An interventional study of Repetitive Transcranial Magnetic Stimulation (rTMS) in Depression, Postpartum, sponsored by University of Macau. Not yet recruiting at 2 sites in Macau. Open to female participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-08-11.
Sponsored by University of Macau · Not applicable, Interventional, and Treatment
The purpose of this study is to identify multimodal biological markers associated with postpartum depression (PPD) and to evaluate the effectiveness of precision brain stimulation treatment. PPD is a common mental health condition after childbirth that can affect maternal well-being and early child development. Current identification of PPD relies largely on clinical assessments and screening questionnaires, which may not fully capture underlying biological changes. This study uses brain activity, cardiac signals, blood-based biomarkers, interoceptive assessments, and clinical measures to characterize multimodal biological profiles associated with PPD and treatment response.
The main questions it aims to answer are:
Participants will:
Participants in the PPD group will:
The study is divided into four core phases, systematically establishing a continuum from mechanistic exploration to clinical intervention:
Phase I: Establishment of Multimodal Biomarker Baselines and Screening of Core Metrics
Objective:
To identify central, peripheral, and psychological-interoceptive markers associated with postpartum depression (PPD).
Description:
This phase aims to establish a multimodal biomarker baseline for PPD and identify candidate biomarkers associated with PPD and evaluate their potential clinical relevance. Participants will be enrolled into two cohorts: pregnant women in their third trimester and non-pregnant healthy controls (HC). The primary rationale for including the non-pregnant HC group is to control for the confounding and widespread physiological, neural, and psychological changes induced by pregnancy and childbirth, thereby avoiding misinterpreting normal perinatal adaptations as PPD-specific pathology.
The perinatal transition involves profound hormonal fluctuations, immune regulation, and autonomic nervous system (ANS) remodeling; thus, even healthy peripartum women without depressive symptoms exhibit distinct physiological and psychological profiles compared to the general female population. By introducing the non-pregnant HC group, we establish an "unconfounded baseline," allowing us to delineate universal perinatal adaptations from specific biomarkers pathologically linked to depressive symptoms.
Preliminary screening for PPD will be conducted using the Edinburgh Postnatal Depression Scale (EPDS). Participants scoring above the clinical cutoff will undergo a structured clinical interview by licensed psychiatrists to confirm PPD diagnosis according to the DSM-5 criteria.
Multimodal Data Collection
All participants will undergo comprehensive multimodal data collection encompassing central nervous system (CNS) activity, autonomic function, peripheral blood biomarkers, and interoceptive function:
- Central Nervous System (CNS): Rest-state electroencephalography (EEG) will be recorded for 10 minutes (eyes closed) using a 128-channel system. Analyses will focus on power spectral features, frontal alpha asymmetry, and vigilance-related EEG dynamics, which have been implicated in affective regulation and depressive symptomatology.
- Autonomic Function: A standard 3-lead electrocardiogram (ECG) will record 10 minutes of resting data to quantify heart rate variability (HRV) and respiratory sinus arrhythmia (RSA). These metrics provide indices of autonomic regulation, particularly parasympathetic/vagal activity. Extant literature indicates that patients with PPD exhibit altered autonomic function, including reduced HRV and RSA, suggesting impaired emotion regulation and stress resilience.
- Peripheral Biomarkers: Fasting venous blood samples will be collected in the early morning to quantify inflammatory markers (e.g., interleukin-6 [IL-6]) and endocrine hormones. Chronic low-grade inflammation has been associated with depressive symptom severity in prior literature.
- Interoceptive Function: Subjective interoceptive sensibility will be evaluated using the Multidimensional Assessment of Interoceptive Awareness-2 (MAIA-2), while objective interoceptive accuracy will be quantified using a heartbeat discrimination task. Interoceptive metrics during the prenatal phase may hold predictive value for PPD, potentially identifying high-risk individuals prior to full symptomatic manifestation.
Core Task Against the current clinical backdrop where screening relies predominantly on self-report scales (e.g., EPDS), this phase aims to identify a reproducible and clinically relevant panel of candidate biomarkers to support subsequent disease trajectory analysis, prediction, and targeted intervention.
