The discovery of tricyclic antidepressants (TCAs) represented by promethazine, led to the formation of the monoamine theory of depression (Barsa and Kline, 1957) which proposed that depression may be caused by a decrease in the availability of monoamine neurotransmitters such as serotonin (5-HT) and noradrenaline (NE) in the central nervous system (CNS), and was one of the early hypotheses aiming to explain the pathophysiology of depression (Krishnan and Nestler, 2008). In the 1950s, the antitubercular drug, iproniazid, was shown to have antidepressant effects in tuberculosis patients, followed by the discovery that iproniazid inhibits the monoamine oxidase (MAO), which is involved in the catabolism of 5-HT, NE, and dopamine (DA) (Shulman et al., 2013). Meanwhile, two other pieces of evidence provide support for this theory, one of which is reserpine is thought to provoke depression essentially through catecholamine depletion (Strawbridge et al., 2023), and the other is that serotonin transporter knockout mice showed depression-like behaviors (Haenisch and Bönisch, 2011). What’s more, the first-line antidepressants increase acute delivery of monoamine neurotransmitters through inhibition of neuronal reuptake (e.g., SSRIs) or inhibition of degradation (e.g., MAOIs), which indicates the crucial role of monoamine neurotransmitters in the onset of depression. Although these hypotheses are constantly being updated, the strong link between monoamine neurotransmitters and the development of depression has never been questioned.

Ber can alleviate depression-like symptoms by modulating the levels of these neurotransmitters. Studies have shown that Ber could improve depressive-like behavior in mice by increasing the levels of NE, 5-HT, and DA in the hippocampus and frontal cortex as detected by high-performance liquid chromatography (HPLC) (Peng et al., 2007; Xu et al., 2021) and enzyme-linked immunosorbent assay (ELISA) (Huang et al., 2023). The 5-HT transporter (5-HTT) is an integral membrane protein that functions as a transporter protein and mediates the reuptake of 5-HT from inter-synaptic space, ensuring its recirculation into new cytoplasmic vesicles, and thus the duration and intensity of the biological action of 5-HT is largely dependent on 5-HTT (Iurescia et al., 2016). A study in the immortalized rat raphe-derived neuronal cell line RN46A cells showed that Ber (100 μM) can increase the mRNA and protein expression of 5-HTT, thereby enhancing the reuptake of 5-HT, which mechanism similar to that of SSRIs (Hu et al., 2012). Furthermore, Ber can also increase 5-HT levels in the hippocampus by regulating enzymes such as tryptophan 5-hydroxylase-1 (TPH1) and indoleamine 2,3-dioxygenase-1 (IDO1), thus shifting the kynurenine (KYN) pathway in tryptophan metabolism more towards the 5-HT pathway for the treatment of depression (Wang et al., 2022c; Ge et al., 2023). In addition, Ber may be an agonist of tyrosine hydroxylase (TH) in Enterococcus, which could lead to the production of L-dopa by the gut microbiota and finally transform into DA in the brain through a vitamin-like effect, thereby improving the brain function (Wang et al., 2021). We hypothesize that berberine may treat depression by modulating gut microbiota, which are likely important players in the diagnosis and treatment of depression due to their involvement in the bidirectional communication system of the gastrointestinal tract with the brain (Cryan et al., 2019).

The cause of depression is far from being a simple deficiency of central monoamines. Subsets of depressed patients have been observed to exhibit volumetric reductions within the hippocampus and other forebrain regions, providing support for another prevalent hypothesis regarding depression, which posits a crucial role for neurodevelopmentally expressed growth factors in regulating plasticity within the adult brain (Monteggia et al., 2004). Several antidepressant treatments such as SSRIs, MAOIs, and SNRIs exhibit a notable cellular effect in the induction of adult hippocampal neurogenesis, a process characterized by the mitotic division of neural progenitors residing in the subgranular zone (SGZ) of the hippocampal region, leading to the formation of new neurons that subsequently undergo differentiation and integration within the dentate gyrus (DG) (Pittenger and Duman, 2008). Also, antidepressants could elevate the levels of various growth factors within the hippocampus, potentially through the modulation of cyclic adenosine monophosphate (CREB) or other transcription regulators, which exerts a significant influence on the process of neurogenesis (Krishnan and Nestler, 2008), further indicating the importance of neurogenesis in combating depression.

