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Abstract

Depression, a mental illness that is receiving increasing attention, is caused by multiple factors and genes and adversely affects social life and health. Several hypotheses have been proposed to clarify the pathogenesis of depression, and various synthetic antidepressants have been introduced to treat patients with depression. However, these drugs are effective only in a proportion of patients and fail to achieve complete remission. Recently, herbal medicines have received much attention as alternative treatments for depression because of their fewer side effects and lower costs. In this review, we have mainly focused on the herbal medicines that have been proven in clinical studies (especially randomized controlled trials and preclinical studies) to have antidepressant effects; we also describe the potential mechanisms of the antidepressant effects of those herbal medicines; the cellular and animal model of depression; and the development of novel drug delivery systems for herbal antidepressants. Finally, we objectively elaborate on the challenges of using herbal medicines as antidepressants and describe the benefits, adverse effects, and toxicity of these medicines.

Keywords

antidepressant herbal medicines cell- and animal-based depressive models benefits and side effects novel drug discovery systems

Depression is a mental illness that adversely affects people's feelings, thoughts, and behaviors, as well as their physical health. The main symptoms of depression include anhedonia, sadness, depressed mood, slow movements.¹ Depression is mainly caused by the interaction of genetic and environmental factors; however, the exact etiology and pathological mechanisms of depression remain unclear.^2,3 Currently, several hypotheses regarding depression are discussed, and the widely accepted potential mechanisms are listed below: (1) The monoamine hypothesis: The insufficient activity of monoamine neurotransmitters has been observed in the central and peripheral nervous systems of patients with depression. Some antidepressants increase the concentration of monoamine neurotransmitters in the synaptic cleft of neurons via several pathways, including the inhibition of serotonin reuptake, norepinephrine reuptake, and serotonin and norepinephrine reuptake, to regulate mood.^4‐6 (2) The hypothalamic–pituitary–adrenal (HPA) axis: Patients with depression were found to have aberrant HPA axis stimulation. The long-term activation of the HPA axis by emotional stress leads to a chronic increase in glucocorticoid levels in the brain, leading to the onset of depression.^7,8 HPA axis imbalance is associated with decreased glucocorticoid receptor (GR) function, ultimately leading to central nervous system dysfunction.^9,10 Antidepressants have been shown to increase the expression and biological functions of GRs in patients with depression as well as in animal and cellular models.^8,11 (3) The neuroinflammation hypothesis: Stress may increase the release of neurotransmitters and pro-inflammatory cytokines (including tumor necrosis factor-α, interleukin (IL)1β, and IL6), which are directly involved in the development of depression.^12,13 (4) The neurotrophic theory: A reduction in brain-derived neurotrophic factor (BDNF) levels was observed in the serum and postmortem brain tissue of patients with depression, and the increased levels of BDNF in the central nervous system are associated with the efficacy of antidepressants.^14,15 In addition to the above hypotheses, the glutamate hypothesis, epigenetic theory, and circadian rhythm play important roles in depression and the effect of antidepressants.^16‐19 Although there are many hypotheses regarding the pathogenicity of depression, the mechanism of action of antidepressants remains to be fully understood, and many challenges remain regarding clinical medication, including the choice of antidepressants and long-term treatment. Therefore, optimizing the efficacy of antidepressants and minimizing their side effects remain a challenge.²⁰ The common side effects of synthetic antidepressants include dry mouth, weight gain, dizziness, headache, sexual dysfunction, and emotional retardation.^21,22 Moreover, in some children and adolescents, antidepressant use may increase the risk of suicidal thoughts and behaviors.²³ In addition, discontinuation syndrome, which mainly comprises flu-like symptoms, sleep disturbances, nausea, balance disturbances, changes in feelings, anxiety, and depression, can occur when continuous antidepressant use is either interrupted or discontinued.²⁴ Thus, herbal medicines, as complementary and alternative treatments, can compensate for the deficiencies of synthetic compounds to a certain extent and have attracted increasing interest worldwide. Herein, we review herbal antidepressants that have undergone randomized controlled trials (RCTs), traditional and novel antidepressant targets, cellular and animal models of depression, and novel antidepressant discovery systems that provide a systematic investigation for the research and development of synthetic and plant-based antidepressants.

Molecular Targets for Antidepressants

According to the abovementioned hypotheses of depression, currently available antidepressants mainly target the monoamine system to alter serotonin (5 HT), norepinephrine, and dopamine levels in the brains of patients with depression.²⁵ Several classes of antidepressants have been approved for the treatment of depression. Early classic antidepressants, such as monoamine oxidase inhibitors (isocarboxazid and selegiline, which target monoamine oxidase) and tricyclic antidepressants (amitriptyline and imipramine, which target the serotonin and norepinephrine transporter), have shown considerable therapeutic effects, but are accompanied by numerous side effects and cardiotoxicity.²⁶ Second-generation antidepressants that target either serotonin or norepinephrine transporters, such as the selective serotonin reuptake inhibitors (SSRIs, citalopram, and fluoxetine), serotonin and norepinephrine reuptake inhibitors (venlafaxine and duloxetine), atypical antidepressants (bupropion and mirtazapine), and multimodal antidepressants (vortioxetine), are characterized by their pharmacodynamics, high safety, convenient administration, and good curative effect and have become popular drugs for the treatment of depression.²⁷ Although various types of antidepressants are available, the remission rate in patients with major depressive disorder (MDD) remains low. Approximately 50% of patients with depression cannot be completely cured by monotherapy with a single antidepressant, and 20%-30% of patients with depression do not respond to specific antidepressants.²⁸ The use of different treatment approaches comparable to monotherapy can easily lead to success in patients with major depression. Currently, treatment strategies combining antipsychotics and herbal medicines have been shown to be safer and more effective.²⁹

