Open AccessReview Advances in Perinatal Depression: A Focus on Screening and Treatment by Haonan Shui Haonan Shui SciProfiles Scilit Preprints.org Google Scholar Haonan Shui is currently a resident physician at the First Affiliated Hospital of Chongqing Medical [...] Read more , Xiaotong Cao Xiaotong Cao SciProfiles Scilit Preprints.org Google Scholar and Xuemei Zhang Xuemei Zhang SciProfiles Scilit Preprints.org Google Scholar Xuemei Zhang is currently the Deputy Director of the Department of Obstetrics at Chongqing She of [...] Read more * Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China * Author to whom correspondence should be addressed. J. Clin. Med. 2026, 15(12), 4465; https://doi.org/10.3390/jcm15124465 (registering DOI) Submission received: 13 April 2026 / Revised: 8 May 2026 / Accepted: 3 June 2026 / Published: 9 June 2026 Abstract Perinatal depression (PND), encompassing both major and minor depressive episodes during pregnancy and up to one year postpartum, is a prevalent and debilitating condition with profound consequences for maternal, infant, and family well-being. Clinical screening of PND remains challenging due to obstacles in early detection, symptom overlap with normal perinatal experiences, lack of standardized screening protocols, and considerable interpatient variability. Furthermore, the complexity of treating PND arises from multiple interconnected factors, including medication safety considerations during pregnancy and lactation, information barriers resulting from the separation of mental health services from obstetric and pediatric care systems, and unique sociocultural obstacles. The absence of systematically integrated care pathways often leads to severe and potentially irreversible outcomes for both mothers and infants. Hence, this review summarizes recent advances in PND screening and treatment, emphasizing the critical transition toward integrated or collaborative care models. Notably, future efforts should focus on overcoming implementation barriers, digital health solutions, task-sharing frameworks, and personalized treatment strategies to ensure equitable access to these innovations for affected populations. Keywords: perinatal depression; screening; treatment; precision medicine; collaborative care models 1. Introduction In recent years, however, the landscape of PND care has begun to evolve, driven by growing recognition of its importance. Significant advances have been made in two key areas: screening and treatment. There is a strengthened consensus advocating for universal, routine screening using validated tools like the Edinburgh Postnatal Depression Scale (EPDS) across the entire perinatal timeline [ 13, 14, 15, 16]. This screening recommendation is consistent with ACOG Clinical Practice Guideline No. 4 (screening and diagnosis of perinatal mental health conditions) [ 17] and the treatment discussion aligns with ACOG Clinical Practice Guideline No. 5 (treatment and management with a focus on psychopharmacotherapy) [ 18] and NICE CG192 (recognition, assessment, treatment, and service organization) [ 19]. Concurrently, the therapeutic strategy has expanded beyond traditional models. Evidence-based psychotherapies, such as interpersonal therapy (IPT) [ 20, 21] and cognitive-behavioral therapy (CBT) [ 22, 23], have been specifically adapted for perinatal populations. The evidence base for the safe use of pharmacotherapy, particularly selective serotonin reuptake inhibitors (SSRIs), during pregnancy and lactation continues to grow, facilitating more informed risk-benefit discussions [ 24, 25, 26]. 2. Methods This is a narrative review of the literature on PND, focusing on screening and treatment. A literature search was conducted in PubMed, Scopus, and Web of Science for articles published between 2015 and 2025. The search strategy combined terms related to perinatal depression (“perinatal depression,” “postpartum depression,” “antenatal depression”) with terms related to the main topics of this review (“screening,” “EPDS,” “biomarkers,” “digital health,” “collaborative care,” “psychotherapy,” “antidepressants,” “brexanolone,” “zuranolone,” and “neuromodulation”). Only peer-reviewed articles, systematic reviews, meta-analyses, randomized controlled trials, and clinical guidelines published in English were included. Reference lists of retrieved articles were manually screened for additional relevant studies. Because this is a narrative review, SANRA (Scale for the Assessment of Narrative Review Articles) guidelines were used to ensure quality and transparency. No quantitative synthesis or meta-analysis was performed. 3. Pathophysiological Mechanisms 3.1. Neuroendocrine Hypothesis 3.1.1. Interaction of Sex Hormone Fluctuations with Monoamine Neurotransmitter Systems Monoamine neurotransmitters, such as serotonin (5-HT), dopamine (DA), and norepinephrine (NE), play a critical role in regulating mood, motivation, and reward. Sex hormones modulate their synthesis, release, and signaling through multiple mechanisms. Besides, PRL levels rise significantly during the perinatal period. As its secretion is tonically inhibited by hypothalamic dopaminergic signaling, elevated PRL may feedback to suppress dopaminergic activity. This inhibition can impair function in the mesolimbic reward pathway, leading to reduced motivation and anhedonia, a core symptom of depression [ 47, 48]. 