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Rhodiola rosea L. as a putative botanical antidepressant.

ABSTRACT

Background: Rhodiola rosea (R. rosea) is a botanical adaptogen with putative anti-stress and antidepressant properties. Evidence-based data supporting the effectiveness of R. rosea for depression in adults is limited, and therefore a comprehensive review of available animal and human studies suggesting a putative antidepressant action is warranted.

Purpose: A review of the literature was undertaken to ascertain studies of possible antidepressant mechanisms of action and studies of the safety and effectiveness of R. rosea extracts in animals and adult humans.

Methods: A search of MEDLINE and the Russian state library database was conducted (up to October 2015) on R. rosea.

Results: Mechanism of action: R. rosea extracts and its purified constituent, salidroside, has been shown to produce a variety of mediator interactions with several molecular networks of neuroendocrine-immune and neurotransmitter receptor systems likely to be involved in the pathophysiology of depression. A wide variety of preclinical in vivo and ex vivo studies with laboratory animals suggests the presence of several biochemical and pharmacological antidepressant-like actions.

Effectiveness: Clinical assessment of R. rosea L. rhizome extracts in humans with various depressive syndromes is based upon results from two randomized, double-blind, placebo-controlled trials of 146 subjects with major depressive disorder and seven open-label studies totaling 714 individuals with stress-induced mild depression (diagnosed as asthenic syndrome or psychoneurosis). Overall, results of these studies suggests a possible antidepressant action for R. rosea extract in adult humans.

Safety: In contrast to most conventional antidepressants, R. rosea extract appears to be well-tolerated in short-term studies with a favorable safety profile.

Conclusions: R. rosea demonstrates multi-target effects on various levels of the regulation of cell response to stress, affecting various components of the neuroendocrine, neurotransmitter receptor and molecular networks associated with possible beneficial effects on mood.

Keywords:

Rhodiola rosea L., Depression

Clinical study

Pharmacology

Molecular networks

1. Introduction

1.1 Use of herbal medicines

Over the last 3 decades, the use of herbal remedies has become widespread. The World Health Organization has estimated that at least 4 billion people, or 80% of the world's population, uses complementary and alternative medicines (CAMs) for some aspect of their health care needs. Between 1990 and 1997, CAM use in the U.S. increased almost 5-fold (Eisenberg et al. 1998), and by 1997 about 33% of Americans used herbal remedies. Over the last decade, many CAM therapies have become mainstream in the US, and it is anticipated that CAM use will continue to increase with growing consumer acceptance. The widespread use of botanical preparations reflects many factors including a rise in the prevalence of chronic diseases, an increase in public access to healthcare information, a reduction in tolerance of medical paternalism, and an increased sense of consumer entitlement to a higher quality of life. These social factors are complemented by an escalating cost of conventional medication which is often seen as more toxic than CAM therapy (Jonas 1998). Because herbal remedies do not undergo the exhaustive testing and regulatory procedures of the U.S. Food and Drug Administration (FDA) applied to conventional drugs, CAM therapies represent a unique marketing opportunity for new and established drug companies. As a result there is an increasing need for scientific research and reliable information on the use of botanical products (Blumenthal 1998). There is also a need for careful evaluation of selected botanical therapies for specific medical conditions in order to "separate the pearls from the mud" (Jonas 1998). However, in the U.S. there is currently no formal mechanism for establishing the safety and efficacy of CAM products by the FDA. This deficiency was noted in a report to the U.S. Congress entitled The White House Commission on Complementary and Alternative Medicine Policy (http: //www.whccamp.hhs.gov/fr1.html; http://www.whccamp.hhs.gov) which concluded that CAM and conventional drugs should be held to the same rigorous standards of good science. This conclusion was echoed in a New England Journal of Medicine editorial which stated that "there cannot be two kinds of medicine--conventional and alternative. There is only medicine that has been adequately tested and medicine that has not, medicine that works and medicine that may or may not work." (Angell and Kassirer 1998)

1.2. Epidemiology and treatment of depression

Depression is one of the most common and debilitating psychiatric conditions with a lifetime prevalence rate of about 16.2% (Murray and Lopez 1997). Epidemiological studies have shown an increased frequency of affective illness with increasing age. In particular, older women have been noted to have an increased risk of depression that is almost twice that of men; attributed to perturbations in sex steroids occurring during the peri- and postmenopausal periods (Anthony and Aboraya 1992; Kessler et al. 1993). Although hormonal factors have been hypothesized to underlie gender differences in vulnerability to mood disorders, evidence for this assertion is lacking (Richardson and Robinson 2000). Other, more compelling factors linked with depression appear to be disproportionately represented in women. For example, disparities in ethnic, cultural, economic, psychosocial, environmental and age longevity differences from men may be more likely to place women at a greater risk for developing depression (Belle and Doucet 2003; Hammen 2003).

Depression is also associated with a high risk of suicide and medical co-morbidity, and nearly 70% of patients with depression have incomplete response after 8 weeks of conventional antidepressant therapy and more than 30% fail to respond at all (Rush et al. 2004, 2006). At least 75% of depressed patients who recover during initial antidepressant therapy will have a relapse or recurrence within 2 years, and 33% will have an episode lasting longer than 2 years (Keller 2001). Although antidepressants (like serotonin reuptake inhibitors) are now standard therapy for depression, many individuals go un-diagnosed and untreated for years. Moreover, of those who do receive antidepressant therapy, many receive inadequate therapy (Rush et al. 2004, 2006). However, despite their widespread use, these agents have substantial limitations. For example, there is limited clinical data showing that these agents provide consistent benefit (versus placebo) in patients with more mild forms of depression (Elkin et al. 1995; Fournier et al. 2010). Most randomized clinical trials of antidepressant efficacy routinely exclude patients with mild illness because of the expectation that conventional antidepressants will not provide an advantage versus placebo. Moreover, treatment-emergent adverse events with conventional antidepressants are more likely to occur in less severely ill patients (Mao et al. 2015), and often result in treatment noncompliance and treatment discontinuation (Hollon et al. 2002). In addition, conventional antidepressants may suppress, rather than eliminate, depressive symptoms in many patients (Hollon and Shelton 2001), and there is little evidence to suggest that symptom suppression reduces overall risk of depressive relapse (Frank et al. 1990). Although conventional antidepressants may be slightly more effective than psychotherapy (DeRubeis et al. 2005), these agents are also associated with substantial adverse events such as weight gain, insomnia, drowsiness, hypertension, reduced libido, suicidal ideation, and withdrawal (Amsterdam et al. 1997; Michelson et al. 1999, 2000; Zajecka et al. 1999).

Finally, conventional antidepressant therapy can constitute a financial burden, with the result that many individuals decline therapy and go un-treated. In addition, individuals may decline antidepressant therapy due to insufficient health insurance, cultural or religious beliefs, or personal reasons related to stigma of mental illness. As a result, many individuals will seek CAM remedies for their depressive symptoms. Thus, it is not surprising that depressive symptoms are among the most common reasons for consumers choosing CAM therapy (Barnes et al. 2004). The identification of safe and effective CAM therapies for depression is, therefore, of public health relevance in reducing the illness-related burden of depression (Fang and Schinke 2007; Givens et al. 2007a, 2007b).