In recent years, ketamine has emerged as a typical rapid-acting antidepressant, an N-methyl-D-aspartate (NMDA) receptor antagonist, and an effective drug for the treatment of depression.³⁰ A clinical study found that ketamine significantly alleviates the symptoms of depression compared to placebo and also provides some relief in the treatment of patients with depression who had suicidal thoughts.^31,32 Based on functional magnetic resonance imaging data, ketamine reverses abnormal changes in the global brain connectivity of the forehead and resolves the stress-induced hypertrophy of nuclear accumulation.^33,34 Regarding biological mechanisms, ketamine may inhibit NMDA receptor activity, participate in α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor activation, and affect downstream signaling pathways related to BDNF.³⁵ Ketamine as a rapid-acting agent (SPRAVATO) has been approved by the Food and Drug Administration (FDA) for the treatment of adults with treatment-resistant depression.^36,37

Cell-Based Systems for Antidepressant Screening

Currently, various cellular models are used to explore the mechanisms of depression and develop effective antidepressants.³⁸ Among the various cellular models, neuronal cells, especially primary neuronal models based on hippocampal and cortical cells, are most commonly used because the cognitive behaviors associated with depressive behavior are mainly mediated in the cortex and hippocampal tissue of patients with depression or in depressed-like rodent models.³⁹ Other major neuronal cell models, including the PC-12 (rat pheochromocytoma), SH-SY5Y (human neuroblastoma cells), and HT-22 (immortalized mouse) models, are also widely used for the in vitro studies of depression-related gene function, neuronal toxicology, and pharmacology.^40‐42 In this study, we focused on these cellular systems to measure the activities of compounds and herbal drugs as antidepressants. The advantages and limitations of each cellular model were also evaluated.

Primary Neuronal Cells

Primary neuronal cells are generally prepared using brain tissue (hippocampus or cortical) of mouse/rat embryos on days 15/16 (cortical) and 17/18 (hippocampal) of gestation.^43,44 The advantage of primary neuronal cells is that they possess all the properties of living neurons and the entire neurotransmitter signaling system. However, the preparation and long-term maintenance of the culture still pose difficulties for researchers.⁴⁵ Currently, primary rodent neuronal cells are used in in vitro studies to investigate neuronal toxicology, pharmacology, electrophysiology, gene expression, development, and the effects of growth factors and hormones. Regarding depression, primary neuronal cell models of the corticosterone (CORT)-induced hippocampus and hypothalamus are used to evaluate the neuroprotective effects of antidepressants or to test new antidepressants.⁴⁶ For example, icariin, from the Chinese medicinal plant Epimedium sagittatum Maxim, inhibits the apoptosis of CORT-induced hippocampal and hypothalamic neurons by activating the PI3K-AKT pathway and inhibiting the p38/MAPK pathway, simultaneously.^47,48 Another study based on a cellular model also reported that agmatine inhibited the corticosterone (CORT)-induced apoptosis of primary hippocampal neurons and that the mechanism involved AKT and ERK and the activation of nuclear transcription factor 2.⁴⁹ In addition to CORT, cell apoptosis inducers such as NMDA, glutamate, staurosporine, and doxorubicin may elicit the injured cell model that has been studied for the neuroprotective effects of antidepressants and other agents on cortical and hippocampal neurons.^50,51 Since neurotrophic factors (such as BDNF) are significantly reduced in patients with depression and depression-like behaviors in animals, primary neuronal cell models in combination with BDNF detection can be used as a theoretical basis for screening antidepressant agents. A rapid detection and highly sensitive reporter gene system was established in primary cortical and hippocampal neuronal cells to characterize the specific activation spectrum of BDNF and cAMP response element (CRE) promoters, from which compounds with resistant depressive or neuroprotective agents were successfully identified.⁵² After silencing the BDNF gene in primary hippocampal neurons, neuronal cell survival was decreased and depression-like behavioral symptoms were induced, which were reversed by the Chinese medicinal preparation, Kai-xin-san.⁵³ A significant reduction in neuronal plasticity markers was observed in the prefrontal cortex and hippocampus of patients with depression. This phenomenon can be simulated by damaging hippocampal neurons with noxious substances, resulting in the NMDA receptor-mediated reduction of postsynaptic currents in hippocampal neurons, which can be reversed by antidepressants (eg, smoringa and hypericin).^54,55 In addition to these cerebellar granule cell models,⁵⁶ embryonic cortical progenitor cells,⁵⁷ hippocampal neural stem cells,⁵⁸ and fetal midbrain neural stem cells⁵⁹ have been developed to test new compounds with neuroprotective effects and to find potential antidepressants.

