Pathogenesis of depression and the potential for traditional Chinese medicine treatment

Depression is a prevalent mental disorder that significantly diminishes quality of life and longevity, ranking as one of the primary causes of disability globally. Contemporary research has explored the potential pathogenesis of depression from various angles, encompassing genetics, neurotransmitter systems, neurotrophic factors, the hypothalamic-pituitary-adrenal axis, inflammation, and intestinal flora, among other contributing factors. In addition, conventional chemical medications are plagued by delayed onset of action, persistent adverse effects, and restricted therapeutic efficacy. In light of these limitations, the therapeutic approach of traditional Chinese medicine (TCM) has gained increasing recognition for its superior effectiveness. Numerous pharmacological and clinical studies have substantiated TCM’s capacity to mitigate depressive symptoms through diverse mechanisms. This article attempts to summarize the mechanisms involved in the pathogenesis of depression and to describe the characteristics of herbal medicines (including compounded formulas and active ingredients) for the treatment of depression. It further evaluates their effectiveness by correlating with the multifaceted pathogenesis of depression, thereby furnishing a reference for future research endeavors.


Introduction
Major Depressive Disorder (MDD), or depression for short, is a chronic, recurrent, and potentially life-threatening mental disorder that not only reduces people's quality of life, but also imposes a heavy burden on individuals and their families in terms of health, finances, work, interpersonal relationships, etc., (Sim et al., 2015).MDD is characterized by symptoms such as low mood, cognitive impairment, anhedonia, worthlessness, social phobia, and suicide.Based on the most recent statistics provided by the World Health Organization, it is estimated that over 350 million individuals globally are afflicted by MDD, which accounts for approximately 5% of the global population, making it the fourth most common disease in the world (World Health Organization, 2022).Furthermore, under the influence of the new coronavirus pandemic, the prevalence of depression has risen by 28% (COVID-19 Mental Disorders Collaborators, 2021).In addition, the occurrence of MDD also significantly increases the risk of patients developing other diseases such as cardiovascular disease, stroke, Alzheimer's disease, and epilepsy (Mathers and Loncar, 2006).
MDD is mainly treated with traditional antidepressants of the monoamine class (López-Muñoz and Alamo, 2009).Such drugs suffer from long onset of action, persistent side effects, and limited therapeutic efficacy (only 50% of patients achieve complete remission) (Deussing and Arzt, 2018) Therefore, it is particularly urgent to find antidepressant drugs that are effective and have fewer side effects.TCM is a natural product with a long history of medication, and it is widely accepted that it is safe and has few side effects.Screening antidepressant formulas and active ingredients from TCM is a promising alternative and may become a major trend in the treatment of MDD in the future.To facilitate research on MDD and the development of new antidepressants, we have compiled an overview of the pathogenesis of MDD and the corresponding therapeutic modalities offered by TCM.This compilation aims to provide a valuable reference for further studies in this field.