1.3. Overview of CAM treatment of depression

--Data from a national survey from 1990 to 1997 found that CAM use for depression symptoms rose from 20.2% to 40.9% (Eisenberg 1998), while a subsequent survey of individuals with mental disorders confirmed these findings (Unitzer et al. 2000; Druss and Rosenheck 2000). Kessler et al. (2001a) noted that psychiatric symptoms like depression, anxiety, fatigue, and insomnia are among the most frequent reasons for CAM use. Moreover, many individuals taking conventional antidepressants will augment these with CAM agents or switch to CAM therapy due to antidepressant-induced side effects, inadequate response, cost, or a desire to exert personal control over their treatment (Brown and Gerbarg 2001; Wu et al. 2007; Stratton and McGivern-Snofsky 2008).

In a follow up survey (Tindle et al. 2005), herbal remedy use for depression rose from 12.1% to 18.6%. In a separate survey more than 2000 U.S. adults, 53.6% of respondents endorsing depressive symptoms reported using CAM therapy in the preceding year, with herbal remedies near the top of the list (Kessler et al. 2001b). A recent literature survey of CAM treatment studies of late-life mood and anxiety disorders for the period 1966-2006, identified 885 studies of which only 33 met minimal inclusion criteria of [greater than or equal to] 30 subjects treated for [greater than or equal to] 2 weeks. Overall, 67% of the studies were positive, with positive studies generally having a lower Scientific Quality of Investigation score for methodology (versus negative studies) (Meeks et al. 2007).

Although evidence-based data to support the efficacy of many herbal remedies for depression is limited, several recent reviews are of relevance. The most frequently studied remedies were St. John's Wort (Hypericum perforatum), s-adenosylmethionine, tryptophan (TRP), 5-hydroxytryptophan (5-HTP), and omega-3 fatty acids. Other CAM remedies with less evidence of antidepressant activity include folic acid, lavendula augustifolia, ginko biloba, chamomile, and crocus sativus.

1.4. Rhodiola rosea--an overview

1.4.1. General

There are several comprehensive monographs describing the cultivation, photochemistry, and pharmacology of R.rosea (Saratikov 1973; Kelly 2001; Brown et al. 2002; Saratikov and Krasnov 2004; Panossian and Wikman 2005; Panossian et al. 2010; Cuerrier and Ampong-Nyarko 2014).

Briefly, R. rosea, also known as roseroot or golden root, belongs to the family Crassulaceae (Panossian et al. 2010). It has a long history as a medicinal plant in Iceland, Norway, Sweden, France, Greece, and Russia. Traditional folk medicine used R. rosea to increase endurance and work performance, longevity, tolerance to high altitude sickness, and to treat fatigue, weakness, impotence, and other nervous system disorders. In Siberia, a bouquet of golden root is still given to couples on their wedding to enhance fertility. In Asia, R. rosea tea is used to treat and prevent flu-like infection during the winter. Mongolian doctors prescribe it for cancer and tuberculosis. For centuries, the location of golden root and the process of R. rosea extraction were guarded secrets. Siberians secretly transported the herb down ancient trails to the Caucasus where it was traded for Georgian wine, garlic, and honey. In 1961, GV Krylov, a Russian botanist and taxonomist, led an expedition to the cedar taiga in the Altai mountains of Siberia where he located and identified golden root as R. rosea. These extracts were found to contain compounds, termed 'adaptogens', that protected animals and humans from mental and physical stress, toxins, and infections. The quest for CAMs to enhance physical and mental endurance led to the discovery of phenylpropanoids, which were specific to R. rosea. In Sweden, R. rosea was classified as an adaptogenic remedy in 1985 (Sandberg and Bohlin 1993). The Swedish Pharmaceutical Lakemedelsboken 1997/98 described R. rosea as a plant with a 'stimulant' action in the group of registered herbal medicines (Sandberg 1998). In Denmark, R. rosea was registered as a medical product in the category of botanical drugs (Sandberg 1998). Botanicals are widely used in Scandinavia to increase mental capacity during stress, as a psychostimulant, and as a general adaptogen (Sandberg 1998). R. rosea has also been used to enhance emotional tone and affect.

At least 140 compounds have been identified in R. rosea rhizomes extract that may have medicinal properties (Panossian et al. 2010; Saratikov and Krasnov 2004). Among 86 nonpolar monoterpene hydrocarbons, monoterpene and aliphatic alcohols, geraniol (a rose-like odor substance) was the most abundant volatile constituent of R. rosea (Rohloff 2002). Its oxygenated glucoside rosiridin (Kurkin and Zapesochnaya 1986) has been shown to be a potent inhibitor of monoamine oxidase A and B in vitro (van Diermen et al. 2009), suggesting a possible mechanism for R. rosea's putative antidepressant, anxiolytic and activating properties in animals and humans. In addition, more than 50 polar compounds (including monoterpenes, cyanogenic glycosides, phenylpropanoids, flavonoids, flavolignans and other gallic acid derivatives) may also contribute to its CNS actions (Kurkin, and Zapesochnaya 1986; Saratikov and Krasnov 2004; Panossian et al. 2010).

1.4.2. Effects on CNS

The direct stimulation of noradrenalin, dopamine, serotonin and cholinergic receptors in selected brain regions may produce the complex psychotropic, stimulant, and adaptogen actions of R. rosea's (Saratikov et al. 1978; Lazarova et al. 1986; Petkov et al. 1986). For example, small doses of R. rosea extract, or of its active constituent rodosin, were found to increase spontaneous bio-electrical activity of the brain possibly via effects on the reticular formation in the brainstem (Saratikov et al. 1965, 1978; Marina 1968; Marina and Alekseeva 1968; Saratikov 1973; Kurkin and Zapesochnaya 1986),while medium doses of R. rosea enhanced conditioned avoidance behavior in rats and facilitated learning based upon positive reinforcement (Saratikov et al. 1965, 1973). Furthermore, a single dose of R. rosea extract improved learning and retention in rats subjected to the maze negative (punitive) reinforcement test after 24 h and after 10 days post R. rosea administration (Lazarova et al. 1986; Petkow et al. 1986). A recent electroencephalographic study of rat frontal cortex, hippocampus, striatum and reticular formation in animals given R. rosea showed a frequency pattern comparable to that of methylphenidate and the antidepressant paroxetine within 35 min of administration (Dimpfel 2013).

2. Methods

We used STN-easy service, which is based on all comprehensive databases, including BIOSIS, CAplus, TOXCENTER, EMBASE, NAPRALET, PubMed, etc. https://stneasy.fiz-karlsruhe.de/ html/english/loginl.html?service=STN

We used also, original publications from Russian State Library in Moscow.

Additionally, we used the library of the Swedish Herbal Institute, which maintains a complete collection of full text Russian articles and their English versions on this topic collected since 1943.

3. R. rosea for the treatment of depression

3.1. Evidence based on studies in animals

Wikman and Panossian (2002) initially showed that various extracts of R. rosea root and rhizome exhibited antidepressant-like activity in mice exposed to the Porsolt behavioral despair forced swimming test. Using this paradigm, R. rosea extract activity was comparable with that of imipramine and amitriptyline, and superior to that of Hipericum perforatum L extract. Perfumi and Mattioli (2007) demonstrated significant, albeit not dose-dependent, induction of antidepressant-like effects of a single oral dose of R. rosea extract 10, 15mg/kg and 20mg/kg in mice. Subsequently, Mattioli et al. (2009) found that repeated administration of R. rosea extract for 3 weeks reversed stress-induced elevations in sucrose intake, stress related behaviors, weight gain and dysregulated estrous cycles in female rats following 6 weeks of chronic mild stress. These effects were comparable to those of the antidepressant fluoxetine; although neither R. rosea nor fluoxetine influence the behavioral and physiological parameters in non-stressed animals (Mattioli et al. 2009).

