomic and gut microbiome analyses; (4) Resting-state fMRI scanning, with primary extraction of voxel-mirrored homotopic connectivity (VMHC), and optional exploration of ALFF and FCD; (5) Scale assessments: HAMD-17, HAMA, and TESS. Follow-up visits (Weeks 4, 8, 12) for patient groups include only scale assessments and adverse event recording, without repeated blood draws or imaging.

5. Outcome Definitions Primary outcome: 12-week response rate, defined as the proportion of patients with ≥50% reduction in HAMD-17 total score from baseline (χ² test between groups).

Secondary outcomes: (1) 12-week remission rate (HAMD-17 ≤7); (2) Trajectory of depressive symptoms across time points (repeated-measures ANOVA); (3) Incidence of treatment-emergent adverse events (TESS); (4) Dropout rate due to adverse events; (5) Concordance between initial drug choice and PGx recommendations (descriptive, intervention group only); (6) Time to reach stable effective dose (survival analysis); (7) Frequency of medication adjustments (Mann-Whitney U test).

Exploratory outcomes: (1) Efficacy differences across distinct metabolic phenotypes; (2) Correlations of baseline VMHC and blood biomarkers with 12-week efficacy; (3) Case-control comparisons of all biomarker dimensions; (4) Construction of a comprehensive predictive model integrating clinical, imaging, blood, and genomic features using multivariate logistic regression or machine learning (e.g., random forest, SVM), with cross-validation for performance evaluation (AUC, sensitivity, specificity).

6. Sample Size Justification Sample size is calculated for the primary outcome (two independent proportions, χ² test) using PASS 15.0. Parameters: α=0.05 (two-sided), power 1-β=0.80. Based on published literature, the 12-week response rate for conventional treatment is estimated at 50% (P₁), and the PGx-guided group is expected to achieve 70% (P₂), an absolute difference of 20%. The required sample size is 86 per group. Accounting for a 20% dropout rate, the adjusted sample size is 107.5 per group, rounded up to 110 per group, yielding a total of 220 patients to ensure adequate statistical power.

7. Statistical Analysis Plan Analyses will be performed using SPSS 26.0 and R 4.0. Efficacy analysis follows the intention-to-treat (ITT) principle with multiple imputation for missing data; per-protocol analysis serves as a sensitivity check. Baseline comparisons use t-tests or Mann-Whitney U tests for continuous variables and χ² or Fisher's exact tests for categorical variables. Repeated measures are analyzed using mixed-effects models or repeated-measures ANOVA, adjusting for baseline values. Biomarker exploration: Case-control comparisons use ANCOVA (adjusting for age, sex, etc.); correlation analyses use Pearson/Spearman coefficients. Predictive modeling: Candidate variables with P<0.10 in univariate analysis enter multivariate logistic regression (forward stepwise) or machine learning algorithms. Internal validation employs 5-fold cross-validation, with AUC assessing discrimination and calibration curves assessing goodness-of-fit.

8. Data Management and Quality Control Data are recorded in an electronic data capture (EDC) system with double-entry verification. Biological samples are aliquoted, coded, and stored at -80°C with routine quality checks. MRI data are processed independently by two blinded neuroradiologists. All adverse events are assessed for severity and causality by study physicians and reported to the ethics committee. Independent monitoring audits are conducted periodically.

9. Ethical Approval and Informed Consent This study has been approved by the Ethics Committee of the Fourth Affiliated Hospital of Zhejiang University School of Medicine. Written informed consent is obtained from all patient participants (or their legal guardians) prior to any study procedures. For healthy controls, data are derived from an anonymized health check-up database archived before January 31, 2026; original consent covered research use, and the ethics committee granted a waiver of re-consent.

10. Study Timeline The total study duration is 36 months from ethics approval: 6 months for preparation and training, 24 months for enrollment and 12-week follow-up completion, and 6 months for data cleaning, statistical analysis, and final reporting.