By modulating monoamine transmitters
The monoamine hypothesis is the first theory in the history of MDD, and this hypothesis suggests that the possible pathogenesis of MDD is a decrease in monoamine neurotransmitter metabolism in the synaptic gap (Schildkraut et al., 1972).Monoamine neurotransmitters are an important class of excitatory neurotransmitters that include two major groups, catecholamines and indoleamines.Catecholamines include norepinephrine (NE) and dopamine (DA), and indoleamines are mainly serotonin (5-HT) (Jovanovic et al., 2022).Many functions in the body are regulated by the monoaminergic system.For instance, anxiety and fear disorders involve 5-HT, which is also related to pain sensitivity control and neurohormonal regulation (Bazian and Grigor'ian, 2006).NE and DA are associated with mood and eroticism, respectively, and are involved in the regulation of selective attentional processes, learning, locomotion, and reward activities (Goddard et al., 2010;Shen et al., 2012).Whereas the monoamine hypothesis is a classic prediction of depression, the underlying pathophysiology of depression is based on decreased levels of monoamine neurotransmitters in the synaptic gap (Delgado, 2000).It has also been found that drugs that act through various mechanisms to increase synaptic monoamine concentrations can improve symptoms of depression (Hirschfeld, 2000).However, it is important to note that the monoamine hypothesis is not without its criticisms.Some researchers argue that the hypothesis oversimplifies the complex etiology of depression and fails to account for other neurotransmitter systems, such as glutamate and GABA, which may also play a role in the development of MDD (Cryan et al., 2008).Additionally, not all individuals with depression respond positively to traditional monoamine-based antidepressant medications, suggesting that other factors may be at play in the development of depression (Pariante, 2017).
Overall, while the monoamine hypothesis has been influential in shaping our understanding of depression and guiding treatment approaches, it is important to continue to research and explore other potential mechanisms involved in the pathology of MDD in order to develop more effective treatments for this debilitating condition.Modulation of synaptic gap monoamine neurotransmitter concentrations and inhibition of monoamine oxidase may be one of the antidepressant mechanisms in Traditional Chinese Medicine (TCM) (Xin-xi, 2011).Research has shown that the active ingredients in TCM can improve the levels of different monoamine transmitters.For example, in a study involving a chronic mild stress (CMS) depressed mouse model, administration of ginkgolide at varying doses (3 mg/kg/d, 6 mg/kg/d, 12 mg/kg/d) was able to increase the levels of dopamine (DA) and serotonin (5-HT) in the hippocampal tissues of the mice and downregulate the levels of monoamine oxidase-A, thereby improving the depression-like behavior of the mice (Yang et al., 2020).Another active ingredient, crocin, found in the Chinese medicine saffron, was also studied in a chronic unpredictable stress (CUMS) mouse model, where crocin at a dosage of 25 mg/kg/d was Different hypotheses of the pathogenesis of MDD.
Frontiers in Pharmacology frontiersin.orgfound to alleviate depressive symptoms by modulating the metabolic level of tryptophan, the precursor of 5-hydroxytryptophan, as demonstrated in metabolomics studies (Luo et al., 2023).TCM active ingredients are known to regulate the levels of different monoamine transmitters through various channels, targets, and levels.For instance, Yuanzhi-1 was found to block synaptic reuptake of monoamine transmitters and simultaneously increase the levels of 5-HT, DA, and norepinephrine (NE) in the synaptic gap.Monoamine oxidase inhibitors (MAOIs) were one of the first drugs used to treat depression but were phased out because of large side effects (Finberg, 2014).In contrast, a recent study found that curcumin at 50 mg/kg/d could improve the despairing behavior of rifampicin-and buprenorphine-induced mice by acting similarly to MAOIs, whereas curcumin did not have a direct activating effect on monoamines and did not have a significant inhibitory effect on the reuptake of monoamine neurotransmitters (Chen et al., 2006).More studies of herbal active ingredients or extracts to increase the intersynaptic concentration of monoamines in response to depression are shown in Table 1.

