Phytochemistry and pharmacology of anti-depressant medicinal plants: A review

Biomedicine & Pharmacotherapy Volume 104, August 2018, Pages 343-365 Biomedicine & Pharmacotherapy Author links open overlay panelJeanetteMartinsBrijeshS Sunandan Divatia School of Science, NMIMS (Deemed-to-be) University, 3rd Floor, Bhaidas Sabhagriha Building, Bhaktivedanta Swami Marg, Vile Parle (W), Mumbai 400 056, India Received 30 January 2018, Revised 3 May 2018, Accepted 8 May 2018, Available online 25 May 2018. crossmark-logo https://doi.org/10.1016/j.biopha.2018.05.044 Get rights and content Highlights • The monoamine theory is the main focus behind action of many therapeutic drugs. • Therapies focus on receptor/transporter/monoamine oxidase inhibition/activation. • Anti-depressant mechanisms of several plants are still unexplored. • Phytochemical compounds have vast potential for anti-depressant therapy. Abstract Stress renders an individual to experience mental pressure and exhaustion which brings about feelings of anxiety, depression, anger and/or other negative emotions. Depression affects a person’s state of mind, behaviour, health and is often associated with suicide. The use of anti-depressant drugs as therapeutic agents is associated with symptoms such as, delayed onset of action, side-effects, drug–drug and dietary interactions, sexual dysfunction, cardiac toxicity, etc. Thus, there is need to target these issues and improve current treatment options. Medicinal plants have long been used in discovering novel treatment strategies and compounds with promising roles in treating various disease conditions. There has been an increase, worldwide, in the use of medicinal plants and herbs for developing nutraceuticals for treatment of depression and other psychiatric disorders. Medicinal plants in their natural forms are valuable as they are rich in various phytochemical compounds. These phytochemical compounds have pharmacological roles in treating various diseases conditions; apart from being widely available in nature and commercially beneficial. The phytochemical compounds in plants are constantly being explored through various experimental studies to determine the molecular basis of how medicinal plants work in relation to drugs and diseases and to develop neutraceuticals for improving conditions. This review summarizes 110 medicinal plants and their phytochemical constituents that have been shown to possess anti-depressant activity. This review also highlights the various mechanisms of anti-depressant action of some of these plants and their plant parts like roots, stem, leaves, flowers, fruit or whole plant; phytochemical compounds showing anti-depressant activity such flavanoids, steroids, saponins, sugars, lectins, alkaloids, etc.; and various anti-depressant screening models used such as tail suspension test, forced swim test, chronic unpredictable stress test, sucrose preference test, monoamine oxidase inhibition assay, learned helplessness test, open field test, hole board test, etc. However, mechanistic evaluation of many of these plants still needs to be investigated and explored. Graphical abstract Download high-res image (271KB)Download full-size image Previous article Next article Abbreviations HPAhypothalamic pituitary adrenocortical axis SERTserotonin transporter NETnorepinephrine transporter DATdopamine transporter CUMSchronic unpredictable mild stress test SPTsucrose preference test LHlearned helplessness OFTopen field test BrdUbromodeoxyuridine assay BDNFbrain-derived neurotrophic factor Keywords Depression Medicinal plants Serotonin TST FST MAO Antidepressant 1. Introduction 1.1. Depression and its forms Depression is a syndrome that is generally comprised of loss of interest, anxiety, disturbance in sleep, loss of appetite, lack of energy and suicidal thoughts, which can be recurrent. Stress is the main trigger of depression that is constant in today's world. It manifests itself as the body’s reaction towards a stimulus, displayed in the form of mental, physical and/or an emotional response [1]. Depression is initiated through stress and stressful situations that are difficult to solve and can cause a person to suffer and function poorly in everyday life. Under worst circumstances it can lead to suicide. According to the International Statistical Classification of Diseases and Related Health Problems (ICD-10) by the World Health Organization (WHO) [2] and the Diagnostic and Statistical Manual (DSM-V) by the American Psychiatric Association [3], there are multiple variations of depression that a person can suffer from. Depending on the number and severity of symptoms, a depressive episode can be categorized as: mild to moderate depression, major to severe depression and bipolar affective disorder. According to the National Institute of Mental Health (NIMH), depression is also seen to occur in the following forms: perinatal depression, seasonal affective disorder, disruptive mood dysregulation and premenstrual dysphoric disorder [[4], [5], [6], [7]]. 1.2. Disease burden Depression is a main cause of distress worldwide. The WHO reports more than 300 million people across the world suffer from depression which accounts for 4.4% of the world’s population [8]. Fig. 1 shows cases of depression (in millions) that are prevalent in different regions of the world. There has also been an 18% increase in cases of depression from 2005 to 2015, worldwide. The burden of depression, globally, is seen to be 50% higher for females than in males and is the leading cause of disease burden for women in high, low- and middle-income countries. The WHO Mental Health Action Plan 2013–2020, launched in 2008, ensures that the WHO member states commit themselves to work towards the global target of reducing the suicide rate in countries by 10% by 2020 [8]. Fig. 1 Download high-res image (143KB)Download full-size image Fig. 1. Cases of depression (in millions) prevalent in different regions of the world [8]. 1.3. Rating scales in diagnosing depression Two major governing bodies have laid down certain criteria to be considered for a person to be diagnosed as depressed or not. These are the ICD-10 and the DSM-V [2,3]. A number of clinician-rated and patient-rated scales have also been developed as efficacy measures in depression clinical trials for diagnosing depression in patients (Table 1). The Hamilton Rating Scale for Depression and Montgomery-Asberg Depression Rating Scale are the ones that are commonly used by clinicians and researchers in assessing patient symptoms in diagnosis or for checking the efficacy of drugs in therapy [9]. Table 1. List of various clinician-rated and patient-rated scales for depression [9]. Common Rating Scales for Depression 1. The Hamilton Rating Scale for Depression (HAM-D or HRSD) 2. Montgomery-Asberg Depression Rating Scale (MADRS) 3. Raskin Depression Rating Scale 4. The Beck Depression Inventory (BDI) 5. Inventory of Depressive Symptomatology (IDS or QIDS) Other Rating Scales for Depression 1. Centre for Epidemiological Studies - Depression Scale (CES-D) 2. Center for Epidemiological Studies Depression Scale for Children (CES-DC) 3. Edinburgh Postnatal Depression Scale (EPDS) 4. Goldberg Health Questionnaire (GHQ) 5. Geriatric Depression Scale (GDS) 6. Hospital Anxiety and Depression Scale (HADS) 7. Kutcher Adolescent Depression Scale (KADS) 8. Major Depression Inventory (MDI) 9. Mood and Feelings Questionnaire (MFQ) 10. Newcastle Depression Scales (NDS) 11. Patient Health Questionnaire (PHQ) 12. Weinberg Screen Affective Scale (WSAS) 13. Zung Self-Report Depression Scale (Zung SDS) 1.4. Neurochemistry of depression The monoamine theory of depression has been a major focus of research in the fields of pathophysiology and pharmacotherapy for more than 25 years and most of the antidepressant treatment is based on this theory [10]. This theory states the underlying basis of depression to be as a result of depletion in the monoamine levels of serotonin, norepinephrine, and/or dopamine in the brain [11]. Serotonin, norepinephrine and dopamine are major neurotransmitters in the brain, of which, serotonin or 5-hydroxytryptamine (5-HT) is the neurochemical which primarily affects depression and moods. Serotonin binding sites are located predominantly in the raphe nucleus of the brain and other areas of the brain, including the frontal cortex, the striatum and limbic system, affecting the hypothalamus and hippocampus [12]. Serotonin controls feelings of hunger, appetite, the drive to act, violence, impulsiveness, anxiety, fearfulness, ability to think clearly, perception, etc. Norepinephrine promotes vigilance