Ruirui Shang
Yitong Lu
Haonan Gao
Xia Zhong3
Xiaowen Yu- 1College of Rehabilitation Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
- 2First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
- 3Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, China
- 4Division 4 of Neurology Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- 5Department of Pain Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
Postpartum depression (PPD) is a common postpartum complication mediated by multiple factors, which can lead to dual damage to both maternal and infant health. There is an urgent need to explore alternative intervention strategies, as the current conventional antidepressant medications have drawbacks, including delayed onset, severe side effects, and low patient tolerance. Due to their multi-target potential, certain metabolites derived from traditional Chinese medicine (TCM) and other natural products are being investigated as treatments for PPD. However, a systematic understanding of their molecular mechanisms, grounded in the pathophysiology of PPD, is lacking. Therefore, this article synthesizes recent literature to systematically review the pathophysiological mechanisms of PPD and to elucidate the molecular mechanisms underlying the therapeutic effects of TCM formulas and natural products. This review also critically discusses the limitations of current research—particularly issues related to standardization and safety—and proposes key priorities for future preclinical studies and clinical translation.
1 Introduction
One of the most common postpartum complications is postpartum depression (PPD), which typically manifests within 1 month after childbirth. It is characterized by chronic depression, anger, anxiety, negative emotions, loss of appetite, and, in severe cases, suicidal thoughts and actions (Ushiroyama et al., 2005). In some low- and middle-income countries or regions, suicide within 1 year after childbirth accounts for about 20% of maternal deaths (Lindahl et al., 2005). Furthermore, PPD poses a long-term risk to the behavioral, emotional, and cognitive development of newborns, in addition to negatively affecting the physical and mental health of mothers (Murray, 1992; Murray and Cooper, 1997a; Murray and Cooper, 1997b; Halligan et al., 2007; Feldman et al., 2009). The incidence of PPD is on the rise due to the accelerated pace of modern life and increasing family pressures. Research indicates that PPD is more prevalent in developing countries (15.0%) compared to developed countries (12.0%), with prevalence rates ranging from 5.0% to 26.32% (Liu et al., 2022). Unlike other physiological stages, postpartum women undergo significant changes in hormones, neurotransmitters, and metabolic levels, making the etiology of PPD more complex and distinct from simple depression (Fox et al., 2018).
Conventional antidepressant medications and neurosteroid-based agents (e.g., brexanolone, zuranolone) are current mainstay pharmacotherapies for PPD. However, these medications carry the risk of being transferred to nursing infants (Patterson et al., 2024). In addition, many PPD patients are either not diagnosed in a timely manner, unable to access psychological treatment, or unwilling to take antidepressant medications during pregnancy or lactation due to concerns about the potential impact on their baby. Meanwhile, the therapeutic effects of antidepressant medications typically take several weeks to manifest, and surveys indicate that 15%–30% of patients discontinue their medication prematurely (Gartlehner et al., 2005). Therefore, developing more effective and safer antidepressant pharmacotherapies is an urgent priority. TCM formulas, which are typically complex mixtures of several botanical drugs, are hypothesized to exert their effects via the synergistic actions of their diverse metabolites on multiple pathways (Zhao et al., 2023). Some of these formulas have already been investigated for PPD management. This is supported by the growing body of research on botanical drugs for PPD (Assadi et al., 2011; Dereli et al., 2019) which provides a foundation for further exploring the potential of TCM formulas and natural products in treating this disorder.
PPD has a complex pathophysiology involving the interplay of both social and biological factors. Social causes include excessive stress, marital discord, and single-parent households, while physiological factors encompass immune system abnormalities, neurotransmitter deficits, rapid estrogen decline, and neuroendocrine imbalances (Anokye et al., 2018; Stewart and Vigod, 2019). In recent years, the occurrence and progression of PPD have been linked to pathogenic pathways such as neuroinflammation, aberrant neuroplasticity, dysfunction of the MGB axis, and neuroendocrine abnormalities. These mechanisms interact with each other, forming a complex pathological network underlying PPD. Given the multifactorial pathophysiology of PPD, therapeutic strategies that target multiple pathways simultaneously—such as those employing botanical drugs and their metabolites—are generating increasing research interest. However, a systematic and critical evaluation integrating current knowledge of PPD pathogenesis with the evidence for the molecular mechanisms of TCM interventions is lacking. To provide a solid foundation for advancing fundamental research and clinical translation, this review aims to synthesize current knowledge on the pathogenic mechanisms of PPD and elucidate the pharmacological mechanisms by which TCM and natural products exert their effects against PPD.
2 Methodology
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and systematically searched for research on the pathological mechanisms, TCM interventions, PPD pharmacotherapies and their side effects. Data were sourced from PubMed, Web of Science, and ScienceDirect, with a search time range from January 2000 to the date the search was conducted (April 2024). The search strategy used a combination of subject headings and free-text terms, with English search terms including “postpartum depression”, “neuroinflammation”, “MGB axis”, “HPA axis”, “neuroplasticity”, “neuroendocrine”, “metabolites from traditional Chinese medicine”, “Traditional Chinese Medicine Formulas”, “natural products”, “toxicity”, and combined using Boolean operators (AND/OR). Inclusion criteria were: ① original research papers published in English; ② studies based on animal, cell model, or clinical trials of PPD; ③ studies describing the pathogenesis of postpartum depression (PPD); Exclusion criteria were: ① non-English literature; ② reviews, conference abstracts, case reports, and other gray literature; ③ duplicate publications; ④ studies lacking clear objectives, methodologies, or data related to PPD or traditional Chinese medicine or natural products interventions; ⑤ studies that did not provide sufficient experimental design or detailed data information. Literature screening was independently completed by two researchers, who first screened through titles and abstracts to exclude studies that clearly did not meet the criteria. Subsequently, the remaining literature was read in full text for further screening, and discrepancies were resolved through cross-checking. A total of 137 articles were finally included for systematic analysis (Figure 1).
Figure 1. Flowchart of literature retrieval and screening.
3 Pathological mechanism of PPD
3.1 Neuroinflammation
The term neuroinflammation is now commonly used to refer to all immune activity within the central nervous system (CNS) in response to both acute and chronic diseases, including traumatic, infectious, ischemic, autoimmune, and degenerative conditions. Originally, it was used to describe the inflammatory response of microglia under pathological conditions (Nie et al., 2018). Accumulating evidence suggests a link between neuroinflammation and the pathophysiology of PPD. Neuroinflammation, which plays a dual role in exacerbating damage and contributing to repair, is considered crucial in the prognosis of many neurological diseases, including depression. One of the most common and serious disorders affecting the central nervous system is depression, and growing interest has been directed toward the link between depression and neuroinflammation. Numerous studies have shown that levels of inflammatory markers are elevated in individuals with depression. According to a meta-analysis, the clinical use of certain anti-inflammatory medications, such as statins, cytokine inhibitors, minocycline, and nonsteroidal anti-inflammatory drugs, has led to a significant reduction in depressive symptoms in some patients with severe depression (Köhler-Forsberg et al., 2019).
Research has shown that activation of the neuroimmune system during pregnancy-related stress significantly increases the levels of four pro-inflammatory substances in the serum of multiparous rats: interleukin-1α (IL-1α), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). This leads to a disruption of the neurotransmitter system, potentially contributing to the pathological development of inflammatory depression. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are crucial for human health. It is noteworthy that multiple studies in recent years have found that omega-3 polyunsaturated fatty acids can reduce pregnancy-related neuroinflammatory responses and exert antidepressant effects by inhibiting the production of pro-inflammatory cytokines and regulating neurotransmitter systems (Tang et al., 2018a). Further research has also found that, The CNS contains myeloid innate immune cells known as microglia, which have neuroprotective properties in both healthy and diseased states. Lipopolysaccharide (LPS) immune stimulation significantly activates microglia in the hippocampus of female mice, promoting the release of pro-inflammatory cytokines and inducing anxiety and depressive-like behavior. Notably, there is a significant positive correlation between the extent of microglia activation, the severity of depressive behavior, and the levels of neuroinflammatory markers. This suggests that neuroinflammatory pathways play a critical role in the development of depression. Furthermore, short postpartum separation (PS) during lactation can effectively inhibit excessive microglial activation, reduce the neuroinflammatory response, and significantly enhance the recovery of female mice from LPS-induced behavioral defects. These findings provide a theoretical basis for the prevention and treatment of PPD (Wu et al., 2021).
The cytoplasmic oligomer NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) is one of many inflammasome complexes, which are multiprotein signaling complexes. Inflammasomes are notably associated with autoimmune disorders and various self-inflammatory conditions in humans. Chronic stress can significantly activate the NLRP3 inflammasome pathway in the hippocampus, triggering neuroinflammatory responses and leading to an increase in postpartum depressive-like behavior. Exercise during pregnancy can regulate prolactin levels, which not only directly inhibits neuroinflammation but also exerts significant anti-inflammatory and neuroprotective effects on hippocampal tissue. This regulation helps prevent postpartum anxiety and depressive-like behaviors by systematically inhibiting hippocampal neuroinflammation, especially the NLRP3 inflammasome pathway. Moreover, prenatal stress significantly activates the NLRP3 inflammasome in the hippocampus, leading to the increased release of pro-inflammatory cytokines, cortical neuroinflammation, and neurodegeneration, ultimately resulting in offspring exhibiting depressive-like behavior. This clarifies how NLRP3 inflammasome activation plays a crucial role in the etiology of PPD (Özdamar et al., 2022). In summary, neuroinflammation plays a critical role in PPD, including abnormal activation of microglia, the release of NLRP3 inflammasomes, and the production of pro-inflammatory cytokines. Targeting neuroinflammation is a promising strategy for treating PPD.
3.2 MGB axis
The MGB axis has been implicated in various mood disorders, including PPD. This axis refers to the bidirectional communication between gut microbiota and brain function (Donald and Finlay, 2023). Despite the anatomical separation between the gut and brain, there is growing evidence that the gut microbiota and the CNS communicate bidirectionally (Ahmed et al., 2022). The MGB axis has been proposed as the communication link between gut bacteria and the CNS. Increasing research suggests that disturbances in gut microbiota composition in individuals with depression can influence both the pathological and physiological progression of the disorder in a variety of ways (Liu et al., 2023).