3.1.2. HPA Axis Dysregulation: The Role of Cortisol Dynamics in Depressive Symptoms 3.2. Neuroinflammation and Immune Activation The neuroinflammation and immune activation hypothesis offers a critical perspective for understanding PND. It proposes that adaptive immunological changes inherent to the perinatal period may become disordered under specific conditions. Such dysregulation promotes a pro-inflammatory state within the central nervous system, ultimately contributing to the development of depressive symptoms. The core pathway involves intricate crosstalk between peripheral immunity and the brain, with the principal mechanisms summarized in the cascade model presented in Figure 2 [ 58]. 3.2.1. Balancing Immune Tolerance with Pro-Inflammatory Cytokine Activity in Pregnancy 3.2.2. The Microbiota–Gut–Brain Axis: Modulating Mood Through Perinatal Gut Microbiota Changes Overall, the neuroinflammation and immune activation hypothesis provides a mechanistic framework for perinatal depression. Under certain conditions, such as psychological stress and gut microbiota dysbiosis, the physiological immune adaptations of the perinatal period may progress to a pathological inflammatory state. This pathological cascade contributes to the development of PND through several distinct mechanisms, including the disruption of neurotransmitter balance, dysregulation of HPA axis function, and impairment of neural plasticity. These findings provide a compelling scientific basis for developing targeted therapeutic strategies for PND, such as anti-inflammatory treatments and microbiota-based interventions employing probiotics or prebiotics [ 78]. 3.3. Genetic and Epigenetic Insights The pathogenesis of PND involves a complex interplay between genetic susceptibility and epigenetic regulation. Recent evidence indicates that specific genetic polymorphisms and their interaction with environmental factors, combined with dynamic epigenetic modifications, collectively constitute the molecular basis of PND. The core mechanisms can be systematically illustrated by the framework presented in Figure 3. 3.3.1. Genetic Susceptibility: The Role of Gene-Environment Interactions 3.3.2. Epigenetic Modifications: From Dynamic Regulation to Biomarker Potential Epigenetic modifications play a critical regulatory role in PND through their dynamic changes and hold significant promise as biomarkers. The placenta, acting as a critical maternal-fetal interface, exhibits DNA methylation patterns that sensitively reflect the cumulative effects of prenatal environmental exposures [ 87, 88]. For instance, hypermethylation of the glucocorticoid receptor gene (NR3C1) in the placenta may impaired negative feedback of the HPA axis, and subsequent postpartum cortisol dysregulation [ 89, 90]. Similarly, hypermethylation of the oxytocin receptor gene (OXTR) correlates with impaired mother-infant interactions and postnatal mood disturbances, suggesting its potential as a specific biomarker for PND subtypes with prominent social-behavioral deficits [ 91, 92, 93]. Beyond placental markers, easily accessible peripheral blood-based epigenetic signatures, such as differentially expressed miRNAs show considerable translational potential for early PND detection [ 94, 95, 96]. These miRNAs are implicated in disease pathogenesis likely through their regulation of inflammatory pathways and genes involved in neuroplasticity. 4. Screening and Diagnosis of Perinatal Depression: Integration of Multidimensional Strategies Early identification and accurate diagnosis of PND are key to improving maternal and infant prognosis. The current practice and research have surpassed single scale screening and are evolving towards a multidimensional model that integrates clinical evaluation, biomarkers, and digital technology. Screening, diagnosis, and risk prediction serve distinct purposes in perinatal depression care. Screening employs brief instruments (e.g., EPDS, PHQ-9) to identify probable cases, diagnosis requires clinical confirmation by a trained professional, and risk prediction aims to identify individuals at elevated risk before symptom onset. The tools discussed in this section should not be considered interchangeable. 4.1. Standardized Scales: Cornerstone, Optimization and Limitations The EPDS remains the most widely used global tool for screening PND. Its primary advantages lie in its brevity, ease of administration, and high acceptability, making it suitable for primary care settings and routine obstetric follow-ups. However, as its application has expanded across diverse global populations, several limitations have become increasingly apparent, primarily in the following three aspects. Firstly, there are population differences in its sensitivity and specificity [ 98, 99, 100]. Multiple systematic reviews indicate that the optimal cutoff scores for the EPDS vary across countries, ethnicities, and cultural contexts. For instance, in some Asian populations, commonly used cutoff values may be too low, resulting in insufficient sensitivity, whereas in certain high-income welfare societies, the same cutoff may exhibit reduced specificity, leading to false-positive results. These variations highlight that the interpretation of EPDS scores requires localized validation based on population-specific characteristics rather than simple reliance on international norms. Secondly, the scale demonstrates limited cross-cultural adaptability [ 101, 102, 103, 104]. The emotional expressions referenced in certain items (e.g., “self-blame” or “self-accusation”) may carry significantly different connotations and levels of acceptability across cultural contexts. Without rigorous