Depression, PostpartumMOTHER-TMSNCT07757815
Multimodal Biomarkers and Precision TMS for Postpartum Depression
A study testing Repetitive Transcranial Magnetic Stimulation (rTMS) in people with Depression, Postpartum, run by University of Macau at 2 sites in Macau.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 45 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Depression, Postpartum
- What is being tested?
- Repetitive Transcranial Magnetic Stimulation (rTMS)
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 290 participants
- Where
- 2 sitesMacau
- Study dates
- 1 Sep 2026to 31 Aug 2031
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Biological female, aged 18-45 years.
- For HR-PPD and LR-PPD groups: Pregnant women in the third trimester (≥ 32 weeks gestation) with a singleton pregnancy.
- For HR-PPD group: Beck Depression Inventory (BDI) score ≥ 14 during the third trimester.
- For LR-PPD group: BDI score < 14 during the third trimester, with no history of depression.
- For HC group: Healthy women with no pregnancy in the past 12 months.
- No history of central nervous system diseases or major medical/surgical conditions.
- No history of medication use that may interfere with EEG or ECG measurements.
- Willing and able to complete baseline and follow-up assessments and provide written informed consent.
Who cannot join
- Multiple pregnancies, preterm labor, or severe pregnancy complications (e.g., pre-eclampsia, gestational diabetes with complications).
- Life-threatening emergencies during delivery (e.g., amniotic fluid embolism, major hemorrhage).
- Cognitive impairment or language barriers that hinder cooperation with assessments.
- History of major psychiatric disorders (e.g., schizophrenia, bipolar disorder).
- Other conditions that, in the opinion of the investigator, make the participant unsuitable for the study.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Macau2 sites
Kiang Wu Hospital
Macao, 999078
the Center for Cognitive and Brain Sciences, Research Building N21
Macao, 999078
Cheng-Teng Ip, Ph.D, (853) 8822-9378, chengtengip@um.edu.mo
Juha Silvanto, Ph.D, (853) 8822-4930, juhasilvanto@um.edu.mo
About this study
Official title: Multimodal Biomarkers and Robot-Guided Precision TMS for Early Detection and Treatment of Postpartum Depression
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:
Read more
- What multimodal biological differences exist between women with diagnosed PPD and healthy comparison groups, including postpartum and non-postpartum controls?
- Which biological or psychological markers can predict whether a patient will respond well to repetitive transcranial magnetic stimulation (rTMS) treatment?
- Can a clinical model be created to help doctors choose the best treatment based on these markers? The study focuses on characterizing multimodal biological differences in women with diagnosed PPD and examining clinical response profiles following rTMS treatment, rather than predicting the onset of PPD in the general population.
Participants will:
- Undergo electroencephalography (EEG) using a 128-channel cap to measure neural activity.
- Have electrocardiography (ECG) recorded to analyze heart rate variability and autonomic function.
- Provide blood samples to measure inflammatory cytokines, endocrine levels, and metabolic markers.
- Complete Interoceptive Assessments (tasks to measure awareness of internal body signals) and clinical psychological surveys.
- Complete follow-up assessments via online surveys and scheduled visits at 2 weeks, 1 month, and 3 months postpartum.
Participants in the PPD group will:
- Receive 4 weeks of high-precision, robot-guided rTMS treatment (20 sessions total).
- Undergo pre-intervention multimodal assessments, including EEG, ECG, blood biomarkers, and interoceptive tasks, to identify potential predictors of clinical response to rTMS treatment.
Read the detailed description
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.
- EEG Acquisition: Record 10 minutes of resting-state EEG data (eyes closed) using a 128-channel EEG system. Analyses will focus on neurodynamic indicators related to emotional regulation, including power spectral features, frontal alpha asymmetry, and vigilance regulation.
- ECG Acquisition: Record 10 minutes of resting-state ECG data using a 3-lead ECG system to calculate HRV and RSA.
- Blood Biomarkers: Collect early-morning fasting venous blood samples to quantify inflammatory cytokines (IL-6) and endocrine profiles.
- 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.
- Multidimensional Online Assessment: Follow-ups will repeatedly measure participants' psychological and physiological states remotely. Psychologically, the EPDS will serve as the primary screening tool for depressive symptoms, supplemented by anxiety-depression inventories, quality-of-life metrics, and postpartum pain VAS to evaluate pain intensity and functional impact. 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.