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Haiyan XIE, MD; Phone Number: +86 0579-89935006; Email: 8015138@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Clinical diagnosis of Major Depressive Disorder (MDD) according to DSM-5 criteria
2. Age between 18 and 60 years
3. Baseline HAMD-17 total score ≥ 17
4. Ability to provide written informed consent

Exclusion Criteria:

1. History of other psychiatric disorders (e.g., bipolar disorder, schizophrenia)
2. Presence of severe physical illnesses or major central nervous system diseases
3. History of sedative-hypnotic, alcohol, or substance abuse
4. Pregnancy, lactation, or planning to become pregnant during the study
5. Significant abnormalities in ECG, complete blood count, or liver/kidney/thyroid function tests

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pharmacogenomics-Guided Antidepressant Therapy; Patients receive pharmacogenomic testing via buccal swab at baseline. The test detects polymorphisms in CYP2D6, CYP2C19, CYP3A4/5, CYP1A2, CYP2B6, CYP2C9, HTR2A, and SLC6A4. Clinicians select antidepressant type and starting dosage based on the genotype report (metabolizer phenotype) to optimize efficacy and minimize adverse drug reactions.	Diagnostic test: Pharmacogenomic Testing; Buccal swab collection for targeted genotyping of polymorphisms in CYP2D6, CYP2C19, CYP3A4/5, CYP1A2, CYP2B6, CYP2C9, HTR2A, and SLC6A4. The assay classifies patients into ultrarapid, normal, intermediate, or poor metabolizer phenotypes for CYP450 enzymes, and provides response/risk predictions for SSRIs (escitalopram, sertraline, fluoxetine, paroxetine, fluvoxamine, citalopram), SNRIs (venlafaxine, duloxetine, milnacipran), mirtazapine, and bupropion. A written report with genotype-based drug and dosage recommendations is issued to the clinician.; Other Names: PGx Genotyping; CYP450 Genotyping Panel; Antidepressant Genetic Test
Active Comparator: Guideline-Based Conventional Antidepressant Therapy; Patients undergo a sham buccal swab procedure without genetic analysis. Clinicians prescribe antidepressants following the Chinese Depression Prevention and Treatment Guidelines, based on clinical experience, symptom profiles, prior medication history, and physical condition. Medication adjustments are allowed during the 12-week follow-up.	Drug: Antidepressant Agents; Oral administration of first-line or second-line antidepressants approved for major depressive disorder, including selective serotonin reuptake inhibitors (SSRIs: escitalopram, sertraline, fluoxetine, paroxetine, fluvoxamine, citalopram), serotonin-norepinephrine reuptake inhibitors (SNRIs: venlafaxine, duloxetine, milnacipran), noradrenergic and specific serotonergic antidepressants (NaSSA: mirtazapine), and bupropion. Dosing follows clinical guidelines. In the experimental arm, selection and initial dosage are guided by the pharmacogenomic test report; in the conventional arm, selection and dosage are determined by physician expertise and standard care guidelines. Dose adjustments are permitted at Weeks 4, 8, and 12 based on efficacy and tolerability.; Other Names: Bupropion; Mirtazapine; SSRIs; SNRIs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Title: 12-Week Response Rate Defined by HAMD-17 Score Reduction	Unit: percent. The proportion of participants achieving a clinical response, defined as a reduction in HAMD-17 score of 50% or greater from baseline.	From baseline to Week 12.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
12-Week Remission Rate Defined by HAMD-17 Total Score	Unit: percent. The proportion of participants achieving remission, defined as a HAMD-17 total score of 7 or less. Assessments are conducted by trained psychiatrists blinded to group allocation.	Week 12.
Longitudinal Trajectory of Depressive Symptoms Assessed by HAMD-17 Over 12 Weeks	Unit: score (0-52 scale points). Change in depressive symptom severity over time assessed by the Hamilton Depression Rating Scale (HAMD-17).	Baseline, Week 4, Week 8, and Week 12.
Incidence of Treatment-Emergent Adverse Events Assessed by the TESS Scale	Unit: percent. The incidence of treatment-emergent adverse events assessed by the Treatment Emergent Symptom Scale (TESS).	From randomization through Week 12.
Proportion of Participants Withdrawing Due to Adverse Drug Reactions	Unit: percent. The proportion of participants who discontinue the study due to adverse drug reactions.	From randomization through Week 12.
Time to Reach Stable Effective Antidepressant Dose	Unit: days. Time required from treatment initiation to reaching a stable and effective antidepressant dose.	From randomization through Week 12.