Work Packages Define rigorous recruitment criteria and cohort stratification (third-trimester pregnant women vs. non-pregnant healthy controls), ensuring precise matching for age, parity, and educational attainment.
Phase II: Third-Trimester Baseline Data Collection (T0) Objective: This phase aims to collect comprehensive multimodal biomarker data during the third trimester of pregnancy to capture critical physiological and psychological transitions from pregnancy to the postpartum period. This will establish a longitudinal baseline for subsequent disease trajectory tracking and early prediction, while identifying core metrics with potential clinical utility across risk strata. The non-pregnant (HC) group will complete an identical laboratory protocol to provide comparative diagnostic data.
Work Packages:
Participants will undergo assessments integrated within the standardized postpartum clinical workflow of the hospital, spanning psychological scales, pain assessments, and peripheral blood sampling:
- Blood Biomarkers: Early-morning fasting venous blood will be drawn to analyze inflammatory profiles (IL-6) and endocrine hormones.
- Psychological and Pain Assessment: Initial screening for depressive symptoms will utilize the EPDS, complemented by anxiety-depression scales and quality-of-life inventories. Pain evaluation will be conducted using the Visual Analog Scale (VAS) and pain-related emotional response questionnaires. Labor pain has been shown to precipitate or exacerbate depressive symptoms; thus, pain and emotional responses will be specifically logged 3 days postpartum to explore their interactive dynamics.
Phase III: Postpartum Follow-Up and Dynamic Disease Trajectory Analysis Objective: This phase aims to map the dynamic trajectory of PPD from pregnancy through 3 months postpartum, integrating multimodal physiological and psychological metrics to identify early predictors capable of forecasting PPD onset and severity. Longitudinal tracking will evaluate the feasibility of predictive models and elucidate temporal relationships between depressive symptoms and biomarkers.
Work Packages:
- Longitudinal Follow-up: Online follow-up surveys will be administered to the same cohort at 2 weeks (T1), 1 month (T2), and 3 months postpartum (T3). All participants who completed the acute postpartum assessment in Phase II will be scheduled for these longitudinal time points.
These intervals are determined by epidemiological data and clinical observations to span the acute recovery and intermediate adaptation phases postpartum, thereby capturing critical periods of symptom and physiological evolution.
Interoceptive function will be assessed using the MAIA-2 to evaluate subjective interoceptive sensibility. Data will be securely captured via an encrypted survey platform (e.g., Qualtrics) to guarantee data integrity and participant compliance.
- Statistical Modeling: Longitudinal statistical models (e.g., linear mixed-effects models, latent growth curve modeling) will be utilized to analyze trajectories of metrics across time points. We will evaluate the predictive power of third-trimester and acute postpartum baseline measures on subsequent depressive symptoms, pain, and psychological functioning, specifically examining variables such as interoceptive mismatch (sensibility-accuracy discrepancy), attenuated HRV, and elevated inflammatory markers in early risk stratification.
Work Packages:
- rTMS Intervention Protocol: Patients meeting the diagnostic criteria for PPD (including, but not limited to, participants from the Phase I cohort) will undergo an international standardized rTMS protocol targeting the left dorsolateral prefrontal cortex (DLPFC).
The intervention will be administered by specialized physicians certified in clinical rTMS protocols. Motor threshold (MT) determination and stimulation targeting will be executed utilizing a robot-guided neuronavigation system.
The coil positioning error will be restricted to less than 1 mm, providing significantly higher targeting precision over the traditional "5 cm rule" to optimize stimulation targeting consistency.
Stimulation Parameters: 10 Hz frequency will be administered at 120% of the resting motor threshold (rMT), with a 4-second train duration and a 26-second inter-train interval, totaling 3,000 pulses per session.
The intervention will span 4 weeks for a total of 20 sessions (5 sessions per week). A 20-session regimen was selected to balance therapeutic dosage with the scheduling constraints and treatment tolerance of postpartum women caring for newborns while maintaining consistency with prior clinical trials in similar populations.
The study aims to identify core features predictive of individual differences in treatment response and construct a predictive model. Model performance will be evaluated using cross-validation metrics, including AUC, sensitivity, and specificity, together with assessments of clinical feasibility for future applications.