translation, back-translation, and cultural adaptation processes, respondents’ understanding of these items may be biased, compromising the validity of the screening. Therefore, the EPDS must undergo localized reliability and validity testing before application rather than being used via direct translation. Thirdly, its applicability during pregnancy is limited. Originally designed for postpartum populations, the EPDS has certain constraints when used in pregnancy [ 105, 106, 107]. Common physiological discomforts during gestation (e.g., fatigue, sleep changes, appetite fluctuations) overlap considerably with depressive symptoms, making it difficult for the scale to effectively distinguish whether such symptoms originate from physiological changes or psychological pathology. This may reduce the specificity of depression assessment during pregnancy. Beyond these psychometric limitations, screening alone does not improve outcomes unless it is linked to a clear referral and follow-up pathway. Without such integration, screening may increase detection without reducing morbidity. 4.2. Emerging Screening Tools and Models To address the limitations of conventional screening tools, several innovative screening and assessment strategies have emerged in recent years, aiming to enhance the precision and efficiency of perinatal depression identification. These advancements are primarily manifested in the following three aspects. First, the optimization and innovation of screening tools have led to the development for specific populations [ 99, 108, 109, 110]. For instance, the modified Patient Health Questionnaire for pregnancy (PHQ-9-P) adjusts items that overlap with common physiological experiences during gestation, such as fatigue and sleep changes [ 111, 112]. This refinement effectively reduces interference from somatic symptoms, thereby significantly improving the specificity of depression screening in pregnant individuals. Second, the digital integration of screening processes has become a significant trend in implementation [ 113, 114, 115, 116, 117]. Embedding standardized questionnaires into obstetric electronic health record systems or dedicated mobile health applications enables the automation of the screening workflow. This approach not only alleviates the workload of healthcare providers but also transcends temporal and spatial constraints, substantially improving screening coverage and ensuring continuity in follow-up. Finally, the development and application of clinical prediction models represent a paradigm shift from singular metric reliance toward multidimensional risk assessment [ 118, 119, 120, 121]. To address the limitation of questionnaire scores being influenced by transient emotional states, advanced models incorporating multisource data have been developed. These models employ statistical methodologies, including machine learning, to integrate diverse risk factors spanning obstetric complications, psychiatric comorbidities, and psychosocial stressors within a unified multivariate predictive framework. Through the synthesis of these heterogeneous data sources, such models facilitate enhanced risk stratification and more precise quantification of individual susceptibility, thereby establishing an evidence-based foundation for implementing early, targeted preventive interventions. 4.3. Emerging Biomarkers: Seeking Objective Diagnostic Evidence Biomarker research in PND seeks to identify candidate markers and emerging auxiliary tools that may eventually support case identification and diagnosis. Nevertheless, most of the markers discussed below remain investigational and require further validation prior to clinical application. Second, some clinical observations show that elevated levels of pro-inflammatory cytokines, such as C-reactive protein (CRP) and interleukin-6 (IL-6), in the peripheral blood of affected individuals. These findings not only provide empirical support for the neuroinflammation hypothesis but also suggest that inflammatory markers could serve as references for subtyping the disorder or evaluating treatment response. Sominsky et al. [ 122] reported that compared to pregnant women with normal pre-pregnancy weight, those with pre-pregnancy obesity (BMI ≥ 30) exhibited significantly elevated levels of pro-inflammatory cytokines, such as IL-6 and tumor necrosis factor-α (TNF-α) in peripheral blood during early and mid-pregnancy. Mediation analysis revealed that increased levels of IL-6 and TNF-α significantly mediated the association between pre-pregnancy obesity and more severe antenatal depressive symptoms, indicating that a substantial portion of the depression risk attributable to obesity is mechanistically explained by the upregulation of these inflammatory markers. Furthermore, this study demonstrated that elevated levels of cytokines such as IL-6 and TNF-α can reduce the synthesis of 5-HT and brain-derived neurotrophic factor (BDNF), thereby providing additional evidence supporting their role as critical molecular players in the pathophysiology of PND. Third, placental mechanisms offer another promising avenue. Sha et al. [ 123] revealed significant alterations in the enzymatic profile of the kynurenine pathway in the placentas of women with antenatal depression. Specifically, there was an upregulation of enzymes that shift the pathway toward neurotoxicity—leading to increased production of neurotoxic metabolites such as quinolinic acid (QUIN)—coupled with a downregulation of those promoting neuroprotection. This