By regulating glutamatergic transmitter levels
Glutamate is the predominant excitatory neurotransmitter in the central nervous system and is involved in neuronal excitability, synaptic plasticity, and neurogenesis by activating various receptors, such as N-methyl-D-aspartic acid (NMDA) receptors, AMPA receptors, and metabotropic glutamate receptors (Orrego and Villanueva, 1993).Glutamate (Glu) and a small amount of another inhibitory amino acid neurotransmitter, gammaaminobutyric acid (GABA), synergistically maintain the balance of excitatory/inhibitory circuits (Douglas and Martin, 2007;Sanacora et al., 2012).However, the balance of excitatory and inhibitory circuits has been found to be characteristically disturbed in MDD, mainly by dysfunction of the glutamatergic system, dysregulation of glutamatergic clearance, and metabolic regulatory mechanisms, which cause persistent glutamate accumulation.Structural and functional changes in regions related to mood and cognition and reduced synaptic activity are caused by excitotoxicity (e.g., excessive stimulation of glutamate receptors), which may lead to core symptoms of MDD, such as depressed mood, anhedonia, and cognitive dysfunction (Patel et al., 2015).
Glial glutamate transporter protein-1 (GLT-1) is one of the major Na-driven glutamate transporter proteins and plays an important role in maintaining control of synaptic glutamate concentration, and dysregulated expression of GLT-1 induces depressive symptoms (Weng et al., 2014).Schisantherin B is a lignan substance isolated from the traditional Chinese medicine Schisandra chinensis (Turcz.).Recent studies have shown that a single dose of Schisantherin B (15 mg/kg/d) can increase GLT-1 levels and alleviate symptoms of FST-induced depression in FST-induced depressed mice by   (Liu et al., 2014).More antidepressant mechanisms of herbal active ingredients by modulating glutamate transmitter levels are shown in Table 2.In summary, abnormalities in the glutamatergic system are one of the recognized hypotheses in the pathogenesis of depression.Although there are fewer studies on the antidepressant effects of Chinese herbal medicines through glutamate, there is indeed some evidence of the effects of the active ingredients of Chinese herbal medicines on the glutamatergic system in the depressive process.This calls for more research to find the exact mechanism in order to develop new approaches and drugs in the treatment of depression.

By improving HPA axis dysfunction
Various mood and cognitive disorders have been associated with the pathophysiology of the HPA axis.The HPA axis may be hyperactive in MDD patients, as studies have demonstrated (Keller et al., 2017).The regulation of the HPA axis primarily occurs through the influence of the hippocampus, which governs the secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamic paraventricular nucleus (PVN).The anterior pituitary is stimulated by CRH to produce adrenocorticotropic hormone (ACTH), which then prompts the adrenal cortex to generate and release glucocorticoids (cortisol in humans and corticosterone in rodents) into the blood.Exogenous or endogenous stress may impair certain functions in the HPA axis, such as glucocorticoid resistance, i.e., dysfunction of the glucocorticoid receptor (GR), which impairs the negative feedback it mediates, and cause the pituitary gland and adrenal glands to enlarge, resulting in the disruption of the overstimulated HPA axis and increased levels of cortisol (CORT) in patients with depression (Figure 3) (Anacker et al., 2011;Nikkheslat et al., 2020).Therefore, the search for active ingredients of herbal medicines that can improve hippocampuspituitary-adrenal axis dysfunction is a focus that requires urgent attention.Encouragingly, a large number of studies have been reported to elucidate the active ingredients of herbal medicines to alleviate depression by modulating the HPA axis, as well as their mechanisms of action.
Icariin, a flavonoid constituent isolated from Epimedium, was investigated in a chronic social defeat stress (CSDS)-induced mouse model of depression.The results showed that oral administration of 25 mg/kg and 50 mg/kg of Icariin reversed the CSDS-induced reduction in the duration of social interactions and attenuated the downregulation of serum GR and the increase in corticosterone levels in mice.The overexpression of CRH and ACTH as well as chronically elevated serum levels of CORT may contribute to the depressive-like behaviors (Vincent and Jacobson, 2014).Salidroside is a key active ingredient isolated from Rhodiola rosea.Salidroside, a key active ingredient isolated from Rhodiola rosea, was studied in a rat model of olfactory bulbectomy-induced depression.The results showed that oral administration of Salidroside (20 mg/kg/d/d, 40 mg/kg/d/d) significantly shortened the immobilization time of FST and TST and significantly increased the expression of GR and brain-derived neurotrophic factor (BDNF).In addition, Salidroside attenuated the expression of hypothalamic CRH and significantly reduced serum corticosterone levels.Suggesting that the antidepressant activity possessed by Salidroside may be mediated primarily by ameliorating abnormal HPA axis function (Yang et al., 2014).Rats were and exposed to a series of unpredictable mild stressors to establish a CUMS depression model, and after 19 days of gavage administration of Puerarin (a flavonoid glycoside extracted from the traditional Chinese medicine Pueraria lobata), it was found that   3.