PC-12 Cells

PC-12 cells, derived from the adrenal glands as a part of the HPA axis, are the standard cell line for studies on depression and antidepressant mechanisms.⁶⁰ PC-12 cells are often used alone (combined with primary neuronal cell cultures) in animal behavioral experiments to study the antidepressant effects of synthetic substances and natural products. The standard assay, using the PC-12 cell line to screen for potential antidepressant activity, mainly involves the CORT-induced and nerve growth factor (NGF)-stimulated PC-12 cell damage models. The degree of damage is usually assessed by measuring a series of activity experiments in cells treated with CORT which include cell survival, lactate dehydrogenase release, and cell apoptosis rates; intracellular calcium ion concentration; mitochondrial apoptotic pathway-mediated changes in mitochondrial membrane potential; cytochrome C release; apoptotic caspase family activation; and DNA fragment generation.^61‐66 Synthetic compounds (such as fluoxetine, venlafaxine, and agomelatine) and natural low-molecular-weight compounds (such as quercetin, icarin, coumarin, saikosaponin D, saponins, saiko-total saponins, pigeon pea leaf alcohol extracts, ginseng water extracts, and other traditional Chinese medicine [TCM] extracts) reportedly have significant neuroprotective effects in the CORT-induced PC-12 cell injury model.^67‐73 Under NGF induction, the proliferation and growth of PC-12 cell neurites, which exhibit a differentiated phenotype resembling primary cultured sympathetic neurons, are suspended. Therefore, NGF-induced PC-12 cell models have been widely used to study depression and the effects of antidepressants. Using the NGF-induced PC-12 cell model, synthetic compounds (such as paroxetine, citalopram, fluoxetine, and sertraline), as well as natural low-molecular-weight compounds (such as carnosic acid, isorhamnetin, rosmarinic acid, and hypericin perforation leaflet), significantly alter the physiological activity of the PC-12 cell line.^65,74‐77 In addition to the abovementioned cell models, other PC-12 cell injury models, such as the oxidative stress (hydrogen peroxide)-mediated, 6-hydroxydopamine-induced, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced, and glutamatergic overactivation (glutamate, NMDA)-mediated models of PC-12 cell injury, have been used to study the neuroprotective effects of antidepressants.^78‐83 Due to the good properties of simple transfection, a reporter gene-based system was introduced to screen compounds with antidepressant activity. The transient transfection of vectors containing the reported fusion gene into PC-12 cells was performed to study the effect of antidepressants on the pathway of CRE-binding protein directed gene transcription.⁸⁴ By reporter-gene based system combing, researchers have measured the optimization and tolerability of Kai-xin-san.⁸⁵

SH-SY5Y Cells

SH-SY5Y cells are widely used to study the mechanisms of depression and the effects of antidepressants in in vitro models. It allows for the study of both neurotoxicity and neuroprotection, but it has the disadvantage of frequent differentiation during cell culture. Using the SH-SY5Y cell line, synthetic antidepressants and natural products have been used to measure the neuroprotective effects in the glucocorticoid- or oxidative stress-induced SH-SY5Y cell injury.^86‐89 In the CORT-induced SH-SY5Y cell injury model, the bioactivity of ethanol extracts of Radix polygalae was measured by 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and bromodeoxyuridine (BrdU) cell proliferation assay, and it was found that Polygala oligosaccharide esters exert some neuroprotective effect.⁸⁷ Using oxidative stress-induced SH-SY5Y cells, Bupleuri radix was found to exert an antidepressant effect which was mainly related to its antioxidant property.⁹⁰ Tianeptine was found to exert a considerable neuroprotective effect in SH-SY5Y cells damaged by taurosporine and adriamycin; this effect was associated with the dysregulation of the expression of the MAPK/ERK1/2 and PI3K-Akt signaling pathways.⁵⁰ In summary, an increasing number of pharmacological studies have been performed using the SH-SY5Y cell line to investigate the cytotoxic or neuroprotective effects of natural products and drug candidates, which may be a key point for measuring the side effects of new drugs.^91‐93

In addition to the abovementioned cell lines, there are other cell lines—the HT-22, AR-5, and the C6 cell line of rat glioma—in which the neuroprotective effects of antidepressants have been studied. Currently, the apparent protective effects of 17β-estradiol, melatonin, flavonoids, curcumin, and some herbal drug extracts on oxidative stress- or glutamate-induced HT-22 cell damage have been elucidated.^94‐97 Regarding the glucocorticoid-treated AR-5 cell line, which can simulate impaired hippocampal neuroplasticity in animal models of depression, the effects of various antidepressants on corticotrophin-releasing factor receptors have been demonstrated.⁹⁸ Since C6 cells characteristically exhibit high levels of synthesis and release of glial cell-derived neurotrophic factor (GDNF), a C6 cell-based model was used to investigate the effects of various antidepressants on GDNF production and release.⁹⁹

Various cell models have been developed to study the mechanisms underlying depression and antidepressants. Cell models are of great importance for excluding toxic drugs with side effects and for preliminarily screening drugs with antidepressant effects. However, the disadvantage of cell models is their altered gene expression profile compared to in situ cells, which have higher receptor expression. Therefore, cell models are often combined with studies on rodent models of depression to determine the cell-specific antidepressant mechanisms of drugs.^100,101

Animal Models of Depression

In the development of new drugs, animal models have proven to be an effective approach to evaluate antidepressant activity and pharmacodynamics in preclinical studies. In addition, animal models provide a means for understanding the interactions between the genetic factors, environmental factors, and internal molecular mechanisms of depression.¹⁰² Rodent depression models typically involve the administration of acute or chronic distress stimuli, drug induction, and gene knockout. Chronic unpredictable mild stress (CUMS) and learned helplessness (LH) models mediated by pressure stimuli are widely used in studies on the treatment of depression with synthetic agents and TCM.¹⁰³

In the CUMS model, rodents are exposed to chronic mild or unpredictable stress stimuli over a period to elicit depression-like behavior. CUMS is currently the most widely used, reliable, and effective rodent model of depression. In CUMS rats, curcumin was found to ameliorate anhedonia, memory loss, and decreased autonomic activities and reverse the abnormal expression of BDNF and ERK in the hippocampus.⁵³ A recent study using CUMS mice reported that curcumin exerted an antidepressant effect in the forced swimming and elevated plus maze tests and a potential antioxidant effect in the in vitro 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) test.¹⁰⁴ Bupleuri radix was administered to CUMS rats, and it was found that the drug exerted a protective effect on body weight, sugar water preference rate, and autonomic activity. In addition, Bupleuri radix regulated changes in neurotransmitters and their metabolites in the hippocampus and prefrontal areas of CUMS rats.¹⁰⁵ Another important herbal medicine, ginseng total saponins, was observed to exert an antidepressant effect in the CUMS model; this effect was mainly associated with the upregulation of BDNF mRNA and monoaminergic neurotransmitters, the shortening of immobility time in the forced swimming test, and the moderation of the reduction in sugar water consumption and active curiosity.¹⁰⁶ The CUMS model has become an important tool for evaluating the antidepressant effects of test compounds in the preclinical phase.