by increasing arousal and alertness. It also enhances memory formation and retrieval. Dopamine functions mainly in motor control, reward-motivated behaviour and in the release of various hormones besides other functions [13]. Fig. 2 illustrates the pathways through which these neurotransmitters function. Fig. 2 Download high-res image (762KB)Download full-size image Fig. 2. Neurotransmitter pathways in the brain. (A) Noradrenergic neurons are confined to certain areas of the brain such as the caudal ventrolateral part of the medulla, the solitary nucleus of the brainstem and the spinal cord, where they function in control of body fluid metabolism, food intake and in response to stressful situations. The most important source of norepinephrine in the brain is the locus coeruleus. It sends projections to every major part of the brain and the spinal cord. (B) The serotonin binding sites is located predominantly in the raphe nucleus of the brain and spread to all areas of the brain, including the frontal cortex, striatum and limbic system, affecting the hypothalamus and hippocampus. (C) The dopaminergic pathways project from the substantia nigra pars compacta and ventral tegmental area into the striatum and form one component of a sequence of pathways known as the corticobasal ganglia thalamocortical loop which is used in the study of many psychiatric illnesses. (D) In the central nervous system, acetylcholinergic projections are found from the basal forebrain to the cerebral cortex and hippocampus. It supports the cognitive functions of these target areas. 1.4.1. Serotonin receptors The 5-HT receptors control the release of many neurotransmitters and hormones. They also influence biological and neurological processes such as anxiety, appetite, mood, memory, learning, cognition, nausea and sleep [13]. Hence, they have been used as therapeutic targets for various pharmacological drugs. There are seven serotonin receptor classes namely 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, 5-HT7, which are further divided into various subclasses: 5-HT1 A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1 F; 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, 5-HT5B, 5-HT6 and 5-HT7. [14]. Studies have reported that patients with major depression show changes in 5-HT1A receptor as well as a reduction in its density at the postsynaptic terminal [15,16]. Genetic studies have also shown that individuals with a high density and activity of 5-HT1A autoreceptors are more prone to mood disorders and respond poorly to antidepressant treatment [17]. This suggests that 5-HT1A receptor antagonists may possess anti-depressant activity. Activation of 5-HT1B heteroreceptors promotes anti-depressant behaviour and 5-HT1B receptor knockout mice have been reported to display highly aggressive behaviour and have increased preference for alcohol [18,19]. Therefore, 5-HT1B receptor activation may play an important role in anti-depressant activity. Unlike the 5-HT1A and 5-HT1B receptors, the clinical significance of other subclasses of 5-HT1 receptors (5-HT1D, 5-HT1E, 5-HT1F) still remains unclear. Studies have also shown that antipsychotic drugs and antidepressant tricyclic drugs augment the clinical response to SSRIs via their interaction with α2 adrenoceptors and the 5-HT2A receptor in treatment-resistant patients. This indicates the significance of these receptors in anti-depressant activity [20,21]. Lack of 5-HT2B receptors has been shown to be associated with impulsive behaviour in individuals and suicidal intent due to changes in serotonin neurotransmission to certain regions of the brain [22]. This suggests that 5-HT2B receptor agonists may help bring about anti-depressant activity. Preclinical studies have also shown that selective and nonselective 5-HT2C antagonists potentiate the effects of SSRIs on brain serotonin levels and also significantly augment the effect of SSRI drugs in behavioural models of depression [23]. More recently, 5-HT3 receptor antagonism with drug ondansetron has been reported to potentiate the increase in extracellular 5-HT produced by SSRI citalopram in rat forebrain [24]. Conductier et al., demonstrated the inhibitory response of serotonergic neurons to SSRI drug citalopram in 5-HT4 knockout mice, suggesting this receptor to be significant in maintaining the firing activity of serotonergic neurons during SERT inhibition [25]. 5-HT6 antagonists such as SB-399885 have been reported to exert antidepressant effects in the forced swim and tail suspension test models of depression in rats and mice [26]. Studies have also demonstrated anti-depressant and anxiolytic effects of 5-HT7 receptor antagonist SB-269970 in rodents, as well as a synergistic interaction between sub-effective doses of this drug and anti-depressants [27]. Thus, anti-depressant activity is brought about by drugs acting as agonists and antagonists to the 5-HT receptors. 1.4.2. Norepinephrine receptors Adrenergic or noradrenergic receptors are of two main types: alpha (α) and beta (β), both of which are targets for adrenalin and noradrenaline. They have the following subtypes: α receptor subtypes: α1 A, α1B, α1D, α2A, α2B, α2C; β receptor subtypes: β1, β2 and β3 [28]. During stressful conditions, high levels of norepinephrine are released into the prefrontal cortex (PFC) [29,30]; which stimulate the α1 receptors and impair PFC functioning [31]. Birnbaum and co-workers showed that inclusion of the α1 receptor antagonist, urapidil reversed the impairments observed in PFC functioning; suggesting that α1 antagonists may aid in anti-depressant activity [31]. The function of α1B and α1D receptors and their mode of action as anti-depressants require further investigation. Studies have also demonstrated that young monkeys [32,33] and aged monkeys and rats [32,34,35] with impaired working memories showed significant improvements when treated with α2 agonists such as clonidine and guanfacine. These data suggest that drugs and plants acting as α2 agonists may bring about anti-depressant activity as well as improve the performance of working memory by restoring levels of neurotransmitters in young and old patients. Also, knockout of the α2C receptor subtype in rodents showed reduced depressive behaviour in response to stressful situations when experimented in the forced swim test model of depression; suggesting that α2C receptor antagonists may be effective in inducing anti-depressant activity and treating stress-induced psychiatric disorders [36]. However, there is limited data regarding the function of α2B receptor and its role in depression needs to be further studied in detail. Activation of the β adrenergic receptors has been known to play an important role in long-term memory consolidation in the amygdala and the hippocampus [37]. Like α1 receptors, the β1 receptor is also likely to impair PFC functioning during stressful conditions and so, based on this observation, inclusion of β1 antagonists like betaxolol showed improvements in the performance of working memory in rats and monkeys [38]. Al-Tubuly et al. later showed the anti-depressant effect of the anti-anxiety drug alprazolam to be via activation of the β2 adrenergic receptor [39]. Amibegron (SR-58611A), a selective β3 receptor agonist, significantly reduced the depressive behaviour as examined in the forced swim test model in rats suggesting that anti-depressant action is brought about by drugs acting as β3 receptor agonists [40]. Thus, anti-depressant activity is also brought about by targeting α and β noradrenergic receptor function. 1.4.3. Dopamine receptors Dopamine receptors comprise of two families: D1 receptor family consisting of subtypes D1and D5 and D2 receptor family consisting of subtypes D2, D3 and D4. The most abundant and studied subtypes are the D1 and D2 receptors [41]. Studies have shown that D1 receptors are involved in bringing about anti-depressant activity. Synthetic drugs like SKF-38393 and A68930 have been shown to induce anti-depressant activity as examined in the rat forced swim test by acting as selective D1 receptor agonists [42]. Li et al. also showed that pre-treatment with D2 and D3 receptor antagonist, haloperidol, significantly inhibited the antidepressant effect of ketamine in the mouse forced swim test, indicating that the anti-depressant action of ketamine might be through activation of D2 and D3 receptors [43]. Moreover, Chourbaji and co-workers demonstrated that D3 receptor knockout mice exhibited depressive behaviour in the forced swim test and the learned helplessness paradigms of behavioural models, suggesting that the presence and activation of the D3 receptor being essential for bringing about anti-depressant activity [44]. These studies indicate that drugs acting as agonists to D1 and D2 dopaminergic receptors may show potential anti-depressant activity. 