By regulating neurotrophic factor levels
Neuroplasticity, the process of growth and adaptation at the neuronal level, plays a crucial role in the modification of neurogenesis and the morphology of mature neurons.However, restricted neurogenesis and disturbances in neuronal morphology can contribute to the development of MDD-like symptoms (Castrén, 2013;Allen and Lyons, 2018).Neuroplasticity, including synaptic plasticity, neurotransmission, neuronal survival, growth, and differentiation, is regulated by a combination of neurotrophic factors such as BDNF, glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF) (Song et al., 2017).These factors work synergistically to enhance and support neuroplasticity processes (Thoenen, 1995;Wang et al., 2022).Therefore, modulation of neurotrophic factor levels may be the direction of herbal medicine to improve depression.
There has been a large body of evidence demonstrating the effects of active ingredients in herbal medicines on the levels of neurotrophic factors.For example, resveratrol, a natural polyphenol, was found to improve CUMS-induced depressive-like behavior and cognitive deficits in mice by activating the Sirt1/miR-134 pathway and upregulating downstream cAMP response element-binding  Frontiers in Pharmacology frontiersin.org08 protein (CREB)/BDNF levels in the hippocampus (Shen et al., 2018).Long-term administration of ginsenoside Rg1 (40 mg/kg/d for 5 weeks) significantly ameliorated neuronal structural abnormalities and biochemical changes induced by CUMS stress and prevented depressive-like behaviors in rats with CUMS, which may be based on the mechanism of neuroprotective and antidepressant-like effects exhibited through activation of the CREB-BDNF system in the basolateral amygdala (Zhu et al., 2016).Ethanolic extracts of Dendrobium flowers increased the expression of NGF and BDNF at both transcriptional and protein levels, decreased immobilization time and increased sucrose consumption in a forced swimming test in mice (Zhu et al., 2021).It suggests that the antidepressant effects of the Dendrobium flowers may be related to the modulation of neurotrophic factor levels.Table 4 exhibits other Central Asian active ingredients and extracts that target neurotrophic factors.

By improving inflammation
In the past few decades, a growing body of evidence has highlighted the involvement of systemic immune activation and inflammatory processes in the development of MDD (Maes, 1999;Gibney and Drexhage, 2013).Inflammation, which arises from the activation of the immune system, typically manifests as a localized response triggered by irritation, injury, or infection.However, when dysregulated, immune cells and mechanisms within the body can contribute to the onset of diseases like MDD (Murphy et al., 2007).There is evidence that patients with depression have elevated levels of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6) (Beurel et al., 2020).This may indicate the presence of inflammatory processes in patients with MDD.
Using LPS-induced depressed mice, after gavage administration of Chiisanoside (5.0 mg/kg/d), it effectively reduced serum IL-6 and TNF-α levels, as well as improved oxidative stress-related indices, and significantly increased immobility time of TST and FST, suggesting that Chiisanoside may improve depression by modulating the levels of inflammatory factors.Under stress, NF-κB is activated to promote the production of IL-1β proximate (Bian et al., 2018).Fan et al. (2018) found that pretreatment with Curcumin (40 mg/kg/d) for 5 weeks ameliorated the depressive-like effects and suppressed the inflammatory response and neuronal structural abnormalities in CUMS-exposed mice, with a mechanism of action similar to that of IL-1β or NF-κB antagonists.There is evidence that High Mobility Group Box 1 (HMGB1) can play an important role in neurodegenerative diseases by mediating neuroinflammation (Chi et al., 2015).Icariin was found to promote HMGB1 translocation to the nucleus and, on the one hand, inhibit HMGB1-RAGE anti-inflammatory signaling and, on the other hand, may activate TLR4-NF-κB signaling and increase p65 expression in the nucleus to promote nerve regeneration, effectively improving social avoidance behavior in the social interaction test and time spent in the central area in the open field test in rats (Liu L. et al., 2019).Other studies involving the improvement of immune and inflammatory dysregulation mechanisms are shown in Table 5.