- Phase IV: Repetitive Transcranial Magnetic Stimulation (rTMS) Intervention and Treatment Response Predictive Modeling Objective: To examine clinical outcomes following rTMS treatment in patients diagnosed with PPD and to construct a treatment response predictive model leveraging multimodal baseline data.
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.
- Pre-intervention Multimodal Assessment: Prior to rTMS initiation, participants will undergo multimodal baseline evaluations, including EEG spectral analyses, HRV/RSA metrics, peripheral biochemical and inflammatory profiling, and subjective/objective interoceptive assessments (MAIA-2, Body Perception Questionnaire-Short Form [BPQ-SF], and heartbeat discrimination task).
- Predictive Modeling: Machine learning algorithms (e.g., LASSO regression, Random Forest, Support Vector Machines) will be applied to analyze associations between baseline multimodal feature spaces and clinical treatment outcomes.
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.
- Conditions
- Depression, Postpartum
- Being tested
- Repetitive Transcranial Magnetic Stimulation (rTMS)
- Keywords
- Repetitive Transcranial Magnetic Stimulation, Electroencephalography, Postpartum Depression, Biomarkers, Electrocardiography, Interoception, Machine Learning, Blood biomarkers, Hormonal Measures, Interleukin-6 (IL-6), Multidimensional Assessment of Interoceptive Awareness-2 (MAIA-2), Body Perception Questionnaire-Short Form (BPQ-SF), WHO Quality of Life Instrument-Short Form (WHOQOL-BREF), Hamilton Depression Rating Scale (HAMD-17), Beck Depression Inventory-II (BDI-II)
- Medical subject headings
- Depression, Postpartum
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Repetitive Transcranial Magnetic Stimulation (rTMS)Device
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).
| Study group | Role | What they receive |
|---|---|---|
| Patients with PPD | Experimental | 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. Receives: Device: Repetitive Transcranial Magnetic Stimulation (rTMS) |
| Woman in late pregnancy | No intervention | 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-Parturient Control (HC) | No intervention | 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Secondary outcomes (4)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Before initiation of rTMS treatment and after completion of 20 rTMS sessions (4 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Aug 2026
- Study start1 Sep 2026 (estimated)
- Primary completion1 Sep 2030 (estimated)
- Study completion31 Aug 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (19)Papers the sponsor has linked to this study.
- Other trials for Depression, PostpartumStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 290 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Macau
- Sponsor type
- University, hospital or other
- Collaborators
- Kiang Wu Hospital
- Responsible party
- Principal investigator, Cheng Teng IP, University of Macau
- Investigators
- Cheng Teng Ip, PhD, Study chair, Institute of Collaborative Innovation, University of Macau
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07757815
- Sponsor's protocol ID
- BSE-1885-2026
- Acronym
- MOTHER-TMS
- Status last verified
- Aug 2026
- First submitted
- 28 Jul 2026
- Last updated
- 11 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- 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.
Publications
Peng L, Fu C, Xiong F, Zhang Q, Liang Z, Chen L, He C, Wei Q. Effects of repetitive transcranial magnetic stimulation on depression symptoms and cognitive function in treating patients with postpartum depression: A systematic review and meta-analysis of randomized controlled trials. Psychiatry Res. 2020 Aug;290:113124. doi: 10.1016/j.psychres.2020.113124. Epub 2020 May 29.
PubMed 32521378Garnaat SL, Fukuda AM, Yuan S, Carpenter LL. Identification of Clinical Features and Biomarkers that may inform a Personalized Approach to rTMS for Depression. Pers Med Psychiatry. 2019 Nov-Dec;17-18:4-16. doi: 10.1016/j.pmip.2019.09.001. Epub 2019 Oct 18.
PubMed 33954269Khalsa SS, Adolphs R, Cameron OG, Critchley HD, Davenport PW, Feinstein JS, Feusner JD, Garfinkel SN, Lane RD, Mehling WE, Meuret AE, Nemeroff CB, Oppenheimer S, Petzschner FH, Pollatos O, Rhudy JL, Schramm LP, Simmons WK, Stein MB, Stephan KE, Van den Bergh O, Van Diest I, von Leupoldt A, Paulus MP; Interoception Summit 2016 participants. Interoception and Mental Health: A Roadmap. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018 Jun;3(6):501-513. doi: 10.1016/j.bpsc.2017.12.004. Epub 2017 Dec 28.