In the LH model, experimental animals were mainly given an unavoidable and uncontrollable electric shock to develop depressive behavior, which is an important tool in the study of the pathogenesis of depression.¹⁰⁷ Using the LH model, curculigosides were found to reduce the time of immobility in the forced swimming and tail suspension tests, increase the expression of BDNF, mediate the AKT-mTOR pathway, and improve depression-like behavior and memory impairment.¹⁰⁸ Ginkgo biloba (EGB 761) was administered to rats with LH at doses of 50 and 100 mg/kg and significantly improved error avoidance and relieved the stress stimulus.¹⁰⁹ LH rats that received Yueju pill showed improved depressive behavior, and the underlying mechanism of the antidepressant Yueju pill was associated with increased BDNF expression and decreased eukaryotic elongation factor 2 phosphorylation.¹¹⁰ In the mice behavior test using the tail suspension and forced swimming tests, Yueju pill was used to examine its antidepressant effect, which may mediate the inhibition of NMDA receptors and the NO/cGMP pathway.¹¹¹ Plantago asiatica, Scrophularia ningpoensis, and Ilex pubescens also reportedly exert antidepressant effects in the LH model.¹¹²

In general, animal models can partially simulate the state of depression, but they cannot fully reproduce patients’ suicidal behavior and difficult-to-observe symptoms such as mood swings. Nevertheless, the CUMS and LH models, which can reflect the depressive state of animals, have become effective methods of studying the effect of antidepressants and TCM in depression.¹¹³

Herbal Medicine as Antidepressants

Based on clinical data, herbal medicines exert an effective antidepressant effect, especially in patients with mild-to-moderate depression.¹¹⁴ In addition, herbal medicines have fewer side effects compared to synthetic antidepressants. In recent decades, herbal medicines have been prescribed worldwide as complementary and alternative medicines to treat depression.¹¹⁵ We have systematically searched the Medline/PubMed database using the following keywords: depression,” “herbal medicines,” “botanical medicine,” and “double-blind randomization.” The articles retrieved mainly include preclinical and clinical studies, meta-analyses, and review studies reporting herbal medicines with potential antidepressant effects in clinical and preclinical in vitro and in vivo tests. Of note, this review mainly focused on herbal medicines which have been proven (in RCTs) to have clinical antidepressant effects and also described herbal medicines for which there is relatively strong evidence of antidepressant efficacy without RCT results.

Hypericum perforatum L.

Hypericum perforatum L., also known as St. John's wort (SJW), is a widely studied medicinal plant that is used to treat depressive symptoms; some of its important chemical components have been shown to exert antidepressant effects.^116‐119 The two main components, hypericin and hyperforin, together with polyphenols and flavonoids, are responsible for these antidepressant effects.^120,121 In rats treated for depressive behavior, the natural products of SJW—rutin, hypericin, and pseudohypericin—have been shown to improve depressive behavior in the forced swimming test within a certain concentration threshold.^122‐124 STW3-VI, a standardized SJW extract, significantly decreased plasma adrenocorticotropic hormone (ACTH) and CORT levels induced by chronic stress in rats and mice.¹²⁵ Moreover, STW3-VI increases the neutral growth of HT22 cells and inhibits the upregulation of inflammatory factors in lipopolysaccharide (LPS)-induced HT22 cells.¹²⁶

From a clinical perspective, a meta-analysis of 29 RCTs (n = 5489) showed that hypericum preparations had better antidepressant properties than placebo (relative risk [RR] = 1.28; 95% confidence interval [CI]: 1.10–1.49) and that its therapeutic efficacy was not worse than that of SSRIs and tricyclic antidepressants (RR = 1.00; 95% CI: 0.90–1.11).¹²⁷ A study by Kasper et al suggested that hypericum was effective for the long-term prevention of recurrent depression.¹²⁸ The adverse effects of hypericum are low, and the number of subjects withdrawn from clinical trials ranged from 0% to 5.7%, which was not significantly different from placebo.¹²⁹ Hypericum formulations are slightly better tolerated than serotonin reuptake inhibitors.¹³⁰ Remotiv (from Ze 117), a SJW commercial product, has been shown to relieve stress, mild depression, and nervous tension and maintain emotional balance. Preclinical studies have shown that Remotiv modulates neurotransmitters, including presynaptic serotonin, norepinephrine, and dopamine membranes in the cleft and postsynaptic spaces. The long-term administration of Remotiv also reduces presynaptic neurotransmitter reuptake, increasing neurotransmitter concentrations in the synaptic cleft.^131‐134 Research has also shown that the depression-relieving effects of SJW extract are associated with an increase in gamma-aminobutyric acid (GABA) receptors and circulating GABA levels.¹³⁵ In summary, as the most popular herbal medicine, SJW exerts the same effective antidepressant effect as various standard prescription antidepressants for mild-to-moderate major depression.

Rhodiola rosea L.