Ber could protect hippocampal nerves directly. MicroRNA (miR), a non-coding RNA with a size of approximately 22 nucleotides, frequently modulates gene expression at the post-transcriptional level. Mounting evidence indicates numerous miRNAs are specifically expressed or enriched in the brain, with aberrant miRNA expressions accompanying various neurological disorders in depression sufferers as well as depressive-like animals (Allen and Dwivedi, 2020; Fan et al., 2022). Studies showed that miR-34a overexpression in depressed mice impaired neurogenesis, and targeted inhibition of miR-34a expression by Ber could reverse this process and play an antidepressant role (Yi et al., 2021). Previous research suggested disrupting Jun N-terminal kinase (JNK)-Akt signaling could prevent hippocampal neuron apoptosis during ischemic brain damage (Gong et al., 2016). Zhang et al. demonstrated that the insulin-like growth factor receptor (IGFR) inhibitor remarkably enhances JNK and Akt expression, thereby inhibiting the Ber-augmented proliferation in hippocampal pyramidal neurons, which indicated a potential neuroprotective role for Ber (2 mg/kg/d) in the facial nerve axotomy damage mice model (Zhang et al., 2018).

In addition, Ber can also indirectly promote neurogenesis by modulating the levels of brain-derived neurotrophic factor (BDNF). BDNF, a neurotrophic factor that increases the proportion of neural stem cells that differentiate into neurons, and promotes the survival, proliferation, and maturation of neurons in the adult olfactory bulb and DG (Eliwa et al., 2017), has been validated as a key factor in promoting synaptic plasticity for antidepressant effects (Erickson et al., 2012; Zhang et al., 2016). Wang et al. demonstrated that exogenous BDNF administration and genetically engineered deletion of the DG resulted in the induction and attenuation of antidepressant response, respectively (Wang et al., 2022). Ber (100 mg/kg) can attenuate the depressive-like behavior (detected by SPT, FST, and open-field test (OFT)) by increasing BDNF expression in the hippocampal CA1 region (MA et al., 2012; Shen et al., 2016), and overexpressing BDNF can reverse the effects of miR-34b-5p and miR-470-5p on depressive-like behavior in CUMS mice (Zhan et al., 2021). Moreover, in de-ovulated model mice, the detection of CREB and eukaryotic translation elongation factor 2 (eEF2) suggested that Ber (10 mg/kg) can improve depression through the BDNF/CREB/eEF2 pathway, and the onset of action is 2–4 weeks faster than SSRI (Fan et al., 2017).

The HPA axis is an important component of the neuroendocrine system, which has a close relationship with depression, with up to 40%–60% of depressed patients having hypercortisolemia or other HPA axis abnormalities (Keller et al., 2017). The activation of the HPA axis is characterized by an increase in hypothalamic production of corticotrophin-releasing factor (CRF), followed by increased pituitary release of adrenocorticotrophin (ACTH). There is strong evidence that stressful situations activate the HPA axis and increase circulating levels of glucocorticoid (GC) (Haleem and Gul, 2020), while overactivity of the HPA axis and increased circulating GC can affect brain serotonin and dependent responses to stress, precipitating depression (Haleem, 2022). Moreover, the observed correlation between heightened cortisol levels and the onset of depression may be attributed to the deleterious impact of excessive adrenal activity on the hippocampus (Mikulska et al., 2021). Chronic stress or the dysregulation of GC negative feedback receptors can result in elevated GC levels that can lead to significant damage to the hippocampus and hypothalamus (Hu et al., 2016). Ultimately, this neurogenic damage can lead to the proliferation of oligodendrocytes and exacerbation of depressive symptoms (Komoltsev and Gulyaeva, 2022). Chronic antidepressant treatment can restore the negative feedback function of the HPA axis, which either precedes or coincides with the relief of depression symptoms (Gobinath et al., 2014).

At present, many studies have demonstrated that Ber inhibits the abnormal activity of the HPA axis. In chronic unpredictable mild stress (CUMS)-induced mice, Ber (150 mg/kg) combined with ginsenosides could upregulate the expression levels of BDNF and downregulate the levels of corticosterone (CORT) and ACTH in plasma. Thereby attenuating depressive-like behaviors, including reducing the immobility time in FST, upregulating the percentages of sugar water preference in SPT and the activity times in EPM, increasing the maximum travel distance, total travel distance, and time spent at the area center in the OFT (Zhang et al., 2021). For the upstream hormones of CORT and ACTH, Ber (50 mg/kg) significantly reduced the expression of hypothalamic CRH and TH and showed greater improvement in depression and anxiety-like behavior (detected FST, EPM) in chronic morphine withdrawal rats (Lee et al., 2012). In addition, since excessive CORT is one of the important triggers for the onset of depression, quantitative proteomics of depressed mice revealed the inhibitory effects of CORT on the expression of mitochondrial oxidative phosphorylation-related proteins, and Ber could antagonize this effect and protect the neuronal physiological functions, which might be one of the mechanisms of the antidepressant effects of Ber (Gong et al., 2019).