Antidepressant like activity of R. rosea extract ([ED.sub.50] = 7.0mg/kg), or R. rosea extract combined with piperine and various purified constituents (e.g., rhodioloside, rosavin, rosin, rosarin, tyrosol, cinnamic alcohol, cinnamaldehyde and cinnamic acid) was compared with--imipramine and Hypericum perforatum extract in rats exposed to the Porsolt behavioral despair test (Panossian et al., 2008a, 2008b; Kurkin et al. 2006). At 20 mg/kg, R. rosea extract exhibited a greater antidepressant-like effect than either imipramine 30 mg/kg or H. perforatum 20 mg/kg. Rhodioloside (salidroside), and tyrosol (Fig. 1) were the active constituents of the R. rosea extract; whereas rosavin, rosarin, rosin, cinnamic alcohol, cinnamaldehyde, cinnamic acid were inactive. A fixed combination of rhodioloside, rosavin, rosarin and rosin was more active than any of the individual components alone, suggesting a synergistic activity (Panossian et al., 2008b). Although rosiridine has been found to be an active inhibitor of MAO-A enzyme in a MAO-A bioassay of mitochondrial membrane fractions of insect cells containing human recombinant MAO-A and MAO-B (van Diermen et al. 2009), its concentration is so minute in R. rosea extract to preclude MAO inhibition as the cause of antidepressant-like activity (van Diermen et al. 2009).

Antidepressant-like effects of salidroside were also found in the olfactory bulbectomized rat model of depression. Chronic treatment for 2 weeks with salidroside significantly reduced TNF-[alpha] and IL-1[beta] levels and increased glucocorticoid receptor and brain-derived neurotrophic factor (BDNF) expression in the hippocampus, as well as reducing the production of hypothalamic corticotropin-releasing hormone (CRH) and serum corticosterone (Yang et al. 2014).

R. rosea extract 1500 mg/kg also appeared to enhance serotonin levels and promote proliferation and differentiation of neural stem cells in the hippocampus of the stress-induced rat model of depression--a process thought to play a possible role in repairing injured hippocampal neurons (Qin et al. 2008; Chen et al. 2009). These findings are supported by other studies in rats (e.g., Mannucci et al. 2012). Similarly, oral administration of R. rosea extract 0.1 mL produced a significant increase in rat brainstem concentrations of noradrenalin, dopamine and serotonin (versus that of control rats). In addition, the concentrations of noradrenalin and dopamine decreased, and the concentration of serotonin increased, in the cerebral cortex (versus control rats). In contrast, while hypothalamic concentrations of noradrenalin and dopamine increased 3-fold, serotonin significantly decreased compared to control rats (Stancheva and Mosharrof 1987). R. rosea extract also enhanced the effects of neurotransmitters in the brain via increasing the permeability of the blood brain barrier to precursors of dopamine and serotonin (Stancheva and Mosharrof 1987).

Panossian et al. (2007) examined mediators of stress response (i.e., protein kinase (PK), phosphorylated kinase (JNK), nitric oxide (NO), cortisol, testosterone, prostaglandin [E.sub.2], leukotrene, and thromboxane) before and after 7 days of rhodioloside (salidroside), extracts of E. senticosus, S. chinensis, R. rosea, Bryonia alba, P. ginseng, or placebo in laboratory rabbits exposed to 2h of immobilization stress. JNK, NO, and cortisol increased by 200-300% (versus baseline) in the placebo group; while, NO and cortisol concentrations were unchanged. Rhodioloside and extracts of S. chinensis and R. rosea produced the greatest inhibition of stress-induced JNK (Panossian et al. 2007).

3.2. Active principles and possible mechanisms of action in depression

While most conventional antidepressant drugs for depression modulate brain monoamine and indolamine activity (Nutt 2008) recent data suggest that the antidepressant effect of R. rosea may be associated with key mediators of stress response, regulation of homeostasis of HPA axis activity (Fig. 2), modulation of G-protein coupled receptor (GPCR) signaling pathways (Fig. 3) and other molecular networks involved in depression (Panossian et al. 2012, 2013, 2014) (Tables 1-4). Mechanisms of action of R. rosea extract (and its active constituents) were studied in experiments on isolated cells (Panossian et al. 2012, 2013, 2014; Wiegant et al. 2008; Boon-Niermeijer et al. 2000; Schriner et al. 2009), nematodes (Wiegant et al. 2009), laboratory animals (Panossian et al. 2007, 2008a, 2008b; Panossian and Wagner 2005; Prodius et al. 1997) and humans (Olsson et al. 2009).

Another putative antidepressant mechanism of R. rosea extract may be its effect on neuropeptide-Y (NPY) mediated upregulation of heat shock protein Hsp-70 which, in turn, down-regulates stress-induced JNK protein (suppressing glucocorticoid receptors and increasing cortisol) (Panossian et al. 2007) (Fig. 2). NPY is thought to play a role in the pathophysiology of depression (Heilig et al. 1988). Several studies have suggested that NPY may produce antidepressant-like activity in the rat forced swimming test (Redrobe et al. 2002; Stogner and Holmes 2000). Human studies have also suggested that NPY may play a "buffering" role in adaptation to stress (Morales-Medina et al. 2010; Morgan et al. 2001; Morgan et al. 2000). Pre-clinical and clinical evidence also suggests a mood and cognitive enhancing action for NPY (Fletcher et al. 2010; Morgan et al. 2000). For example, NPY has been shown to mediate monoamine and serotonin receptors involved in stress induced depression (Crespi 2011; Quarta et al. 2011; Luo et al. 2008; Hokfelt et al. 1999), and, higher levels of NPY have been observed in soldiers who present with low psychological distress or who belong to the elite Special Forces branch (Morgan et al. 2001). In contrast, reduced levels of NPY have been observed in some individuals with major depression and in brain tissue of suicide victims (Morales-Medina et al. 2010). R. rosea and salidroside appear to stimulate expression and release of NPY in neuroglial cells (Panossian et al. 2012). If depression is associated with reduced levels of NPY expression, this finding may suggest a possible mechanism for R. rosea's putative antidepressant activity.

Other possible mediators of an antidepressant activity for R. rosea are Hsp70 and JNK (Fig. 2), which are known to interact with GRs (Grad and Picard 2007) that may be involved in the pathogenesis of depression (Barden 2004; Budziszewska 2002; Chrousos and Kino 2009; Juruena et al. 2013). In this regard, R. rosea extract regulates more than 50 genes involved in regulation of behavior, mood and depressive disorders (Panossian et al. 2013, 2014) (Tables 1-4). For example, among deregulated genes are genes encoding G-Protein Coupled Receptors (GPCR), which are localized on the cell membranes and play an important role in transmitting signals from many hormones, neurotransmitters, and other signaling molecules inside the cell. Thus, salidroside down-regulates the HTRIA gene encoding serotonine G-protein coupled receptors, which is known to activate an intracellular second messenger cascade resulting in excitatory or inhibitory neurotransmission. Activation of serotonin receptors modulate the release of many neuro- transmitters including glutamate, GABA, DA, NA, and acetylcholine, as well as many hormones including oxytocin, prolactin, vasopressin, cortisol, corticotropin, substance P, and others. These observations suggest that the effects of R. rosea and salidroside on expression of genes involved in regulation of functions of CNS can be associated with beneficial effects of Rhodiola in depression (Panossian et al. 2014).