Rhodiola rosea L. (RL), also called “golden root,” is used as an herbal plant in northern Europe and some countries in Asia, mainly to improve the symptoms of depression.¹³⁶ RL extract elicited depression-like behaviors, such as a decreased sugar preference rate and exploration behavior in mice exposed to CUMS.¹³⁷ The psychopharmacological mechanisms of RL in the depression-like behavior model were mainly related to the inhibition of monoamine oxidase A, the modulation of the content of 5-HT, and the cell proliferation and number of neurons in depressed rats and mice.^138,139 Salidroside (SA), the primary bioactive compound in RL, exerts antidepressant activity in olfactory bulbectomized rats, which may be related to the regulation of the anti-inflammatory pathway and HPA axis activity.¹⁴⁰ In mice with LPS-induced depression-like behavior, SA treatment significantly attenuated LPS-induced inflammation, reduced NE and 5-HT levels in the prefrontal cortex, and increased the expression levels of BNDF and TrkB within the BDNF/TrkB signaling pathway.¹⁴¹ A clinical trial of the standardized RL extract—SHR-5—was conducted in a randomized, double-blind, placebo-controlled study of 89 patients with mild-to-moderate depression. Overall, depression and other emotional symptoms significantly improved, and no serious side effects were noted.¹⁴² Another randomized placebo-controlled trial in 57 patients with mild-to-moderate depression found that RL had fewer adverse events and was better tolerated, although its antidepressant effect was less than that of sertraline.¹⁴³

Echium amoenum Fisch. & Mey.

E. amoenum, also known as borage, is cultivated in most parts of Europe, particularly in the Mediterranean region. The main medicinal parts of the plant are the flowers and leaves, which have antioxidant, anti-inflammatory, and analgesic effects, among others, and can relieve depression in both humans and animal models.^144‐146 The active ingredients of E. amoenum include γ-linolenic acid, α-linolenic acid, δ6-fatty acryloyl desaturase, δ8-sphingolipid desaturase, pyrrolizidine alkaloids, mucilages, resin, potassium nitrate, calcium, and inorganic acids.¹⁴⁷ The antidepressant activity of E. amoenum may be related to its flavonoid, saponin, and unsaturated sterol components because the antidepressant activity of flavonoids is reportedly comparable to that of fluoxetine and imipramine.¹⁴⁸ An in vitro study reported that the oral administration of an aqueous E. amoenum extract (125 mg/kg) for 2 weeks increased serotonin and dopamine levels in the cerebrospinal fluid (CSF) of reserpine-induced depressed rats.¹⁴⁹ A recent study showed that, in the forced swimming test, the oral administration of an extract of E. amoenum (5 mg/kg) for 15 days ameliorated manganese (Mn²⁺)-induced depression-like behaviors, including weight gain, sucrose consumption, and immobility time.¹⁴⁶ In addition, E. amoenum attenuates Mn²⁺ neurotoxicity by decreasing the levels of reactive oxygen species (ROS), lipid peroxidation, and apoptosis in the hippocampus of Mn²⁺-treated rats.¹⁵⁰ A preliminary randomized double-blind clinical trial suggested that the administration of an aqueous extract of E. amoenum (375 mg/day for 6 weeks) improved depressive symptoms, as assessed by the Hamilton Depression Scale at 4 weeks. However, there was no significant difference between the E. amoenum and placebo groups at the sixth week.¹⁵¹ In a recent clinical study comparing the efficacy of E. amoenum syrup with that of citalopram, E. amoenum was shown to be more effective than citalopram in relieving depressive symptoms and had fewer complications than citalopram at 8 weeks.¹⁵²

Lavandula angustifolia Mill. (Lavender)

Lavender, a member of the mint family (Lamiaceae), is widely cultivated in Europe, North and East Africa, the Mediterranean, Southwest Asia, and India.¹⁵³ Lavenders can be used as ornamental plants in gardens and landscapes, but also as culinary herbs. Lavender essential oil contains fat-soluble constituents such as linalool and linalyl acetate, which have significant curative effects in a number of neurological disorders, especially depression, stress, and anxiety, according to the European Medicines Agency.^154,155 In the hydrogen peroxide-induced SH-SY5Y cell damage model, lavender essential oil was found to exert neuroprotective effects by modulating NMDA receptors, SERT, and hydrogen peroxide-induced neurotoxicity.⁴¹ Hritcu et al found that rats exposed to lavender essential oil for seven days showed significantly reduced depressive behaviors in the elevated plus maze and forced swimming tests.¹⁵⁶ Based on the high-dose CORT-induced rats depressive model, it was also found that lavender essential oil ameliorates depression-like behavior and increases neurogenesis and dendritic complexity in rats.¹⁵⁷ Currently, there are many clinical studies on the antidepressant effects of lavender. Akhundzad et al designed a small (n = 45) randomized clinical trial over 4 weeks to investigate the use of lavender tincture in combination with imipramine. The results showed that a combination of imipramine and Lavandula tincture exerted a synergistic effect and was more effective than imipramine treatment alone. Moreover, lavender tincture can be used as a complementary medication in the treatment of mild-to-moderate depression.¹⁵⁸ For postpartum depression, Conrad et al performed 4 weeks of either lavender essential oil inhalation therapy or TCM massage therapy; the Edinburgh Postnatal Depression Scale (EPDS) and Generalized Anxiety Disorder 7 (GAD-7) scores significantly improved with fewer adverse effects.¹⁵⁹ Meanwhile, lavender is recommended as a third-line adjunctive therapy for mild-to-moderate adult MDD (Level 3 evidence) by the Canadian Network for Mood and Anxiety Treatment Clinical Guidelines.¹⁶⁰

Crocus sativus L.