The pathophysiology of PPD is significantly influenced by the MGB axis. Studies have linked higher prenatal depression ratings to lower gut microbiome species richness, diversity, and evenness (Nel et al., 2025). Compared to healthy controls, PPD patients exhibit relatively low Firmicute abundance and notable variations in the presence of several key genera. Notably, the levels of certain genera, such as Phascolarctobacteria, Lachnospiraceae, Faecalibacterium, and Tyzzerella_3, are correlated with the severity of PPD (Zhou et al., 2020). The relationship between gut microbiota and PPD has also been investigated using the Mendelian randomization method, which further demonstrated that alterations in gut microbiota increase the risk of PPD (Sun et al., 2024). Animal studies have identified specific gut microbiota key to the development of PPD (Tian et al., 2021). Furthermore, antidepressant medications like fluoxetine (FLX) have been shown to exert anti-PPD effects by regulating the gut microbiota (Ramsteijn et al., 2020; Zheng et al., 2023). This further confirms the critical role of the MGB axis in the pathophysiological process of PPD.
The use of specific prebiotics and probiotics is generally safe and well tolerated. Research has shown that specific probiotic strains, such as Lactobacillus rhamnosus, can significantly reduce the incidence of PPD and anxiety in pregnant and postpartum women, while being safe and tolerable for both mother and baby (Slykerman et al., 2017). Lactobacillus casei may alleviate PPD by modulating the brain-derived neurotrophic factor (BDNF)-extracellular signal-regulated kinase 1/2 (ERK-1/2) pathway, gut microbiota composition, brain monoamine levels, and oxidative stress (Yang et al., 2022). Furthermore, L. rhamnosus has been shown to enhance mother-infant bonding affected by PPD, reduce prenatal psychological burden, and improve maternal mental health (Benlakehal et al., 2025). Some studies suggest that anti-inflammatory medications could prevent and treat depression by altering the composition and quantity of beneficial gut bacteria, highlighting the potential of targeting gut microbiota and the NLRP3 inflammasome as strategies for preventing PPD. The NLRP3 inflammasome plays a crucial role in the MGB axis (Getachew et al., 2018; Song et al., 2022; Liu et al., 2020). Additionally, postpartum obesity increases the risk of PPD, and high dietary fiber intake has been identified as a promising nutritional strategy to prevent anxiety behaviors associated with prenatal obesity through the MGB axis (Liu et al., 2020). Research also suggests that malfunction of neuroplasticity and inflammasomes may be crucial in mediating the link between stress and gut microbiota composition (Zhou et al., 2023). Beyond posing a threat to maternal physical and mental health, PPD has been linked to negative effects on infant behavior and development. Studies indicate that maternal PPD may influence the neurological development of offspring by altering the composition of infant fecal microbiota and metabolites (Zhou et al., 2024). Therefore, identifying key gut microbiota strains and their functional metabolites related to neurodevelopment is essential for developing new treatment strategies for both mothers and infants affected by PPD.
In conclusion, PPD is strongly associated with alterations in particular bacterial genera and the overall composition of gut microbiota via the MGB axis. A promising direction for future research lies in the prevention and treatment of PPD through targeted microbiota modulation and the use of specialized probiotic interventions.
3.3 Neural plasticity
A fundamental concept in neuroscience, neuroplasticity refers to the brain’s ability to form new neural connections in response to learning, adaptation, and injury. This flexibility is essential for cognitive processes such as memory and learning, as well as for recovery after brain damage. Neuroplasticity can be divided into two main categories: structural plasticity and functional plasticity. Structural plasticity involves changes in neurogenesis, dendritic spine formation, and axonal growth and repair mechanisms. Functional plasticity, on the other hand, modifies the interactions between neurotransmitters and receptors, allowing the brain to adapt and maintain function without changing its physical structure (Chen S. et al., 2024).
The development and incidence of PPD are closely linked to neuroplasticity. Ketamine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has shown significant and rapid antidepressant effects (within hours) when used to treat refractory depression (Smith-Apeldoorn et al., 2022). Research indicates that S-ketamine (esketamine), the S-enantiomer of ketamine, enhances synaptic function by increasing synaptic protein levels and transmission efficiency, helping to combat depression. Notably, low-dose S-ketamine may have a unique dual effect of both antidepressant and anti-anxiety properties, while high-dose S-ketamine does not exhibit this effect (Ren et al., 2022). Anxiety and depression are heavily influenced by disruptions in the excitatory/inhibitory (E/I) ratio in the cortex, leading to abnormal functional connectivity and synaptic alterations in excitatory and inhibitory neurotransmitters (Hartmann et al., 2017; Lener et al., 2017; Pham and Gardier, 2019). Administering classic Wnt signaling agonists to restore Wnt signaling can help rebalance the E/I ratio and alleviate depression-related symptoms by enhancing the plasticity of gamma-aminobutyric acid (GABA) and dopaminergic synapses (Ye B. et al., 2023).
Recent studies have shown that the functional imbalance of the GABAergic system and neurosteroid withdrawal play a key role in the pathogenesis of PPD. Allopregnanolone (ALLO) is the main metabolite of progesterone, which can act as a positive allosteric modulator of GABAA receptors, enhancing inhibitory transmission and maintaining emotional stability (Wang, 2011). Clinical observations have found that the level of ALLO increases significantly during pregnancy and decreases rapidly after childbirth, triggering the so-called neurosteroid withdrawal syndrome (Maguire and Mody, 2008). This hormonal shift leads to the restructuring of GABAA receptor subunits and a reduction in inhibitory control, resulting in emotional imbalance (Maguire and Mody, 2008; Smith et al., 2007). Clinical studies further confirm that reduced ALLO levels in the third trimester of pregnancy are significantly associated with depressive symptoms (Hellgren et al., 2014). Furthermore, the intravenous agent Brexanolone (an ALLO derivative) has demonstrated rapid and sustained antidepressant efficacy in patients with PPD, further supporting the GABAA receptor–neurosteroid withdrawal hypothesis (Me et al., 2018).
The hippocampus of rodents produces new neurons throughout their lifespan, a process known as adult hippocampal neurogenesis (AHN) (Moreno-Jiménez et al., 2021). As a unique form of neural circuit plasticity, AHN is fundamental to cognitive and emotional regulation. Short PS can activate AHN in female mice, enhancing their cognition and improving resistance to PPD-like behavior (Zhou et al., 2025). The novel σ-1 receptor agonist YL-0919 activates the σ-1 receptor, regulates GABA/glutamate signaling, restores the balance of excitation and inhibition in the brain, and promotes hippocampal plasticity, providing insight for the development of new PPD treatments (Ren et al., 2024). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that uses magnetic fields to regulate brain regions associated with depression (Garcia et al., 2010). Studies have shown that rTMS combined with oxytocin (OT) can enhance the alleviation of PPD-like behavior through mechanisms such as glial cell activity regulation and synaptic plasticity enhancement (Amin et al., 2025). In addition, music therapy may prevent PPD by protecting synaptic plasticity from oxidative stress and inflammatory damage caused by estrogen imbalance (Fu et al., 2025a). Environmental enrichment (EE) has been found to effectively reduce neuronal inflammation, apoptosis, and synaptic plasticity damage, thereby alleviating PPD-like behavior induced by maternal-infant separation in female mice (Chen G. et al., 2024). Overall, the pathophysiology and treatment of PPD are significantly influenced by neuroplasticity, including neurotransmitters, synaptic plasticity, and neurogenesis. Controlling neuroplasticity represents a key strategy for PPD treatment.
3.4 Neuroendocrine
The neuroendocrine system, which regulates and balances hormone secretion and function, serves as the connection between the endocrine glands and the CNS (Datta et al., 2023). An essential component of this system, the hypothalamic-pituitary-adrenal (HPA) axis, plays a critical role in controlling the body’s stress response and various other physiological functions (Zheng et al., 2024).
During pregnancy and the postpartum period, the maternal hypothalamic-pituitary-adrenal (HPA) axis functions differently, and these changes may be closely linked to the development of PPD. Research has shown that postpartum women with depression exhibit reduced HPA reactivity and weakened circadian rhythm changes in cortisol levels compared to women without depression (De Rezende et al., 2018). Additionally, plasma or serum levels of docosahexaenoic acid (DHA) in women with PPD are significantly lower than in asymptomatic individuals. Studies have found that the reduction of DHA, particularly in women with multiple pregnancies, may be associated with altered expression of glucocorticoid receptors (GR), which exacerbates depressive-like behavior and activates the HPA axis (Tang et al., 2018b). GR, a crucial signaling molecule of the HPA axis, is linked to anxiety and depressive-like behaviors and is downregulated in the hippocampus during postpartum withdrawal symptoms (Wang et al., 2020). Furthermore, PPD appears to result from both prenatal stress and inhibition of postpartum HPA axis activity (HPA-AA). Studies suggest that hair steroid analysis may be used to predict the risk of PPD (Sadeghi-Bahmani et al., 2025). Multiple stressors have been shown to induce PPD by affecting the HPA axis. Chronic psychological stress during pregnancy, for example, can disrupt adaptive changes in the maternal neuroendocrine system by altering HPA axis activity (Zoubovsky et al., 2020). Stress, along with fluctuations in ovarian hormones, can also contribute to PPD by disrupting HPA axis components, such as corticotropin-releasing factor, cortisol, and GR (Payne and Maguire, 2019). Vasopressin, which is vital to the stress response (Seth et al., 2016), has also been implicated in PPD, as it may promote dysfunction of the HPA axis (Kashkouli et al., 2023). However, it is important to note that long-term HPA axis dysfunction, as measured by hair cortisol concentration at 12 months postpartum, does not mediate the substantial increase in PPD risk and symptoms associated with childhood maltreatment (Blecker et al., 2025).
HPA axis dysfunction interacts with other pathological processes, collectively contributing to the development of PPD and related complications. Postartum female mice exposed to low-resource environments may experience a lack of pleasure, elevated cortisol levels, and neuroinflammation. These changes can lead to the development of PPD and postpartum hypertension, which are driven by elevated corticosterone levels and neuroinflammation (Jones et al., 2025). The mechanisms through which poverty exacerbates depression are believed to include HPA axis dysregulation, neuroinflammation, and dietary changes, which result in excessive circulating lipids and blood sugar (Osborne et al., 2020; Lloyd-Jones et al., 2022). Studies have shown that mice treated with high levels of postpartum corticosterone (CORT) exhibit HPA axis activation, depressive-like behavior, and impaired maternal care. Notably, maternal CORT-induced PPD can also impair offspring HPA axis function (Xie et al., 2025). In terms of intervention, FLX, the most commonly used prescription medication for maternal depression, combined with EE, has been shown to significantly increase OT levels in the brain. This combination helps alleviate anxiety and depressive behaviors by reducing HPA axis dysfunction in mothers following stress exposure (Bashiri et al., 2021). Additionally, n-3 polyunsaturated fatty acids (PUFAs) may improve PPD by modifying HPA axis function, reducing neuroinflammation, and regulating related miRNAs through the 5-hydroxytryptamine pathway (Choi et al., 2020). In summary, the dynamic changes and dysregulation of the postpartum HPA axis form a core pathological mechanism of PPD by affecting key molecules such as GR, mediating various stress responses, and interacting with other pathological processes.