3.3. Human studies suggestive of R. rosea antidepressant-like activity

3.3.1. Early R. rosea studies of neurasthenic disorders

Many early R. rosea studies were performed in the former Soviet Union and were poorly designed and conducted (Table 5). Standardized psychological measures were rarely used, and many did not use randomization or blinding techniques. Moreover, Soviet diagnostic nosology was much different from those used in most other countries (Rezvyy et al. 2005; Keith and Regier 1989; Miller 1985). For example, the Soviet diagnosis of asthenia included a heterogeneous group of subjects with a variety of psychological and physical symptoms, making study results difficult to interpret. Key symptomatic characteristics of the Soviet asthenic syndrome were generalized weakness, reduced work capacity, concentration and memory problems, irritability, headaches, insomnia, and anorexia. The symptoms tended to occur after intensive work requiring mental exertion.

The anti-asthenic action of R. rosea in healthy individuals was initially reported by Krasik et al. (1970a, 1970b), and appeared to be confirmed in 128 individuals age 17-55 years old with pronounced fatigue (Krasik et al. 1970a, 1970b). Several early open-label studies of asthenic syndrome also suggested that R. rosea extract may also be effective in reducing associated depression-like symptoms. For example, Mikhailova (1983) reported that 58 patients with exogenous organic asthenia, characterized by general weakness and fatigue, diurnal worsening of fatigue in the morning, and hypersomnia during the day (i.e., symptoms suggestive of DSM-1V bipolar type II depression) were reduced during R. rosea extract administered for 1-4 months. Only one patient reported an adverse event (i.e., sleep disorder). However, this was an open-label, uncontrolled study.

The effect of R. rosea extract on various types of Soviet era neuroses was initially reported in an open-label study of 20 healthy subjects and 45 patients with symptoms of insomnia, irritability and somatic complaints (Saratikov et al. 1965). R. rosea extract had beneficial effects in 16 of 20 patients after three days of single dose administration with improvement of stereotypical answers and resignation reaction, improved memory as well as active and passive attention, and other symptoms of depression. After 10 days of repeated R. rosea administration, motor and cognitive symptoms improved with an increase in conditional motor reflex values and an improvement in the interaction of motor and cognitive systems in all 45 patients. There was also an improvement in appetite, irritability and anxiety levels.

In other psychiatric disorders, R. rosea was observed to confer a synergistic effect when used in combination with psychotropic drugs (Sudakov et al. 1986). The authors hypothesized that the positive effects of R. rosea resulted from a stimulant action and reduction in side effects produced by the psychotropic drugs. Moreover, the addition of R. rosea to the nootropic drug therapy seemed to lend an additive benefit to the nootropic treatment in patients with amnestic and cognitive disorders (Sudakov et al. 1986); although this benefit was less pronounced in patients with agitated dementia (Sudakov et al. 1986).

Similarly, Brichenko et al. (1986) reported that patients in depressive states of varying aetiology spent less time in hospital, experienced increase in activities, interest, and physical productivity, and a reduction in side effects of their antidepressant when R. rosea was added to their antidepressant treatment regimen. Although the mechanism of side effect reduction during tricyclic antidepressant therapy is unknown, R. rosea also appears to have a similar beneficial effect on side effects of neuroleptic medication in patients with schizophrenia (Krasik et al. 1970a, 1970b)--suggesting an anti-dopaminergic action.

On the strength of these, and other clinical reports, the Pharmacological Committee of the Ministry of Health of the Soviet Union recommended the medicinal use of R. rosea extract for patients with asthenia syndrome, various neuroses, vascular dystonia, hypotension, and asthenic schizophrenia (Mashkovskij 1977; Rhizome and roots of Rhodiola rosea, 1990; Extractum Rhodiolae fluidum 1996). R. rosea extract was also recommended for (i) its stimulant properties for healthy individuals with fatigue, post-viral asthenia, reduced libido, impotence, and to counteract side effects of various anticholinergic psychotropic drugs.

3.3.2. More recent R. rosea studies

In the more modern diagnostic era, one open-label study by Bystritsky et al. (2008) examined R. rosea (Rhodax[R]) 340 mg daily for 10 weeks in 10 subjects with DSM-IV generalized anxiety disorder (GAD), Table 5. In this open-label, proof-of-concept study, a significant reduction in mean Hamilton Anxiety Rating Scale (HRSA) (Hamilton 1959) scores was observed at endpoint (p = 0.01), and this finding also appeared to be associated with a similar reduction in Hamilton Depression Rating Scale (HRSD) (Hamilton 1960) scores at endpoint (p = 0.001).

Darbinyan et al. (2007) conducted a randomized, double-blind, placebo-controlled trial of R. rosea (SHR-5) extract (Swedish Herbal Institute, Vallberga, Halland, Sweden) in 89 subjects with mild to moderate DSM-IV major depressive disorder, aged 18-70 years old. Subjects received either R. rosea extract 340 mg daily (n = 31), R. rosea extract 680 mg daily (n = 29), or placebo (n = 29) for 6 weeks. At study endpoint, the mean HRSD score significantly declined for both doses of R. rosea (p < 0.0001, respectively). No significant reduction in HRSD score was observed during placebo (p = 0.2206). Endpoint analysis found lower mean HRSD scores for both R. rosea treatment conditions versus placebo (p < 0.001, respectively) (Panossian and Wikman 2014). Although this was a randomized, double-blind controlled study, the outcome magnitude of the difference in HSRD scores among the three treatment conditions have been questioned--as a true drug-placebo difference for each R. rosea dosing group of this magnitude is unlikely in an under-powered pilot trial of this design.

More recently, Mao et al. (2014, 2015) performed a randomized double-blind, 12-week, proof-of-concept trial of R. rosea versus sertraline (a conventional antidepressant) versus placebo. The study sought to obtain preliminary safety and efficacy data on the relative antidepressant action of R. rosea extract versus sertraline in outpatients with mild to moderate major depressive disorder (Mao et al. 2014, 2015). Subjects were at least 18 years old and had a DSM-IV Axis I diagnosis of major depressive disorder ascertained using the Structured Clinical Interview for DSM-IV interview format (First et al. 2001). Subjects had a minimum baseline total HRSD score 10 and a baseline Clinical Global Impression Severity (CGI/S) (Guy 1976) score of 3 ('mild') or 4 ('moderate'). Exclusion criteria were a primary DSM-IV Axis I diagnosis other than depression, use of a conventional or alternative psychotropic agent, actively suicidal, uncontrolled medical condition pregnant or nursing, or receiving medication known to produce mood changes.

Identically appearing capsules containing either pharmaceutical grade R. rosea (SHR-5) powdered extract 340 mg (standardized to a content of rosavin 3.07% / rhodioloside 1.95%) (Swedish Herbal Institute, Vallberga, Halland, Sweden), sertraline 50 mg HCl (North Star Pharmaceuticals, Memphis, TN), or placebo (i.e., lactose monohydrate NF) (Spectrum[R] Quality Products, New Brunswick, NJ) were dispensed. All SHR-5 product was administered under IND #105,063 issued by the U.S. Food and Drug Administration.

The primary outcome was the change in 17-item HRSD score, with change in CGI/C (Guy 1976), and Beck Depression Inventory (BD1) scores (Beck et al. 1961) as secondary outcomes. A standardized treatment emergent adverse event profile was also obtained (National Institute of Mental Health 1985).