imbalance concurrently depletes the substrate for 5-HT synthesis. Together, these mechanisms drive the pathogenesis of PND. These findings indicated that the expression levels of enzymes like IDO1 in the placenta, or the ratio of kynurenine to tryptophan along with neurotoxic metabolite levels in peripheral blood, hold promise as future objective biomarkers for predicting or diagnosing PND. Furthermore, this study suggests that modulating the balance of the placental kynurenine pathway may represent a novel therapeutic strategy for preventing or treating PND. Additionally, the role of the gut–brain axis is increasingly recognized. Xu et al. [ 124] reported that compared to healthy perinatal women, pregnant individuals with depression or anxiety exhibit a significant reduction in the α-diversity of their gut microbiota. β-diversity analysis further confirms distinct overall microbial community structures between the clinical and control groups. These differences are characterized by a marked decrease in beneficial bacterial genera, such as the short-chain fatty acid-producing Faecalibacterium and certain members of the Lachnospiraceae family, alongside a relative enrichment of inflammation-associated taxa like Escherichia-Shigella. Researchers hypothesize that this microbial shift may contribute to a systemic low-grade inflammatory state by reducing beneficial metabolites (e.g., butyrate) and increasing circulating pro-inflammatory agents such as lipopolysaccharide (LPS), thereby aligning with the neuroinflammation hypothesis of perinatal depression. These specific microbial signatures hold promise as minimally invasive biomarkers for predicting the risk of perinatal mood disorders. Finally, extracellular vesicles, particularly exosomes, have garnered attention due to their ability to cross the blood-brain barrier and carry biological information from their cells of origin, including neurons. Specific microRNAs (e.g., miR-132, miR-124) detected in peripheral blood exosomes exhibit expression profiles associated with PND [ 125]. These molecules show promise as novel, minimally invasive biomarkers that may indirectly reflect central nervous system status, offering a new window into disease identification. In summary, integrative approaches combining endocrine, inflammatory, placental, microbial, and vesicular markers are advancing our understanding of PND pathogenesis and paving the way for improved diagnostic and therapeutic strategies. 4.4. Application of Digital Technology: Passive Monitoring and Objective Early Warning In a culturally informed approach, Wang and colleagues [ 135] developed the “The Baby Coming You Ready” (BCYR) care model, which centers on digital, holistic, and strengths-based assessment. By exploring various explainable artificial intelligence (XAI) techniques, they constructed a culturally sensitive and strengths-oriented predictive model to assess perinatal psychological distress in Indigenous mothers. This study demonstrates the potential of XAI-based models in predicting psychological distress among Indigenous mothers, with the capacity to provide clear and human-interpretable explanations of how key factors interact and collectively influence outcomes. Despite the promise of digital tools, several limitations remain. Data privacy, algorithmic bias, and false positives are ongoing concerns. Digital exclusion may disproportionately affect low-income and rural populations. Moreover, most of these tools still lack external validation in diverse, real-world settings. Overall, current approaches to screening and diagnosing PND are undergoing a paradigm shift, moving from reliance on subjective reports toward the integration of multimodal information. An ideal future framework may involve initial large-scale screening and continuous monitoring of high-risk populations using clinical prediction models and digital technologies, followed by precise assessment combining standardized scales and promising biomarkers. Such a multimodal strategy would significantly enhance the accuracy of early PND detection, creating critical opportunities for personalized intervention. 5. The Evolving Landscape of PND Treatment: From Traditional Protocols to Novel Interventions The clinical management of PND has undergone considerable diversification in recent years. Therapeutic approaches have expanded beyond conventional pharmacotherapy and psychotherapy to incorporate novel targeted agents, neuromodulation techniques, and individualized precision interventions. Critical to treatment formulation is the comprehensive balancing of efficacy, safety (with particular attention to potential impacts on the fetus or infant) and accessibility to achieve an optimized clinical outcome. 5.1. Stepped-Care Framework A stepwise model based on symptom severity is recommended: Mild symptoms: psychoeducation, monitoring, lifestyle interventions, peer support. Mild-to-moderate PND: CBT, IPT, guided digital therapy, collaborative care. Moderate-to-severe PND: psychotherapy plus pharmacotherapy, risk-benefit counseling. Severe, suicidal, psychotic, or treatment-resistant cases: urgent psychiatric care, specialty referral, neuromodulation, rapid-acting treatments (brexanolone, zuranolone). 