3.5 Other aspects
The occurrence and development of PPD are influenced by various factors, making in-depth research into its mechanisms, prediction, and treatment strategies crucial. Studies have shown that aberrant signaling in the central amygdala, involving lipid transport protein type prostaglandin D synthase (L-PGDS)/prostaglandin D2 (PGD2), disrupts Src protein phosphorylation, leading to astrocyte atrophy and ultimately resulting in PPD in mice (Sheng et al., 2024). Pathway analysis also suggests that DNA methylation patterns associated with hippocampal synaptic plasticity could play a key role in the onset of PPD (Guintivano et al., 2014). A meta-analysis of genome-wide association studies identified genetic links between PPD and major depression, bipolar disorder, anxiety, PTSD, insomnia, menarche age, and polycystic ovary syndrome. Notably, cell enrichment analysis revealed that the only FDA-approved medication for PPD shares a mechanism of action with GABAergic neurons (Guintivano et al., 2023). Furthermore, postpartum mice subjected to environmental stressors, such as reduced nighttime light exposure, may exhibit depressive-like behavior. This effect is likely mediated by disruptions in circadian rhythms and gene expression patterns (Lin et al., 2025). Changes in the levels of specific metabolites, including decanoic acid, dodecanoic acid, arachidic acid, behenic acid, and L-tryptophan, found in cerebrospinal fluid, show strong correlations with PPD symptoms. Due to their high discriminatory performance, these metabolites have potential as predictive biomarkers for PPD (Sheng et al., 2023). Moreover, another study suggests that assessing thyroid function, inflammatory markers (such as ferritin and C-reactive protein), pregnancy-related hormones (such as estrogen and progesterone), vitamin D levels, and coagulation indicators, in addition to clinical evaluations, may help identify individuals at high risk for perinatal depression early on (Ciolac et al., 2025).
Research has suggested that hippocampal CA3 signaling protein 3A (sema3A) may be a potential therapeutic target and plays a crucial role in the pathophysiology of PPD (Chen et al., 2025). Furthermore, studies have shown that PHD finger-containing protein 1 (BRPF1) and the bromodomain of lysine demethylase 3A (KDM3A) are important regulatory factors for iron toxicity sensitivity in PPD. This molecular axis is primarily regulated by the transcription of glutathione peroxidase 4 (GPX4) and the cysteine/glutamate antiporter SLC7A11, which help maintain redox homeostasis. Disruption of this pathway can trigger a neuropathic cascade reaction. Therefore, drug-targeted interventions within these pathways offer a promising neuroprotective strategy for PPD treatment (Lan et al., 2025). In summary, the pathogenesis of PPD involves multiple signaling pathways and complex molecular interactions, many of which remain poorly understood. To lay a solid foundation for developing more effective preventive and therapeutic strategies, it is essential for future studies to continue exploring and methodically analyzing the physiological and pathological mechanisms underlying PPD. Identifying key regulatory nodes and potential intervention targets will be critical for advancing both basic research and clinical application (Figure 2; Table 1).
Figure 2. Pathological mechanisms of PPD. The pathological mechanisms of PPD involve neuroinflammation, microbial gut brain axis, neural plasticity, neuroendocrine. When the relevant pathological mechanisms are impaired or affected, they respond through pathways that lead to the development of PPD.
Table 1. Pathological mechanism information of PPD.
4 Molecular mechanisms of natural products
Several medicinal plants and their characterized metabolites, such as those from Hypericum perforatum L. (Hypericaceae) have been investigated or applied in the context of PPD management. Among its characterized metabolites, hypericin is particularly important for its pharmacological activity (Butterweck and Schmidt, 2007; Zhai et al., 2015; Grundmann et al., 2006). Studies suggest that the metabolite hypericin may alleviate PPD symptoms by modulating glucocorticoid metabolism, upregulating estrogen receptor expression, and reducing neuroinflammation (Zhai et al., 2022). Existing reviews and clinical reports indicate that the overall tolerance is good, but mild gastrointestinal discomfort and photosensitivity may occur (Brockmöller et al., 1997; Woelk et al., 1994), individual cases have manic episodes (Burt et al., 1999). The use of H. perforatum L. (Hypericaceae) in early pregnancy has not been shown to significantly increase the risk of premature birth, stillbirth, or major malformations (Moretti et al., 2009), but some studies suggest that the incidence of neonatal malformations may be slightly higher than in the general population (Kolding et al., 2015). Overall, the evidence suggests safety, but further high-quality research is needed to validate its long-term safety and interactions (Rodríguez-Landa and Contreras, 2003; Zepeda et al., 2023). Total Glycosides of Paeonia, a standardized extract from the roots of Paeonia lactiflora Pall. (Paeoniaceae), contains paeoniflorin as its primary metabolite (Zhang and Wei, 2020). Paeoniflorin, as a key glycoside in Paeonia plants, has garnered attention for its potential neurotrophic effects (Li et al., 2017). BDNF, which plays a critical role in regulating emotional disorders, is notably influenced by Paeoniflorin. Imbalanced levels of BDNF are strongly linked to depression, and paeoniflorin may improve PPD by modulating BDNF and activating the mTOR signaling pathway (Erickson et al., 2012; Haile et al., 2014). In addition, paeoniflorin has shown positive effects on Translocator Protein (TSPO), an 18 kDa protein with known anti-anxiety and anti-depressant properties (Chen et al., 2022; Rupprecht et al., 2009; Costa et al., 2012). Toxicity studies indicate that paeoniflorin has low acute toxicity, minimal subacute and chronic toxicity, and no genetic or mutagenic effects (Ou et al., 2025). However, it is important to note that paeoniflorin and its metabolites are primarily excreted via the kidneys (Shao et al., 2017). Therefore, patients with impaired kidney function may require dosage adjustments to avoid medication accumulation and potential toxicity. Another promising metabolite is timosaponin B-Ⅲ, a steroidal saponin isolated from the rhizomes of Anemarrhena asphodeloides Bunge (Asparagaceae). In PPD mouse models, TB-Ⅲ has exhibited antidepressant effects. Its mechanisms of action are believed to involve the regulation of inflammatory cytokines, BDNF signaling, and synaptic plasticity (Zhang et al., 2017).
Stevioside, a key diterpenoid metabolite derived from the leaves of Stevia rebaudiana (Bertoni) Bertoni (Asteraceae), is widely known as a calorie-free sweetener due to its potent sweetness (250–300 times sweeter than sucrose) (Chatsudthipong and Muanprasat, 2009). Recent studies suggest that gestational obesity, induced by a high-fat diet during pregnancy, is positively correlated with depression, anxiety, and cognitive impairment in pregnant rats (Liu et al., 2020). Interestingly, stevioside has been shown to reverse PPD-like behavior and cognitive impairments caused by high-fat diets. The mechanism of action involves repairing intestinal barrier structure, reducing serum LPS levels, inhibiting microglial activation, and reducing the release of pro-inflammatory cytokines. Furthermore, stevioside enhances brain antioxidant capacity and improves mitochondrial function, offering a promising therapeutic approach for PPD (Ye et al., 2024). Another notable metabolite in the realm of TCM is Epigallocatechin-3-gallate (EGCG), a catechin polyphenol found in Camellia sinensis (L.) Kuntze, Theaceae. Known for its anti-inflammatory, antioxidant, and neuroprotective properties, EGCG has shown potential as a therapeutic agent for various illnesses, including mental health disorders (Chakrawarti et al., 2016). Research indicates that Sema3A, a molecule elevated in certain mental illnesses (Van Battum et al., 2015), is associated with severe depression (Zhou et al., 2017). As a downstream target of Sema3A, glycogen synthase kinase 3β (GSK3β) is thought to play a role in depression pathology. Studies suggest that EGCG can reduce depressive-like behaviors in mice by increasing the phosphorylation levels of GSK3β and decreasing Sema3A expression in the hippocampus. This indicates that EGCG may hold promise as a potential treatment for PPD, especially by targeting the neuroinflammatory and synaptic plasticity pathways involved in depression (Xu et al., 2023).
Curcumin, the primary curcuminoid metabolite of Curcuma longa L. (Zingiberaceae) (a member of the ginger family), has been used as both a culinary spice and a medicinal plant in South Asia for thousands of years (Kunnumakkara et al., 2017; Farzaei et al., 2018). Clinical trials have shown that curcumin can effectively reduce postpartum anxiety and depression. Its mechanism of action involves synergistic effects across multiple pathways, including neurotransmitter regulation, HPA axis modulation, inflammation inhibition, antioxidant activity, and promotion of neural nutrition (Hamlbar et al., 2025). Curcumin is non-mutagenic and non-genotoxic, making it a relatively safe option. However, some studies indicate that curcumin may be poorly absorbed in the gastrointestinal system. Oral administration of 6g/day has been deemed safe for 4–7 weeks, although gastrointestinal discomfort can occur in some individuals (Soleimani et al., 2018). Resveratrol (RSV), a polyphenolic metabolite found in red grape skins (Vitis vinifera L., Vitaceae), red wine, and peanuts, is an activator of Silent Information Regulator 1 (Sirt1), which plays a key role in processes like oxidative stress, glucose and lipid metabolism, and cell cycle regulation (Manetti et al., 2022). Research indicates that RSV (Wang et al., 2018) can reduce PPD-like behavior in mice by blocking the AKT/mTOR signaling pathway, promoting SIRT1 activation, and inducing autophagy (Ye S. et al., 2023). However, RSV has low solubility and poor bioavailability, which significantly limits its effectiveness in vivo (Walle et al., 2004). Moreover, the safety profile of resveratrol requires careful evaluation. Studies suggest that its effects are not only dose-dependent but also involve complex hormone-modulating activities, while high doses can be toxic (Calabrese et al., 2010). Therefore, comprehensive preclinical studies are imperative to establish a safe therapeutic window, especially for the vulnerable postpartum population. In summary, while both curcumin and RSV show promise in alleviating PPD symptoms, more research is required to optimize their use and ensure safety, especially with regard to their bioavailability, toxicity, and molecular mechanisms.