Oxidative stress is another important factor that impairs neuroplasticity and contributes to the development of depression, it serves as a primary catalyst for neurodegeneration because reactive oxygen species (ROS) possess a profound relationship with a diverse array of pathophysiological processes (Bitanihirwe and Woo, 2011). When cells fail to maintain redox homeostasis and consequently generate proinflammatory mediators, cell necrosis ensues. The brain is particularly vulnerable to oxidative stress due to its elevated oxygen consumption, substantial lipid content, and relatively weak antioxidant defense system (Fesharaki-Zadeh, 2022). A clinical investigation demonstrated an elevated level of serum malondialdehyde (MDA) among individuals suffering from MDD, in comparison to a control population (Sarandol et al., 2007). In CUMS-induced depressed mice, the synthesis of peroxides such as MDA increased and the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) decreased (Cheng et al., 2018), and antidepressant drugs could increase the levels of antioxidant enzymes, including catalase (CAT), SOD, and GSH-Px, in depressed patients or animals (Sherkawy et al., 2018; Meejuru et al., 2021; Mishra et al., 2021), the above suggests that improving the oxidative stress state might be an important direction for the treatment of depression.

In the study for type 2 diabetes mellitus (T2DM) model mice, Ber could increase the mRNA expression of SOD in the liver and the activities of SOD and CAT in the kidney tissue (Chatuphonprasert et al., 2013), which showed that Ber has a role in combating oxidative stress. What’s more, Ber was involved in the regulation of the GSH/GSH-Px antioxidant system in diabetic patients (Ma et al., 2018), indicating that Ber plays a role in ameliorating oxidative stress, and studies have shown that many signaling pathways may be involved. Sirtuin1 (SIRT1) is a deacetylase with excellent antioxidant properties whose expression level is significantly increased by Ber and triggers the transcription of forkhead box protein O (FoxO) target genes, including SOD, that affects the oxidative stress state (Hill et al., 2000; Chen and Yang, 2017). Ber mediates the inhibition of oxidative stress through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway (Yang et al., 2011; Mo et al., 2014) and the antioxidant activity of Ber can be eliminated by pharmacological blockade of Nrf2 in neurons and macrophages, verifying that the effects of Ber may be related to Nrf2 (Wen et al., 2020). However, fewer studies are validating the antidepressant effects of Ber from the perspective of oxidative stress, and the association between the two needs to be further explored in the future.

Oxidative stress is always linked to inflammation. Inflammatory cells produce ROS, which can activate intracellular signaling and lead to the activation of proinflammatory genes. Peripheral cytokines undoubtedly have a role in behavioral effects, as evidenced by data indicating that blocking peripheral cytokines tightens the blood-brain barrier (BBB), and stopping BBB breakdown demonstrates antidepressant effects (Cheng et al., 2018). Beurel et al. demonstrated that peripheral cytokines can reach the brain maybe through “leaky” regions of the BBB, through a neural route via afferent nerve fiber cytokine receptors that relay the signal to the brain parenchyma, and through infiltration of immune cells (Beurel et al., 2020). At the molecular level, proinflammatory cytokines can reduce the supply of 5-HT, DA, and NE by increasing the expression and function of presynaptic 5-HT reuptake transporter proteins and activating the IDO to reduce related monoamine precursors (Maes et al., 2011). Moreover, inflammation affects growth factors, such as BDNF in the DG of the hippocampus, resulting in the damage of neuronal integrity, including neurogenesis, long-duration potentiation, and dendritic germination (Miller and Raison, 2016), which is important in the onset of depression. A meta-analysis found that depression is associated with concurrent and future inflammation in children and adolescents (Colasanto et al., 2020), Similarly, depressed patients were confirmed to have greater levels of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1, IL-4, IL-5, IL-12, interferon-γ (IFN-γ), and C-reactive protein (CRP) in their blood (Hussain et al., 2016), while antidepressant treatment significantly could reduce peripheral levels of IL-6, TNF, IL-10 (Köhler et al., 2018). Furthermore, anti-inflammatory drug supplementary use of antidepressants appears to boost antidepressant efficacy, and treatment-resistant depressive patients may benefit from anti-inflammatory drugs as well (Raison et al., 2013). The above supports that inflammation is closely associated with the pathogenesis of depression.