By regulating the intestinal flora
The human gut flora is a diverse and complex ecosystem consisting of trillions of microorganisms, including bacteria, viruses, archaea, and fungi (Kc et al., 2020), that have a role in Frontiers in Pharmacology frontiersin.org15 human health.Gut flora participate in a bidirectional communication pathway with the central nervous system (CNS), known as the microbiota-gut-brain axis (Dinan and Cryan, 2017;Chang et al., 2022).In contrast, dysbiosis disrupts the brain-gutmicrobiota axis, induces a neuroimmune inflammatory response, disrupts the function of the intestinal mucosa and the blood-brain barrier, and directly stimulates the vagus nerve, enteric nervous system, spinal nerves, and HPA axis.These interactions have been implicated in the development of neurological disorders, including MDD (Tang and Cao, 2021).
As the link between gut flora and the onset of depression becomes more deeply understood, more and more studies are finding that herbs can improve depression by regulating gut flora.Patchouli essential oil, the main active ingredient in patchouli, is used in aromatherapy for stress relief.Oral administration of patchouli essential oil (0.8 mL/kg) significantly attenuated the depression-like behavior induced by CUMS stress in mice in FST.It was found to increase the relative abundance of several probiotics (including Bacteroides and Blautia) and improve the levels of metabolites short-chain fatty acids (SCFAs) and restore hippocampal 5-HT levels regarding the gut microbiota as analyzed by 16S rRNA gene sequencing (Ouyang et al., 2024).In addition, changes in gut flora affect the immune system and generate an inflammatory response, which in turn induces or exacerbates the depressive response (Peirce and Alviña, 2019).The establishment of a CUMS rat model of depression significantly increased the abundance of beneficial bacteria (Lactobacillus and Oscillospira) in the rat gut after the intervention of administering a certain amount of Astragaloside IV, as well as modulating the imbalance of Th17/Treg cells and the abnormal levels of anti-inflammatory and pro-inflammatory factors.This resulted in improved depression-like behavior in rats, as evidenced by weight gain, upregulation of sucrose preference, and decreased immobility time.This implies that Astragaloside IV is able to improve the inflammatory response by regulating intestinal flora, which in turn reduces depressive symptoms (Liu et al., 2024).We have compiled a list of active ingredients of some Chinese herbal medicines (Table 6), which have antidepressant effects by modulating the intestinal flora.
In summary, intestinal flora-associated depression has received much attention in recent years.As the interactions and relationships between changes in intestinal flora and depression become clearer and clearer, the mechanism of antidepressant effects of traditional Chinese medicines by regulating intestinal flora will continue to be revealed.

Application of classical and famous Chinese medicine formulas in antidepressants
Depression has a complex and diverse etiology and pathogenesis, and single-targeted therapeutic strategies with traditional antidepressants may be ineffective.In contrast, Chinese herbal formulas, with their systemic properties and multi-targeting characteristics, may provide advantages for the treatment and prevention of depression.In traditional Chinese medicine, Chinese herbal formulas are commonly used drug therapies, consisting of a combination of multiple Chinese medicines, providing a material basis for the diversity of antidepressant mechanisms.They can adapt to the characteristics of the diversity of causative factors and the complexity of lesions in depression through the integration of the regulating effects of multi-link, multi-level, and multi-targets.At the same time, different Chinese medicines can synergistically enhance antidepressant efficacy through mutual promotion and enhancement (Zhuang et al., 2023).
In the records of traditional Chinese medicine, many Chinese herbal formulas have been proposed and applied to treat depression ("yu-shen" in Chinese medicine theory).Some of the classical formulas are hundreds or even thousands of years old and are still used in current clinical practice.In this paper, we summarize eight classic TCM formulas (Table 7), which have been shown to have multiple mechanisms of action and targets.Among them, Xiaoyao San (XYS), Chaihu Shuogan San (CHSGS), and Kaixin San (KXS) have received strong attention for their remarkable efficacy.We will focus on a systematic review of these three classic prescriptions.