Study drug was initiated at one capsule daily for the first 2 weeks. Subjects with [less than or equal to] 50% reduction in HRSD score (versus baseline) had the dose increased to 2 capsules daily during weeks 3 and 4 of therapy. This procedure was continued every 2 weeks for subjects with [less than or equal to] 50% reduction in HRSD score (versus baseline) up to a maximum dose of 4 capsules daily by study weeks 6 through 12 of therapy. Subjects unable to tolerate study drug had their dosage reduced to a minimum of 1 capsule daily. Outcome measurements were obtained at baseline and after 2, 4, 6, 8 and 12 weeks of treatment. The study was powered to detect relatively large differences between treatment conditions and to identify trends in the data that might inform future study design.

There was no statistically significant difference in change over time for HRSD scores among treatment groups (p = 0.79), and the decline in HRSD scores by week 12 was slightly greater for sertraline (-8.2, 95% confidence interval [CI], -12.7 to -3.6) versus R. rosea (-5.1, 95% CI: -8.8 to -1.3) and placebo (-4.6, 95% CI: 8. to -0.6). There was also no statistically significant difference in change over time in BDI or CGI/C scores among treatment conditions (p = 0-28 and p = 017, respectively). However, there were clinically meaningful odds ratios (95% CI) of global improvement by week 12 (versus placebo) of 1.39 (0.38-5.04) and 1.90 (0.448.20) for R. rosea and sertraline, respectively; indicating that subjects on R. rosea had 1.4 times the odds of improvement, and subjects on sertraline had 1.9 times the odds of improvement, by week 12 of treatment versus placebo.

In contrast, more subjects reported study-related adverse events using sertraline (63.2%) versus R. rosea (30.0%) or placebo (16.7%) (p = 0.012). Two subjects prematurely discontinued sertraline treatment; while no subject prematurely discontinued R. rosea or placebo.

3.4. Possible benefits and limitations

The development of a safe and effective alternative botanical pharmacotherapy for depression would be of public health interest for individuals unable, or unwilling, to use conventional antidepressant therapy. Perhaps the greatest limitation to understanding the potential antidepressant benefit of R. rosea is the relative lack of any supporting data from older clinical trials conducted in the former Soviet Union. In this regard, virtually all of the older R. rosea studies were uncontrolled, not adequately powered, randomized, unblended, included subjects with more than a single psychiatric or psychological diagnosis, used un-validated diagnoses, employed arbitrary R. rosea therapy doses for undefined durations, used no conventional antidepressant or stimulant comparator, and provided no longitudinal objective symptom ratings over time. None of the studies utilized an active or inert placebo, and few used pharmaceutical grade botanical product. Moreover, none of the earlier R. rosea studies included subjects diagnosed with syndromes easily recognized by Western diagnostic nosologies, and none used longitudinal statistical procedures to examine results.

In contrast, the small body of randomized, double-blind, placebo-controlled studies with standardized, pharmaceutical-grade R. rosea extract may be thought to represent the first generation of controlled efficacy and tolerability trials for depression. Despite the limitations of these preliminary R. rosea trials, the overall findings suggest that R. rosea may produce modest antidepressant effects in subjects with mild to moderate depression, and may be almost as effective as conventional antidepressants albeit with superior tolerability.

Nevertheless, we would note that these modern studies, despite their well-designed and well-controlled aspects, had substantial limitations. For example, the Darbinyan et al. (2007) study reported significant reductions in mean HRSD endpoint scores for R. rosea extract 340 mg daily (n = 31) and R. rosea extract 680 mg daily (n = 29) (p< 0.0001, respectively), while there was no significant reduction in HRSD endpoint score for placebo (n = 29) (p = 0.2206). These results, however, are inconsistent with other modern 3-arm randomized controlled antidepressant trials; given the fact that the Darbinyan et al. (2007) study was insufficiently powered to show a significant drug-placebo difference. In contrast, the Mao et al. (2015) study was deliberately not powered to identify statistically significant differences between R. rosea and sertraline or placebo efficacy. Nevertheless, while this study identified a somewhat greater (albeit nonsignificant) antidepressant effect for sertraline versus R. rosea, R. rosea was substantially better tolerated than sertraline.

Despite these shortcomings, these studies suggest that R. rosea may represent a potential alternative treatment for individuals who are intolerant to conventional antidepressants or seek to avoid them. Moreover, it appears that R. rosea may exert its antidepressant effects via a broad spectrum of putative mechanisms which make it an attractive treatment from both a heuristic and mechanistic view point. Although the preliminary trials of R. rosea suggest an advantageous safety and tolerability profile compared to conventional antidepressant drugs, we would also acknowledge several disadvantages to R. rosea. For example, botanical extracts, while highly purified and standardized to active constituents, are still highly complex mixtures of many compounds which may have variable positive and negative effects depending on factors that have crucial impact on reproducibility of pharmacological activity (e.g., growing conditions, regional terroir, genus differences). These production disadvantages set botanical medications against conventional antidepressant drugs which, while less well tolerated, have the advantage of being a single, synthetic, reproducible, compound that always remains identical from batch to batch during production. Moreover, a particular standardized, botanical extract may have a different pharmacokinetic and pharmacodynamic dose-effect compared to a similar botanical extract with a different pharmaceutical standardization. For example, the maximal active antidepressant dose of SHR-5 brand of R. rosea extract might be inactive for a different extract of R. rosea--although both products were extracted from Rhodiola roots that have chemical compositions not identical to one another.

Finally, we acknowledge the difficulties in producing even the purest botanical medicinal products, and further acknowledge that providing reproducible effectiveness over time may be a serious challenge and a limitation of botanical medications in general. However, despite these limitations, the development of botanical remedies for depression and other mental disorders is clearly of interest and may represent a promising potential for future safe, effective, and affordable remedies with superior tolerability and a minimum of adverse events.

4. Conclusion

The considerable advances of quantitative functional genomics now provides more molecularly targeted candidates of disease. Despite these advantages, we are still at the stage of polypharmacy of targeted drugs. While some multi-target drugs offer modest efficacy advantages over single target drugs (and multi-target botanical agents), this is usually offset by unacceptable side effects. As a result, some scientists are turning toward a multi-layered network model of disease, particularly for neuropsychiatric diseases. This has prompted some mainstream drug makers to develop drug candidates with large therapeutic indices plus simultaneous effects on multiple genomic pathways. Paradoxically, such a search prompts a return to pharmocognosy, whereby botanicals, like R. rosea, will be nature's answer to simultaneously impacting multiple functional networks.

The work described herein is a beginning, and the path ahead is daunting, given that each plant has multiple genotypes. At least now there is growing recognition that botanical preparations must be standardized and tested without bias according to regulatory standards. If these efforts can attract funding, and are accomplished with scientific integrity, especially for those botanicals with long-standing claims of broadest-based efficacy in multiple diseases, then botanical medicines may lead the way back to a new understanding of acute and chronic disease.

ARTICLE INFO

Article history:

Received 2 December 2015

Revised 9 February 2016

Accepted 14 February 2016

Conflict of interest

Dr. Amsterdam is not a member of any industry-sponsored advisory board or speaker's bureau, and have no financial interest in any pharmaceutical, nutraceutical or medical device company.

Dr. Panossian is not a member of any industry-sponsored advisory board or speaker's bureau. He is an employee of Swedish Herbal Institute, but is not a shareholder in the company.

Acknowledgments

The authors thank Dr. Mark Kramer for suggested improvements in presentation of clinical detail and for his insightful contribution to the conclusion of this review. The views expressed herein are those of the authors alone and not necessarily those of any other person or entity. Due to journal limitations of space, this review does not permit a full exposition of the extent of clinical and pre-dinical studies of R. rosea in neuropsychiatric disorders.