Longitudinal Tracking Timeline
Multimodal assessments are scheduled at four chronological time points:
T0: Baseline (third trimester of pregnancy) T1: 2 weeks postpartum remote follow-up T2: 1 month postpartum remote follow-up T3: 3 months postpartum remote follow-up For the intervention arm (patients with PPD), multimodal evaluations will be locked at the pre-intervention period.
569 studies on the registry are indexed under Depression, Postpartum; 134 are open to participants now.
This study's planned enrollment of 290 is above the median of 104 across 454 interventional studies indexed under Depression, Postpartum.
Browse Depression, Postpartum studies →University of Macau is the lead sponsor of 14 studies on the registry; 10 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
ECG (electrocardiogram)
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participants diagnosed with postpartum depression ((n=40) will receive standardized repetitive transcranial magnetic stimulation (rTMS) treatment targeting the left dorsolateral prefrontal cortex. Multimodal biomarkers will be evaluated as predictors of treatment response.
Device: Repetitive Transcranial Magnetic Stimulation (rTMS)
Pregnant women in the third trimester of pregnancy (n=200) will be recruited from the obstetrics outpatient clinics and inpatient wards of Mirror Lake Hospital. Participants will undergo comprehensive multimodal assessments during late pregnancy, including psychological questionnaires, electroencephalography (EEG), autonomic measures, inflammatory markers, and hormonal measures. Follow-up assessments will be conducted at 2 weeks, 1 month, and 3 months postpartum to investigate longitudinal changes associated with postpartum depression risk and progression.
Healthy non-pregnant and non-postpartum women (n=50) recruited from the University of Macau and the local community. This group consists of age-matched individuals with no history of psychiatric disorders, serving as a baseline control.
Participants diagnosed with postpartum depression will receive a standardized repetitive transcranial magnetic stimulation (rTMS) intervention targeting the left dorsolateral prefrontal cortex (DLPFC). Treatment will be administered by trained clinicians using a neuronavigation-assisted rTMS system. Resting motor threshold (RMT) will be determined prior to treatment, and coil positioning will be guided by a robotic navigation system with a localization error of less than 1 mm. Stimulation will be delivered at 10 Hz and 120% of the individual resting motor threshold. Each train will last 4 seconds with an inter-train interval of 26 seconds, for a total of 3,000 pulses per session. Participants will receive 20 treatment sessions over 4 weeks (5 sessions per week).
Postpartum depressive symptom severity measured by the Edinburgh Postnatal Depression Scale (EPDS)
The EPDS total score ranges from 0 to 30, with higher scores indicating greater postpartum depressive symptom severity. Scores of 10 or above indicate elevated depressive symptoms, while scores of 13 or above are commonly used as a threshold for probable postpartum depression. The EPDS will serve as the primary measure of postpartum depressive symptom severity and risk identification. EPDS scores will be tracked longitudinally from late pregnancy through 3 months postpartum to characterize symptom development and identify high-risk individuals.
Time frame: T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment
Self-reported depressive symptom severity measured by the Beck Depression Inventory-II (BDI-II)
The BDI-II will be used to assess self-reported depressive symptom severity. The BDI-II total score ranges from 0 to 63, with higher scores indicating more severe depressive symptoms. Scores of 0-13 indicate minimal depression, 14-19 mild depression, 20-28 moderate depression, and 29-63 severe depression.
Time frame: T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment
Depression severity measured by the 17-item Hamilton Depression Rating Scale (HAMD-17)
The HAMD-17 total score ranges from 0 to 52, with higher scores indicating greater depression severity. Scores of 0-7 are generally considered normal, 8-16 mild depression, 17-23 moderate depression, and ≥24 severe depression.
Time frame: T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment
Quality of life measured by the WHO Quality of Life Instrument-Short Form (WHOQOL-BREF)
The WHOQOL-BREF is a 26-item self-report questionnaire used to assess quality of life across four distinct domains: Physical Health (7 items), Psychological Health (6 items), Social Relationships (3 items), and Environment (8 items). Each item is rated on a 5-point Likert scale. Raw domain scores are mathematically transformed to a linear 0 to 100 scale for each domain according to the official WHO guidelines. Scores range from 0 to 100, where higher scores represent a better perceived quality of life in that specific domain.