The anti-inflammatory effects of Ber have long been well documented (Zhang et al., 2019; Wang et al., 2020; Naz et al., 2022), and many studies have shown that the effects of Ber in reducing neuropsychiatric symptoms are related to its anti-inflammatory effects. Ber (100 mg/kg) reduced the levels of IL-1β, IL-6, and TNF-α in the hippocampus and inhibited the activation of microglia in mice, thus alleviating their depressive symptoms (detected by SPT, novelty-suppressed feeding test (NSFT)) induced by CUMS (Liu et al., 2017). In another animal model, depressive symptoms complicated by inflammatory pain were significantly improved after Ber (50 mg/kg) intervention, which may be related to the reduction of IL-1β, IL-6, and TNF-α levels (Xu et al., 2018). Meanwhile, proteomics analysis of reserpine-induced depressed mice revealed that retinoic acid-inducible gene I (RIG-I) was highly expressed in the model group while negative in the Ber group, whereas RIG-I-mediated neuroinflammation may be involved in the pathogenesis of depression (Yang et al., 2022). In addition, activation of neuronal nitric oxide synthases (NOS) raises the concentration of NO, which ultimately leads to the development of depression (Adell, 2020; Kang et al., 2020), while the inhibitory effects of Ber on inducible NOS has been recognized (Zhu et al., 2018; Zhu et al., 2019). The tripartite motif (TRIM) family is a subfamily of E3 ubiquitin ligases that regulate the ubiquitination of target proteins in biological processes such as proliferation, apoptosis, development, differentiation, inflammation, and immunology. Yang et al., 2023 showed that Ber inhibits NLRP3 inflammasome activity by increasing Trim65 conjugation to NLRP3 and NLRP3 ubiquitination, effectively alleviates depressive symptoms (detected by SPT, FST, OFT, and tail suspension test (TST)), and reduces hippocampal neuronal functional damage in CUMS mice.

JTW, composed of Rhizoma Coptidis and Cinnamon (Figure 2A), has been applied for insomnia since ancient times, and its antidepressant effects are been explored. JTW can ameliorate depression-like symptoms in depression mice induced by chronic restraint stress (CRS), and has a protective effect on the damage to hippocampal neurons (Tang et al., 2022). Bai et al., 2022 found that JTW could ameliorate CORT-induced depressive-like behaviors and neuronal damage and enhance the levels of monoamine neurotransmitters in the serum of mice, which were also seen in the LPS-induced mice (Zhe et al., 2017). The therapeutic effects of JTW in the above experiments all involved an anti-inflammatory response. In addition, the metabolomics of serum from CUMS-induced rats showed that the antidepressant effects of JTW may be attributed to the regulation of amino acid metabolism, glycerophospholipid metabolism, and energy metabolism (Jiao et al., 2021).

ZJP, a classic herbal formula consisting of Rhizoma Coptidis and Evodia Rutaecarpa (Figure 2B) is widely used clinically to treat gastrointestinal diseases, and there have been confirmed that ZJP may have a role in alleviating depressive-like behavior. Wang et al. found that ZJP can improve CUMS-induced depression-like behavior via the TPH2/5-HT pathway (Wang et al., 2023). And the anti-inflammatory and antidepressant effects of ZJP are primarily attributed to the promotion of the ubiquitination of MyD88 and the inhibition of the activation of downstream inflammatory signals (Wang et al., 2020; Tao et al., 2023). Except for ZJP itself, the ethanol extract of ZJP also showed antidepressant-like effects in reserpine-induced depressed mice with a mechanism involving the central monoaminergic neurotransmitter system (Wang et al., 2013).

HLJDD includes Rhizoma Coptidis, Scutellariae Radix, Cortex Phellodendri, and Fructus Gardeniae (Figure 2C), and has been implicated as effective in treating inflammation-related diseases. HLJDD was able to alleviate depressive-like behaviors in colitis mice by inhibiting the Trem2/Dap12 signaling pathway in the microglia of the lateral habenula (Zheng et al., 2023). Additionally, network pharmacology analysis and metabolomics examination revealed that tryptophan metabolism serves as the primary target for HLJDD in CUMS mice, and SLC6A4 and MAOA within the tryptophan metabolic pathway were effectively modulated by Ber, baicalein, tetrahydro berberine, candicine, could be classified as the primary antidepressant targets for HLJDD (Qu et al., 2021), highlighting the key role of Ber in HLJDD.

BXXXD is a formula consisting of seven herbs including Pinelliae Rhizoma, Scutellariae Radix, Zingiberis Rhizoma, Ginseng Radix, Glycyrrhizae Radix, Coptidis Rhizoma, and Jujubae Fructus (Figure 2D), which can lower lipids and alleviate depressive disorders, but fewer studies have been conducted to date. Liao et al. showed that BXXXD may exert a therapeutic effect by modulating the abundance of gut microbiota and thus intervening lipid metabolism in the peripheral and hippocampus (Liao et al., 2023). Another network pharmacology suggested the antidepressant effects of BXXXD are related to drug response, steroid metabolism, lipid metabolism, inflammatory response, oxidative stress response, and other biological functions (Yu et al., 2020), which need further validation.