5.2. Pharmacotherapy 5.2.1. Risk–Benefit Considerations for Traditional Anti-Depressants 5.2.2. Breakthrough Targeted Therapies 5.2.3. Cautious Exploration of Hormone Therapy Estrogen supplementation therapy is derived from the “estrogen withdrawal” hypothesis, which posits that the rapid decline in estrogen levels during the perinatal period is a significant trigger for depressive episodes. However, the clinical application of this therapy remains subject to considerable controversy. Its therapeutic efficacy has yielded inconsistent conclusions across studies, lacking consistent high-level evidence for support. More critically, both pregnancy and the puerperium are inherently high-risk periods for thrombogenesis, and the administration of exogenous estrogen further elevates the risk of thromboembolic events [ 37, 144]. Consequently, this intervention has not been incorporated into standard treatment guidelines for perinatal depression and is reserved only as an exploratory option within rigorously selected individual cases. 5.3. Advances in Non-Pharmacological Interventions 5.3.1. Innovations in Psychotherapy Several studies have evaluated the efficacy of these models. For instance, Danaher et al. [ 152] evaluated the efficacy of the e-health program “MomMoodBooster2” for PND management. Results demonstrated that compared to the conventional care group, the e-health intervention group exhibited more significant improvements in depression severity and stress levels, particularly when integrated with universal depression screening and referral protocols, suggesting the e-health program holds substantial potential for implementation. In a comprehensive meta-analysis, Li et al. [ 153] evaluated the short- and long-term effects of cognitive behavioral therapy (CBT) on PND. The results demonstrated that CBT, both as a monotherapy or integrated with other approaches, was effective in reducing depressive symptoms. Significant effects were observed in the short term (SMD −0.69, 95% CI: −0.83 to −0.55) and were sustained in the long term (SMD −0.59, 95% CI: −0.75 to −0.42). While not all trials have shown preventive effects, Nishi et al. [ 145] found no preventive effect of iCBT on the onset of perinatal Major Depressive Episodes (MDE), they suggested that iCBT may still confer benefits in preventing perinatal depression among pregnant individuals with subthreshold depressive symptoms. Similarly, a meta-analysis conducted by Cuijpers et al. [ 154] on psychological treatments for PND demonstrated that psychological interventions are potentially effective in treating PND, with treatment effects lasting for at least 6–12 months. Additionally, these interventions may exert beneficial influences on social support, anxiety, functional impairment, parenting stress, and marital stress. The overall effect size was g = 0.67 [95% CI 0.45–0.89; number needed to treat = 4.39], with high heterogeneity (I 2 = 80%; 95% CI 75–85). Task-sharing and implementation strategies further enhance the scalability of PND interventions. Singla et al. [ 155] clearly demonstrated that treatment delivered by non-specialist practitioners via telephone was non-inferior to that provided by professional specialists in reducing depressive symptoms, indicating comparable core efficacy between the two delivery approaches. This task-sharing telemedicine model demonstrated high acceptability and engagement, confirming its feasibility and patient adoption in real-world settings. This study provides rigorous scientific evidence that delegating psychotherapy tasks to trained non-specialists through telephone delivery constitutes an effective, feasible, and highly promising strategy to address the substantial treatment gap in perinatal depression at scale. In a clinical trial (NCT05353491), Rahman and colleagues [ 156] developed a technology-assisted a peer-delivered version of the Thinking Healthy Programme (THP-TAP). The study revealed that among 846/980 (86.3%) participants assessed at 3 months postpartum, the remission rate difference was 8.91%, with a lower limit of the one-sided 97.5% confidence interval of 4.25%, which exceeded the prespecified noninferiority margin of −10% ( p for noninferiority < 0.0001). The findings clearly demonstrate that combining trained peers with lived experience and technology-assisted delivery creates a novel intervention for perinatal depression that is noninferior to specialist-delivered therapy in efficacy, while potentially offering greater accessibility, relatability, and cost-effectiveness. Faro and colleagues [ 157] investigated whether the strategy of Implementation Facilitation can successfully integrate an evidence-based mental health intervention—the “Mothers and Babies” curriculum—into established maternal and infant home visiting programs in the United States. The study focuses on evaluating the effectiveness of Implementation Facilitation, which, distinct from the mental health intervention itself, functions as an “engine” or “catalyst” to promote the successful adoption of the curriculum. This research addresses a critical public health challenge in real-world settings: how to systematically integrate scientifically validated interventions into preexisting, high-workload community service systems. Collectively, these advances underscore a shift toward more accessible, scalable, and integrative models of PND care. By combining digital tools, task-sharing, peer support, and implementation science, healthcare systems can expand the delivery of effective psychological interventions to broader populations, including those in underserved and high-risk settings. Notably, a meta-analysis of randomized trials by Miguel et al. [ 158] reached a clear and important conclusion: in randomized trials of psychotherapy for depression, the treatment effects (effect sizes) derived from patient self-reports are systematically and significantly larger than those based on clinician ratings. The authors strongly recommend that future clinical trials should include and report outcomes from both self-report measures (e.g., BDI, PHQ-9) and clinician-rated instruments (e.g., HAMD, MADRS) to provide more comprehensive and reliable evidence of treatment efficacy. This finding underscores that optimal clinical decision-making should integrate patient self-reports with clinician assessments, treating them as complementary rather than interchangeable sources of information. Among these approaches, traditional CBT and IPT have the strongest efficacy evidence but limited scalability. ICBT and group IPT offer better scalability, albeit with modestly lower effect sizes. Peer-delivered and task-sharing models show comparable efficacy in resource-limited settings and may improve equity, although fidelity monitoring remains a challenge. 5.3.2. Therapeutic Applications of Neuromodulation Esketamine has shown preliminary evidence for preventing postpartum depression in one meta-analysis; however, it remains an emerging intervention and requires perinatal safety data before clinical use. 5.3.3. Lifestyle and Nutrition as a Preventive Strategy Evidence from large-scale prospective cohort studies indicates that regular physical activity and adherence to a Mediterranean dietary pattern are associated with a significantly reduced risk of developing perinatal depression. The underlying mechanisms may involve the modulation of inflammatory responses, enhancement of neuroplasticity, and stabilization of hypothalamic-pituitary-adrenal axis function. In terms of nutritional interventions, supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) demonstrates adjunct therapeutic value, particularly for individuals with low baseline serum omega-3 fatty acid levels. In a meta-analysis employing a random-effects model, Tsai et al. [ 164] reported that vitamin D supplementation yielded small to moderate effect sizes (SMD: 0.52; 95% CI: 0.84 to 0.20) in ameliorating PND. Therefore, it is speculated that daily intake of 1800–3500 IU vitamin D may confer some degree of therapeutic benefit for perinatal depression. Neurobiological evidence further substantiates these findings. Jafarabady et al. [ 165] reported that women with PND exhibit significantly lower peripheral blood levels of BDNF compared to healthy perinatal controls. A meta-analysis demonstrated significantly reduced BDNF levels in individuals with antenatal depression (SMD: –0.31; 95% CI: –0.48 to –0.13; p = 0.0008; I 2 = 71%) as well as in those with postpartum depression (SMD: –0.61; 95% CI: –0.99 to –0.22; p = 0.0002; I 2 = 77%). These findings provide a neurobiological basis for the therapeutic efficacy of interventions known to elevate BDNF levels—such as regular physical exercise, certain antidepressant medications, and transcranial magnetic stimulation—in the management of perinatal depression. Furthermore, this evidence positions BDNF as a promising auxiliary objective biomarker and suggests that pharmacological agents directly targeting the BDNF system represent a viable future research direction. Lifestyle factors such as sleep and body weight also play critical roles. Yang et al. [ 166] indicated that, compared to the reference group sleeping 8–9 h per day, women reporting either less than 5 h or more than 10 h of daily sleep exhibited significantly elevated risks across all outcome measures. Specifically, in the shortest sleep duration group, each additional hour of sleep was associated with a 0.79-fold reduction in the risk of neonatal low birth weight (95% CI: 0.67–0.93); conversely, in the longest sleep group, each additional hour increased the risk by 1.40-fold (95% CI: 1.06–1.84). These results suggest that abnormal sleep duration—whether insufficient or excessive—elevates associated risks, underscoring the importance of maintaining healthy sleep patterns to mitigate the risk of PND. Similarly, Ventriglio et al. [ 167] confirmed a U-shaped relationship: both low BMI (underweight) and high BMI (overweight/obesity) were associated with increased risks of adverse pregnancy outcomes. Notably, the risks were particularly pronounced among women with obesity, who demonstrated significantly higher probabilities of developing gestational hypertension/preeclampsia, gestational diabetes, requiring cesarean delivery, and delivering macrosomic infants. More critically, both underweight and overweight/obese women exhibited elevated risks of perinatal depression compared to those with normal BMI. These findings highlight the necessity for enhanced screening for perinatal depression and the provision of early psychological support for women at both extremes of the BMI spectrum. In summary, integrative approaches addressing nutrition, physical activity, sleep, and metabolic health provide a multidimensional strategy for the prevention and adjunct treatment of perinatal depression, supported by growing epidemiological and neurobiological evidence. 