5 Molecular mechanisms of traditional Chinese medicine formulas
With its long history of treating various ailments, TCM constitutes a prime example of ethnopharmacology. Ethnopharmacology, the interdisciplinary study of traditionally used medicinal substances, provides a key framework for understanding TCM (Assadi et al., 2011). With its rich cultural heritage, TCM employs a diverse arsenal of plant-based remedies, minerals, and animal products to treat a wide range of diseases, including PPD. Consequently, the application of TCM in modern therapy, particularly for PPD, is gaining increasing attention as it may offer novel, multi-target mechanisms derived from these traditional practices.
Sugemule-7 is a TCM formulation composed of several botanical drugs, including Nutmeg (Myristica fatua Houtt. (Myristicaceae)), Amomum cardamomum L. (Zingiberaceae), Clove (Syzygium aromaticum (L.) Merr. and L.M. Perry (Myrtaceae)), Asparagus (Asparagus cochinchinensis (Lour.) Merr. (Asparagaceae)), Gymnadenia conopsea (L.). R. Br. (Orchidaceae), Aquilaria agallocha Roxb. (Thymelaeaceae), Siberian solomonseal rhizome (Polygonatum sibiricum Redouté (Asparagaceae)) (Shi et al., 2023). Research on its constituent botanical drugs, such as Myristica fragrans (nutmeg), has identified metabolites with neuroprotective, antioxidant, and anti-inflammatory properties (Barman et al., 2021; Valderrama, 2000). Preclinical studies suggest that the formulation Sugemule-7 might have potential in alleviating PPD, as indicated by mechanisms involving neuroprotection, reduction of oxidative stress and neuroinflammation, and enhancement of synaptic plasticity (Fu et al., 2025b).
Shen-Qi-Jie-Yu-Fang (SJF) is a TCM formulation composed of the following eight botanical drugs: Astragalus membranaceus (Fisch.) Bunge (Fabaceae), Codonopsis pilosula (Franch.) Nannf. (Campanulaceae), Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H.F. Chow (Rhamnaceae), Cornus officinalis Siebold & Zucc. (Cornaceae), Curcuma zedoaria (Christm.) Roscoe (Zingiberaceae), Citrus reticulata Blanco (Rutaceae), Citrus medica L. (Rutaceae), Angelica sinensis (Oliv.) Diels (Apiaceae). Activation of the T cell system has been linked to the susceptibility of emotional disorders (Drexhage et al., 2011). CD4+CD25+ regulatory T (Treg) cells, a subset of CD4+ T-helper cells, play a key role in inhibiting excessive T cell responses. Research indicates functional impairments between pro-inflammatory cytokines and regulatory T cells (Tregs) at various stages of PPD. Studies show that SJF and FLX may mitigate this functional impairment by controlling the expression of CD4+CD25+ Treg cells, gp130, IL-1RI, and the serum concentrations of IL-1β and IL-6 (Li et al., 2016). Moreover, soluble epoxide hydrolase (sEH) inhibitors can alleviate inflammatory responses by increasing the levels of Epoxyeicosatrienoic acids (EETs), thereby rapidly improving the depressive state of mice (Ren et al., 2016). By blocking the inflammatory signaling system in the hippocampal tissue of PPD rats specifically the arachidonic acid metabolic pathway and nuclear factor kappa-B (NF-κB), SJF appears to have an effect similar to that of sEH inhibitors, helping to reduce the symptoms of PPD (Jingya et al., 2024).
919 Granules is a nationally patented TCM formulation consisting of the following botanical drugs: Actinidia chinensis Planch. (Actinidiaceae), Salvia miltiorrhiza Bunge (Lamiaceae), Atractylodes macrocephala Koidz. (Asteraceae), Epimedium brevicornu Maxim. (Berberidaceae), Wolfiporia cocos (F.A. Wolf) Ryvarden & Gilb. (Polyporaceae), Bupleurum chinense DC. (Apiaceae), Schisandra chinensis (Turcz.) Baill. (Schisandraceae), Alpinia katsumadai Hayata (Zingiberaceae), C. reticulata (pericarp), and Pseudostellaria heterophylla (Miq.) Pax (Caryophyllaceae). Research into the mechanisms of 919 Granules has explored its potential interaction with various endogenous signaling pathways. For example, it is hypothesized that the formulation may influence the activity of anandamide, a fatty acid amide that, through its receptors, regulates processes such as angiogenesis (Bezuglov et al., 1998) and water homeostasis (Hamberger and Stenhagen, 2003). Another molecule of interest is 5-AVAB, a trimethyl molecule essential for the growth and development of the embryonic nervous system (Haikonen et al., 2022). Research suggests that 919 Syrup may help alleviate PPD by boosting 5-AVAB, reducing erucamide levels in the hippocampal region of mice, and increasing the diversity of gut bacteria, including Bacteroidetes and Lactobacillus (Zheng et al., 2023). Another study indicates that 919 Syrup regulates gut flora and modifies metabolites to enhance hippocampal GABA/glutamate system activity, thus reducing PPD symptoms (Tian et al., 2021). However, an excess of pro-inflammatory cytokines in peripheral blood can damage the blood-brain barrier (BBB) by triggering astrocyte activation and decreasing transendothelial resistance. This allows peripheral immune cells or cytokines to enter the brain, causing inflammation, which can, in turn, contribute to depression. Excessive levels of IL-1β have been shown to damage the BBB (Hauptmann et al., 2020; Argaw et al., 2006; Hu et al., 2022). 919 Granules have been shown to reduce PPD symptoms by controlling IL-1β levels (Wang et al., 2024). In summary, TCM formulas such as Sugemule-7, SJF, and 919 Granules have shown efficacy in alleviating PPD, and their effects involve various molecular mechanisms. However, further clarification is needed regarding the specific metabolites of these compounds, including identifying the key active metabolites and determining which metabolites can cross the BBB to exert therapeutic effects on the CNS (Figure 3; table 2).
Figure 3. Mechanisms of action of Natural products and traditional Chinese medicine formulas. TCM can exert antidepressant effects in PPD through relevant targets and signalling pathways, including enhancing neuroplasticity, alleviating neuroinflammation, modulating monoamine neurotransmitters, regulating oxidative stress, stabilizing the HPA axis, protecting the blood-brain barrier, and maintaining the gut-brain axis balance. These actions further contribute to the treatment of PPD by relieving symptoms via appropriate pathological mechanisms.
Table 2. Information on the effects of natural products and TCM formulas.
6 Discussion
PPD is a common emotional disorder that poses significant risks to both the mother’s and child’s physical and mental wellbeing. Despite its prevalence, the pathophysiology of PPD remains unclear, and there are currently no fully effective intervention strategies to prevent or completely reverse the condition. These challenges represent a persistent issue in contemporary clinical practice. Preclinical evidence summarized in this review suggests the therapeutic potential of certain TCM formulations and metabolites for PPD management, primarily mediated through multiple pathways including neuroinflammation and the MGB axis. Such a multi-target approach is consistent with the principles of network pharmacology. However, translating these promising findings into clinical practice faces substantial challenges. Therefore, a key area of current research should focus on leveraging the unique advantages of TCM while compensating for the single-target limitations of conventional pharmacotherapy. Conducting in-depth research into multi-target therapies for PPD, with a goal of achieving effects similar to modern “cocktail therapy”, should be a priority. This topic is not only of scientific importance but also a growing area of social concern.
The current preclinical evidence base for many botanical drugs and their characterized metabolites in PPD has critical limitations that hinder clinical translation. This body of evidence largely depends on animal and in vitro models, lacks robust clinical validation, and carries insufficient safety data, particularly for lactating women. Firstly, from the perspective of research methodology, most preclinical studies exhibit deficiencies in plant material identification, extract standardization, and experimental reporting. According to the ConPhyMP guidelines (Heinrich et al., 2022), research reproducibility depends on the standardized documentation of plant species, extraction processes, and chemical composition. However, a considerable proportion of studies in this field do not adhere to these fundamental standards. This lack of adherence severely undermines the credibility and comparability of the reported findings. Additionally, the physicochemical properties of certain metabolites from these botanical drugs, such as low bioavailability, poor chemical stability, and limited BBB penetration, significantly hinder their ability to reach the CNS. Furthermore, the heterogeneity in the cultivation conditions of raw botanical materials, non-standardized processing methods, and substantial batch-to-batch variations in metabolite concentrations pose challenges for maintaining quality control. These inconsistencies not only restrict the clinical applicability of botanical drug-based interventions but also complicate efforts to understand the mechanisms underlying their putative effects.
More importantly, any bioactive substance can have both pharmacological effects and off-target effects on normal tissues (Guo et al., 2023). The metabolites derived from botanical drugs used in TCM are no exception and carry potential toxicological risks and side effects (Bernstein et al., 2021). However, comprehensive assessments of the side effects and long-term risks associated with these metabolites are still lacking in the literature, especially concerning their impact on healthy tissues when multiple constituents are combined. However, the existing literature severely lacks systematic safety assessments adhering to the ConPhyMP framework. This guideline emphasizes that toxicological assessments of plant extracts and their metabolites should be regarded as equally important as pharmacodynamic studies, particularly during the lactation period—a physiologically sensitive stage. At present, research on the off-target effects, chronic toxicity, and potential risks arising from the synergistic interactions among multiple constituents of TCM remains almost nonexistent, which constitutes one of the major barriers to its clinical translation. One of the major obstacles hindering the clinical translation of active metabolites from TCM is the absence of a systematic safety evaluation framework.