Concordance Between PGx Recommendations and Prescribed Medication	Unit: percent. The percentage of prescriptions that are concordant with pharmacogenomic recommendations.	Baseline (time of first prescription).
Frequency of Antidepressant Regimen Adjustments Within 12 Weeks	Unit: count. The total number of antidepressant regimen adjustments made during the study period.medication adjustments (including dose changes, drug switches, or addition of adjunctive therapy) made during the 12-week treatment period due to either insufficient therapeutic response or unacceptable adverse effects. This outcome reflects the clinical practicality and stability of the treatment strategy in each arm. The adjustment frequency is compared between the pharmacogenomics-guided therapy group and the conventional treatment group using the Mann-Whitney U test. Descriptive statistics (median, interquartile range) will be reported for each group.	From randomization through Week 12.
Incidence of Clinically Significant Laboratory Abnormalities	Unit: percent. Proportion of participants developing clinically significant laboratory abnormalities.	Baseline to Week 12.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amplitude of Low-Frequency Fluctuation (ALFF) Levels	Unit: z-score. Comparison of ALFF z-scores between MDD patients and healthy controls using ANCOVA.	Baseline
Functional Connectivity Density (FCD)	Unit: z-score. Comparison of baseline FCD z-scores between groups.	Baseline
Correlation Between Baseline VMHC and Change in HAMD-17 Score at 12 Weeks	Unit: Pearson correlation coefficient (r). Correlation analysis between baseline voxel-mirrored homotopic connectivity (VMHC) and change in HAMD-17 score.	Baseline VMHC with Week 12 HAMD-17 change
Serum C-Reactive Protein (CRP) Concentration	Unit: mg/L Description: Case-control t-test/Mann-Whitney; within-patients, Pearson correlation with baseline HAMD-17 and Week-12 % change.	Baseline
Serum Interleukin-6 (IL-6) Concentration	Unit: pg/mL	Baseline
Serum Brain-Derived Neurotrophic Factor (BDNF) Concentration	Unit: ng/mL Description: Same as #14.	Baseline
Serum Thyroid-Stimulating Hormone (TSH) Concentration	Unit: mIU/L Description: Same case-control and correlation analyses.	Baseline
Serum Free Triiodothyronine (FT3) Concentration	Unit: pmol/L Description: Same case-control and correlation analyses.	Baseline
Serum Free Thyroxine (FT4) Concentration	Unit: pmol/L Description: Same case-control and correlation analyses.	Baseline
Multimodal Integrated Predictive Model Performance for 12-Week Response	Unit: Area under ROC curve (AUC), sensitivity (percent), specificity (percent). Performance of the logistic regression model integrating clinical, PGx, VMHC, and blood biomarkers.	Baseline predictors with Week 12 outcome
Genotype-Phenotype Associations with 12-Week Clinical Outcomes	Unit: Odds ratio (OR). Association of CYP2D6/CYP2C19 metabolizer phenotypes with response, remission, and adverse events.Description: Compare response/remission/AE rates across CYP2D6/CYP2C19 metabolizer phenotypes. Chi-square/Fisher's for categorical; ANOVA/Kruskal-Wallis for continuous % reduction.	Baseline genotyping; outcomes at Week 12

Collaborators and Investigators

• Sponsor: The Fourth Affiliated Hospital of Zhejiang University School of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): January 19, 2029
• Study Completion (Estimated): January 19, 2029

Study Registration Dates

• First Submitted: June 28, 2026
• First Submitted That Met QC Criteria: July 29, 2026
• First Posted (Actual): July 31, 2026

Study Record Updates

• Last Update Posted (Actual): July 31, 2026
• Last Update Submitted That Met QC Criteria: July 29, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Inflammation; Magnetic Resonance Imaging; Biomarkers; Pharmacogenetics; Personalized Medicine; Antidepressive Agents
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Pathological Conditions, Signs and Symptoms; Behavior; Depression; Inflammation; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Membrane Transport Modulators; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Serotonin Agents; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Health Services; Health Care Facilities Workforce and Services; Preventive Health Services; Central Nervous System Agents; Genetic Testing; Genetic Techniques; Genetic Services; Diagnostic Services; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Ketones; Propiophenones; Mirtazapine; Serotonin and Noradrenaline Reuptake Inhibitors; Bupropion; Antidepressive Agents; Selective Serotonin Reuptake Inhibitors; Pharmacogenomic Testing
• Other Study ID Numbers: KY-2025-327

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No