PubMed 29884281Olbrich S, Sander C, Minkwitz J, Chittka T, Mergl R, Hegerl U, Himmerich H. EEG vigilance regulation patterns and their discriminative power to separate patients with major depression from healthy controls. Neuropsychobiology. 2012 Jun;65(4):188-94. doi: 10.1159/000337000. Epub 2012 Apr 26.
PubMed 22538271Ganho-Avila A, Poleszczyk A, Mohamed MMA, Osorio A. Efficacy of rTMS in decreasing postnatal depression symptoms: A systematic review. Psychiatry Res. 2019 Sep;279:315-322. doi: 10.1016/j.psychres.2019.05.042. Epub 2019 Jun 10.
PubMed 31196691Cox EQ, Killenberg S, Frische R, McClure R, Hill M, Jenson J, Pearson B, Meltzer-Brody SE. Repetitive transcranial magnetic stimulation for the treatment of postpartum depression. J Affect Disord. 2020 Mar 1;264:193-200. doi: 10.1016/j.jad.2019.11.069. Epub 2019 Nov 13.
PubMed 32056750Olbrich S, Arns M. EEG biomarkers in major depressive disorder: discriminative power and prediction of treatment response. Int Rev Psychiatry. 2013 Oct;25(5):604-18. doi: 10.3109/09540261.2013.816269.
PubMed 24151805Ip CT, Olbrich S, Ganz M, Ozenne B, Kohler-Forsberg K, Dam VH, Beniczky S, Jorgensen MB, Frokjaer VG, Sogaard B, Christensen SR, Knudsen GM. Pretreatment qEEG biomarkers for predicting pharmacological treatment outcome in major depressive disorder: Independent validation from the NeuroPharm study. Eur Neuropsychopharmacol. 2021 Aug;49:101-112. doi: 10.1016/j.euroneuro.2021.03.024. Epub 2021 Apr 25.
PubMed 33910154Liu H, Zhang Y, Gao Y, Zhang Z. Elevated levels of Hs-CRP and IL-6 after delivery are associated with depression during the 6 months post partum. Psychiatry Res. 2016 Sep 30;243:43-8. doi: 10.1016/j.psychres.2016.02.022. Epub 2016 Feb 16.
PubMed 27359302Hartmann R, Schmidt FM, Sander C, Hegerl U. Heart Rate Variability as Indicator of Clinical State in Depression. Front Psychiatry. 2019 Jan 17;9:735. doi: 10.3389/fpsyt.2018.00735. eCollection 2018.
PubMed 30705641Ip CT, Ganz M, Dam VH, Ozenne B, Ruesch A, Kohler-Forsberg K, Jorgensen MB, Frokjaer VG, Sogaard B, Christensen SR, Knudsen GM, Olbrich S. NeuroPharm study: EEG wakefulness regulation as a biomarker in MDD. J Psychiatr Res. 2021 Sep;141:57-65. doi: 10.1016/j.jpsychires.2021.06.021. Epub 2021 Jun 18.
PubMed 34175743Ip CT, de Bardeci M, Kronenberg G, Pinborg LH, Seifritz E, Brunovsky M, Olbrich S. EEG-vigilance regulation is associated with and predicts ketamine response in major depressive disorder. Transl Psychiatry. 2024 Jan 26;14(1):64. doi: 10.1038/s41398-024-02761-x.
PubMed 38272875Arns M, Bruder G, Hegerl U, Spooner C, Palmer DM, Etkin A, Fallahpour K, Gatt JM, Hirshberg L, Gordon E. EEG alpha asymmetry as a gender-specific predictor of outcome to acute treatment with different antidepressant medications in the randomized iSPOT-D study. Clin Neurophysiol. 2016 Jan;127(1):509-519. doi: 10.1016/j.clinph.2015.05.032. Epub 2015 Jun 27.
PubMed 26189209Noda M, Sato Y, Suetsugu Y, Morokuma S. Interoception is associated with anxiety and depression in pregnant women: A pilot study. PLoS One. 2022 May 6;17(5):e0267507. doi: 10.1371/journal.pone.0267507. eCollection 2022.