1.4.4. Neurotransmitter transporters (DAT, NET and SERT) Anti-depressants such as the selective serotonin reuptake inhibitors (SSRIs) and the dual acting serotonin and norepinephrine reuptake inhibitors (SNRIs), which account for more than 90% of the global anti-depressant market, have been reported to bring about anti-depressant activity by targeting and inhibiting the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) in neuronal membranes. DAT, NET and SERT function in re-uptake of their respective neurotransmitters into the pre-synaptic neuron after its release from the pre-synaptic terminal. Inhibition of DAT, NET and SERT prevents re-uptake and thus increases the levels of neurotransmitters dopamine, norepinephrine and serotonin respectively, in the brain. Therapeutic drugs in anti-depressant treatment target these transporters thereby alleviating depressive symptoms. Fig. 3 illustrates this mechanism of anti-depressant action. A very well documented study is the mechanism of action of SSRI drug escitalopram in SERT inhibition [45]. The selectivity and inhibition potential of various classes of currently used anti-depressant drugs have also been extensively studied in inhibiting SERT, NET and DAT [46]. This represents another mechanism of anti-depressant action besides drug-receptor interaction. Fig. 3 Download high-res image (305KB)Download full-size image Fig. 3. Role of dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) in neurotransmitter re-uptake. Anti-depressant drugs such as the selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine reuptake inhibitors (NRIs) like reboxetine and other psychoactive drugs like cocaine, amphetamine, 3,4-methylenedioxymethamphetamine (MDMA) also known as ecstasy, etc. have been shown to bring about anti-depressant activity by targeting and inhibiting the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) in neuronal membranes. DAT, NET and SERT function in re-uptake of their respective neurotransmitters into the pre-synaptic neuron after its release from the pre-synaptic terminal. Inhibition of DAT, NET and SERT prevents re-uptake and thus increases the levels of neurotransmitters dopamine, norepinephrine and serotonin respectively, in the brain. Therapeutic drugs in anti-depressant treatment target these transporters thereby alleviating depressive symptoms. Abbreviations: L-3,4-dihydroxyphenylalanine (L-DOPA), dopamine (DA), dopamine transporter (DAT), amphetamine (Amph), 1-methyl-4-phenylpyridinium (MPP+), norepinephrine (NA), norepinephrine transporter (NET), serotonin (5-HT), serotonin transporter (SERT), 3,4-methylenedioxymethamphetamine (MDMA). 1.4.5. Monoamine oxidase enzyme inhibitors Inhibition of monoamine oxidase has been extensively studied in elucidating the mechanism of anti-depressant action of various drugs and plant compounds. Monoamine oxidases (MAOs) comprise of a class of enzymes that bring about the oxidative deamination of amines such as serotonin, norepinephrine and dopamine in the nerve cell. In humans, they exist in two isoforms– MAO-A and MAO-B. MAO-A brings about the oxidative deamination of serotonin, melatonin and noradrenaline whereas MAO-B breaks down phenethylamine and benzylamine. Both forms break down dopamine, tyramine and tryptamine equally [47]. Inhibition of this class of enzymes by various drugs and plant compounds, arrests the neurotransmitter breakdown process thus increasing their concentration in the brain and bringing about anti-depressant activity [48]. Fig. 4 illustrates this mechanism of anti-depressant action. Thus, plants and novel drug compounds acting as MAO-A and MAO-B inhibitors can bring about anti-depressant activity. Fig. 4 Download high-res image (310KB)Download full-size image Fig. 4. Role of monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors in bringing about anti-depressant action. Monoamine oxidases which exist in two isoforms in humans– MAO-A and MAO-B bring about the oxidative deamination of catecholamines such as serotonin, norepinephrine and dopamine. Catechol-O-methyltransferase (COMT) also comprise of a class of enzymes that degrade these catecholamines. MAO-A brings about the oxidative deamination of serotonin, melatonin and noradrenaline whereas MAO-B breaks down phenethylamine and benzylamine. Both forms break down dopamine, tyramine and tryptamine equally, although MAO-B is more selective in dopamine metabolism. Inhibition of these enzymes by various drugs, arrests the neurotransmitter breakdown process thus increasing the concentration of neurotransmitters in the brain and bringing about anti-depressant activity. Abbreviations: Monoamine oxidase A (MAO-A), monoamine oxidase inhibitor (MAOI), serotonin (5-HT), catechol-O-methyltransferase (COMT), monoamine oxidase B (MAO-B). 1.4.6. Neurobiological theories Recent theories in neurobiology propose that a deficit in adult neurogenesis in the hippocampus may be a result of major depressive disorder and that the mechanism of action of anti-depressant drugs may involve promoting neurogenesis [49]. The brain-derived neurotrophic factor (BDNF) which plays a major role in neuronal growth, survival, maturation and synaptic plasticity in the brain is present in the hippocampus. Stress suppresses synthesis of BDNF in the hippocampus and anti-depressant drugs increase its synthesis and signalling in the hippocampus and the frontal cortex [50]. Depressed patients show low serum BDNF concentrations with loss of hippocampal volume and decreased neuronal proliferation, correlating with the severity of depression. These effects are reversed with antidepressant drugs or electroconvulsive treatment [50,51]. In a post mortem study, the brains of patients depressed at the time of death also showed significant differences between the BDNF concentrations in the hippocampus of antidepressant-treated and untreated subjects [50]. In 2003, Santarelli and co-workers demonstrated the involvement of antidepressants in adult hippocampal neurogenesis. In addition, their study showed that 5-HT1A knockout mice do not exhibit neurogenesis or respond behaviorally to SSRI treatment, implicating that these receptors are also involved in anti-depressant-mediated neurogenesis [52]. Thus, drugs and plant-based molecules that increase BDNF levels in the hippocampus may show potential anti-depressant activity. 2. Current prevention and treatment strategies Current prevention and treatment strategies for depression include nonpharmacological and pharmacological treatment. Nonpharmacological treatments include psychotherapeutic measures, exercise and yoga, music therapy, wake therapy, mindfulness-based therapies (MBT), electroconvulsive therapy, vagus nerve stimulation, cranial electrotherapy, etc. [53]. Acute effects of depression can include dehydration, infection, ulcers, deep vein thrombosis, etc. while chronic effects of depression may include both cardiovascular disease and osteoporosis [54]. Hence, physical activity and fitness are recommended in depression cases and management of depression emphasizes on mobilization, nutrition and adequate hydration. Psychotherapeutic measures such as Cognitive Behavioral Therapy (CBT) and Interpersonal Psychotherapy (IPT) are effective and mostly preferred in cases of adolescent depression. CBT is a process that corrects self-thoughts leading to certain moods and behaviours. IPT treatment resolves interpersonal difficulties like, social isolation, prolonged grief, and role transition [55]. CBT, IPT or attachment-based family therapies have been demonstrated to reduce depressive symptoms in adolescents [56]. Exercise, yoga and music therapies are important as they help a person’s mood and sleep. Wake therapy or sleep deprivation is of particular interest because effect is observed the day after therapy. It is a therapy that falls under chronotherapeutics, which is a process that manipulates biological rhythms and helps improve disorders quickly. It is more effective in endogenous than in neurotic depression (70% vs 48% response) [57]. Pharmacological treatment of depression involves several classes of anti-depressant drugs which are somewhat superior to those of psychotherapy, especially in cases of chronic major depression [58]. The tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) were the first choice for pharmacological treatment of clinical depression. Although they are considered to be effective, they have increasingly been replaced by the Selective Serotonin Reuptake Inhibitors (SSRIs) and the Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), which have improved safety and side effect profiles. Electroconvulsive therapy is usually a last resort for people who do not respond to medications and are at a high risk of suicide. Vagus nerve stimulation and cranial electrotherapy stimulation devices are utilized in such cases and have been given authorization by the US Food and Drug Administration [59]. A combination of medication and psychotherapy is thus preferred in complex cases of depression. 