Time frame: T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment
Body perception and autonomic awareness measured by the Body Perception Questionnaire-Short Form (BPQ-SF)
The BPQ-SF is a 46-item self-report instrument used to evaluate subjective interoceptive awareness and bodily perception via two primary subscales rated on a 5-point Likert scale: the Body Awareness subscale (26 items, score range 26 to 130), where higher scores indicate greater awareness of visceral and physical states, and the Autonomic Reactivity subscale (20 items, score range 20 to 100), where higher scores reflect higher perceived autonomic nervous system reactivity to stress, with higher total scores across both domains indicating elevated somatic hyper-vigilance or reactivity.
Time frame: T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment
Interoceptive sensibility measured by the Multidimensional Assessment of Interoceptive Awareness-2 (MAIA-2)
The MAIA-2 is a 37-item self-report questionnaire used to measure multi-dimensional subjective interoceptive awareness across 8 subscales (Noticing, Not-Distracting, Not-Worrying, Attention Regulation, Emotional Awareness, Self-Regulation, Body Listening, and Trust) rated on a 6-point Likert scale. Scores for each subscale are calculated as the average of its item responses, resulting in an independent score range of 0 to 5 per domain, where higher scores across all dimensions indicate more functional, adaptive, and highly developed subjective interoceptive capacities.
Time frame: T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment
Heartbeat Discrimination Task
The Heartbeat Discrimination Task is an objective measure of interoceptive accuracy, where participants judge whether a series of auditory or visual triggers are presented in sync or out of sync with their own heartbeats. Performance is quantified using the standard cross-correlation or psychophysical sensitivity index, where higher scores represent greater objective interoceptive accuracy.
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Resting-state EEG functional connectivity biomarkers
Resting-state EEG functional connectivity biomarkers will be calculated from 128-channel EEG recordings to characterize alterations in large-scale neural network organization associated with postpartum depression and treatment response. Functional connectivity analyses will evaluate inter-regional communication patterns and network-level synchronization across cortical regions. Connectivity measures may include phase-based synchronization and other validated connectivity metrics to quantify altered functional integration and segregation within brain networks. These EEG functional connectivity biomarkers will be examined as candidate neurophysiological markers associated with depressive symptom severity and potential predictors of clinical response to robot-guided repetitive transcranial magnetic stimulation (rTMS) treatment.
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
EEG Vigilance Regulation
Vigilance regulation patterns will be evaluated using a validated vigilance algorithm that classifies sequential 1-second resting-state EEG segments into distinct alertness levels: Stage 0 (highest alertness), Stages A1/A2/A3 (sustained wakefulness), Stages B1/B2/B3 (lowered vigilance), and Stage C (sleep onset). The study quantifies the temporal evolution and spatial distribution of these stages. Key metrics include the presence of "hyperstability" (prolonged adherence to high-alertness stages) or "instability" (rapid, premature decline to low-vigilance stages), indicating central autonomic and alertness dysregulation associated with postpartum depression.
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Quantitative EEG (qEEG) Biomarkers
Quantitative EEG (qEEG) biomarkers will be derived from 10-minute eyes-closed resting-state EEG recordings acquired using a 128-channel EEG system. qEEG analyses will characterize neural oscillatory activity and cortical dynamics associated with postpartum depression and treatment response. qEEG features will include: (1) Power spectral features, including spectral power across canonical frequency bands (delta, theta, alpha, beta, and gamma), to characterize alterations in neural oscillatory activity; (2) Frontal alpha asymmetry (FAA), calculated from predefined frontal electrode regions using log-transformed alpha power differences between hemispheres, as a marker of affective regulation and depressive symptomatology; and (3) Aperiodic spectral parameters and EEG complexity features, including 1/f characteristics, to characterize background neural dynamics and cortical information processing. These qEEG biomarkers will be examined as candidate neurophysiological markers associated wi
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Heart Rate Variability (HRV) Metrics
Short-term heart rate variability (HRV) will be quantified from resting-state electrocardiography (ECG) recording to assess autonomic nervous system regulation. Lower HRV values reflect diminished vagal tone, autonomic dysregulation, and heightened emotional vulnerability associated with postpartum depression risk.