Crocus sativus, also known as saffron, is mainly grown in the Mediterranean region, East Asia, and the Iranian–Turkish region. Saffron extract contains more than 150 volatile and aroma-forming ingredients, mainly terpenes, terpene alcohols, and their esters. Saffron and saffron aldehyde are the two active constituents of saffron and are reportedly responsible for its antidepressant effects. As early as the early 11th century, Avicenna introduced the various uses of saffron in the treatment of depression and insomnia. In the last decade, a number of clinical studies have been conducted.^161,162 First, Akhondzadeh et al conducted a 6-week randomized, double-blind, controlled clinical trial for the treatment of depression comparing the antidepressant efficacy of 30 mg/day of saffron stigma extract with that of 100 mg/day of imipramine. The results showed that these two treatment groups could significantly reduce the Hamilton score, with no significant difference between the two treatment groups.¹⁶³ Meanwhile, Noorbala et al conducted a 6-week randomized, double-blind, antidepressant-controlled clinical trial of 30 mg/d saffron extract for the treatment of mild-to-moderate depression, and compared it with 20 mg/d fluoxetine; they reported that saffron at the abovementioned dose was similar in efficacy to that of fluoxetine (F = 0.13, df = 1, P = 0.71); this finding was replicated in a subsequent 8-week randomized, double-blind, fluoxetine-controlled clinical trial.¹⁶⁴ In a 6-week double-blind, placebo-controlled, randomized trial with 40 patients with MDDs, the Hamilton Depression Scale score in the group treated with saffron petals had a significantly better effect than the placebo (df = 1, F = 16.87, P < 0.001), which supports the efficacy of saffron petals in the treatment of mild-to-moderate depression.¹⁶⁵

Other Herbal Antidepressants

Besides the above-described antidepressant herbs that have undergone double-blind trials (Table 1), the following herbal medicines have shown credible antidepressant effects in preclinical trials, despite lacking sufficient RCT evidence: (1) Panax ginseng C.A. Mey.: In vitro experiment on P. ginseng has shown that Rg1 has neuroprotective properties and less toxicity. The Council for Alternative Medicine part of the Swedish study conducted a randomized, double-blind, placebo-controlled trial of Panax ginseng in menopausal women. After 16 weeks of using the Mental Health Questionnaire (PGWB) and the Women's Health Questionnaire (WHQ), the PGWB and WHQ scores did not differ between the P. ginseng (n = 193) and placebo groups; however, depressive symptoms were significantly improved. These findings need to be confirmed by more randomized placebo-controlled trials.¹⁶⁶ (2) Ginkgo biloba L. (GB): In several preclinical studies, GB was found to reverse LPS-induced depression-like symptoms in male rats, possibly related to its inhibitory activity against monoamine oxidase-B.¹⁶⁷ The mechanism of GB-associated antidepressant activity also involves biological pathways, such as inflammation, GABA activity, and nitrous oxide activity.¹⁶⁸ (3) Valeriana officinalis L.: V. officinalis extract has been recommended by traditional medicine systems and pharmacopeias for the treatment of symptoms such as depression, mild insomnia, and nervousness. The preclinical studies of animal models have confirmed that valerian extract has antidepressant effects in the forced swimming and elevated plus maze tests.¹⁶⁹ (4) Crataegus pinnatifida Bge.: In a recent study, C. pinnatifida reportedly exerted antidepressant and anxiolytic effects in an animal model with stressed mice. Further studies on its mechanism of action found that C. pinnatifida activated 5-HT1A receptors and increased BDNF levels in the prefrontal cortex, producing pharmacodynamic activity similar to that of the novel herbal treatments (NHTs) and escitalopram.¹⁷⁰

Table 1.

Summary of Mechanisms of Action, Major Active Constituents, and Side Effects of Herbal Medicines.