5.4. Toward Precision Medicine in Perinatal Depression The following approaches remain emerging and speculative; none are currently validated for the routine clinical management of PND. Pharmacogenomics-guided personalized prescribing represents a key strategy for enhancing treatment response rates in perinatal depression [ 168, 169, 170]. By analyzing specific genetic polymorphisms in patients, it becomes possible to predict individual sensitivity to different antidepressants and assess the risk of adverse drug reactions. This approach enables precision medication selection, ultimately optimizing therapeutic outcomes. Moreover, Interventions targeting the microbiota–gut–brain axis offer a novel perspective for the management of perinatal depression. Research indicates that specific probiotic strains and prebiotics can exert positive effects on mood regulation through multiple mechanisms, including modulation of gut microbial composition, enhancement of intestinal barrier function, and reduction of pro-inflammatory mediators [ 171, 172, 173, 174]. These microecological interventions are characterized by their high safety profile and ease of implementation, indicating considerable potential for clinical application. Pritschet and colleagues [ 175] noted that current approaches seeking “average” neurobiological markers and providing “standard” therapeutic regimens yield variable efficacy across individuals, with a substantial proportion of patients showing limited treatment response. To address this, the authors developed an advanced neuroimaging methodology—Precision Functional Mapping (PFM)—which involves repeated, longitudinal functional MRI scans of the same individual to delineate their unique and fine-grained “functional connectome.” By applying PFM during preconception or early pregnancy, it becomes possible to identify person-specific risk biomarkers and predict individual responses to different treatments, such as specific SSRIs, cognitive behavioral therapy, or transcranial magnetic stimulation. This work advocates a paradigm shift from “trial-and-error” interventions based on population averages toward precisely tailored interventions grounded in the functional circuitry of the individual brain. In summary, the treatment of perinatal depression has entered a new era characterized by multimodal and personalized approaches. The future direction involves integrating rapidly acting targeted medications, highly accessible psychotherapeutic interventions, non-invasive neuromodulation techniques, and biomarker-informed preventive strategies to provide tailored therapeutic solutions for diverse patient needs. 6. Discussion Several interventions for PND are already supported by high-quality evidence and are clinically actionable. These include universal screening with the EPDS, evidence-based psychotherapies (cognitive-behavioral therapy and interpersonal therapy), selective serotonin reuptake inhibitors (particularly sertraline), and collaborative care models that integrate mental health services into obstetric settings. In contrast, a number of promising approaches remain investigational and are not yet ready for routine care. Biomarkers (e.g., brain-derived neurotrophic factor, inflammatory cytokines, microRNAs), digital phenotyping (e.g., voice analysis, wearables), microbiome-targeted interventions, precision functional mapping, and esketamine all require further validation prior to clinical adoption. Major implementation barriers persist, including stigma, a global shortage of mental health specialists, fragmented care systems, a lack of culturally adapted screening and treatment tools, and limited access to novel treatments such as brexanolone and zuranolone due to their high cost and infrastructure requirements. 7. Current Challenges Despite significant advances in the research of PND, its effective prevention, diagnosis, and treatment continue to face a series of complex challenges. These challenges span cultural, social, clinical, and scientific dimensions, requiring equally diverse and multifaceted response strategies. 7.1. Stigmatization and Underrepresentation 7.2. Resource Constraints and Clinical Decision Dilemmas Another issue is clinical decision for lactating patients requiring pharmacological treatment demands exceptional caution [ 186, 187]. According to pharmacokinetic data, priority should be given to drugs with relatively low infant doses that are transferred to breast milk. In addition, it is essential to clearly communicate to patients and their families that the negative impact of untreated maternal depression on mother-infant interaction and early child development typically far outweighs the potential risks associated with antidepressant exposure via breast milk. This understanding is crucial for promoting treatment adherence. The final plan should be jointly developed by both doctors and patients on a fully informed basis. Shared decision-making and collaborative obstetric-psychiatric care are essential when treating lactating patients. Infant monitoring and the risk of untreated maternal depression must be carefully weighed. Protocols should be established prior to initiating antidepressants in breastfeeding mothers. 7.3. Translational Bottlenecks Moreover, the translation of basic research findings into clinical practice also encounters some hurdles. On one hand, existing animal models are difficult to fully simulate the complex hormonal fluctuations, social and psychological factors, and subjective emotional experiences during the human perinatal period. On the other hand, the pathway for validating and implementing biomarkers is protracted. Despite the identification of numerous potential biomarkers, their translation into clinically usable tools requires overcoming significant challenges, including standardizing detection assays, establishing clinical cut-off values, and conducting validation in large-scale prospective cohorts. To advance biomarker research, future studies should incorporate the following: prospective cohort designs, preregistration of biomarker panels, standardized assays, external validation in independent populations, and specification of clinically meaningful outcome thresholds. 