Future studies should focus on the following areas to overcome existing bottlenecks:
1. Rigorous evaluation of efficacy and safety through large-scale, multi-center, randomized double-blind placebo-controlled trials to assess the effects of characterized TCM metabolites and formulations on PPD patients; (2) Integrate single-cell sequencing, spatial multi-omics techniques, and systems biology methods to deepen multidimensional mechanism analysis, revealing the core system interaction network and multi-target mechanisms of TCM interventions; (3) Develop personalized treatment plans based on biomarkers and explore the optimization and integration of precision interventions alongside nonpharmacological interventions; (4) Development of novel intelligent targeted delivery technologies (e.g., cell-penetrating peptides or multifunctional nanocarriers with active targeting ligands) to overcome the poor CNS delivery of active TCM metabolites. (5) Establishment of a standardized quality control system covering the entire supply chain of botanical drugs. In future basic research, strict adherence to international consensus guidelines such as ConPhyMP is essential. This requires standardization at every stage, from material traceability and chemical characterization of extracts to the reporting of pharmacological and toxicological data. Such rigorous practices are fundamental for generating high-quality, reproducible evidence and laying a solid foundation for clinical translation. By integrating these strategies, it is expected that we will gain a clearer understanding of the scientific basis of TCM in preventing and treating PPD, thereby providing a theoretical foundation for the development of safe and effective new therapies, facilitating their industrial transformation and clinical application, and ultimately improving maternal and infant health outcomes.
Author contributions
RS: Writing – original draft. YL: Writing – review and editing. HG: Writing – review and editing. XZ: Writing – review and editing. XY: Writing – review and editing. GL: Writing – review and editing.
Funding
The authors declare that financial support was received for the research and/or publication of this article. This work was supported by the 2025 Shandong University of Traditional Chinese Medicine Graduate Quality Improvement and Innovation Program (YJSTZCX2025020 and YJSTZCX2025166), Qilu Biancang TCM Talent Cultivation Project (Lu Wei Han [2024] No. 78), Postdoctoral Fellowship Program (Grade) of China Postdoctoral Science Foundation under Grant Number GZB20240036, Peking University Medical Youth Science and Technology Innovation Yangfan Programme (BMU2025YFJHPY006), The Fundamental Research Funds for the Central Universities.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Generative AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Ahmed, H., Leyrolle, Q., Koistinen, V., Kärkkäinen, O., Layé, S., Delzenne, N., et al. (2022). Microbiota-derived metabolites as drivers of gut–brain communication. Gut Microbes 14, 2102878. doi:10.1080/19490976.2022.2102878
Amin, N., Hussein, A. B., Ye, Q., Chen, S., Wu, F., Yuan, X., et al. (2025). Combination of rTMS and oxytocin agonist attenuate depression-like behavior after postpartum depression in mice. Brain Res. 1851, 149459. doi:10.1016/j.brainres.2025.149459
Anokye, R., Acheampong, E., Budu-Ainooson, A., Obeng, E. I., and Akwasi, A. G. (2018). Prevalence of postpartum depression and interventions utilized for its management. Ann. Gen. Psychiatry 17, 18. doi:10.1186/s12991-018-0188-0
Argaw, A. T., Zhang, Y., Snyder, B. J., Zhao, M. L., Kopp, N., Lee, S. C., et al. (2006). IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J. Immunol. 177, 5574–5584. doi:10.4049/jimmunol.177.8.5574
Assadi, A., Zarrindast, M. R., Jouyban, A., and Samini, M. (2011). Comparing of the effects of hypericin and synthetic antidepressants on the expression of morphine-induced conditioned place preference. Iran. J. Pharm. Res. 10, 916–926.
Barman, R., Bora, P. K., Saikia, J., Kemprai, P., Saikia, S. P., Haldar, S., et al. (2021). Nutmegs and wild nutmegs: an update on ethnomedicines, phytochemicals, pharmacology, and toxicity of the Myristicaceae species. Phytother. Res. 35, 4632–4659. doi:10.1002/ptr.7098
Bashiri, H., Houwing, D. J., Homberg, J. R., and Salari, A. A. (2021). The combination of fluoxetine and environmental enrichment reduces postpartum stress-related behaviors through the oxytocinergic system and HPA axis in mice. Sci. Rep. 11, 8518. doi:10.1038/s41598-021-87800-z
Benlakehal, R., Gaetano, A., Charlet, R., Bouwalerh, H., Cogez, V., Harduin-Lepers, A., et al. (2025). Probiotic L. reuteri treatment in stressed rats improves maternal care and corrects corticosterone-BDNF-oxytocin balance offering insights for maternal postpartum distress treatment. Sci. Rep. 15, 23544. doi:10.1038/s41598-025-05848-7
Bernstein, N., Akram, M., Yaniv-Bachrach, Z., and Daniyal, M. (2021). Is it safe to consume traditional medicinal plants during pregnancy? Phytother. Res. 35, 1908–1924. doi:10.1002/ptr.6935
Bezuglov, V. V., Bobrov, M. Yu, and Archakov, A. V. (1998). Bioactive amides of fatty acids. Biochem. (Mosc) 63 (1), 22–30.
Blecker, M. K., Klusmann, H., Engel, S., Haering, S., Meyer, C., Skoluda, N., et al. (2025). The predictive role of childhood maltreatment for long-term HPA axis regulation, chronic stress and postpartum depression. J. Affect Disord. 391, 119914. doi:10.1016/j.jad.2025.119914
Brockmöller, J., Reum, T., Bauer, S., Kerb, R., Hübner, W. D., and Roots, I. (1997). Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 30, 94–101. doi:10.1055/s-2007-979527
Butterweck, V., and Schmidt, M. (2007). St. John’s wort: role of active compounds for its mechanism of action and efficacy. Wien Med. Wochenschr 157, 356–361. doi:10.1007/s10354-007-0440-8
Calabrese, E. J., Mattson, M. P., and Calabrese, V. (2010). Resveratrol commonly displays hormesis: occurrence and biomedical significance. Hum. Exp. Toxicol. 29, 980–1015. doi:10.1177/0960327110383625
Chakrawarti, L., Agrawal, R., Dang, S., Gupta, S., and Gabrani, R. (2016). Therapeutic effects of EGCG: a patent review. Expert Opin. Ther. Pat. 26, 907–916. doi:10.1080/13543776.2016.1203419
Chatsudthipong, V., and Muanprasat, C. (2009). Stevioside and related compounds: therapeutic benefits beyond sweetness. Pharmacol. Ther. 121, 41–54. doi:10.1016/j.pharmthera.2008.09.007
Chen, J., Zhu, W., Zeng, X., Yang, K., Peng, H., and Hu, L. (2022). Paeoniflorin exhibits antidepressant activity in rats with postpartum depression via the TSPO and BDNFmTOR pathways. Acta Neurobiol. Exp. (Wars). 82, 347–357. doi:10.55782/ane-2022-033
Chen, S., Wang, K., Wang, H., Gao, Y., Nie, K., Jiang, X., et al. (2024a). The therapeutic effects of saikosaponins on depression through the modulation of neuroplasticity: from molecular mechanisms to potential clinical applications. Pharmacol. Res. 201, 107090. doi:10.1016/j.phrs.2024.107090
Chen, G., Zhang, Y., Li, R., Jin, L., Hao, K., Rong, J., et al. (2024b). Environmental enrichment attenuates depressive-like behavior in maternal rats by inhibiting neuroinflammation and apoptosis and promoting neuroplasticity. Neurobiol. Stress 30, 100624. doi:10.1016/j.ynstr.2024.100624
Chen, Q., Xu, F., Wu, H., Xie, L., Li, H., Jiao, C., et al. (2025). Inhibition of semaphorin 3A in hippocampus alleviates postpartum depression-like behaviors in mice. Mol. Neurobiol. 62, 7723–7737. doi:10.1007/s12035-025-04752-5
Choi, J.-E., Kim, E.-Y., and Park, Y. (2020). N-3 PUFA improved pup separation-induced postpartum depression via serotonergic pathway regulated by miRNA. J. Nutr. Biochem. 84, 108417. doi:10.1016/j.jnutbio.2020.108417
Ciolac, L., Bernad, E. S., Tudor, A., Nițu, D. R., Buleu, F., Popa, D. I., et al. (2025). Postpartum depression: interacting biological pathways and the promising validation of blood-based biomarkers. J. Clin. Med. 14, 4286. doi:10.3390/jcm14124286
Costa, B., Da Pozzo, E., and Martini, C. (2012). Translocator protein as a promising target for novel anxiolytics. Curr. Top. Med. Chem. 12, 270–285. doi:10.2174/156802612799078720
Datta, A., Saha, C., Godse, P., Sharma, M., Sarmah, D., and Bhattacharya, P. (2023). Neuroendocrine regulation in stroke. Trends Endocrinol. Metab. 34, 260–277. doi:10.1016/j.tem.2023.02.005
De Rezende, M. G., Rosa, C. E., Garcia-Leal, C., de Figueiredo, F. P., Cavalli, R. d. C., Bettiol, H., et al. (2018). Correlations between changes in the hypothalamic-pituitary-adrenal axis and neurochemistry of the anterior cingulate gyrus in postpartum depression. J. Affect Disord. 239, 274–281. doi:10.1016/j.jad.2018.07.028
Dereli, F. T. G., Ilhan, M., and Akkol, E. K. (2019). New drug discovery from medicinal plants and phytoconstituents for depressive disorders. CNS Neurol. Disord. Drug Targets 18, 92–102. doi:10.2174/1871527317666181114141129
Donald, K., and Finlay, B. B. (2023). Early-life interactions between the microbiota and immune system: impact on immune system development and atopic disease. Nat. Rev. Immunol. 23, 735–748. doi:10.1038/s41577-023-00874-w