3. Medicinal plants in treatment of depression Many of the modern-day medicines are derived from plants. The use of traditional medicine still plays an important role in basic health needs in developing countries and has become a normative basis for maintaining good health [60]. Herbal remedies and plant products as therapeutic agents have seen an increase in industrialised societies and in the treatment of both depression and anxiety as well. About three-quarters of the world population depend on traditional medicines for their primary healthcare needs [61]. The therapeutic value of medicinal plants is reflected in the percentage of medical prescriptions of which 25% are derived from plants [62]. Cragg et al. reported that 157 of 520 drugs (30%) were natural products or their derivatives [63]. In the expanded version of this study, Newman et al. found that over 60 and 75% of these drugs are used in the areas of cancer and infectious diseases, respectively [64]. Studies have demonstrated that many phytochemicals such as saponins, alkaloids, polyphenols, triterpenoids, essential oils, fatty acids and flavonoids possess anxiolytic and antidepressant-like effects [65]. The acceptance of herbal medicines in therapy has grown as a result of improvements in their quality and better treatment outcomes. Table 2 shows 110 medicinal plants that have been reported to have anti-depressant activity. The table highlights the mechanistic evaluation of different plants in bringing about anti-depressant activity, plant parts that have been investigated like roots, stem, leaves, flowers, fruit or whole plant; phytochemical compounds showing anti-depressant activity such as flavanoids, steroids, saponins, sugars, lectins, alkaloids, etc.; and various anti-depressant screening models used, such as tail suspension test, forced swim test, chronic unpredictable stress test, sucrose preference test, monoamine oxidase inhibition assay, learned helplessness test, open field test, hole board test, etc. Various classes of phytocompounds that have been evaluated with for their anti-depressant activity are described below. Table 2. Mechanism(s) of action and phyto-chemical compounds of Ethnological plants showing anti-depressant activity. Plant Ethnological diversity of the plant Family and common name Part(s) of plant showing anti-depressant activity Type of extract(s) used Models/Tests performed Mechanism(s) of anti-depressant activity Neutraceutical compounds responsible References Agapanthus campanulatus Provinces of South Africa: Eastern Cape, Lesotho, KwaZulu-Natal, Gauteng and Mpumalanga Family:Agapanthaceae Common name: Bell agapanthus Leaves, Flowers, Roots Aqueous, Ethanolic [3H]-citalopram- binding assay, TST, FST, Serotonin transporter (SERT), Norepinephrine transporter (NET) and Dopamine transporter (DAT) uptake inhibition assay High affinity for SERT, Inhibition of SERT, NET and DAT Flavonoids [119,120] Akebiae fructus Chinese herb found in: Jiangsu, Anhui, Zhejiang, and Hunan provinces of China Family: Lardizabalaceae Common name: Akebia Fruit Fruit powder Ethanolic TST, FST, Chronic unpredictable mild stress test (CUMS), Locomotor activity, Sucrose preference test (SPT), Monoamine uptake assay High affinity for SERT, NET and DAT; affinity being highest for NET > DAT > SERT; seen for both rat and human transporters. Also, inhibits uptake activity of all three transporters in a dose dependant manner; inhibition of NET being the highest Hederagenin [85,86] Albizzia julibrissin Iran (Persia), The Republic of Azerbaijan, China and Korea. Also planted in California's Central Valley, Central Texas and Oklahoma Family: Fabaceae Common names: Mimosa, pink siris or Persian silk tree Stem bark Ethanolic TST Via activation of the serotonergic system through the 5-HT1A receptor system Saponins [66] Albizzia lebbeck Indomalaya, New Guinea and Northern Australia Family: Fabaceae Common names: Lebbek Tree, Flea Tree, Frywood, Siris tree Bark Ethanolic TST, FST, Locomotor activity – – [233] Allium cepa Central, western, eastern Asia and worldwide Family: Amaryllidaceae Common names: Bulb onion, common onion Bulb powder Aqueous FST, Locomotor activity Prevented an increase in the metabolite/neurotransmitter ratio; suggesting its mechanism as an inhibitor of Monoamine oxidase (MAO) Quercetin glycosides (Flavonoids) [121] Aloysia polystachya Desert, subtropical and temperate regions of America Family: Verbenaceae Common names: Beebrushes,; Té de burro Aerial parts Hydro-alcoholic FST – – [172,196] Anemarrhena asphodeloides Native to China, Korea and Mongolia Family:Asparagaceae Common name: Zhi Mu Leaves – FST, MAO Inhibition assay Via interaction with norepinephrine (NE) and Serotonin (5-HT) systems, Inhibition of MAO-A and MAO-B activities Sarsasapogenin [87] Aniba riparia Central Amazonia and Guiana Family:Lauraceae Common names: Louro-rosa, Canela-cheirosa Unripe fruit Ethanolic TST, FST Via interaction with serotonergic, noradrenergic and dopaminergic receptor systems Riparin II, Riparin III [71,72] Apocynum venetum Linn. North America; South eastern Europe: Italy, Bulgaria, Ukraine; Temperate Asia: China, Kazakhstan, Siberia Family: Apocynaceae Common names: Luobuma, European dogbane or Dogbane leaf Leaves Ethanolic FST, Locomotor activity, TST Increase in NE and Dopamine (DA) levels in the hippocampus. Interaction with dopaminergic D1 and D2 receptor systems Hyperoside, Isoquercitrin (Flavonoids) [117,118] Areca catechu Tropical Pacific, Asia, parts of East Africa and Islands of the West Indies Family:Arecaceae Common names: Betel nut, Chalia, Pinang palm, Indian nut Areca nut Ethanolic FST, TST, Locomotor activity, MAO Inhibition assay Increase in 5-HT and NE levels in the hippocampus, MAO-A inhibitor Possibly Saponins Compound(s) responsible for MAO inhibition still need to be identified [70,122,123] Artemisia absinthium Eurasia, Northern Africa, Canada and Northern United States Family: Asteraceae Common names: Worm wood, Absinthe wormwood Aerial parts Methanolic TST, FST – – [136,185] Asparagus racemosus Nepal, Sri Lanka, India and the Himalayas Family: Asparagaceae Common names: Wild asparagus, Shatavari Roots Methanolic FST, Learned helplessness (LH), TST, Locomotor activity, MAO Inhibition assay Inhibition of MAO-A and MAO-B activities, Via interaction with serotonergic, noradrenergic, dopaminergic, and GABAergic receptor systems – [69,113] Bacopa monnieri Southern and Eastern India, Australia, Europe, Africa, Asia and North and South America Family:Plantaginaceae Common names: Brahmi, Water hyssop, Thyme-leafed gratiola Whole plant Methanolic FST, LH, Foot shock stress, Shuttle box test Via interaction with serotonergic, noradrenergic receptor systems and Inhibition of MAO-A and MAO-B activities – [[73], [74], [75], [76],186] Benincasa hispida (Thunb.) Cogn. South and Southeast Asia, Indonesia, Japan Family: Cucurbitaceae Common names: Ash gourd, Kushmanda, Petha, White gourd, Winter gourd, Winter melon, White pumpkin, Ash pumpkin Fruits, Seeds Methanolic, Aqueous TST, FST, Locomotor activity, MAO-A assay, Object recognition task, Morris water maze Via interaction with serotonergic, noradrenergic, dopaminergic and GABAergic receptor systems, Inhibition of MAO-A activity – [114,141] Boophone distica South Africa Family:Amaryllidaceae Common names: Gifbol, Bushman poison bulb, Tumble weed Bulb Ethanolic [3H]-citalopram- binding assay, TST, FST, SERT, NET and DAT uptake inhibition assay Inhibition of SERT, NET and DAT Buphanidrine, Buphanamine (Alkaloids) [119,120,161] Bupleurum falcatum Europe and Western Asia Family: Apiaceae Common names: Chinese Thorough wax – Methanolic TST – – [179,228] Camellia sinensis East Asia and Southeast Asia Family: Theaceae Common names: Green tea, White tea Leaves, Buds Ethanolic, Methanolic, Aqueous TST, FST, Hole cross test, Open field test (OFT), Thiopental sodium induced sleeping time test – Theanine [188,207,220,222,229] Canavalia brasiliensis Hawaiian Islands Family:Fabaceae Common name: Brazilian jackbean Seeds – FST Via