8. Prospect and Conclusions In conclusion, addressing PND is a public health issue that demands systematic solutions. Providing genuinely effective support for affected populations requires breaking through biomedical research bottlenecks, addressing sociocultural barriers, reducing global resource disparities, and respecting patients’ participation in decision-making. Clinically, integrated care pathways should link routine screening to timely diagnostic assessment, stepped treatment according to symptom severity, emergency referral protocols for suicidality or psychosis, and longitudinal mother–infant or family follow-up. Such pathways are essential to reducing the morbidity and mortality associated with perinatal depression. Author Contributions Conceptualization, H.S. and X.Z.; methodology, H.S.; investigation, H.S. and X.C.; writing—original draft preparation, H.S. and X.C.; writing—review and editing, X.Z.; visualization, H.S. and X.C.; supervision, X.Z.; project administration, X.Z. All authors have read and agreed to the published version of the manuscript. Funding This research was funded by Theoretical and practical research on the construction of medical postgraduate curriculum system from the perspective of classified training—taking obstetrics and gynecology postgraduate as an example, grant number 030102050502jgxm-dfxm-202506. The APC was funded by this project. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement This review article does not report original research data. All referenced studies are publicly available as cited in the reference list. Conflicts of Interest The authors declare no conflicts of interest. References Neuroendocrine hypothesis explains the pathogenesis of PND. 5-HT: serotonin; DA: dopamine; NE: norepinephrine; HPA: hypothalamic-pituitary-adrenal axis; PND: perinatal depression. Neuroendocrine hypothesis explains the pathogenesis of PND. 5-HT: serotonin; DA: dopamine; NE: norepinephrine; HPA: hypothalamic-pituitary-adrenal axis; PND: perinatal depression. Neuroinflammation and immune activation explain the pathogenesis of perinatal depression. BDNF: brain-derived neurotrophic factor. Neuroinflammation and immune activation explain the pathogenesis of perinatal depression. BDNF: brain-derived neurotrophic factor. Explanation of the pathogenesis of PND from the perspectives of genetics and epigenetics. 5-HTTLPR: serotonin transporter gene; miRNA: microRNA; NR3C1: glucocorticoid receptor gene; OXTR: oxytocin receptor gene. Explanation of the pathogenesis of PND from the perspectives of genetics and epigenetics. 5-HTTLPR: serotonin transporter gene; miRNA: microRNA; NR3C1: glucocorticoid receptor gene; OXTR: oxytocin receptor gene. Summary of pathophysiological mechanisms in perinatal depression. Summary of pathophysiological mechanisms in perinatal depression. Mechanism Key Evidence Type Clinical Relevance Limitations Translational Status Neuroendocrine (HPA axis, 5-HT, DA, NE) Human cohort studies, biomarker assays Supports use of SSRIs and neuroactive steroids Correlation vs. causation; individual variability Clinically actionable Neuroinflammation Cytokine levels (IL-6, TNF-α), animal models Potential anti-inflammatory targets Mostly observational; causal evidence lacking Experimental Microbiota–gut–brain axis Human microbiome studies Probiotic/prebiotic interventions Small sample sizes; confounders Exploratory Genetic (5-HTTLPR, BDNF) Candidate gene studies Personalized risk assessment Inconsistent replication Investigational Epigenetic (DNA methylation, miRNA) Placental and blood studies Early biomarkers Validation needed Emerging Current clinical progress in some cases of perinatal depression. NCT: National Clinical Trial. Current clinical progress in some cases of perinatal depression. NCT: National Clinical Trial. NCT Number Status Conditions Interventions NCT06074250 Phase 2 Phase 3 Perinatal depression Perinatal anxiety Dietary supplement: fish oil, Dietary supplement: probiotics, Behavioral: prebiotics, Behavioral: diet quality NCT04998721 Phase 2 Depression, Postpartum efficacy, Self anxiety Behavioral: promoting first relationships-brief Behavioral: perinatal collaborative care NCT04685148 Phase 1 Phase 2 Major depressive disorder Postpartum depression Drug: transdermal patch estradiol Drug: transdermal patch placebo NCT05552053 Phase 2 Phase 3 Depression, Postpartum Perinatal depression Anxiety in pregnancy Stress, Psychological Device: MWSH plus candlelit care Device: MWSH Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Shui, H.; Cao, X.; Zhang, X. Advances in Perinatal Depression: A Focus on Screening and Treatment. J. Clin. Med. 2026, 15, 4465. https://doi.org/10.3390/jcm15124465 Shui H, Cao X, Zhang X. Advances in Perinatal Depression: A Focus on Screening and Treatment. Journal of Clinical Medicine. 2026; 15(12):4465. https://doi.org/10.3390/jcm15124465 Shui, Haonan, Xiaotong Cao, and Xuemei Zhang. 2026. "Advances in Perinatal Depression: A Focus on Screening and Treatment" Journal of Clinical Medicine 15, no. 12: 4465. https://doi.org/10.3390/jcm15124465 Shui, H., Cao, X., & Zhang, X. (2026). Advances in Perinatal Depression: A Focus on Screening and Treatment. Journal of Clinical Medicine, 15(12), 4465. https://doi.org/10.3390/jcm15124465