PubMed 35522683Garfinkel SN, Manassei MF, Hamilton-Fletcher G, In den Bosch Y, Critchley HD, Engels M. Interoceptive dimensions across cardiac and respiratory axes. Philos Trans R Soc Lond B Biol Sci. 2016 Nov 19;371(1708):20160014. doi: 10.1098/rstb.2016.0014. Epub 2016 Oct 10.
PubMed 28080971
Study at a glance
From the registry record, last updated by the sponsor on 11 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Multimodal Biomarkers and Robot-Guided Precision TMS for Early Detection and Treatment of Postpartum Depression
- ClinicalTrials.gov ID
- NCT07757815
- Acronym / sponsor ID
- MOTHER-TMS / BSE-1885-2026
- Conditions
- Depression, Postpartum
- Keywords
- Repetitive Transcranial Magnetic Stimulation, Electroencephalography, Postpartum Depression, Biomarkers, Electrocardiography, Interoception, Machine Learning, Blood biomarkers
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 290 participants (estimated)
- Lead sponsor
- University of MacauUniversity, hospital or other
- Collaborators
- Kiang Wu Hospital
- Study start
- 1 Sep 2026 (estimated)
- Primary completion
- 1 Sep 2030 (estimated)
- Study completion
- 31 Aug 2031 (estimated)
- First posted
- 11 Aug 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- What multimodal biological differences exist between women with diagnosed PPD and healthy comparison groups, including postpartum and non-postpartum controls?
- Which biological or psychological markers can predict whether a patient will respond well to repetitive transcranial magnetic stimulation (rTMS) treatment?
- Can a clinical model be created to help doctors choose the best treatment based on these markers? The study focuses on characterizing multimodal biological differences in women with diagnosed PPD and examining clinical response profiles following rTMS treatment, rather than predicting the onset of PPD in the general population.
Participants will:
- Undergo electroencephalography (EEG) using a 128-channel cap to measure neural activity.
- Have electrocardiography (ECG) recorded to analyze heart rate variability and autonomic function.
- Provide blood samples to measure inflammatory cytokines, endocrine levels, and metabolic markers.
- Complete Interoceptive Assessments (tasks to measure awareness of internal body signals) and clinical psychological surveys.
- Complete follow-up assessments via online surveys and scheduled visits at 2 weeks, 1 month, and 3 months postpartum.
Participants in the PPD group will:
- Receive 4 weeks of high-precision, robot-guided rTMS treatment (20 sessions total).
- Undergo pre-intervention multimodal assessments, including EEG, ECG, blood biomarkers, and interoceptive tasks, to identify potential predictors of clinical response to rTMS treatment.
Detailed description
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.
- EEG Acquisition: Record 10 minutes of resting-state EEG data (eyes closed) using a 128-channel EEG system. Analyses will focus on neurodynamic indicators related to emotional regulation, including power spectral features, frontal alpha asymmetry, and vigilance regulation.
- ECG Acquisition: Record 10 minutes of resting-state ECG data using a 3-lead ECG system to calculate HRV and RSA.
- Blood Biomarkers: Collect early-morning fasting venous blood samples to quantify inflammatory cytokines (IL-6) and endocrine profiles.
- 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.
- Multidimensional Online Assessment: Follow-ups will repeatedly measure participants' psychological and physiological states remotely. Psychologically, the EPDS will serve as the primary screening tool for depressive symptoms, supplemented by anxiety-depression inventories, quality-of-life metrics, and postpartum pain VAS to evaluate pain intensity and functional impact. 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.
- Phase IV: Repetitive Transcranial Magnetic Stimulation (rTMS) Intervention and Treatment Response Predictive Modeling Objective: To examine clinical outcomes following rTMS treatment in patients diagnosed with PPD and to construct a treatment response predictive model leveraging multimodal baseline data.
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.
- Pre-intervention Multimodal Assessment: Prior to rTMS initiation, participants will undergo multimodal baseline evaluations, including EEG spectral analyses, HRV/RSA metrics, peripheral biochemical and inflammatory profiling, and subjective/objective interoceptive assessments (MAIA-2, Body Perception Questionnaire-Short Form [BPQ-SF], and heartbeat discrimination task).
- Predictive Modeling: Machine learning algorithms (e.g., LASSO regression, Random Forest, Support Vector Machines) will be applied to analyze associations between baseline multimodal feature spaces and clinical treatment outcomes.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Patients with PPD | Experimental | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)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. |
| Woman in late pregnancy | No intervention | –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-Parturient Control (HC) | No intervention | –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. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- Biological female, aged 18-45 years.