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Jay D. Amsterdam (a), *, Alexander G. Panossian (b)

(a) Depression Research Unit, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia, PA, USA

(b) Research and Development Unit, Swedish Herbal Institute, Vallberga, Holland, Sweden

Abbreviations: 5-HTP, 5-hydroxytryptophan; BDA, Beck Depression Inventory; CAM, complementary and alternative medicines; CGI/C, Clinical Global Impression--Change over time; CGI/S, Clinical Global Impression--Severity; CNS, central nervous system; CRA, corticotropin-releasing hormone; DSM-1V, Diagnostic and Statistical Manual, Fourth Edition; GABA, gamma amino butyric acid; GAD, generalized anxiety disorder; GPCR, G-protein coupled receptor; HPA, hypothalamus--pituitary--adrenals axis; HRSA, Hamilton Anxiety Rating Scale; HRSD, Depression Rating Scale; JNK, stress activated phosphorylated c-Jun N-terminal kinases; MAO-A, monoamine oxidase A; NA, nor-adrenalin; NO, nitric oxide; NPY, neuropeptide Y; PK, protein kinase.

* Corresponding author. Tel.: +1 215 662 3462.

E-mail address: jamsterd@mail.med.upenn.edu (J.D. Amsterdam).

http://dx.doi.org/10.1016/j.phymed.2016.02.009

Table 1
Target molecules affected by R. rosea and salidroside.

Target molecule           Test article   Cell type/animal

BNDF                      Salidroside    Hippocampus, rats and mice
CREB                      Salidroside    Neural stem cells; respiratory
                                         epithelial cells
                                         HBE16 cells
CREB tCREB/MITF/          R. rosea       Mouse melanoma cells (B16F0)
  tyrosinase pathway        hydrolisate
TrkB                      Salidroside    Hippocampus, rats and mice
Glucocorticoid receptor   Salidroside    Hippocampus, rats;
Corticotropin-releasing   Salidrosid     Hippocampus, rats;
  hormone (CRH)
Serotonin receptor 1A     R. rosea       Brain, rat
                            extract
Serotonin                 R. rosea       Hippocampus, rat
                            extract
                                         Brain, rat
                          Salidroside    Prefrontal cortex, mice
Noradrenaline             Salidroside    Prefrontal cortex, mice
MAO-A                     R. rosea       Insect mitochondrial MOA
                            extracts,      containing fraction
                            Rosiridin
P-JNK                     R. rosea       Blood serum, rabbits
                            Salidroside
NO                        R. rosea       Blood serum, rabbits
                            Salidroside
Cortisol                  R. rosea       Human saliva. Blood serum,
                                         rabbits
                          R. rosea
                            Salidroside
NPY                       Salidroside    Human neuroglia cell line T98G
HSF1                      Salidroside    Human neuroglia cell line T98G
Hsp70                     Salidroside    Human neuroglia cell line T98G

Target molecule           Test article   Concentration/Dose

BNDF                      Salidroside    20 and 40 mg/kg
                                         12 and 24 mg/kg
CREB                      Salidroside    5 [micro]M
                                         50 and 100 [micro] M
CREB tCREB/MITF/          R. rosea
  tyrosinase pathway        hydrolisate
TrkB                      Salidroside    12 and 24 mg/kg
Glucocorticoid receptor   Salidroside    20 and 40 mg/kg
Corticotropin-releasing   Salidrosid     20 and 40 mg/kg
  hormone (CRH)
Serotonin receptor 1A     R. rosea       5,10,20, 40 mg/kg
                            extract
Serotonin                 R. rosea       1.5, 3.0, 6.0 g/kg
                            extract
                                         5,10,20, 40 mg/kg
                          Salidroside    12 and 24 mg/kg
Noradrenaline             Salidroside    12 and 24 mg/kg
MAO-A                     R. rosea       10(-5)M
                            extracts,
                            Rosiridin
P-JNK                     R. rosea       1.0 mg/kg, 0.5 mg/kg
                            Salidroside
NO                        R. rosea       1.0 mg/kg, 0.5 mg/kg
                            Salidroside
Cortisol                  R. rosea       576 mg daily
                          R. rosea       1.0 mg/kg, 0.5 mg/kg
                            Salidroside
NPY                       Salidroside    1-10 [micro] M
HSF1                      Salidroside    1-10 [micro] M
Hsp70                     Salidroside    1-10 [micro] M

Target molecule           Test article   Effect

BNDF                      Salidroside    Increase
CREB                      Salidroside    ?
                                         Activity decrease
CREB tCREB/MITF/          R. rosea       Inhibits
  tyrosinase pathway        hydrolisate
TrkB                      Salidroside    Increase
Glucocorticoid receptor   Salidroside    Increase
Corticotropin-releasing   Salidrosid     Decrease
  hormone (CRH)
Serotonin receptor 1A     R. rosea       Increase
                            extract
Serotonin                 R. rosea       Increase
                            extract
                                         Increase
                          Salidroside    Decrease
Noradrenaline             Salidroside    Decrease
MAO-A                     R. rosea       Inhibits
                            extracts,
                            Rosiridin
P-JNK                     R. rosea       Decrease
                            Salidroside
NO                        R. rosea       Decrease
                            Salidroside
Cortisol                  R. rosea       Decrease
                          R. rosea
                            Salidroside
NPY                       Salidroside    Increase
HSF1                      Salidroside    Increase
Hsp70                     Salidroside    Increase

Target molecule           Test article   Reference

BNDF                      Salidroside    Yang et al. (2014)
                                         Zhu et al. (2015)
CREB                      Salidroside    Jin et al. (2016)
                                         Li et al. (2013)
CREB tCREB/MITF/          R. rosea       Chiang et al. (2014)
  tyrosinase pathway        hydrolisate
TrkB                      Salidroside    Zhu et al. (2015)
Glucocorticoid receptor   Salidroside    Yang et al. (2014)
Corticotropin-releasing   Salidrosid     Yang et al. (2014)
  hormone (CRH)
Serotonin receptor 1A     R. rosea       Mannucci et al. (2012)
                            extract
Serotonin                 R. rosea       Qin et al. (2008)
                            extract      Chen et al. (2009)
                                         Mannucci et al. (2012)
                          Salidroside    Zhu et al. (2015)
Noradrenaline             Salidroside    Zhu et al. (2015)
MAO-A                     R. rosea       Van Dearman et al. (2009)
                            extracts,
                            Rosiridin
P-JNK                     R. rosea       Panossian et al. (2007)
                            Salidroside
NO                        R. rosea       Panossian et al. (2007)
                            Salidroside
Cortisol                  R. rosea       Olsson et al. (2009)
                          R. rosea       Panossian et al. (2007)
                            Salidroside
NPY                       Salidroside    Panossian et al. (2012)
HSF1                      Salidroside    Panossian et al. (2012)
Hsp70                     Salidroside    Panossian et al. (2012)

Table 2
Effect of Rhodiola on genes involved in mood and depressive disorders.

