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.
Clinical diagnosis of Major Depressive Disorder (MDD) according to DSM-5 criteria
Age between 18 and 60 years
Baseline HAMD-17 total score ≥ 17
Ability to provide written informed consent
History of other psychiatric disorders (e.g., bipolar disorder, schizophrenia)
Presence of severe physical illnesses or major central nervous system diseases
History of sedative-hypnotic, alcohol, or substance abuse
Pregnancy, lactation, or planning to become pregnant during the study
Parallel
Pharmacogenomic Testing
Diagnostic testBuccal 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.
Antidepressant Agents
DrugOral 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.
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.
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.
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).
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).
Proportion of Participants Withdrawing Due to Adverse Drug Reactions
Unit: percent. The proportion of participants who discontinue the study due to adverse drug reactions.
Amplitude of Low-Frequency Fluctuation (ALFF) Levels
Unit: z-score. Comparison of ALFF z-scores between MDD patients and healthy controls using ANCOVA.
Functional Connectivity Density (FCD)
Unit: z-score. Comparison of baseline FCD z-scores between groups.
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.
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.
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