Drexhage, R. C., Hoogenboezem, T. H., Versnel, M. A., Berghout, A., Nolen, W. A., and Drexhage, H. A. (2011). The activation of monocyte and T cell networks in patients with bipolar disorder. Brain Behav. Immun. 25, 1206–1213. doi:10.1016/j.bbi.2011.03.013
Erickson, K. I., Miller, D. L., and Roecklein, K. A. (2012). The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist 18, 82–97. doi:10.1177/1073858410397054
Farzaei, M. H., Zobeiri, M., Parvizi, F., El-Senduny, F. F., Marmouzi, I., Coy-Barrera, E., et al. (2018). Curcumin in liver diseases: a systematic review of the cellular mechanisms of oxidative stress and clinical perspective. Nutrients 10, 855. doi:10.3390/nu10070855
Feldman, R., Granat, A., Pariente, C., Kanety, H., Kuint, J., and Gilboa-Schechtman, E. (2009). Maternal depression and anxiety across the postpartum year and infant social engagement, fear regulation, and stress reactivity. J. Am. Acad. Child. Adolesc. Psychiatry 48, 919–927. doi:10.1097/CHI.0b013e3181b21651
Fox, M., Sandman, C. A., Davis, E. P., and Glynn, L. M. (2018). A longitudinal study of women’s depression symptom profiles during and after the postpartum phase. Depress Anxiety 35, 292–304. doi:10.1002/da.22719
Fu, Q., Qiu, R., Yao, T., Liu, L., Li, Y., Li, X., et al. (2025a). Music therapy as a preventive intervention for postpartum depression: modulation of synaptic plasticity, oxidative stress, and inflammation in a mouse model. Transl. Psychiatry 15, 143. doi:10.1038/s41398-025-03370-y
Fu, Q., Qiu, R., Liang, J., Wu, S., Huang, D., Qin, Y., et al. (2025b). Sugemule-7 alleviates oxidative stress, neuroinflammation, and cell death, promoting synaptic plasticity recovery in mice with postpartum depression. Sci. Rep. 15, 1426. doi:10.1038/s41598-025-85276-9
Garcia, K. S., Flynn, P., Pierce, K. J., and Caudle, M. (2010). Repetitive transcranial magnetic stimulation treats postpartum depression. Brain Stimul. 3, 36–41. doi:10.1016/j.brs.2009.06.001
Gartlehner, G., Hansen, R. A., Carey, T. S., Lohr, K. N., Gaynes, B. N., and Randolph, L. C. (2005). Discontinuation rates for selective serotonin reuptake inhibitors and other second-generation antidepressants in outpatients with major depressive disorder: a systematic review and meta-analysis. Int. Clin. Psychopharmacol. 20, 59–69. doi:10.1097/00004850-200503000-00001
Getachew, B., Aubee, J. I., Schottenfeld, R. S., Csoka, A. B., Thompson, K. M., and Tizabi, Y. (2018). Ketamine interactions with gut-microbiota in rats: relevance to its antidepressant and anti-inflammatory properties. BMC Microbiol. 18, 222. doi:10.1186/s12866-018-1373-7
Grundmann, O., Kelber, O., and Butterweck, V. (2006). Effects of st. John’s wort extract and single constituents on stress-induced hyperthermia in mice. Planta Med. 72, 1366–1371. doi:10.1055/s-2006-951710
Guintivano, J., Arad, M., Gould, T. D., Payne, J. L., and Kaminsky, Z. A. (2014). Antenatal prediction of postpartum depression with blood DNA methylation biomarkers. Mol. Psychiatry 19, 560–567. doi:10.1038/mp.2013.62
Guintivano, J., Byrne, E. M., Kiewa, J., Yao, S., Bauer, A. E., Aberg, K. A., et al. (2023). Meta-analyses of genome-wide association studies for postpartum depression. Am. J. Psychiatry 180, 884–895. doi:10.1176/appi.ajp.20230053
Guo, C., Huang, Q., Wang, Y., Yao, Y., Li, J., Chen, J., et al. (2023). Therapeutic application of natural products: NAD+ metabolism as potential target. Phytomedicine 114, 154768. doi:10.1016/j.phymed.2023.154768
Haikonen, R., Kärkkäinen, O., Koistinen, V., and Hanhineva, K. (2022). Diet- and microbiota-related metabolite, 5-aminovaleric acid betaine (5-AVAB), in health and disease. Trends Endocrinol. Metab. 33, 463–480. doi:10.1016/j.tem.2022.04.004
Haile, C. N., Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Foulkes, A., et al. (2014). Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. Int. J. Neuropsychopharmacol. 17, 331–336. doi:10.1017/S1461145713001119
Halligan, S. L., Murray, L., Martins, C., and Cooper, P. J. (2007). Maternal depression and psychiatric outcomes in adolescent offspring: a 13-year longitudinal study. J. Affect Disord. 97, 145–154. doi:10.1016/j.jad.2006.06.010
Hamberger, A., and Stenhagen, G. (2003). Erucamide as a modulator of water balance: new function of a fatty acid amide. Neurochem. Res. 28, 177–185. doi:10.1023/A:1022364830421
Hamlbar, E. P., Mirghafourvand, M., Shaseb, E., and Kamalifard, M. (2025). The effect of curcumin on postpartum depression and anxiety in primiparous women: a double-blind randomized placebo-controlled clinical trial. BMC Complement. Med. Ther. 25, 157. doi:10.1186/s12906-025-04798-x
Hartmann, J., Dedic, N., Pöhlmann, M. L., Häusl, A., Karst, H., Engelhardt, C., et al. (2017). Forebrain glutamatergic, but not GABAergic, neurons mediate anxiogenic effects of the glucocorticoid receptor. Mol. Psychiatry 22, 466–475. doi:10.1038/mp.2016.87
Hauptmann, J., Johann, L., Marini, F., Kitic, M., Colombo, E., Mufazalov, I. A., et al. (2020). Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood–brain barrier. Acta Neuropathol. 140, 549–567. doi:10.1007/s00401-020-02187-x
Heinrich, M., Jalil, B., Abdel-Tawab, M., Echeverria, J., Kulić, Ž., McGaw, L. J., et al. (2022). Best Practice in the chemical characterisation of extracts used in pharmacological and toxicological research-The ConPhyMP-Guidelines. Front. Pharmacol. 13, 953205. doi:10.3389/fphar.2022.953205
Hellgren, C., Åkerud, H., Skalkidou, A., Bäckström, T., and Sundström-Poromaa, I. (2014). Low serum allopregnanolone is associated with symptoms of depression in late pregnancy. Neuropsychobiology 69, 147–153. doi:10.1159/000358838
Hu, S., Lee, H., Zhao, H., Ding, Y., and Duan, J. (2022). Inflammation and severe cerebral venous thrombosis. Front. Neurol. 13, 873802. doi:10.3389/fneur.2022.873802
Jingya, L., Song, L., Lu, L., Zhang, Q., and Zhang, W. (2024). Effect of shenqi jieyu formula on inflammatory response pathway in hippocampus of postpartum depression rats. Heliyon 10, e29978. doi:10.1016/j.heliyon.2024.e29978
Jones, K., Smith, S., Smith, J., Castillo, A., Burkes, A., Howard, A., et al. (2025). Postpartum dams exposed to a low-resource environment display neuroinflammation, elevated corticosterone, and anhedonia-like behavior. J. Appl. Physiol. 138, 666–680. doi:10.1152/japplphysiol.00871.2024
Kashkouli, M., Jahanian Sadatmahalleh, S., Ziaei, S., Kazemnejad, A., Saber, A., Darvishnia, H., et al. (2023). Relationship between postpartum depression and plasma vasopressin level at 6–8 weeks postpartum: a cross-sectional study. Sci. Rep. 13, 3518. doi:10.1038/s41598-022-27223-6
Köhler-Forsberg, O., N Lydholm, C., Hjorthøj, C., Nordentoft, M., Mors, O., and Benros, M. E. (2019). Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: Meta-analysis of clinical trials. Acta Psychiatr. Scand. 139, 404–419. doi:10.1111/acps.13016
Kolding, L., Pedersen, L. H., Henriksen, T. B., Olsen, J., and Grzeskowiak, L. E. (2015). Hypericum perforatum use during pregnancy and pregnancy outcome. Reprod. Toxicol. 58, 234–237. doi:10.1016/j.reprotox.2015.10.003
Kunnumakkara, A. B., Bordoloi, D., Padmavathi, G., Monisha, J., Roy, N. K., Prasad, S., et al. (2017). Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br. J. Pharmacol. 174, 1325–1348. doi:10.1111/bph.13621
Lan, J., Zhou, Y., Deng, L., Liu, H., Hong, W., Jing, R., et al. (2025). Epigenetic regulation of ferroptosis by the KDM3A/BRPF1 transcriptional axis confers neuroprotection in postpartum depression mouse model. J. Affect Disord. 388, 119690. doi:10.1016/j.jad.2025.119690
Lener, M. S., Niciu, M. J., Ballard, E. D., Park, M., Park, L. T., Nugent, A. C., et al. (2017). Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine. Biol. Psychiatry 81, 886–897. doi:10.1016/j.biopsych.2016.05.005
Li, J., Zhao, R., Li, X., Sun, W., Qu, M., Tang, Q., et al. (2016). Shen-Qi-Jie-Yu-Fang exerts effects on a rat model of postpartum depression by regulating inflammatory cytokines and CD4+CD25+ regulatory T cells. Neuropsychiatr. Dis. Treat. 12, 883–896. doi:10.2147/NDT.S98131
Li, J., Huang, S., Huang, W., Wang, W., Wen, G., Gao, L., et al. (2017). Paeoniflorin ameliorates interferon-alpha-induced neuroinflammation and depressive-like behaviors in mice. Oncotarget 8, 8264–8282. doi:10.18632/oncotarget.14160
Lin, B., Zheng, N., Li, B., Wang, W., Luo, T., Fan, Y., et al. (2025). Dim light at night induces depression-like behaviors during the postpartum period through circadian rhythm related pathways in mice. Transl. Psychiatry 15, 191. doi:10.1038/s41398-025-03405-4
Lindahl, V., Pearson, J. L., and Colpe, L. (2005). Prevalence of suicidality during pregnancy and the postpartum. Arch. Womens Ment. Health 8, 77–87. doi:10.1007/s00737-005-0080-1
Liu, Z., Li, L., Ma, S., Ye, J., Zhang, H., Li, Y., et al. (2020). High-dietary fiber intake alleviates antenatal obesity-induced postpartum depression: roles of gut microbiota and microbial metabolite short-chain fatty acid involved. J. Agric. Food Chem. 68, 13697–13710. doi:10.1021/acs.jafc.0c04290