interaction with serotonergic, noradrenergic and dopaminergic receptor systems Lectins [67] Carthamus tinctorius L. Western states and Canadian Prairie provinces Family: Asteraceae Common name: Safflower – Aqueous, Ethanolic TST, FST – – [187] Casimiroa edulis Eastern Mexico, Central America and Costa Rica Family: Rutaceae Common names: Zapote blanco, Matasano, Sleepy zapote Leaves Hydroalcoholic FST – – [195] Cayratia japonica Australia and Asia Family: Vitaceae Common names: Bushkiller, Yabu Garashi, Japanese Cayratia Herb Whole plant, Fruit Methanolic MAO Inhibition assay MAO inhibition Flavonoids [88] Centella asiatica Wetlands of Asia Family:Apiaceae Common names: Asiatic pennywort, Indian pennywort Leaves Ethanolic FST, Hole board test (HBT) Involved in ameliorating the function of HPA axis and increasing levels of monoamine neurotransmitters Total triterpenes [150,151,217] Cimicifuga racemosa Eastern North America Family:Ranunculaceae Common names: Actaea racemosa, Black cohosh, Black snakeroot – Ethanolic, Isopropanolic-aqueous extracts TST Partial agonist of serotonin receptor subtypes – [106] Cissampelos sympodialis Northeastern Brazil, Asia Family: Menispermaceae Common names: Milona, Bindweed Leaves Ethanolic, Hydroalcoholic FST – Total tertiary alkaloids [138,200] Citrus paradisi var. duncan. Florida, Texas, Barbados, USA and Asia Family: Rutaceae Common name: Grapefruit Leaves Methanolic FST – – [165] Clitoria ternatea Linn. Tropical equatorial Asia, Indonesia and Malaysia Family:Fabaceae Common names: Butterfly pea, Blue-pea, Cordofan-pea Roots, Aerial parts Ethanolic, Methanolic TST, FST, Locomotor activity – – [174,205] Coleus forskohlii Tropical Africa, Asia and Australia Family: Lamiaceae Common names: Plectranthus barbatus, Indian Coleus – – FST Increasing brain cAMP availability Forskolin [184,236] Convolvulus pluricaulis India, Burma Family: Convolvulaceae Common name: Shankhpushpi Whole plant Ethanolic TST, FST, Locomotor activity Possibly through restoration of brain monoamines – [155] Crocus sativus L Asia, Mediterranean and Irano-Turanian region Family: Iridaceae Common names: Saffron, Autumn crocus Petal, Stigma Aqueous, Ethanolic FST Induces dopamine and glutamate release in the brain Kaempferol, Safranal, Crocin [156,169,170] Curcuma longa Southeast Asia Family:Zingiberaceae Common name: Turmeric Rhizome Aqueous TST, FST, MAO Inhibition assay Inhibition of MAO-A activity in mouse whole brain Turmerone [182,244] Echium amoenum Northern Iran and Caucasus Family:Boraginaceae Common names: Boraginace, Ox-tongue Flowers Aqueous Clinical trial setting – – [216] Eleutherococcus senticosus Northeast Asia Family:Araliaceae Common names: Siberian Ginseng, Eleuthero, Ciwujia, Ezo-ukogi Root bark Aqueous FST – – [178] Emblica officinalis Parts of India and Indonesia Family: Phyllanthaceae Common names: Phyllanthus emblica, Indian gooseberry, Dhatrik, Amla Fruit Aqueous TST, FST, MAO Inhibition assay, Locomotor activity Inhibition of MAO-A activity – [124,125] Epimedium brevicornum Asia, China and Mediterranean region Family: Berberidaceae Common names: Barrenwort, Bishop's hat, Fairy wings, Yin yang huo – – CUMS – Icariin (Flavonoid) [204] Galphimia glauca Parts of South America and Amazon Basin Family: Malpighiaceae Common names: Thryallis, Noche buena Aerial parts Methanolic FST – – [210] Gastrodia elata Nepal, Bhutan, India, Japan, North Korea, Siberia, Taiwan and China Family: Orchidaceae Rhizome Hydroalcoholic, Ethanolic TST, FST Possibly by regulating both serotonergic and dopaminergic systems – [149,168,247] Gentiana kochiana Central and southern Europe, The Alps, Cevennes and Pyrenees Family: Gentianaceae Common names: Gentiana acaulis, Ciminalis acaulis, Gentiana excisa Aerial parts Diethylether FST, MAO Inhibition assay Inhibition of MAO-A activity Xanthones (Gentiacaulein) [89] Glycyrrhiza glabra Southern Europe and parts of Asia Family: Fabaceae Common name: Liquorice Roots Aqueous, Hydroalcoholic, Ethanolic TST, FST, Locomotor activity, MAO Inhibition assay Mediated by increase in brain NE and DA, Inhibition of MAO-A activity – [[126], [127], [128],231] Glycyrrhiza uralensis Asia, parts of China Family: Fabaceae Common name: Chinese liquorice Roots Aqueous SPT, FST, TST, CUMS, Locomotor activity Increased 5-HT and NE in the mouse hippocampus, hypothalamus and cortex Liquiritin, Isoliquiritin (Flavonoids) [157,237,246] Gossypium herbaceum Sub-Saharan Africa and Arabia Family:Malvaceae Common name: Levant cotton Leaves Aqueous – Activation of adenyl cyclase-cAMP pathway in signal transduction system – [177] Hippeastrum vittatum Regions of the Americas, Argentina, Mexico and the Caribbean Family: Amaryllidaceae Common name: Knight's-star-lily Bulb Ethanolic FST – Montanine (Alkaloid) [153] Humulus lupulus Europe, Western Asia and North America Family: Cannabaceae Common name: Hops – CO2 extract FST – Alpha-acids [245] Hypericum canariense Canary Islands, Australia, New Zealand, California and Hawaii Family: Hypericaceae Common name: Canary Islands St. John’s-wort Aerial parts Methanolic FST – – [189] Hypericum caprifoliatum Canary Islands, Southern Brazil Family: Hypericaceae – Cyclo hexane, Lipophilic FST Monoamine uptake inhibition; possible relation to its capacity to inhibit Na+ influx Phloroglucinol derivatives [90,91,234] Hypericum perforatum Parts of Europe and Asia Family: Hypericaceae Common name: St John's wort – Hydroalcoholic Escape deficit models, Anhedonia test, FST – Hyperforin [147,163] Hypericum reflexum Canary Islands Family: Hypericaceae Common names: Cruzadilla, Hiperico, Hierba cruz Aerial parts Methanolic FST – – [190] Inula japonica Europe, Asia and Africa Family: Asteraceae Common names: Petrollinia, Cupularia, Orsina Flowers Alcoholic – – Japonicins (Flavonol) [243] Japanese valerian roots Europe and Parts of Asia Family: Caprifoliaceae Common name: Hokkai-Kisso, Garden valerian, setwall, all-heal Roots Ethanolic FST – – [214] Kaempferia parviflora Thailand Family: Zingiberaceae Common names: Thai black ginger, Thai ginseng, Krachai Dam Rhizome Ethanolic FST – – [167] Kielmeyera coriacea Cerrado and Pantanal vegetation in Brazil Family: Calophyllaceae Common name: Pau Santo Stems Dichloromethane, hydroethanolic FST Antagonist at 5-HT1A autoreceptors Monoamine uptake inhibition Xanthones [77,[107], [108], [109], [110]] Lafoensia pacari Brazil, Paraguay Family:Lythraceae Common names: Pacari, Mangaba-brava Stem bark Ethanolic TST, FST – – [162] Lavandula angustifolia Mediterranean regions - Spain, France, Italy, Croatia Family:Lamiaceae Common names: Lavender, True lavender, English lavender, Narrow-leaved lavender Flowers Aqueous FST – Linalool, Linalyl acetate [171,175] Lepidium meyenii Meseta de Bombón Family:Brassicaceae Common name: Maca, Maino, Ayak chichira Hypocotyls Aqueous FST – – [209] Lobelia inflata Eastern North America, South eastern Canada Family: Campanulaceae Common names: Indian tobacco, Indian weed, Pukeweed, Asthma weed, Gagroot Leaves Methanolic FST Possibly through activation of noradrenergic activity Beta-amyrin palmitate [225,226] Magnolia officinalis China Family: Magnoliaceae Common names: Houpu Magnolia, Magnolia-bark Bark Aqueous FST, TST, CUMS – Magnolol, Dihydroxydihydromagnolol, Honokiol [198,240] Marsilea minuta Linn. Asia, Africa Family:Marsileaceae Common names: Susnisak, Small water clover Whole plant Ethanolic TST, FST – – [143] Melissa officinalis South-central Europe, Mediterranean, Basin, Iran, Central Asia and America Family: Lamiaceae Common names: Lemon balm, Balm mint Leaves Ethanolic FST – – [230] Mimosa pudica South and Central America, Asia Family:Fabaceae Common names: Touch-me-not, Sensitive plant, Sleepy plant Leaves Aqueous FST – – [193] Mitragyna speciosa Southeast Asia, Thailand, Indonesia, Malaysia, Myanmar and Papua New Guinea Family: Rubiaceae Common names: Ketum, Kratom Leaves Methanolic TST, FST – Mitragynine [173] Momordica charantia Asia, Africa and Caribbean Family: Cucurbitaceae Common names: Bitter melon, Bitter gourd, Bitter squash Whole plant – TST, FST Dependant on serotonergic, noradrenergic, dopaminergic, muscarinic cholinergic receptor systems – [111] Mondia whitei Sub-Saharan African regions Family: Apocynaceae Common names: White’s ginger, African ginger, Ogombo, Mukombelo, Mulondo – Ethanolic [3H]-citalopram-binding assay, SERT, NET and DAT uptake inhibition assays, TST, FST, Locomotor activity Affinity for SERT – [120] Morinda officinalis Southeast Asia, China, Vietnam, India Family: Rubiaceae Common names: Indian Mulberry, Ba ji tian Roots Aqueous FST, Locomotor activity Binds selectively to 