Herbal medicine	Possible mechanism of antidepressive effect	Working time	Side effects	Is it a food supplement ?
Hypericum perforatum (St John's wort)	⋄ Modulation of monoamine transmission via Na + channel ⋄ Nonselective inhibition of re-uptake of serotonin, dopamine, norepinephrine ⋄ Decreased degradation of neurochemicals ⋄ Increased binding/sensitivity/density to 5-HT1A,B ⋄Dopaminergic activity (prefrontal cortex) ⋄Inhibited neuronal release of glutamate ⋄ Neuroendocrine modulation ⋄ Anti-depressant activity in animal models	Its antidepressant effects need to be extended over a period of time	Mild stomach upset，diarrhea，dry mouth，headache，fatigue，dizziness，anxiety，restlessness，tingling，allergic skin reactions，sexual or erectile dysfunction，life damage，psychosis (rare).	St John's wort is considered a dietary supplement by the FDA.
Rhodiola rosea	⋄ Neuroendocrine modulation (inhibition of cortisol, stress-induced protein kinases, nitric oxide) ⋄ Monoamine oxidase A inhibition ⋄ Monoamine modulation ⋄ Normalization of 5-HT and anti-stress effects in animal depression models	Its antidepressant effects need to be extended over a period of time	Rhodiola may be safe if taken for 6-12 weeks. Rhodiola may cause dizziness, dry mouth, or excessive salivation. There is not enough reliable information to know if Rhodiola is safe when taken long term.	The leaves and shoots are eaten raw, having a bitter flavor, or cooked like spinach, and are sometimes added to salads. An extract is sometimes added as a flavoring to vodkas.
Echium amoenum (Borage)	⋄ Antidepressant mechanism currently unknown	Its antidepressant effects need to be extended over a period of time	Based on the available evidence, it is reasonable to conclude that Echium amoenum causes hepatotoxic and nephrotoxic effects in a dose- and time-dependent manner.	--
Lavender (Lavandula spp.)	⋄ GABA modulation (based on volatile constituents) ⋄ Anxiolysis shown in animal models (elevated plus maze and open field tests)	Its antidepressant effects need to be extended over a period of time	Lavender can usually be taken with food. It is probably safe to take as a medicine. Side effects include constipation, diarrhea and headache. Lavender is probably safe to use on the skin. It is usually well tolerated, but can sometimes cause skin irritation.	The flowers yield abundant nectar, from which bees make a high-quality honey. Monofloral honey is produced primarily around the Mediterranean Sea and is marketed worldwide as a premium product. Flowers can be candied and are sometimes used as cake decorations. It is also used to make “lavender sugar.”
Saffron (Crocus sativus)	⋄ Re-uptake inhibition of monoamines (dopamine, norepinephrine, serotonin) ⋄ NMDA receptor antagonism ⋄ GABA-α agonism	Its antidepressant effects need to be extended over a period of time	Saffron is commonly consumed as a spice or to color food. Saffron may be safe when taken as a medication in doses up to 100 mg daily for up to 26 weeks. Some common side effects include drowsiness, stomach problems, and nausea or vomiting. Allergic reactions are also possible. Taking large amounts of saffron by mouth may not be safe. High doses of 5 g or more can cause poisoning. Doses of 12–20 g can cause death. If you apply saffron to the skin, there is not enough reliable information to know if it is safe or what side effects it may have.	--
Panax ginseng (Ginseng)	⋄ HPA-axis modulation ⋄ Monoamine modulation (dopamine, serotonin) ⋄ Anti-inflammatory and antioxidant effects ⋄ Nitric oxide synthase inhibition	Its antidepressant effects need to be extended over a period of time	Oral intake of Panax ginseng for 6 months may be safe. If taken for more than 6 months, P. ginseng may not be safe. It may have some hormone-like effects and may be harmful in the long run. The most common side effect is sleep disturbance. Rare side effects that have been reported include severe skin rashes, liver damage, and severe allergic reactions. When used on the skin, there is not enough reliable information to know if P. ginseng is safe. It may cause side effects such as irritation and burning.	--
Crataegus pinnatifida	⋄Antidepressant effects were induced by increasing BDNF levels in the PFC and hippocampus of stressed mice	Its antidepressant effects need to be extended over a period of time	Hawthorn is possibly safe for most adults when used at recommended doses short-term (up to 16 weeks). It is not known whether hawthorn is safe when used long-term. In some people, hawthorn can cause nausea, stomach upset, fatigue, sweating, headache, dizziness, palpitations, nosebleeds, insomnia, agitation, and other problems.	In northern Chinese cuisine, the ripe fruits of C. pinnatifida are used for the desserts tanghulu and shanzhagao. It is also used to make the traditional sweets haw flakes and haw rolls, as well as candied fruit slices, jam, jelly, and wine. It is also traditionally used as the final ingredient in Cantonese sweet and sour sauce, although it has now been partially replaced by ketchup.
Ginkgo biloba (Ginkgo)	⋄ Modulation of cholinergic and monoamine pathways ⋄ Antioxidant, anti-PAF, anti-inflammatory effects ⋄ GABAergic effects ⋄ Nitric oxide activity	Its antidepressant effects need to be extended over a period of time	Oral administration of Ginkgo biloba extract may cause some minor side effects such as stomach upset, headache, dizziness, and allergic skin reactions. G. biloba extract may also increase the risk of bruising and bleeding or cause cardiac arrhythmias. Roasted seeds or raw G. biloba may not be safe for oral use. Consuming more than 10 seeds per day may cause severe side effects such as seizures. Consumption of fresh seeds may result in death.	The nut-like gametophytes inside the seeds are particularly prized in Asia and are a traditional Chinese food. Ginkgo nuts are used in congee and often served on special occasions such as weddings and Chinese New Year (as part of the vegetarian dish Buddha's delight).

Novel Drug Delivery Systems for Herbal Antidepressants

Evidence from preclinical in vitro and in vivo experiments shows that some natural products and herbal medicines have strong antidepressant properties and few side effects, suggesting the need for the development of new drugs.¹⁷¹ However, only a few herbal medicines have passed the clinical phase and have been translated into clinical therapeutics. Compared with synthetic small compounds, herbal drugs are poorly soluble, permeable, and photodegradable, resulting in undesirable bioavailability through the blood–brain barrier (BBB).¹⁷²

Several novel drug delivery systems (NDDS) have been developed to improve the efficacy of drug molecules. These NDDS mainly include oral enteric-coated formulations, transdermal delivery, nasal therapies, nanotechnology-based products such as polymeric and lipidic nanoparticles, self-emulsifying NDDS, liposomes, nanostructured lipid carriers (NLCs), and nanodevices. Herein, we focus on liposomes and nanopreparations that have been used in the development of antidepressants and herbal medicines.^173,174

Liposomes are ultra-microsphere carriers composed of a lipid bilayer; they are typical examples of nano-drug delivery systems. Liposomes can be easily modified, have high efficiency and targeting ability, and can be used for drug delivery via the BBB. Comparison of the distribution of piperine in the brains of male Wistar rats treated with piperine-encapsulated liposomes and those treated with oral piperine showed that the administration of intranasal liposomes resulted in a higher concentration of piperine and a significantly higher antidepressant and cognitive activity.¹⁷⁵ In another study, the antidepressant effects of quercetin were investigated using liposomes. Behavioral tests showed that quercetin liposomes substantially enhanced the antidepressant effect in rats compared with nasal administration.¹⁷⁶