Disease or Function   p-Value     Molecules                     # Mole
Annotation                                                      cules

Mood disorders        3.73E--04   ADRA2B, ALOX12, AQP4, CA9,    22
                                  CACNB2, CCKBR, CHRNA1, CHR
                                  NB4, CHRNG, DDC, ESR1,
                                  GRIA3, GRIK2, GRIN1, KCNK2,
                                  MTNR 1A, MYOM1, NCAM1,
                                  NDUFS7, PDE11A, SCN11A,
                                  SCN2B

Depressive disorder   7.90E--04   ADRA2B, AQP4, CACNB2,         14
                                  CCKBR, CHRNA1, CHRNB4,
                                  CHRNG, ESR1, GRIA3, GRIN1,
                                  KCNK2, MYOM1, NCAM1, PDE11A

Table 3
Effect of Rhodiola on genes involved in depression ([section]).

         Entrez Gene Name and summary--target              Fold
Symbol   protein; http://www.ncbi.nlm.nih.gov/gene/        change

ADRA2B   Adrenoceptor alpha 2B Alpha-2-adrenergic          2.928
         receptors are members of the G
         protein-coupled receptor superfamily. These
         receptors are critical for regulating the
         neurotransmitter release from sympathetic
         nerves and adrenergic neurons in the central
         nervous system.

AQP4     Aquaporin 4 This gene encodes a member of         3.01
         the aquaporin family of intrinsic membrane
         proteins that function as water-selective
         channels in the plasma membranes of many
         cells. The encoded protein is the
         predominant aquaporin found in the brain.

CACNB2   Calcium channel, voltage-dependent, beta 2        -3.387
         subunit This gene encodes a subunit of a
         voltage-dependent calcium channel protein
         that is a member of the voltage-gated
         calcium channel superfamily.

CCKBR    Cholecystokinin B receptor This gene encodes      -2.621
         a G-protein coupled receptor for gastrin and
         cholecystokinin (CCK), regulatory peptides of
         the brain and gastrointestinal tract.

CHRNA1   Cholinergic receptor, nicotinic, alpha 1          -2.77
         (muscle) The muscle acetylcholine receptor
         consists of five subunits of four different
         types: two alpha subunits and one beta.
         gamma, and delta subunit. This gene encodes
         an alpha subunit that participates in
         acetylcholine binding/channel gating.

CHRNB4   Cholinergic receptor, nicotinic, beta 4           5.464
         (neuronal)

CHRNG    Cholinergic receptor, nicotinic, gamma            -5.028
         (muscle) The mammalian acetylcholine
         receptor is a transmembrane glycoprotein
         with several subunits. This gene encodes the
         gamma subunit, which participates in
         neuromuscular organogenesis and ligand
         binding.

ESR1     Estrogen receptor 1 This gene encodes an          -7.516
         estrogen receptor, which is a ligand-activated
         transcription factor composed of several
         domains that are important for hormone
         binding, DNA binding, and transcription
         activation. The protein localizes to the
         nucleus, and estrogen and its receptors are
         essential for sexual development and
         reproductive function, as well as the
         development of other tissues, such as bone.
         Estrogen receptors are also involved in
         pathological processes including breast
         cancer, endometrial cancer, and osteoporosis.

GRIA3    Glutamate receptor, ionotropic, AMPA 3            3.031
         Glutamate receptors are the predominant
         excitatory neurotransmitter receptors in the
         mammalian brain and are activated during
         various normal neurophysiologic processes.
         These receptors are heteromeric protein
         complexes composed of multiple subunits
         that are arranged to form ligand-gated ion
         channels.

GRIN1    Glutamate receptor, ionotropic,                   3.864
         N-methyl-D-aspartate 1 The protein
         encoded by this gene is a critical subunit of
         the N-methyl-D-aspartate receptors. These
         members of the glutamate receptor channel
         superfamily are heteromeric protein
         complexes with multiple subunits arranged
         to form a ligand-gated ion channel. These
         subunits are critical for the plasticity of
         synapses, which is believed to support
         memory and learning.

KCNK2    Potassium channel, subfamily K, member 2          3.411
         This gene encodes one of the members of
         the two-pore-domain background potassium
         channel protein family. This type of
         potassium channel is formed by two
         homodimers that create a channel that
         releases potassium from the cell to control
         the resting membrane potential.

MYOM1    Myomesin 1                                        2.732

NCAM1    Neural cell adhesion molecule 1 This gene         2.657
         encodes a cell adhesion protein that is
         involved in cell-to-cell interactions and
         cell-matrix interactions during development
         and differentiation. The encoded protein is
         involved in the development of the nervous
         system and cells involved in the expansion of
         T cells and dendritic cells, which are critical
         for immune surveillance.

PDE11A   3',5'-cyclic-nucleotide phosphodiesterase         5.776
         (PDE) The 3',5'-cyclic nucleotides cAMP and
         cGMP are the second messengers among
         numerous signal transduction pathways. The
         3',5'-cydic nucleotide phosphodiesterases
         (PDEs) catalyze the hydrolysis of cAMP and
         cGMP to form the corresponding
         5'-monophosphates and provide a
         mechanism for down-regulating cAMP and
         cGMP signaling. This gene encodes a
         member of the PDE protein superfamily.

         Depression-related Biological Process and
Symbol   Role in Cell

ADRA2B   Activation of MAPK cascade; activation of
         protein kinase B activity; adrenergic
         receptor signaling pathway; cell-cell
         signaling; GPCR-signaling pathway;
         negative regulation of epinephrine and
         norepinephrine secretion; positive
         regulation of neuron differentiation;
         signal transduction

AQP4     Nervous system development; protein
         homooligomerization; renal water
         absorption; response to glucocorticoid
         stimulus; response to radiation; sensory
         perception of sound; transmembrane
         transport; regulation of dopamine and
         L-glutamic acid

CACNB2   Axon guidance; calcium ion import;
         calcium ion transport; neuromuscular
         junction development; synaptic
         transmission; visual perception

CCKBR    Behavioral defense response; feeding
         behavior; phospholipase C-activating
         G-protein coupled receptor signaling
         pathway; GABAergic; positive regulation
         of synaptic transmission, glutamatergic;
         sensory perception; signal transduction;
         regulation of alpha catenin

CHRNA1   Ion transmembrane transport;
         musculoskeletal movement;
         neuromuscular synaptic transmission;
         neuron homeostasis; signal transduction;
         synaptic transmission

CHRNB4   Behavioral response to nicotine; ion
         transport; locomotor behavior; regulation
         of membrane potential; regulation of
         neurotransmitter secretion; smooth
         muscle contraction; synaptic
         transmission; synaptic transmission

CHRNG    Acetylcholine-activated cation-selective
         channel activity; acetylcholine receptor
         activity; cation transport; ion
         transmembrane transport; muscle
         contraction; regulation of membrane
         potential; signal transduction; synaptic
         transmission

ESR1     Cellular response to estradiol stimulus;
         elevation of cytosolic calcium ion
         concentration; gene expression;
         intracellular steroid hormone receptor
         signaling pathway; male gonad
         development; negative regulation of the
         I-kappaB kinase/NF-kappaB cascade;
         phospholipase C-activating G-protein
         coupled receptor signaling pathway;
         positive regulation of the nitric oxide
         biosynthetic process; signal transduction;
         transcription

GRIA3    Glutamate receptor signaling pathway; ion
         transmembrane transport; ion transport;
         regulation of receptor recycling; synaptic
         transmission; long-term potentiation.
         long-term depression, plasticity.
         excitatory postsynaptic potential,
         depolarization, depotentiation,
         depression,

GRIN1    Apoptosis, plasticity, synaptic transmission,
         long-term potentiation, cell death,
         transmembrane potential, excitotoxicity.
         cytotoxicity, communication, homeostasis

