Home-based Transcranial Direct Current Stimulation in Postpartum Depression: the Feasibility Study and Pilot Study

Study aims and endpoints:

Aim 1: Conduct a feasibility study to

1. Determine the feasibility and acceptability of the combined intervention in PPD, by estimating the feasibility and acceptability of i) the home-based tDCS intervention; ii) the eHealth system; iii) the teleHealth system, by women and HP. 2. Determine the feasibility and acceptability of data collection and data analysis procedures of outcome and moderator variables for efficacy studies, namely of psychological functioning of mothers and babies (including neurodevelopment), the dyad, cost-benefit, and neuroinflammatory and stress levels; specifically, acceptability and compliance with the procedures will be evaluated 3. Evaluate the safety of the combined intervention in PPD 4. Estimate the parameters for the protocol of the future multicentric RCT aimed to establish the efficacy of the combined intervention

Aim 2: Conduct a pilot study to

a) Gather preliminary evidence of the efficacy of the combined intervention in PPD as measured by psychological functioning of mothers, babies and the dyad, neuroinflammatory and stress levels and quality of life (QoL), and the role of study moderators (genetic/epigenetic profiles of mothers and babies) in affecting main outcomes.

Study design. Feasibility studies aim to inform large RCT studies. Thus, for the feasibility study, the investigators aim to inform the practicality of the future Phase-III RCT and to unveil threats to the validity of the efficacy outcomes. Within a users'-centred approach and co-designed methodology, the investigators will assess safety, feasibility of the intervention, and feasibility of procedures for outcomes' assessment. Additionally, the investigators will estimate recruitment/retention and sample size. A consequent underpowered pilot study will be conducted following the achieved static protocol, based on the assumption that the procedures are well defined, serving the purpose of gathering preliminary information and testing the study protocol. Both the feasibility and the pilot studies will be open-label, single arm, single-site longitudinal studies.

Procedure. 4MUMS is divided in 3 stages:

Month 1-6 - Pre-feasibility study (Tasks 1-5) - 10 stakeholders (3 practitioners, 2 external expert researchers, 2 patients' representatives, 2 woman woman diagnosed with PPD will be recruited to support the identification of the steps, challenges and solutions to adapt a combined procedure to PPD in a co-design approach exploring their views/experiences with the training materials, assessment procedures and the combined intervention (tDCS + ehealth + teleHealth) using Soterix "1X1 tDCS miniCT" device, model 1601 and ELECTRA-RX (Soterix Medical Inc., NY, US).

Month 7-17 - Feasibility study (Tasks 6-12) Up to 15 medication-free women with mild-severe PPD, their babies and their perinatal Health Practitioner (HP) will be recruited. Recruitment will depend on referrals from Ob-Gyn physicians from the DGONR-CHUC. Women will be informed about 4MUMs and, after consenting, will be assessed for eligibility. Eligible women will be invited to participate and complete monthly screening assessments between the third trimester of pregnancy and up to six months after delivery using the Edinburgh Postnatal Depression Scale. When positive (EPDS\>10) during pregnancy, women will be asked to go on completing screening across trimesters and will be referred to their perinatal mental health (PMH) team. After delivery, these women may be included in the intervention group (IG) if EPDS\>10. Women screening positive in the postpartum will be invited to enter the IG. The HP will be asked to complete acceptability questionnaires at start of the intervention and end of treatment (N=25).

tDCS protocol. tDCS electrodes will be positioned over the dorsolateral prefrontal cortexes (DLPFC), using the Omni-Lateral-Electrode system. OLE results from studies on tDCS montages in the frontal cortex, concluding that current intensity at the DLPFC can be shaped but not focused, balancing increased focality, reduced electric field variability and clinical ease-of-use. The tDCS protocol was selected from previous literature for non-resistant MD and home-based tDCS for MD and will include daily stimulation sessions (2mA, 30 minutes, across three consecutive weeks (5/week). A second tDCS cycle may be repeated if a pre-set benchmark of ≥25% improvement of PPD symptoms is not met at the end of the first cycle.

The tDCS device and the ehealth/teleHealth systems (ELECTRA-RX) are introduced to patients during at-home training. Educational materials are provided through eHealth. tDCS is self-delivered with teleHealth support ensured across the tDCS course. Both eHealth and teleHealth will be delivered through women' cell-phone connected to ELECTRA-RX.

Month 18-34 - Pilot study (Tasks 13-19). Up to 32 medication-free women with mild-severe PPD, their babies and their HP will be recruited. Recruitment, outcomes' assessment procedures and intervention will follow stage 2 adjusted protocol.