Another important NDDS, nanopreparations, considerably improved drug efficacy, reduced side effects, and increased stability.¹⁷⁷ Nanotechnology-based drug delivery systems include various nanostructures, such as polymer nanoparticles, lipid nanoparticles, nanoliposomes, nanomicrobes, and carbon nanotubes, as well as various delivery systems. The encapsulation of effective ingredients of herbal medicine and compounds in nanosystems can promote their passage through the BBB, increasing their concentration in the brain and their antidepressant effects in mood disorders.^178,179 The encapsulation of duloxetine in NLCs significantly shortened the time of forced swimming immobility, increased locomotor activity in behavioral tests of rats, and increased duloxetine levels in the brain and blood.¹⁸⁰ Valdecoxib encapsulated in a NLC gel had a rapid onset and long duration of action, and non-toxicity in the Draize patch test.¹⁸¹ The extract of Hypericum perforatum treated with synthetic nano-gold chloroauric acid was administered to mice stimulated by acute restraint stress, and it significantly improved memory loss, anxiety behavior, and oxidative stress damage in the mice.¹⁸² These rodent model experiments provide strong evidence that nanotechnology-based drug discovery can improve therapeutic efficacy and overcome the problem of the BBB.

NDDS can improve the ability of Chinese medicine to penetrate the BBB and increase the concentration of drugs transported into the brain tissue.¹⁸³ The combination of herbal medicine and novel delivery systems integrates the advantages of the two methods, minimizes the side effects of herbal medicine, and brings out the full healing effect of antidepressants. However, there are challenges to be overcome, including the delivery of the herbal medicine or drug to the exact site of action and the safety or efficacy of the novel herbal medicine delivery system. Therefore, the marketing of herbal medicines and preparations based on NDDS will have to be approved by the FDA.¹⁸⁴

The Benefits and Risks of Herbal Medicines

In general, herbal medicines consist of tissues and unpurified plant extracts and have some advantages, including low cost and fewer side effects.¹¹⁵ In addition, some herbal medicines are available without a prescription and are well tolerated and safe, making them suitable for treating patients for whom conventional treatments have failed or caused intolerable side effects.¹⁸⁵ Thus, natural remedies are a popular alternative or adjunct for people with mild mental illness, and if treatment fails, they do not have serious consequences.¹⁸⁶ Despite increasing evidence of the efficacy and safety of alternative therapies, along with the many Food and Drug Administration (FDA)-approved psychotropic drugs, clinicians need to be aware of the limitations and inadequacy of their clinical evidence. For limitations, herbal medicines lack the characteristics of same concentration, active ingredients, and the same biological chemicals, unlike synthetic antidepressants. In addition, some herbal remedies are not tested with the scientific rigor that is required for conventional drugs, and are not tested for purity and potency. For example, SJW may have monoamine oxidase inhibitory effects or elevate serotonin, dopamine, and norepinephrine levels and should not be prescribed with other synthetic antidepressants. Ginkgo biloba extract may interact with anticoagulants and antiplatelet agents. Panax ginseng is widely used because it is well tolerated; however, it may be responsible for a decreased response to warfarin.¹⁸⁷ At the same time, medicinal plants have a variety of pharmacologically active compounds that may act on multiple potential targets, and it is difficult to perform pharmacokinetic studies on medicinal plants.¹⁸⁸ In conclusion, exploiting the benefits of medicinal plants to avoid potential risks remains a challenge.

Future Strategies for the Treatment of Depression

For thousands of years, hundreds of herbal medicines have been used to treat patients with depression and have extensive clinical application.¹⁸⁹ These herbal medicines, including TCM, Ayurvedic medicine, and Western herbalism, exert therapeutic effects (clinically as monotherapy and complementary therapy) in patients with mild-to-moderate depression. The efficacy and safety of these herbal medicines have been demonstrated in relatively small groups of patients.¹⁹⁰ Many preclinical studies have confirmed that similar to ketamine and synthetic antidepressants, herbal medicines alleviate depression-like behavior in animals and that the neurochemical changes in animals treated with herbal medicines are consistent with those in animals treated with these synthetic antidepressants.¹⁵⁸ The main difference between herbal medicines and synthetic preparations as antidepressants to date is that all synthetic preparations have been approved by the FDA and have had their efficacy and safety demonstrated in clinical and preclinical trials. We have also evaluated the antidepressant effects of herbal medicines in placebo-controlled human trials.¹⁹¹ In conclusion, some natural medicines and their extracts have been used as antidepressants; however, the following efforts should be made to improve these herbal medicines: (1) an effective and uniform standard should be established to control the quality of herbal medicines, (2) effective biomarkers should be identified to evaluate the antidepressant effect of herbal medicines, and (3) better and more efficient delivery systems should be developed for herbal antidepressants.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclose receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (grant number: 31871281), Scientific Research Foundation for Advanced Talents of Shanghai University of Traditional Chinese Medicine, Shanghai Municipal Health Commission (grant number: 2020XGKY12), Scientific Research Foundation of Shanghai Municipal Commission of Health and Family Planning (grant number: 201840336), and Cross-disciplinary Research Fund of Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine (grant number: JYJC201901).

ORCID iD

Qingzhong Wang

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Review of Herbal Medicines for the Treatment of Depression

Abstract

Keywords

Molecular Targets for Antidepressants

Cell-Based Systems for Antidepressant Screening

Primary Neuronal Cells

PC-12 Cells

SH-SY5Y Cells

Animal Models of Depression

Herbal Medicine as Antidepressants

Hypericum perforatum L.

Rhodiola rosea L.

Echium amoenum Fisch. & Mey.

Lavandula angustifolia Mill. (Lavender)

Crocus sativus L.

Other Herbal Antidepressants

Novel Drug Delivery Systems for Herbal Antidepressants

The Benefits and Risks of Herbal Medicines

Future Strategies for the Treatment of Depression

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References