- For HR-PPD and LR-PPD groups: Pregnant women in the third trimester (≥ 32 weeks gestation) with a singleton pregnancy.
- For HR-PPD group: Beck Depression Inventory (BDI) score ≥ 14 during the third trimester.
- For LR-PPD group: BDI score < 14 during the third trimester, with no history of depression.
- For HC group: Healthy women with no pregnancy in the past 12 months.
Key exclusion criteria (5 listed)
- Multiple pregnancies, preterm labor, or severe pregnancy complications (e.g., pre-eclampsia, gestational diabetes with complications).
- Life-threatening emergencies during delivery (e.g., amniotic fluid embolism, major hemorrhage).
- Cognitive impairment or language barriers that hinder cooperation with assessments.
- History of major psychiatric disorders (e.g., schizophrenia, bipolar disorder).
- Other conditions that, in the opinion of the investigator, make the participant unsuitable for the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Repetitive Transcranial Magnetic Stimulation (rTMS)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). | Device | Patients with PPD |
Primary outcome
Postpartum depressive symptom severity measured by the Edinburgh Postnatal Depression Scale (EPDS)
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
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.
Self-reported depressive symptom severity measured by the Beck Depression Inventory-II (BDI-II)
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
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.
Depression severity measured by the 17-item Hamilton Depression Rating Scale (HAMD-17)
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
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.
Quality of life measured by the WHO Quality of Life Instrument-Short Form (WHOQOL-BREF)
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
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.
Body perception and autonomic awareness measured by the Body Perception Questionnaire-Short Form (BPQ-SF)
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
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.
Interoceptive sensibility measured by the Multidimensional Assessment of Interoceptive Awareness-2 (MAIA-2)
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
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.
Heartbeat Discrimination Task
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
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.
Resting-state EEG functional connectivity biomarkers
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
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.
EEG Vigilance Regulation
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
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.
Quantitative EEG (qEEG) Biomarkers
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
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
Heart Rate Variability (HRV) Metrics
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
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.
Respiratory Sinus Arrhythmia (RSA)
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
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.
Serum Interleukin-6 (IL-6) Concentration
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Serum IL-6 concentrations will be quantified using standardized laboratory assays to characterize peripheral inflammatory profiles.
Serum endocrine hormone concentrations
Time frame: T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment
Serum endocrine markers, including cortisol and thyroid-related hormones, will be quantified to characterize neuroendocrine regulation.
4 secondary outcomes
Area Under the Receiver Operating Characteristic Curve for Prediction of rTMS Treatment Response
Time frame: After completion of 20 rTMS sessions (4 weeks)
F1-Score of the Multimodal Model for Prediction of rTMS Treatment Response
Time frame: After completion of 20 rTMS sessions (4 weeks)
Clinical Response to Robot-Guided rTMS Treatment
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
Time frame: Before initiation of rTMS treatment and after completion of 20 rTMS sessions (4 weeks)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Aug 2026.
- Background: PubMed 32521378Peng L, Fu C, Xiong F, Zhang Q, Liang Z, Chen L, He C, Wei Q. Effects of repetitive transcranial magnetic stimulation on depression symptoms and cognitive function in treating patients with postpartum depression: A systematic review and meta-analysis of randomized controlled trials. Psychiatry Res. 2020 Aug;290:113124. doi: 10.1016/j.psychres.2020.113124. Epub 2020 May 29.
- Background: PubMed 33954269Garnaat SL, Fukuda AM, Yuan S, Carpenter LL. Identification of Clinical Features and Biomarkers that may inform a Personalized Approach to rTMS for Depression. Pers Med Psychiatry. 2019 Nov-Dec;17-18:4-16. doi: 10.1016/j.pmip.2019.09.001. Epub 2019 Oct 18.
- Background: PubMed 29884281Khalsa SS, Adolphs R, Cameron OG, Critchley HD, Davenport PW, Feinstein JS, Feusner JD, Garfinkel SN, Lane RD, Mehling WE, Meuret AE, Nemeroff CB, Oppenheimer S, Petzschner FH, Pollatos O, Rhudy JL, Schramm LP, Simmons WK, Stein MB, Stephan KE, Van den Bergh O, Van Diest I, von Leupoldt A, Paulus MP; Interoception Summit 2016 participants. Interoception and Mental Health: A Roadmap. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018 Jun;3(6):501-513. doi: 10.1016/j.bpsc.2017.12.004. Epub 2017 Dec 28.