XYS
XYS is a classic formula in TCM, which was first developed in the Song Dynasty (960-1127 A.D.) from the "TaiPingHuiMin HeJiJvFang" and has been used in the treatment of psychiatric disorders for thousands of years.XYS is made up of eight commonly used Chinese herbs: Chai Hu, Dang Gui, Bai Shao, Bai Zhu, Fu Ling, Sheng Jiang, Bo He, and Zhi Gan Cao.In recent years, a large number of studies have demonstrated that XYS can exert antidepressant effects through various mechanisms.Zhou et al. (2021) found that glutamate and serum CORT levels were abnormally high in the hippocampal CA1 region of CUMS-induced  (Bao et al., 2008;Zhu et al., 2019).

CHSGS
CHSGS was first introduced in the classic medical text "JingYueQuanShu" from the Ming Dynasty.It is composed of Chai Hu, Shao Yao, Xiang Fu, Zhi Ke, Chen Pi, Chuan Xiong, and Gan Cao.In Chinese medicine, it is used to relieve liver qi stagnation.Modern research on it has found that CHSGS is able to alleviate MDD by regulating intestinal flora, reducing inflammation, and increasing monoamine transmitter levels.For example, post-stroke MDD was modeled by subjecting male rats to middle cerebral artery occlusion and chronic unpredictable mild stress.CHSGS (4.4 g/kg/d) was found to modulate microglia polarization by activating the JAK/STAT3-GSK3β/ PTEN/Akt pathway, suggesting that CHSGS can exert antidepressant effects by inhibiting neuroinflammation (Fan et al., 2023).Ma et al. (2022) transplanted gut microbes from CHSGS-treated mice into untreated CUMS mice, restored serum levels of hyocholic acid and 7-ketodeoxycholic acid in depressed mice, increased BDNF levels, and alleviated depression-like symptoms.The comorbidity of epilepsy and MDD is common in neuropsychiatry (Alhashimi et al., 2022).A rat model of depressive epilepsy was established by inducing epilepsy with chronic hairy fructosamine followed by exposure to chronic mild stress, and it was found that CHSGS (2.7 g/kg/d) increased the expression of 5-HT1A receptor mRNA and cell proliferation in the hippocampal dentate gyrus of depressive epileptic rats, which was effective in ameliorating the depressive symptoms (Yang et al., 2016).

KXS
KXS was initially described in the ancient Chinese book "BeiJiQianJinYaoFang" written by Sun Simiao in the Tang Dynasty around the year 652 AD.Initially used to treat dementia and forgetfulness, it is composed of ginseng, Yuan Zhi, shi chang pu, and fu ling.In traditional Chinese medicine theory, MDD is believed to be caused by qi, dampness, and phlegm, ultimately leading to brain dysfunction (Pei et al., 2020).KXS functions to tonify qi, nourish the heart, expel dampness, and resolve phlegm, thus aiding in the treatment of MDD.More and more research indicates that KXS can effectively treat MDD by regulating neurotrophic factors, neurotransmitters, gut microbiota, and inflammation (Fu et al., 2019).In a preclinical study using fluoxetine (7.2 mg/kg/d) as a positive control, administering KXS extract orally at doses of 3 or 10 g/kg/d significantly improved depressive-like behaviors in chronic unpredictable mild stress (CUMS) rats in sucrose preference, forced swimming, and tail suspension tests, thereby alleviating symptoms of anhedonia, despair, and anxiety.Additionally, KXS inhibits the activation of microglial cells and significantly reduces the expression of pro-inflammatory cytokines such as IL-1β, IL-2, and TNF-α in the mouse hippocampus by inhibiting the TLR4/IKK/NF-κB pathway (Qu et al., 2021).KXS also helps regulate neurotrophic factor metabolic pathways; after oral administration of KXS (1.5 g/kg/d) daily for several days, it significantly alleviates depressive symptoms in mice subjected to chronic unpredictable mild stress, as evidenced by increased sucrose consumption, reduced immobility time in forced swimming, and increased locomotor activity.It was found that KXS achieves this effect by upregulating the expression of NGF, BDNF, and Trkb receptors in the hippocampus, which was confirmed by treatment with respective inhibitors tPA-stop and K252a (Zhu et al., 2017).