Liu, X., Wang, S., and Wang, G. (2022). Prevalence and risk factors of postpartum depression in women: a systematic review and meta-analysis. J. Clin. Nurs. 31, 2665–2677. doi:10.1111/jocn.16121
Liu, L., Wang, H., Chen, X., Zhang, Y., Zhang, H., and Xie, P. (2023). Gut microbiota and its metabolites in depression: from pathogenesis to treatment. EBioMedicine 90, 104527. doi:10.1016/j.ebiom.2023.104527
Lloyd-Jones, D. M., Allen, N. B., Anderson, C. A. M., Black, T., Brewer, L. C., Foraker, R. E., et al. (2022). Life’s essential 8: updating and enhancing the American Heart Association’s construct of cardiovascular health: a presidential advisory from the American Heart Association. Circulation 146, e18–e43. doi:10.1161/CIR.0000000000001078
Maguire, J., and Mody, I. (2008). GABAAR plasticity during pregnancy: relevance to postpartum depression. Neuron 59, 207–213. doi:10.1016/j.neuron.2008.06.019
Manetti, M., Rosa, I., Fioretto, B. S., Matucci-Cerinic, M., and Romano, E. (2022). Decreased serum levels of SIRT1 and SIRT3 correlate with severity of skin and lung fibrosis and peripheral microvasculopathy in systemic sclerosis. J. Clin. Med. 11, 1362. doi:10.3390/jcm11051362
Burt, T., Matthews, J., and Weiss, A. P. (1999). Mania associated with st. John's wort. Biol. Psychiatry 46, 1707–1708. doi:10.1016/S0006-3223(99)00233-4
Meltzer-Brody, S., Colquhoun, H., Riesenberg, R., Epperson, C. N., Deligiannidis, K. M., Rubinow, D. R., et al. (2018). Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet 392, 1058–1070. doi:10.1016/S0140-6736(18)31551-4
Moreno-Jiménez, E. P., Terreros-Roncal, J., Flor-García, M., Rábano, A., and Llorens-Martín, M. (2021). Evidences for adult hippocampal neurogenesis in humans. J. Neurosci. 41, 2541–2553. doi:10.1523/jneurosci.0675-20.2020
Moretti, M. E., Maxson, A., Hanna, F., and Koren, G. (2009). Evaluating the safety of st. John’s wort in human pregnancy. Reprod. Toxicol. 28, 96–99. doi:10.1016/j.reprotox.2009.02.003
Murray, L. (1992). The impact of postnatal depression on infant development. J. Child. Psychol. Psychiatry 33, 543–561. doi:10.1111/j.1469-7610.1992.tb00890.x
Murray, L., and Cooper, P. J. (1997a). Effects of postnatal depression on infant development. Arch. Dis. Child. 77, 99–101. doi:10.1136/adc.77.2.99
Murray, L., and Cooper, P. J. (1997b). EDITORIAL: postpartum depression and child development. Psychol. Med. 27, 253–260. doi:10.1017/S0033291796004564
Nel, N. H., Marafie, A., Bassis, C. M., Sugino, K. Y., Nzerem, A., Knickmeyer, R. R., et al. (2025). Edinburgh postpartum depression scores are associated with vaginal and gut microbiota in pregnancy. J. Affect Disord. 371, 22–35. doi:10.1016/j.jad.2024.10.086
Nie, X., Kitaoka, S., Tanaka, K., Segi-Nishida, E., Imoto, Y., Ogawa, A., et al. (2018). The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation. Neuron 99, 464–479.e7. doi:10.1016/j.neuron.2018.06.035
Osborne, M. T., Shin, L. M., Mehta, N. N., Pitman, R. K., Fayad, Z. A., and Tawakol, A. (2020). Disentangling the links between psychosocial stress and cardiovascular disease. Circ. Cardiovasc Imaging 13, e010931. doi:10.1161/CIRCIMAGING.120.010931
Ou, X., Yu, Z., Pan, C., Zheng, X., Li, D., Qiao, Z., et al. (2025). Paeoniflorin: a review of its pharmacology, pharmacokinetics and toxicity in diabetes. Front. Pharmacol. 16, 1551368. doi:10.3389/fphar.2025.1551368
Özdamar, Ü. G., Hekimler Öztürk, K., Erkılınç, G., Dönmez, F., Kumbul Doğuç, D., Özmen, Ö., et al. (2022). Maternal prenatal stress and depression-like behavior associated with hippocampal and cortical neuroinflammation in the offspring: an experimental study. Int. J. Dev. Neurosci. 82, 231–242. doi:10.1002/jdn.10176
Patterson, R., Balan, I., Morrow, A. L., and Meltzer-Brody, S. (2024). Novel neurosteroid therapeutics for post-partum depression: perspectives on clinical trials, program development, active research, and future directions. Neuropsychopharmacology 49, 67–72. doi:10.1038/s41386-023-01721-1
Payne, J. L., and Maguire, J. (2019). Pathophysiological mechanisms implicated in postpartum depression. Front. Neuroendocrinol. 52, 165–180. doi:10.1016/j.yfrne.2018.12.001
Pham, T. H., and Gardier, A. M. (2019). Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies. Pharmacol. Ther. 199, 58–90. doi:10.1016/j.pharmthera.2019.02.017
Ramsteijn, A. S., Jašarević, E., Houwing, D. J., Bale, T. L., and Olivier, J. D. (2020). Antidepressant treatment with fluoxetine during pregnancy and lactation modulates the gut microbiome and metabolome in a rat model relevant to depression. Gut Microbes 11, 735–753. doi:10.1080/19490976.2019.1705728
Ren, Q., Ma, M., Ishima, T., Morisseau, C., Yang, J., Wagner, K. M., et al. (2016). Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress. Proc. Natl. Acad. Sci. U. S. A. 113, E1944–E1952. doi:10.1073/pnas.1601532113
Ren, Z., Wang, M., Aldhabi, M., Zhang, R., Liu, Y., Liu, S., et al. (2022). Low-dose S-ketamine exerts antidepressant-like effects via enhanced hippocampal synaptic plasticity in postpartum depression rats. Neurobiol. Stress 16, 100422. doi:10.1016/j.ynstr.2021.100422
Ren, P., Wang, J.-Y., Chen, H.-L., Wang, Y., Cui, L. Y., Duan, J. Y., et al. (2024). Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus. J. Pharmacol. Sci. 154, 236–245. doi:10.1016/j.jphs.2024.02.003
Rodríguez-Landa, J. F., and Contreras, C. M. (2003). A review of clinical and experimental observations about antidepressant actions and side effects produced by hypericum perforatum extracts. Phytomedicine 10, 688–699. doi:10.1078/0944-7113-00340
Rupprecht, R., Rammes, G., Eser, D., Baghai, T. C., Schüle, C., Nothdurfter, C., et al. (2009). Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science 325, 490–493. doi:10.1126/science.1175055
Sadeghi-Bahmani, D., Brand, S., Meinlschmidt, G., Tegethoff, M., Kurath, J., Bürki, N., et al. (2025). Prepartal stress, prepartal and postpartal hair glucocorticoid concentrations, and symptoms of postpartum depression 3 days and 12 weeks after delivery. Biol. Psychiatry Glob. Open Sci. 5, 100454. doi:10.1016/j.bpsgos.2025.100454
Seth, S., Lewis, A. J., and Galbally, M. (2016). Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: a systematic literature review. BMC Pregnancy Childbirth 16, 124. doi:10.1186/s12884-016-0915-y
Shao, Y., Xu, X., Wang, K., Qi, X. M., and Wu, Y. G. (2017). Paeoniflorin attenuates incipient diabetic nephropathy in streptozotocin-induced mice by the suppression of the toll-like receptor-2 signaling pathway. Drug Des. Devel Ther. 11, 3221–3233. doi:10.2147/DDDT.S149504
Sheng, Z., Liu, Q., Lin, R., Zhao, Y., Liu, W., Xu, Z., et al. (2023). Potential CSF biomarkers of postpartum depression following delivery via caesarian section. J. Affect Disord. 342, 177–181. doi:10.1016/j.jad.2023.09.021
Sheng, Z., Liu, Q., Song, Y., Ye, B., Li, Y., Song, Y., et al. (2024). Astrocyte atrophy induced by L-PGDS/PGD2/src signaling dysfunction in the central amygdala mediates postpartum depression. J. Affect Disord. 359, 241–252. doi:10.1016/j.jad.2024.05.083
Shi, X.-J., Du, Y., Chen, L., Luo, M., and Cheng, Y. (2023). Treatment of polycystic ovary syndrome and its associated psychiatric symptoms with the mongolian medicine nuangong qiwei pill and macelignan. J. Ethnopharmacol. 317, 116812. doi:10.1016/j.jep.2023.116812
Slykerman, R. F., Hood, F., Wickens, K., Thompson, J. M. D., Barthow, C., Murphy, R., et al. (2017). Effect of lactobacillus rhamnosus HN001 in pregnancy on postpartum symptoms of depression and anxiety: a randomised double-blind placebo-controlled trial. EBioMedicine 24, 159–165. doi:10.1016/j.ebiom.2017.09.013
Smith, S. S., Shen, H., Gong, Q. H., and Zhou, X. (2007). Neurosteroid regulation of GABA(A) receptors: focus on the alpha4 and delta subunits. Pharmacol. and Ther. 116, 58–76. doi:10.1016/j.pharmthera.2007.03.008
Smith-Apeldoorn, S. Y., Veraart, J. K., Spijker, J., Kamphuis, J., and Schoevers, R. A. (2022). Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Lancet Psychiatry 9, 907–921. doi:10.1016/S2215-0366(22)00317-0
Soleimani, V., Sahebkar, A., and Hosseinzadeh, H. (2018). Turmeric (curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: review. Phytother. Res. 32, 985–995. doi:10.1002/ptr.6054
Song, X., Wang, W., Ding, S., Wang, Y., Ye, L., Chen, X., et al. (2022). Exploring the potential antidepressant mechanisms of puerarin: Anti-inflammatory response via the gut-brain axis. J. Affect Disord. 310, 459–471. doi:10.1016/j.jad.2022.05.044
Stewart, D. E., and Vigod, S. N. (2019). Postpartum depression: pathophysiology, treatment, and emerging therapeutics. Annu. Rev. Med. 70, 183–196. doi:10.1146/annurev-med-041217-011106
Sun, Y., Fan, C., and Lei, D. (2024). Association between gut microbiota and postpartum depression: a bidirectional mendelian randomization study. J. Affect Disord. 362, 615–622. doi:10.1016/j.jad.2024.07.057
Tang, M., Dang, R., Liu, S., Zhang, M., Zheng, Y., Yang, R., et al. (2018a). Ω-3 fatty acids-supplementary in gestation alleviates neuroinflammation and modulates neurochemistry in rats. Lipids Health Dis. 17, 247. doi:10.1186/s12944-018-0894-2