- Background: PubMed 22538271Olbrich S, Sander C, Minkwitz J, Chittka T, Mergl R, Hegerl U, Himmerich H. EEG vigilance regulation patterns and their discriminative power to separate patients with major depression from healthy controls. Neuropsychobiology. 2012 Jun;65(4):188-94. doi: 10.1159/000337000. Epub 2012 Apr 26.
- Background: PubMed 31196691Ganho-Avila A, Poleszczyk A, Mohamed MMA, Osorio A. Efficacy of rTMS in decreasing postnatal depression symptoms: A systematic review. Psychiatry Res. 2019 Sep;279:315-322. doi: 10.1016/j.psychres.2019.05.042. Epub 2019 Jun 10.
- Background: PubMed 32056750Cox EQ, Killenberg S, Frische R, McClure R, Hill M, Jenson J, Pearson B, Meltzer-Brody SE. Repetitive transcranial magnetic stimulation for the treatment of postpartum depression. J Affect Disord. 2020 Mar 1;264:193-200. doi: 10.1016/j.jad.2019.11.069. Epub 2019 Nov 13.
- Background: PubMed 24151805Olbrich S, Arns M. EEG biomarkers in major depressive disorder: discriminative power and prediction of treatment response. Int Rev Psychiatry. 2013 Oct;25(5):604-18. doi: 10.3109/09540261.2013.816269.
- Background: PubMed 33910154Ip CT, Olbrich S, Ganz M, Ozenne B, Kohler-Forsberg K, Dam VH, Beniczky S, Jorgensen MB, Frokjaer VG, Sogaard B, Christensen SR, Knudsen GM. Pretreatment qEEG biomarkers for predicting pharmacological treatment outcome in major depressive disorder: Independent validation from the NeuroPharm study. Eur Neuropsychopharmacol. 2021 Aug;49:101-112. doi: 10.1016/j.euroneuro.2021.03.024. Epub 2021 Apr 25.
- Background: PubMed 27359302Liu H, Zhang Y, Gao Y, Zhang Z. Elevated levels of Hs-CRP and IL-6 after delivery are associated with depression during the 6 months post partum. Psychiatry Res. 2016 Sep 30;243:43-8. doi: 10.1016/j.psychres.2016.02.022. Epub 2016 Feb 16.
- Background: PubMed 30705641Hartmann R, Schmidt FM, Sander C, Hegerl U. Heart Rate Variability as Indicator of Clinical State in Depression. Front Psychiatry. 2019 Jan 17;9:735. doi: 10.3389/fpsyt.2018.00735. eCollection 2018.
- Background: PubMed 34175743Ip CT, Ganz M, Dam VH, Ozenne B, Ruesch A, Kohler-Forsberg K, Jorgensen MB, Frokjaer VG, Sogaard B, Christensen SR, Knudsen GM, Olbrich S. NeuroPharm study: EEG wakefulness regulation as a biomarker in MDD. J Psychiatr Res. 2021 Sep;141:57-65. doi: 10.1016/j.jpsychires.2021.06.021. Epub 2021 Jun 18.
- Background: PubMed 38272875Ip CT, de Bardeci M, Kronenberg G, Pinborg LH, Seifritz E, Brunovsky M, Olbrich S. EEG-vigilance regulation is associated with and predicts ketamine response in major depressive disorder. Transl Psychiatry. 2024 Jan 26;14(1):64. doi: 10.1038/s41398-024-02761-x.
- Individual participant dataSharing planned: 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Cheng Teng Ip, PhD study chair
Institute of Collaborative Innovation, University of Macau
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Repetitive Transcranial Magnetic Stimulation (rTMS) in people with Depression, Postpartum, run by University of Macau at 2 sites in Macau.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 11 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Macau. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Cheng Teng Ip, PhD ((853) 8822-9378 ext. (853) 8822-245, chengtengip@um.edu.mo), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Postpartum depressive symptom severity measured by the Edinburgh Postnatal Depression Scale (EPDS) (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). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07757815, which also lists 19 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Aug 2026.