Discussion
MDD's pathogenesis is multifaceted and convoluted.Despite the fact that present studies have shed light on its possible pathogenesis from various angles, the extent to which each pathway contributes differs among individuals and still fails to explain the full range of pathogenic mechanisms.Based on this dilemma, new treatments are scarce, and the mechanisms studied are relatively homogeneous, lacking integration and systematic research.MDD is a disease with multiple pathways and factors, which requires in-depth study of the interactions among pathogenic mechanisms and exploration of the intrinsic linkages and molecular pathways through which various pathogenic factors affect each other, rather than just following the causal logic of the association.
With the development of TCM, TCM has received more and more attention due to its outstanding therapeutic effect and fewer side effects.TCM natural monomers are also supplements to traditional antidepressants to minimize adverse effects.These single components have higher biological activity and are more likely to enter cells to exert medicinal effects.They have advantages of fast onset of action and low side effects.In addition, as summarized in this paper, it was found that, compared with traditional synthetic drugs, many of the active ingredients of Chinese medicines do not have a single antidepressant mechanism and can achieve antidepressant effects through multiple pathways.For example, Icariin and Curcumin are able to act on MDD through a variety of mechanisms, such as neurotrophic factor, HPA axis, and inflammation.This may be an advantage of the natural active ingredients of herbal medicine instead of traditional antidepressant drugs.Overall, the natural active ingredients in TCM provide a promising direction for the development of novel antidepressant drugs.
Formulas are one of the most commonly used drug therapies in TCM, especially the classical formulas, which have been in use for a long time and have clear therapeutic effects.To this day, they are still widely used in clinical practice, and a range of herbal combinations provide the material basis for diverse antidepressant mechanisms.However, due to the complexity of the ingredients, current studies have mainly focused on their overall effects on MDD, and the exact relationship between the active ingredients in the formula and the pathogenesis of MDD has rarely been reported.It is also not clear how the multiple ingredients synergize with each other to treat MDD through different mechanisms.
In addition, there are many traditional antidepressant formulas in China, and the antidepressant effects of some of them have not yet been fully explored, including many classical formulas that have been determined to have significant antidepressant effects but have been neglected due to a lack of research.Therefore, more comprehensive and in-depth studies are needed to elucidate the exact active ingredients in classical prescriptions and their molecular pharmacology related to the prevention and treatment of MDD.
In conclusion, this review summarizes the latest information and insights from research on the use of herbal medicines in the treatment of MDD.Much evidence suggests that the antidepressant effects of TCM are definitive and have great potential for development, but the research does contain shortcomings that may seriously constrain the development of novel antidepressants.Firstly, the hypothesis of the pathogenesis of MDD mentioned above still does not provide an adequate explanation for the nature of MDD, although current studies have elaborated the possible pathogenesis of MDD from different perspectives.At the same time, the insufficiency of basic mechanism research also restricts the deeper study of TCM antidepressants, and it is not known through which different unknown pathways TCM can still act on MDD.Secondly, TCM antidepressant studies have mainly focused on the traditional mechanisms of monoamine transmitters, HPA axis, and neurotrophic factors, and the effects of Glu and brain-gut axis on the occurrence of MDD have been well demonstrated by the studies.However, the studies of TCM in treating MDD through these pathways are still lacking in reports.In addition, compared with other drugs that have been widely used, most of the studies on TCM still remain in the preclinical research stage, and there is a lack of clinical trials to elucidate the exact antidepressant effects of TCM.
Therefore, to address the above problems, further development of basic mechanism studies is urgently needed, with a view to developing a unified understanding of the etiology and pathogenesis of MDD, exploring the antidepressant effects of TCM in depth and comprehensively, in order to elucidate the nature of MDD and the moderating effects of TCM, and providing a scientific basis for new means of treating MDD.