Tang, M., Liu, Y., Wang, L., Li, H., Cai, H., Zhang, M., et al. (2018b). An Ω-3 fatty acid-deficient diet during gestation induces depressive-like behavior in rats: the role of the hypothalamo–pituitary–adrenal (HPA) system. Food Funct. 9, 3481–3488. doi:10.1039/C7FO01714F
Tian, X.-Y., Xing, J.-W., Zheng, Q.-Q., and Gao, P. F. (2021). 919 syrup alleviates postpartum depression by modulating the structure and metabolism of gut microbes and affecting the function of the hippocampal GABA/glutamate system. Front. Cell Infect. Microbiol. 11, 694443. doi:10.3389/fcimb.2021.694443
Ushiroyama, T., Sakuma, K., and Ueki, M. (2005). Efficacy of the kampo medicine xiong-gui-tiao-xue-yin (kyuki-chouketsu-in), a traditional herbal medicine, in the treatment of maternity blues syndrome in the postpartum period. Am. J. Chin. Med. 33, 117–126. doi:10.1142/S0192415X05002710
Valderrama, J. C. (2000). Distribution of flavonoids in the Myristicaceae. Phytochemistry 55, 505–511. doi:10.1016/s0031-9422(00)00114-x
Van Battum, E. Y., Brignani, S., and Pasterkamp, R. J. (2015). Axon guidance proteins in neurological disorders. Lancet Neurol. 14, 532–546. doi:10.1016/S1474-4422(14)70257-1
Walle, T., Hsieh, F., DeLegge, M. H., Oatis, J. E., and Walle, U. K. (2004). High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos. 32, 1377–1382. doi:10.1124/dmd.104.000885
Wang, M. (2011). Neurosteroids and GABA-a receptor function. Front. Endocrin 2, 44. doi:10.3389/fendo.2011.00044
Wang, J., Li, J., Cao, N., Li, Z., Han, J., and Li, L. (2018). Resveratrol, an activator of SIRT1, induces protective autophagy in non-small-cell lung cancer via inhibiting akt/mTOR and activating p38-MAPK. Onco Targets Ther. 11, 7777–7786. doi:10.2147/OTT.S159095
Wang, J., Yun, Q., Ma, S.-F., Song, H. R., Guo, M. N., and Zhang, W. N. (2020). Inhibition of expression of glucocorticoids receptors may contribute to postpartum depression. Biochem. Biophys. Res. Commun. 523, 159–164. doi:10.1016/j.bbrc.2019.12.040
Wang, S., Zhao, Y., Yang, Z., Liu, Y., Xu, R., Tu, R., et al. (2024). 919 granules improve postpartum depression through the regulation of abnormal peripheral blood IL-1β. Biomed. Pharmacother. 174, 116623. doi:10.1016/j.biopha.2024.116623
Woelk, H., Burkard, G., and Grünwald, J. (1994). Benefits and risks of the hypericum extract LI 160: drug monitoring study with 3250 patients. J. Geriatr. Psychiatry Neurol. 7, 34–38. doi:10.1177/089198879400701s10
Wu, Z., Zhou, L., Sun, L., Xie, Y., Xiao, L., Wang, H., et al. (2021). Brief postpartum separation from offspring promotes resilience to lipopolysaccharide challenge-induced anxiety and depressive-like behaviors and inhibits neuroinflammation in C57BL/6J dams. Brain Behav. Immun. 95, 190–202. doi:10.1016/j.bbi.2021.03.016
Xie, H., Jiang, Y., Zhang, X., Min, X., Zeng, J., Chen, L., et al. (2025). Corticosterone-induced postpartum depression induces depression-like behavior and impairs hippocampal neurogenesis in adolescent offspring via HPA axis and BDNF-mTOR pathway. Neurobiol. Stress 34, 100708. doi:10.1016/j.ynstr.2025.100708
Xu, F., Wu, H., Xie, L., Chen, Q., Xu, Q., Sun, L., et al. (2023). Epigallocatechin-3-gallate alleviates gestational stress-induced postpartum anxiety and depression-like behaviors in mice by downregulating semaphorin3A and promoting GSK3β phosphorylation in the hippocampus. Front. Mol. Neurosci. 15, 1109458. doi:10.3389/fnmol.2022.1109458
Xu, Q., Sun, L., Chen, Q., Jiao, C., Wang, Y., Li, H., et al. (2024). Gut microbiota dysbiosis contributes to depression-like behaviors via hippocampal NLRP3-mediated neuroinflammation in a postpartum depression mouse model. Brain Behav. Immun. 119, 220–235. doi:10.1016/j.bbi.2024.04.002
Yang, Y., Zhao, S., Yang, X., Li, W., and Si, J. (2022). The antidepressant potential of lactobacillus casei in the postpartum depression rat model mediated by the microbiota-gut-brain axis. Neurosci. Lett. 774, 136474. doi:10.1016/j.neulet.2022.136474
Ye, B., Yuan, Y., Liu, R., Zhou, H., Li, Y., Sheng, Z., et al. (2023a). Restoring Wnt signaling in a hormone-simulated postpartum depression model remediated imbalanced neurotransmission and depressive-like behaviors. Mol. Med. 29, 101. doi:10.1186/s10020-023-00697-4
Ye, S., Fang, L., Xie, S., Hu, Y., Chen, S., Amin, N., et al. (2023b). Resveratrol alleviates postpartum depression-like behavior by activating autophagy via SIRT1 and inhibiting AKT/mTOR pathway. Behav. Brain Res. 438, 114208. doi:10.1016/j.bbr.2022.114208
Ye, J., Shi, R., Fan, H., Wang, D., Xiao, C., Yang, T., et al. (2024). Stevioside ameliorates prenatal obesity induced postpartum depression: the potential role of gut barrier homeostasis. Mol. Nutr. Food Res. 68, 2300255. doi:10.1002/mnfr.202300255
Zepeda, R. C., Juárez-Portilla, C., and Molina-Jiménez, T. (2023). St. John’s wort usage in treating of perinatal depression. Front. Behav. Neurosci. 16, 1066459. doi:10.3389/fnbeh.2022.1066459
Zhai, X., Chen, F., Chen, C., Zhu, C. r., and Lu, Y. n. (2015). LC–MS/MS based studies on the anti-depressant effect of hypericin in the chronic unpredictable mild stress rat model. J. Ethnopharmacol. 169, 363–369. doi:10.1016/j.jep.2015.04.053
Zhai, X., Chen, Y., Han, X., Zhu, Y., Li, X., Zhang, Y., et al. (2022). The protective effect of hypericin on postpartum depression rat model by inhibiting the NLRP3 inflammasome activation and regulating glucocorticoid metabolism. Int. Immunopharmacol. 105, 108560. doi:10.1016/j.intimp.2022.108560
Zhang, L., and Wei, W. (2020). Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony. Pharmacol. Ther. 207, 107452. doi:10.1016/j.pharmthera.2019.107452
Zhang, X.-L., Wang, L., Xiong, L., Huang, F. H., and Xue, H. (2017). Timosaponin B-III exhibits antidepressive activity in a mouse model of postpartum depression by the regulation of inflammatory cytokines, BNDF signaling and synaptic plasticity. Exp. Ther. Med. 14, 3856–3861. doi:10.3892/etm.2017.4930
Zhao, L., Zhang, H., Li, N., Chen, J., Xu, H., Wang, Y., et al. (2023). Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. J. Ethnopharmacol. 309, 116306. doi:10.1016/j.jep.2023.116306
Zheng, Q., Wang, S., Tian, X., Liu, W., and Gao, P. (2023). Fecal microbiota transplantation confirmed that 919 syrup reduced the ratio of erucamide to 5-AVAB in hippocampus to alleviate postpartum depression by regulating gut microbes. Front. Immunol. 14, 1203015. doi:10.3389/fimmu.2023.1203015
Zheng, J. Y., Zhu, J., Wang, Y., and Tian, Z. Z. (2024). Effects of acupuncture on hypothalamic-pituitary-adrenal axis: current status and future perspectives. J. Integr. Med. 22, 445–458. doi:10.1016/j.joim.2024.06.004
Zhou, H., Polimanti, R., Yang, B.-Z., Wang, Q., Han, S., Sherva, R., et al. (2017). Genetic risk variants associated with comorbid alcohol dependence and major depression. JAMA Psychiatry 74, 1234–1241. doi:10.1001/jamapsychiatry.2017.3275
Zhou, Y., Chen, C., Yu, H., and Yang, Z. (2020). Fecal microbiota changes in patients with postpartum depressive disorder. Front. Cell Infect. Microbiol. 10, 567268. doi:10.3389/fcimb.2020.567268
Zhou, L., Wu, Z., Zhao, D., Wang, G., Xiao, L., Wang, H., et al. (2023). Brief pup separation during lactation confers resilience in behavioural deficits induced by chronic restraint stress in postpartum C57BL/6J dams. J. Psychiatry Neurosci. 48, E154–E170. doi:10.1503/jpn.220079
Zhou, L., Tang, L., Zhou, C., Wen, S. W., Krewski, D., and Xie, R. H. (2024). Association of maternal postpartum depression symptoms with infant neurodevelopment and gut microbiota. Front. Psychiatry 15, 1385229. doi:10.3389/fpsyt.2024.1385229
Zhou, L., Wu, Z., Li, Y., Xie, Y., Sun, L., Lin, S., et al. (2025). Adult hippocampal neurogenesis-mediated cognitive behavior participates in stress resilience to anxiety and depression-like behaviors in postpartum dams. Mol. Psychiatry 30, 4868–4880. doi:10.1038/s41380-025-03082-1
Zoubovsky, S. P., Hoseus, S., Tumukuntala, S., Schulkin, J. O., Williams, M. T., Vorhees, C. V., et al. (2020). Chronic psychosocial stress during pregnancy affects maternal behavior and neuroendocrine function and modulates hypothalamic CRH and nuclear steroid receptor expression. Transl. Psychiatry 10, 6. doi:10.1038/s41398-020-0704-2
Keywords: postpartum depression, traditional Chinese medicine, natural products, molecular mechanisms, action targets
Citation: Shang R, Lu Y, Gao H, Zhong X, Yu X and Li G (2025) The role of natural products and traditional Chinese medicine formulas in postpartum depression: mechanism and prospects. Front. Pharmacol. 16:1686499. doi: 10.3389/fphar.2025.1686499
Received: 18 August 2025; Accepted: 19 November 2025;
Published: 02 December 2025.
Edited by:
Banaz Jalil, University College London, United KingdomReviewed by:
Juan Francisco Rodríguez-Landa, Universidad Veracruzana, MexicoRubiahna Vaughn, Montefiore Medical Center, United States
Copyright © 2025 Shang, Lu, Gao, Zhong, Yu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Guoqiang Li, c3Rhcl9ndW9xaWFuZ0AxNjMuY29t; Xiaowen Yu, eXV4aWFvd2VuQHNkdXRjbS5lZHUuY24=
†These authors have contributed equally to this work