5-HT1A receptor Succinic acid, Nystose, 1 F-fructofuranosylnystose, Inulin-type hexasaccharide, Heptasaccharide [78,79] Morus alba China, United States, Mexico, Australia, Kyrgyzstan, Argentina Family: Moraceae Common names: White mulberry, Tuta, Tuti, Toot Leaves Aqueous TST, FST – – [139,215] Myristica fragrans Moluccas of Indonesia, Guangdong, Yunnan, Taiwan, Indonesia, Malaysia, Grenada, Kerala Sri Lanka and South America Family: Myristicaceae Common name: Nutmeg Seeds n-hexane TST, FST – – [154,192] Nardostachys jatamansi Eastern Himalayas, Kumaon, Nepal, Sikkim and Bhutan Family: Caprifoliaceae Common name: Jatamansi Roots, Rhizome Ethanolic TST, FST, MAO Inhibition assay, Chronic restraint stress Inhibition of MAO activity Interaction with GABAB receptors – [129,130,176] Nelumbo nucifera Gaertn Tropical Asia, India, China, Queensland, Australia Family: Nelumbonaceae Common name: Sacred lotus Seeds – FST 5-HT1A receptor agonist Neferine (Alkaloid) [80] Ocimum sanctum Southeast Asia Family: Lamiaceae Common names: Tulsi, Holy Basil Leaves Ethanolic, Aqueous TST, FST – – [148,206,229] Paeonia lactiflora Central and Eastern Asia, Tibet, China, Siberia Family: Paeoniaceae Common names: Peony, Chinese peony, Common garden peony Roots Ethanolic TST, FST, MAO Inhibition assay, Locomotor activity Inhibition of MAO activity, Upregulation of serotonergic systems Paeoniflorin, Albiflorin (Glycosides) [98,99,208] Paullinia cupana Amazon basin, Brazil Family: Sapindaceae Common name: Guarana Seeds – FST – Methylxanthines and possibly others [145,202] Perilla frutescens Southeast Asia, India, China, Korea Family: Lamiaceae Common names: Korean perilla, Beefsteak plant, Shiso, Egoma Leaves – FST, BrdU Immuno histochemistry, CUMS, BDNF ELISA Via dopaminergic mechanism, Cell proliferation in dentate gyrus Apigenin, 2,4,5-trimethoxycinnamic acid, Rosmarinic acid [102,103,131] Piper laetispicum Tropical and sub-tropical regions Family: Piperaceae Common names: Xiao Chang-feng, Shan Hu-jiao, Ye Hu-jiao Stems Hydroethanolic, Ethyl acetate FST – Laetispicine, Leatispiamide A (Alkaloids) [203,238,242] Piper longum India, Nepal, North Africa, Indonesia, Malaysia Family: Piperaceae Common name: Indian long pepper Fruit Ethanolic TST, MAO inhibition assay Inhibition of MAO-A and MAO-B activities Piperine, Methylpiperate [100,101] Piper methysiticum Forst Western Pacific, Tongan and Marquesan Family name: Piperaceae Common name:methysiticum – – MAO Inhibition assay Inhibition of MAO-B activity, Via dopaminergic mechanism Pyrones, Desmethoxyyangonin [95,232] Piper tuberculatum Asia Family name: Piperaceae Common names: Pimenta longa, Pimenta darta Roots Petroleum ether/Ethyl acetate FST – Piplartine (Alkaloid) [158] Polygala tenuifolia China Family: Polygalaceae Common name: Yuan Zhi Roots Aqueous [125I]RTI-55-membrane binding assay, CUMS, BDNF assay, SPT, MAO Inhibition assay Norepinephrine reuptake inhibitors, Inhibition of MAO-A and MAO-B activities Polygalatenosides A and B (1 and 2), YZ-50, 3,6-disinapoyl sucrose [[92], [93], [94]] Protium heptaphyllum Amazon region and Cerrado Family: Burseraceae Common names: Almécega, Breu branco Stem bark – FST – Alpha- and Beta-amyrin (Triterpenes) [140] Psoralea corylifolia India, China Family: Fabaceae Common names: Babachi, Bakuchi, Ravoli Seeds – FST Inhibition of MAO-A and MAO-B activities, Mediated via serotonergic and HPA axis systems Psoralen, Psoralidin (Furocoumarins) [96,97] Ptychopetalum olacoides Amazon rainforest Family: Olacaceae Common name: Marapuama Roots Ethanolic TST, FST Via D1 dopamine and β-noradrenergic receptor systems – [116,223] Radix puerariae Asia, China Family: Fabaceae Common names: Kudzu, Pueraria lobata (Willd.) Ohwi Roots Ethanolic TST, FST – – [241] Rhazya stricta Southern Iran, Afghanistan, Pakistan, India, Iraq, Oman, Yemen, and Saudi Arabia Family: Apocynaceae Common name: Eshvarak Leaves Ethanolic, Aqueous MAO Inhibition assay, FST Inhibition of MAO-A activity – [132,137] Rhizoma acori China Family: Araceae Common names: Shi Chang Pu, Sweetflag Rhizome – Aqueous, Ethanolic TST, FST – – [180,181] Rhodiola rosea Arctic regions of Europe, Britain, Asia and North America Family: Crassulaceae Common names: Golden root, Arctic root Roots Methanolic, Aqueous, Dichloromethane MAO Inhibition assay Via serotonergic system, Inhibition of MAO-A and MAO-B activities Rosiridin [104,105] Rosmarinus officinalis Mediterranean regions Family: Lamiaceae Common name: Rosemary Stems, Leaves Hexane, Ethyl acetate, Ethanolic, Aqueous TST, FST Through the activation of dopamine D1 and D2 receptors Ursolic acid (Triterpenoid), Carnosol, Betulinic acid, 1,8-cineole [83,84,197] Roystonea regia Mexico and parts of Central America and the Caribbean Family: Arecaceae Common names: Cuban royal palm, Florida royal palm, Royal palm Fruit – TST, FST – Fatty acids [146] Salvia divinorum Oaxaca, Mexico Family: Lamiaceae Common names: Diviner's Sage, Ska María Pastora, Seer's Sage – – TST, FST – Salvinorin A [144] Salvia elegans Madrean and Mesoamerican pine-oak forests of Mexico and Guatemala Family: Lamiaceae Common names: Pineapple sage, Mirto, Flor del cerro, Limoncillo, Perritos rojos Leaves, Flowers Hydroethanolic FST – – [194,211] Schinus molle L. Peruvian Andes Family:Anacardiaceae Common names: American pepper, Peruvian peppertree, Escobilla, false pepper, Molle del Peru, Peppercorn tree, Californian pepper tree, Pirul, Peruvian mastic Stems, Leaves Hexane, Ethanolic TST, FST Dependant on serotonergic, noradrenergic and dopaminergic receptor systems Rutin (Flavonoid) [68,81] Schizandra chinensis Northern China and Russia Family: Schisandraceae Common names: Wǔ wèi zi, Five flavour berry Seeds – FST, Reserpine, L-DOPA and Clofelin-induced depression tests Via interaction with noradrenergic receptors – [90] Scrophularia ningpoensis China Family: Scrophulariaceae Common names: Ningpo figwort, Chinese figwort Roots Ethyl acetate LH – – [239] Securidaca longepedunculata Sub-tropical areas of Africa Family: Polygalaceae Common name: Violet tree Roots Aqueous FST – – [135] Senna spectabilis Brazil Family: Fabaceae Common names: Cassia carnival, Crown of gold tree Leaves, Stems, Roots Ethanolic Locomotor activity – Iso-6-spectaline [221] Siphocamphylus verticillatus Brazil Family: Campanulaceae Stems, Leaves Hydroethanolic TST, FST, Synaptosomal uptake of neurotransmitters Inhibition of synaptosomal uptake of [3H]serotonin, [3H]noradrenaline and [3H]dopamine – [133] Sonchus oleraceus Europe and Western Asia Family:Asteraceae Common names: Common sowthistle, Hare’s thistle, Hare's colwort, Milky tassel, Swinies Aerial parts Hydroethanolic, Dichloromethane TST, FST – – [235] Tabebuia avellanedae America, Mexico, Argentina, Paraguay and Bolivia Family: Bignoniaceae Common names: Handroanthus impetiginosus, Tabebuia impetiginosa, Pink Ipê, Pink Lapacho, Pink trumpet tree, Pau d’arco, Ipe-roxo Bark Ethanolic Olfactory bulbectomy, TST – – [159] Tagetes lucida Mexico and Central America Family: Asteraceae Common names:T. florida Sweet, Yerbaniz, Mexican marigold, Pericón, Mexican mint marigold, Mexican tarragon, Cempaxóchitl, Texas tarragon Aerial parts Aqueous, Hexane, Dichloromethane, Methanolic FST, Locomotor activity – – [152,160] Theobroma cacao Tropical regions of Central and South America Family: Malvaceae Common names: Cacao tree, Cocoa tree – Polyphenolic FST, Locomotor activity – Polyphenols, Flavonoids [191,199] Thymus fallax Azerbaijan, Gilan, Khorasan, Kurdestan, Mazandaran, Qazvin and Tehran provinces Family: Lamiaceae Aerial parts Methanolic FST – – [218] Thymus kotschyanus Azerbaijan, Gilan, Khorasan, Kurdestan, Mazandaran, Qazvin and Tehran provinces Family: Lamiaceae Common names: Kahlioti, Kahuti Aerial parts Methanolic FST – – [218] Thymus pubescens Azerbaijan, Gilan, Khorasan, Kurdestan, Mazandaran, Qazvin and Tehran provinces Family: Lamiaceae Common name: Avishan-e-korkaloud Aerial parts Methanolic FST – – [218] Tinospora cordifolia India, Myanmar and Sri Lanka Family: Menispermaceae Common names: Heart-leaved moonseed, Guduchi, Amrta, Cinnodbhava, Giloy Stems Petroleum ether TST, FST, Locomotor activity, MAO Inhibition assay Via interaction with serotonergic, noradrenergic and dopaminergic receptor systems, Inhibition of MAO-A and MAO-B activities – [115] Trichilia catigua Brazil Family: Meliaceae Common names: Catuaba, Catigua Bark Hydroethanolic FST, Monoamine uptake assay Inhibition of dopamine and serotonin uptake – [134] Trigonella foneum-graecum Asia, Iraq Family: Fabaceae Common name: Fenugreek Seeds – FST Via the serotonergic system 4-hydroxyisoleucine [164] Valeriana