Outcomes. Feasibility outcomes will include measures of compliance, acceptability and tolerability for home-based tDCS and for assessment procedures. The multimodal approach to measure the effect of the intervention includes clinical measures of psychological functioning, mother-baby bonding, mothers' levels of neuroinflammatory and stress/cortisol, quality of life (QoL), and child neurodevelopment and temperament. The investigators will study genetic polymorphisms and epigenetic modifications of mothers as moderators of treatment response. The study of child neuroinflammatory, stress/cortisol and epigenetic profiles will support the test of the association between neurodevelopment and mothers' clinical status.

Data analysis. 4MUMs will conduct descriptive analysis for feasibility, estimates of recruitment and retention rates. To observe intervention impact, underpowered analysis will be conducted using repeated measures ANOVA tests (T1,T2/T3/FU) for clinical symptoms, bonding, QoL, stress and neuroinflammatory levels, adjusting to covariates.

Sample size. The sample size for feasibility studies should support the estimate of critical parameters to the necessary degree of precision. For the feasibility study, the investigators will recruit up to 15 participants, until reaching the definite procedures to be tested. The sample size estimate for the pilot study is based on pervious literature, considers just the primary hypothesis of efficacy and accounts for a dropout rate of 20%. The investigators estimate 32 women, to detect an effect size of .60, with a significance alpha level of .05 and .85 power, using repeated measures ANOVA tests. In Coimbra, there are approximately 5000 births per year, which according to the lowest incidence rates in Europe, represent 450 women diagnosed with PPD, around 20% of which with previous psychiatric conditions. However, women naturally hesitate novel treatments, hence the investigators estimate an acceptance rate of 50%, leading to 180 participants/year to be contacted.

Expected results. Our results will inform the multicentred Phase-III RCT protocol in what concerns safety of the procedure, feasibility of the intervention and feasibility of the multimodal approach to measure the impact of tDCS and its moderators. Previous experience suggests that the intervention will be well accepted and tolerated, offering the first step for the development of a novel medication-free intervention, improving the quality of health services while lowering the costs for mothers, families and the health system.

• Change from Baseline on the feasibility of the intervention according to Health Providers [Time frame: At baseline, at end of treatment (cycle 1 or 2; each cycle is 3 weeks) and 1 month follow-up.]
• Feasibility of the intervention - tDCS Adverse Effects [Time frame: Daily during intervention (3 weeks or 6 weeks when adequate) and 1 month follow-up]
• Feasibility of the intervention -Health Technology Users' Satisfaction Survey [Time frame: At the end of treatment (cycle 1 or 2; each cycle is 3 weeks) and 1 month follow-up.]
• Change from Baseline on the feasibility of the assessment procedures - Acceptability of outcomes assessment visits by women [Time frame: At baseline, at the end of treatment (cycle 1 or 2; each cycle is 3 weeks) and 1 month follow-up.]
• Change from Baseline on the feasibility of the assessment procedures - Acceptability of outcomes assessment visits (newborn-infants) [Time frame: At baseline, at the end of treatment (cycle 1 or 2; each cycle is 3 weeks) and 1 month follow-up.]
• Estimate of recruitment [Time frame: At the end of treatment (cycle 1 or 2; each cycle is 3 weeks) and 1 month follow-up.]
• Estimate of retention [Time frame: At the end of treatment (cycle 1 or 2; each cycle is 3 weeks) and 1 month follow-up.]
• Estimate of dropouts [Time frame: At the end of treatment (cycle 1 or 2; each cycle is 3 weeks) and 1 month follow-up.]
• Change from Baseline in Clinical Status according to depressive symptoms. [Time frame: At baseline and weekly during the 3 weeks of tDCS cycle (or during 6 weeks if tDCS cycle 2 is prescribed) and at one month follow-up]
• Change from Baseline in Clinical Status according to anxiety symptoms [Time frame: At baseline and weekly during the 3 weeks of tDCS cycle (or during 6 weeks if tDCS cycle 2 is prescribed) and at one month follow-up]
• Change from Baseline in Clinical Status according to difficulties in emotion regulation. [Time frame: At baseline and weekly during the 3 weeks of tDCS cycle (or during 6 weeks if tDCS cycle 2 is prescribed) and at one month follow-up]
• Change from Baseline in Clinical Status according to Sleep quality [Time frame: At baseline and weekly during the 3 weeks of tDCS cycle (or during 6 weeks if tDCS cycle 2 is prescribed) and at one month follow-up]