FIGURE 2
FIGURE 2Different forms of TCM exert antidepressant effects based on the hypothesis of the pathogenesis of depression.
concentrations of 60 and 120 mg/kg/d/d of Puerarin blocked the increase in serum CRH, CORT, and ACTH, implying that Puerarin's antidepressant mechanism may be related to the regulation of HPA axis function(Qiu et al., 2017).The antidepressant mechanisms of the active ingredients of Chinese medicines by alleviating the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis are shown in Table

FIGURE 3
FIGURE 3Dysregulation of the HPA axis promotes depression.

TABLE 1
Antidepressant mechanisms of Chinese herbal active ingredients modulating monoamine transmitter levels.

TABLE 1 (
Continued) Antidepressant mechanisms of Chinese herbal active ingredients modulating monoamine transmitter levels.

TABLE 2
Antidepressant mechanisms of Chinese herbal medicine active ingredients regulating glutamate levels.
(Continued on following page)Frontiers in Pharmacology frontiersin.org

TABLE 2 (
Continued) Antidepressant mechanisms of Chinese herbal medicine active ingredients regulating glutamate levels.

TABLE 3
Antidepressant mechanism of improving HPA axis dysfunction by Chinese herbal active ingredients.

TABLE 4
Antidepressant mechanism of Chinese herbal medicine active ingredients regulating the level of neurotrophic factor.

TABLE 4 (
Continued) Antidepressant mechanism of Chinese herbal medicine active ingredients regulating the level of neurotrophic factor.Inflammation inhibition and antidepressant mechanism of Chinese herbal active ingredients.

TABLE 6
Antidepressant mechanism of Chinese herbal medicine active ingredients regulating intestinal flora.

TABLE 7 (
Continued) Antidepressant studies of classical formulas.

TABLE 7 (
(Hao et al., 2024)ressant studies of classical formulas.rats,andthattheadministration of XYS (2.224 g/kg/d) significantly reduced glutamate and CORT levels, and improved the depression-like symptoms of the rats.Moreover, the antidepressant effect of XYS may be exerted through the NR2B and PI3K/Akt signaling pathway.In order to treat MDD,Zhu et al. (2019)explored the effects of XYS on depressive behaviors.A CRS rat model of MDD was established, and a 16S rDNA high-throughput method was used to sequence fecal specimens to detect the structure and changes of intestinal flora.The results showed that at the phylum level, XYS regulated the abundance of Bacteroidetes, Proteobacteria, Firmicutes, Chloroflexi, and Planctomycetes.At the genus level, XYS decreased the abundance of Prevotellaceae_Ga6A1_group, Prevotellaceae_UCG-001, and Desulfovibrio, and increased the abundance of Ruminococcaceae in order to improve depression-like behavior.It was also found that this process involves mechanisms that may be related to short-chain fatty acids, lipopolysaccharides, and intestinal inflammation.Recent studies have found that dysbiosis of gut flora can induce the development of depressive-like behaviors through abnormal synaptic pruning of microglia mediated by complement C3, and that XYS was able to inhibit abnormal synaptic pruning by regulating gut flora to improve depressive-like behaviors in CUMS mice(Hao et al., 2024). depressed