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 found 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 inter-synaptic concentration of monoamines in response to depression are shown in Table 1.

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, gamma-aminobutyric 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 promoting PI3K/AKT/mTOR pathways. Excessive accumulation of glutamate in brain tissues is a direct manifestation of the glutamate hypothesis of depression (Weng et al., 2014), so inhibiting excessive elevation of glutamate levels in the brain may be one of the approaches to treating depression with traditional Chinese medicines. Saikosaponin D and Gentiopicroside are the active ingredients in Chai Hu and Gentian, respectively, in which Saikosaponin D (1.50 mg/kg/d, 0.75 mg/kg/d) reduced glutamate levels in the CA1 region of the hippocampus of CUMS-exposed rats by modulating the Homer1-mGluR5 and downstream mTOR signaling pathways, and improved the behavioral performance of the rats in behavioral tests, proving its antidepressant effect (Liu et al., 2022). In contrast, Gentiopicroside (50 mg/kg/d, 100 mg/kg/d, 200 mg/kg/d) significantly reduced the immobility time during the forced swim test and increased the time in the center area in rifampicin-induced pain/depression dichotomy mice and the open-field test by down-regulating the GluN2B receptor in the amygdala, total distance traveled (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.

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 hippocampus-pituitary-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 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 3.

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 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.

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.

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 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-gut-microbiota 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.

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 depressed rats, and that the administration 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). In addition, other studies have shown that XYS can also ameliorate MDD by modulating monoamine neurotransmitters, BDNF, and neuroendocrine levels (Bao et al., 2008; Zhu et al., 2019).

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 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).