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Respiratory Sinus Arrhythmia (RSA)
Respiratory Sinus Arrhythmia (RSA) will be derived from synchronized resting-state ECG and respiration tracking to evaluate cardiorespiratory coupling and parasympathetic nervous system activity. Lower RSA scores represent compromised vagal regulation and reduced stress resilience.
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Serum Interleukin-6 (IL-6) Concentration
Serum IL-6 concentrations will be quantified using standardized laboratory assays to characterize peripheral inflammatory profiles.
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Serum endocrine hormone concentrations
Serum endocrine markers, including cortisol and thyroid-related hormones, will be quantified to characterize neuroendocrine regulation.
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Area Under the Receiver Operating Characteristic Curve for Prediction of rTMS Treatment Response
The area under the receiver operating characteristic curve (AUC) will be used to evaluate the ability of the multimodal machine-learning model to discriminate between participants with and without a prespecified clinical response to repetitive transcranial magnetic stimulation (rTMS). AUC values range from 0.5 to 1.0, with higher values indicating better discrimination.
Time frame: After completion of 20 rTMS sessions (4 weeks)
F1-Score of the Multimodal Model for Prediction of rTMS Treatment Response
The F1-score will be used to evaluate the balance between precision and sensitivity of the multimodal machine-learning model in classifying participants with and without a prespecified clinical response to repetitive transcranial magnetic stimulation (rTMS). The F1-score ranges from 0 to 1, with higher values indicating better classification performance.
Time frame: After completion of 20 rTMS sessions (4 weeks)
Clinical Response to Robot-Guided rTMS Treatment
Clinical response to robot-guided repetitive Transcranial Magnetic Stimulation (rTMS) will be evaluated by changes in depression symptom severity measured using clinician-rated and self-reported depression scales before and after treatment. Treatment response will be defined based on percentage reduction in depressive symptoms and categorical responder status where applicable.
Time frame: Before initiation of rTMS treatment and after completion of 20 rTMS sessions (4 weeks)
Association Between Baseline Multimodal Biomarkers and rTMS Treatment Response
Baseline multimodal biomarkers, including EEG features, autonomic indices, peripheral inflammatory and endocrine markers, and interoceptive measures, will be examined as potential predictors of individual variability in clinical response following rTMS treatment.
Time frame: Before initiation of rTMS treatment and after completion of 20 rTMS sessions (4 weeks)
Fertility Intentions
A structured self-report questionnaire will be used to assess subjective fertility intention and future fertility aspirations. Lower scores or negative responses reflect a reduced intention or aspiration for future fertility. This exploratory measure will be correlated with perinatal depressive symptoms, interoceptive awareness, and quality of life scores to explore how physiological and psychological stress during the transition to motherhood influences future fertility decisions.
Time frame: T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up)
Subjective Experiences and Perceptions of the Traditional Postpartum Ritual ("Sitting-the-Month")
Participants' subjective experiences, cultural compliance, and perceived psychological stress related to the traditional Chinese postpartum confinement ritual ("sitting-the-month") will be evaluated using a structured self-report questionnaire. Scores will capture dimensions of perceived emotional support versus behavioral restriction and interpersonal friction within the family.
Time frame: T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up)
Plan to share: No — Individual participant data will not be shared publicly because this study involves sensitive clinical, psychological, neurophysiological, and biological information collected from postpartum women. Only aggregate-level results will be reported in scientific publications. Access to de-identified data may be considered upon reasonable request and under appropriate ethical and institutional review procedures where applicable.
Start is estimated for Sep 2026; primary completion for Sep 2030, 48 months later.
Of 256 non-industry interventional studies with no phase under Depression, Postpartum, half reached primary completion within 23 months of starting (the median), counting those still running; a quarter within 11 and three quarters within 36. This study's planned 48 months is above that.
Counting every sponsor, half of 262 studies reached it within 23 months; a quarter within 11 and three quarters within 36.
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University of Macau