fauriei Europe, Asia, North America, South America Family: Caprifoliaceae Common name: Valeriana Roots Methanolic, Hexane, Ethyl acetate, Chloroform FST – Sesquiterpenes [183,201] Valeriana officinalis Europe, Asia, North America, South America Family: Caprifoliaceae Common names: Garden valerian, Garden heliotrope, All-heal, Amantilla, Setwall, Phu, Setewale, Capon's Tail, Althea Roots Aqueous, Hydroethanolic, Hydromethanolic FST, Locomotor activity – – [166] Valeriana wallichii Northwest Himalayas, Astore Family: Valerianaceae Common names: Indian Valerian, Tagar-Ganthoda Rhizome, Roots Aqueous, Hydroethanolic, Methanolic, Oil, Dichloromethane TST, FST, Locomotor activity Nitric oxide inhibition – [212,213,227] Vitis vinifera Mediterranean region, Europe, Asia, Morocco, Portugal, Germany, Iran Family: Vitaceae Common names: Common Grape Vine, European grape Seeds Aqueous Anti-stress activity, Nootropic activity – – [224] Withania somnifera India, Nepal, China, Yemen Family: Solanaceae Common names: Ashwagandha, Indian ginseng, Poison gooseberry, Winter cherry Roots Aqueous FST, LH, MAO Inhibition assay – – [142,186] Xysmalobium undulatum South Africa Family: Apocynaceae Common names: Uzara, Milk bush, Milkwort, Wild cotton, Wave-leaved, Bitterhout, Bitterwortel – Ethanolic [3H]-citalopram-binding assay, SERT, NET and DAT uptake inhibition assays, TST, FST, Locomotor activity Affinity for SERT – [120] Zingiber officinale India, China, Japan, Korea, Vietnam, Europe Family: Zingiberaceae Common name: Ginger Rhizome Hydromethanolic TST, FST, Protein-ligand molecular docking Via binding to 5-HT1A receptor Gingerol, Shogoal [82,112] Zizyphus xylopyrus North-Western India, Pakistan and China Family: Rhamnaceae Common names: Katber, Kottai maram, Kotta, Gottai, Kottai Elandai Leaves Ethanolic TST, FST – – [219] The anti-depressant effect of a fraction containing saponin isolated from bark of Albizzia julibrissin was reversed by 5-HT1 A/1B receptor antagonist suggesting the anti-depressant activity of the plant to act via 5-HT1A and 5-HT1B receptor systems [66]. Lectins isolated from Canavalia brasiliensis seeds and from Canavalia ensiformes seeds showed anti-depressant activity via their interaction with serotoninergic (5-HT1A, 5-HT2 receptors), noradrenergic (α2 adrenoceptor) and dopaminergic (D2 receptor) systems [67]. Lectins isolated from leaf extract of Schinus molle L. showed anti-depressant activity via their interaction with serotoninergic (5-HT1A , 5-HT2A/2C, 5-HT3 receptors), noradrenergic (α1, α2 adrenoceptors) and dopaminergic (D1, D2 receptor) systems [68]. Saponin fraction of methanolic root extract of Asparagus racemosus showed anti-depressant activity in forced swim test model of depression, which was indicative of its effect through the serotonergic and adrenergic systems [69]. Abbas et al. showed the anti-depressant activity of nut extract of Areca catechu and its aqueous fraction to be via increasing serotonin and norepinephrine levels in rat hippocampus [70]. Saponins were suggested to be responsible for the anti-depressant activity of Areca catechu nut [70]. Identified and isolated compounds from plants that have been examined for their anti-depressant activity are also mentioned below. Riparin III obtained from unripe fruit of Aniba riparia was reported to show anti-depressant activity in tail suspension and forced swim test models of depression [71]. Also, riparin II from fruit of Aniba riparia showed anti-depressant effects via interaction with serotonergic (5-HT1 A receptor), dopaminergic (D1, D2 receptors) and noradrenergic (α1 adrenoceptor) systems [72]. Bacopa monnieri displayed anti-depressant effects as examined using tail suspension and forced swim test models of depression in mice via interaction with serotonergic, dopaminergic and noradrenergic systems [[73], [74], [75]]. The mixture of Bacopaside I and bacoside A isolated from Bacopa monnieri also inhibited activity of MAO-A and MAO-B isoenzymes [76]. Sela et al. showed the anti-depressant activity of 1,3,7-trihydroxy-2-(3-methylbut-2-enyl)-xanthone, present in large quantities in hydro ethanolic extract of stem of Kielmeyera coriacea, via interaction with 5-HT1A receptor [77]. Morinda officinalis showed anti-depressant activity in the forced swim test model of depression [78]. In a previous study, anti-depressant compounds isolated from the roots of Morinda officinalis: succinic acid, nystose, 1 F-fructofuranosylnystose, inulin-type hexasaccharide and heptasaccharide were identified through chemical and spectroscopic methods [79]. Neferine (alkaloid) isolated from Nelumbo nucifera Gaertn showed anti-depressant activity in the forced swimming test model in mice [80]. Moreover, rutin (flavonoid) isolated from ethanolic extract of aerial parts of Schinus molle showed anti-depressant activity in tail suspension and forced swim test models of depression in mice [81]. Docking studies revealed presence of potential anti-depressant agents such as gingerol, shogoal in Zingiber officinale [82]. Ursolic acid isolated from Rosmarinus officinalis L. showed anti-depressant action through the activation of D1 and D2 receptors [83]. Essential oil, hexane, ethanolic and essential oil free fractions as well as compounds such as carnosol, betulinic acid and 1,8-cineole, isolated from Rosmarinus officinalis L. showed anti-depressant activity in tail suspension test model in mice [84]. Hederagenin from fruit extract of Fructus akebiae produced anti-depressant effects in tail suspension and forced swim test models of depression and also reversed chronic stress induced inhibition of sucrose consumption in rats [85]. Microdialysis studies later showed that administration of hederagenin from fruit extract of F. akebiae significantly increased extracellular concentrations of serotonin, norepinephrine and dopamine in the frontal cortex region in rats [86]. Ren et al. showed the anti-depressant effects of sarsasapogenin from Anemarrhena asphodeloides wherein sarsasapogenin produced a marked increase in noradrenaline and serotonin levels in the hypothalamus and hippocampus, as well as, showed MAO inhibitory activity in the mouse brain [87]. Compounds isolated from Cayratia japonica such as apigenin, luteolin, flavonol and quercetin showed potent anti-depressant inhibitory effects against MAO activity. The flavone glycosides apigenin-7-O-beta-D-glucuronopyranoside and luteolin-7-O-beta-D-glucopyranoside showed mild MAO inhibition. Quercetin, apigenin and luteolin had a more potent inhibitory effect on MAO-A than MAO-B [88]. Tomic et al. showed xanthones isolated from diethylether extract of aerial parts of Gentiana kochiana such as gentiacaulein and gentiakochianin showed anti-depressant effects by strongly inhibiting rat microsomal MAO-A activity [89]. Cyclohexane extract of Hypericum caprifoliatum and its main phloroglucinol derivative were seen to produce anti-depressant effects via interaction with dopamine D1 and D2 receptors and by inhibiting reuptake of serotonin, dopamine and norepinephrine [90]. A later study demonstrated the anti-depressant activity of enriched phloroglucinol fraction from Hypericum caprifoliatum extract [91]. Anti-depressant activity of compounds present in roots of Polygala tenuifolia such as polygalatenosides A and B (1 and 2), YZ-50 and 3,6-disinapoyl sucrose were demonstrated to be through inhibition of norepinephrine reuptake and MAO-A, MAO-B activity levels [[92], [93], [94]]. Kavapyrones from Piper methysiticum Forst have been reported to increase and decrease neurotransmitter levels [95]. Furocoumarins such as psoralen and psoralidin isolated from the seeds of Psoralea corylifolia have shown anti-depressant effects in the forced swim test model of depression by elevating levels of neurotransmitters in rodents [96,97]. Peony glycosides such as paeoniflorin and albiflorin isolated from root extract of Paeonia lactiflora have been reported to produce anti-depressant effects in mice [98]. A later study showed the anti-depressant action of paeoniflorin to be via upregulation of the serotonergic system [99]. Lee et al. showed the anti-depressant activity of alkaloid piperine and its related compounds methylpiperate and guineensine isolated from fruits of Piper longum is through inhibition of MAO-A and MAO-B activity [100,101]. Nakazawa et al. demonstrated the anti-depressant effects of apigenin and 2,4,5-trimethoxycinnamic acid isolated from leaves of Perilla frutescens through the increase of neurotransmitter levels and decrease in turnover of their respective metabolites in the brain [102]. Rosmarinic acid obtained from the leaves of Perilla frutescens have also shown anti-depressant activity by bringing about proliferation of newborn cells in the dentate gyrus of the hippocampus [103]. Rosiridin isolated from root extracts of Rhodiola rosea showed MAO-A and MAO-B inhibition [104]. The mechanism of anti-depressant action of Rhodiola rosea was reported through the serotonergic system and by activation of 5-HT1A receptor [105]. Some crude extracts from plants that have also been examined to possess anti-depressant activity are mentioned below. A 40% 2-propanol rhizome extract from Cimicifuga racemosa was seen to act via interaction with serotonin receptors 5-HT1A , 5-HT1D, and 5-HT7 suggesting possible anti-depressant action via these receptor subtypes [106]. Extract from Kielmeyera coriacea stems exhibited anti-depressant effects in forced swim test model of depression [107,108]. Later studies showed Kielmeyera coriacea stem extract displayed anti-depressant activity via interaction with 5-HT1A receptor [109] and via inhibition of serotonin, norepinephrine and dopamine re-uptake [110]. Ishola et al. demonstrated the anti-depressant activity of Momordica charantia Linn to be via interaction with serotonergic (5-HT2 receptor), noradrenergic (α1 and α2 adrenoceptors), dopaminergic (D2 receptor) systems [111]. Zingiber officinale showed significant anti-depressant activity in tail suspension and forced swim test models of depression [112]. Dhingra and Kumar later showed anti-depressant effect of Asparagus racemosus methanolic root extract via the D2 and α1 receptor systems and through inhibition of MAO-A and MAO-B activity [113]. Anti-depressant activity of fruit extract of Benincasa hispida (Thunb.) Cogn. was shown by Dhingra and Joshi through tail suspension and forced swim test models of depression in mice, via interaction with D2 and α1 receptor systems and through inhibition of MAO-A enzyme activity [114]. The anti-depressant activity of Tinospora cordifolia was brought about by interaction with D2 and α1 receptor systems and through inhibition of MAO-A and MAO-B enzyme activity in mice [115]. Ethanolic root extract of Ptychopetalum olacoides Bentham showed anti-depressant activity mediated through β and D1 receptor systems [116]. Butterweck et al. showed the anti-depressant activity of leaf extract of Apocynum venetum Linn through the forced swim test model of depression [117]. Later, Zheng et al. showed the anti-depressant activity of leaf extract of A. venetum Linn containing hyperoside and isoquercitrin flavonoids to be through noradrenergic and dopamine systems and via interaction with D1 and D2 receptor systems [118]. South African medicinal plants Agapanthus campanulatus, Boophone distica, Mondia whitei and Xysmalobium undulatum which are traditionally used to treat depression, showed anti-depressant activity in the tail suspension and forced swim test models of depression in rodents and also showed affinity for SERT in binding assays. Agapanthus campanulatus and Boophone distica inhibited SERT, NET and DAT transporters [119,120]. Allium cepa powder showed anti-depressant activity in forced swim test model of depression in rats. An increase in brain monoamine levels as opposed to their respective metabolite levels was also observed in rat hippocampus [121]. Dar et al. showed the hexane and aqueous fractions from Areca catechu ethanolic fruit extract inhibited MAO activity in rat brain homogenates [122]. A subsequent study revealed the anti-depressant activity of Areca catechu nut through inhibition of MAO-A activity [123]. Anti-depressant activity of fruit extract of Emblica offcinalis Gaertn demonstrated through the tail suspension and forced swim test models of depression, was shown to interact with D2 and α1 receptors and the serotonergic system. Ascorbic acid, flavonoids, tannins and other polyphenolic substances present in the fruit extract of Emblica officinalis were suggested to be responsible for its anti-depressant activity [124,125]. Anti-depressant activity of Glycyrrhiza glabra was demonstrated through its interaction with D2 and α1 receptor systems [126]. Later studies showed anti-depressant activity of Glycyrrhiza glabra root extract to act through inhibition of MAO-A and MAO-B activity [127,128]. The anti-depressant activity of ayurvedic Nardostachys jatamansi root extract was reported to be due to inhibition of MAO-A and MAO-B activity [129,130]. Essential oils obtained from leaves of Perilla frutescens reported to show anti-depressant effects by restoring stress induced decrease in sucrose levels and by increasing BDNF levels in the brain [131]. Ali et al. demonstrated the anti-depressant activity of Rhazya stricta through inhibition of MAO-A activity [132]. The anti-depressant activity of hydroalcoholic extract from aerial parts of Siphocampylus verticillatus was investigated in the tail suspension and forced swim test models of depression and was seen to be via interaction with D2 and α1 receptor systems [133]. Campos et al. also showed the dopamine-mediated anti-depressant effect of hydroalcoholic extract of Trichilia catigua in rodents [134]. 4. Discussion This review discusses about 110 medicinal plants for their anti-depressant activity along with various mechanisms of anti-depressant action and phytochemical compounds responsible for their activity. However, the mechanistic evaluation of many of these plants still needs to be experimented and explored. Majority of these studies are based on preclinical testing by using various experimental assays and animal models of depression. Only 1–2% of these studies had a clinical setting involved. Majority of these studies analysed the various neurotransmitter receptors involved in anti-depressant activity, the monoamine oxidase inhibition activity of drugs and plants and the SERT, NET and DAT transporter inhibition activity of drugs and plants. Other studies tried to elucidate the mechanism of action of the plants via estimating serotonin, norepinephrine and dopamine neurotransmitter levels in the brain and also by assessing neuronal proliferation and BDNF levels in the brain. The studies also investigated combination therapies using drug and plant systems. The anti-depressant activity for most of the plants involves increasing serotonin, norepinephrine or dopamine levels in the brain which is through the interaction with serotonergic, adrenergic and dopaminergic receptor systems, their respective transporters or through inhibition of monoamine oxidase enzyme. Various drugs have been reported to act either as agonists or antagonists to the neurotransmitter receptors. Some studies show phytocompounds to augment or potentiate the anti-depressant effects of current anti-depressant drugs. Inhibition of A and B isoforms of MAO have also been reported in majority of the studies along with inhibition of the neurotransmitter transporters such as SERT, NET and DAT using radioactive labelling studies. Also, BDNF levels in the brain and its role in neurogenesis have been investigated in some studies with respect to drugs and plants exhibiting anti-depressant activity. 5. Conclusion A large number of medicinal plants and their components are constantly being studied, tested and used in the treatment of depression. Although majority of these studies have a preclinical set-up; they remain preliminary as the understanding of the mechanism of anti-depressant action of many drugs and plants, still remains very inconclusive. Further, there is an immense lack of knowledge in understanding the mechanism of action of majority of the clinically used anti-depressant drugs. Receptor-based assays, transporter-inhibition assays and monoamine oxidase-inhibition based studies have been extensively described in this review with respect to different plants and therapeutic drugs, although, further validation is needed as animal testing models in anti-depressant activity are also limited to basic behavioural tests like the tail suspension test and the forced swim test models of depression in rodents. Majority of the anti-depressant studies also confirm the “probability” of action of drugs and plants via increasing neurotransmitter levels by activating/inhibiting neurotransmitter receptors and transporters or monoamine oxidase enzyme levels. Once these gaps in depression research are filled then not only will this disorder of depression be better understood but also drug–plant systems or drug–drug systems can go a long way in bettering treatment of depression. Conflict of interest The authors declare no conflict of interest. References [1] F. Jones, J. Bright, A. 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