KCNK2    G-protein coupled receptor signaling
         pathway; ion transport; potassium ion
         transmembrane transport; potassium ion
         transport; regulation of ion
         transmembrane transport; stabilization
         of membrane potential; synaptic
         transmission

MYOM1    Muscle contraction

NCAM1    Aging; axon guidance; cell surface receptor
         signaling pathway; learning or memory;
         multicellular organismal response to
         stress; negative regulation of cell death;
         neuron development; neuron projection
         development; organ regeneration;
         peripheral nervous system axon
         regeneration; positive regulation of
         calcium-mediated signaling; regulation of
         the sensory perception of pain; thalamus
         development

PDE11A   cAMP catabolic process; cGMP catabolic
         process; metabolic process; signal
         transduction

Symbol   Related disease

ADRA2B   Attention deficit hyperactivity disorder,
         hypertension, cardiovascular disorder,
         multiple sclerosis, heart disease,
         post-traumatic stress disorder, stroke,
         major depression, bipolar disorder.
         Parkinson's disease, attention deficit
         disorder, psychomotor agitation.
         insomnia, mood disorder, anxiety
         disorder, social anxiety disorder,
         Alzheimer's disease, panic disorder,
         depressive disorder, psychosis

AQP4     Major depression, Huntington's disease.
         Parkinson's disease

CACNB2   Hypertension, hypercholesterolemia.
         hyperlipidemia, mania, depressive
         disorder, migraines, short-QT syndrome
         4, Brugada syndrome, bipolar disorder.
         Alzheimer's disease

CCKBR    Withdrawal syndrome, hypergastrinemia,
         Huntington's disease, major depression,
         hyperphagia

CHRNA1   Depressive disorder, seizures, psychomotor
         agitation, schizophrenia, stroke, coronary
         disease, etc.

CHRNB4   Seizures, psychomotor agitation.
         schizophrenia, schizoaffective disorder.
         depressive disorder

CHRNG    Psychomotor agitation, schizophrenia,
         depressive disorder, Escobar syndrome,
         lethal multiple pterygium syndrome

ESR1     Breast cancer, weight gain, atherosclerosis.
         obesity, depressive disorder, Alzheimer's
         disease, etc.

GRIA3    Tremor, X-linked mental retardation, major
         depression, Alzheimer's disease, bipolar
         disorder

GRIN1    Schizophrenia, Alzheimer's disease.
         Parkinson's disease, bipolar disorder,
         major depression, obsessive-compulsive
         disorder, multiple sclerosis, frontal lobe
         dementia, Lewy body disease, bipolar
         depression, binge eating disorder, opioid
         dependence, morbid obesity, autosomal
         dominant mental retardation type 8,
         attention deficit hyperactivity disorder,
         drug abuse, Down's syndrome, ataxia,
         frontotemporal dementia, anxiety
         disorder, autism, open-angle glaucoma,
         cognition disorder, postoperative pain,
         delirium, Huntington's disease,
         depressive disorder, dementia, breast
         cancer, partial seizure, tuberculosis,
         urinary tract infection, Lennox-Gastaut
         syndrome, epileptic seizure, hypophagia.
         starvation, neurodegeneration, bipolar 1
         disorder

KCNK2    Seizures, major depression, prostatic
         carcinoma, Huntington's disease

MYOM1    Major depression

NCAM1    Major depression, bipolar disorder

PDE11A   Physical disability, cardiovascular disorder,
         diabetes mellitus, major depression

([section]) Adapted from reference Panossian et al., 2014.

Table 4
Top three physiological system functions affected by
Rhodiola, salidroside, triandrin, and tyrosol in T98G cells.

Rhodiola extract

                      p-Value             # Genes

Behavior              7.69E-07-           50
                      1.02E-02

Nervous system        3.60E-06-           65
  function            1.00E-02
Humoral Immune        2.39E-05-           28
  Response            6.52E-03

Salidroside

                      p-Value             # Genes

Behavior              2.14E-06-1.83E-     40
                      02 40

Nervous system        6.77E-05-1.91E-     60
  function            02 60
Cardiovascular        1.13E-04-1.91E-     24
  system function     02 24

Tyrosol

Hair and skin         1.29E-02-           6
development and       3.73E-02
  function
Hematological         1.29E-02-           10
  system function     3.73E-02
Hematopoiesis         1.29E-02-           4
                      3.73E-02

Triandrin

                      p-Value             # Genes

Tissue development    2.53E-03-           14
                      3.74E-02

Cardiovascular        6.86E-03-           4
  system function     3.74E-02
Organismal            6.86E-03-           8
  development         3.74E-02

Table 5
Summary of clinical studies of various Rhodiola preparations
in depression ([section]).

Pathophysiological
condition                     Reference                  Study design

Depression                    Darbinyan et al. (2007)    R,PC,DB
                              Mao et al. (2014, 2015)    R,PC,DB
                              Brichenko et al. (1986)    OL, C
Asthenic--depressive          Krasik et al., (1970a,b)   OL, UC
  syndrome (stress-
  induced mild depression)
                              Krasik et al., (1970a,b)   OL, UC
                              Mikhailova, (1983)         OL
                              Mesheryakova et al.        OL
                                (1975)
Neurosis *** (stress-         Saratikov et al. (1965)    OL
  induced depression)
                              Kaliko and Tarasova        PC, SB
                                (1966)
Anxiety                       Bystritsky et al. (2008)   OL

Pathophysiological            Duration of the    Number of
condition                     treatment, weeks   patients

Depression                    6                  91
                              12                 57
                              ?                  78/56 **
Asthenic--depressive          2-3                128 *
  syndrome (stress-
  induced mild depression)
                              2-3                135/27 *
                              8                  58
                              ?                  25

Neurosis *** (stress-         1.5                65 *
  induced depression)
                              7                  70/80 *

Anxiety                       10                 10

Pathophysiological            Jadad score   Quality level of
condition                     (max 5) (a)   evidence (b)

Depression                    5             1b
                              5             lb
                              0             IIa
Asthenic--depressive          0             --
  syndrome (stress-
  induced mild depression)
                              0             --
                              0             --
                              0             --

Neurosis *** (stress-         0             --
  induced depression)
                              1             IIb

Anxiety                       0             III

* Grade A. Evidence levels quality Ia, Ib--Requires at least
one randomized controlled trial as part of the body of
literature of overall good consistency addressing the
specific recommendation;

* Grade B. Evidence levels IIa, IIb, III--Requires
availability of well-conducted clinical studies but no
randomized clinical trials on the topic of recommendation;

* Grade C. Evidence level IV--Requires evidence from expert
committee reports or opinions and/or clinical experience of
respected authorities but indicates absence of directly
applicable studies of good quality.

([section]) adapted from reference Panossian and Wikman
(2010).

R--Randomized, PC--placebo-controlled; DB--double-blind; SB-
-single blind, CO--crossover, UC--uncontrolled, C-
controlled, OL--open label trial;

* mixed patients population, sick/healthy subjects.

** adjuvant therapy with antidepressants, control group--
tricyclic antidepressants.

*** Neurotic, stress-related and somatoform disorders (F40-F48)

(a) Jadad AR, Moore RA, Carroll D, et al. Assessing the
quality of reports of randomized clinical trials: is
blinding necessary? Control Clin Trials 1996; 17: 1-12.

(b) According to WHO, FDA and EMEA: Ia--meta-analyses of
randomized and controlled studies; IIb--evidence from at
least one randomized study with control; IIa-evidence from
at least one well/performed study with control group; IIb--
evidence from at least one well-performed quasi-
experimental study; III--evidence from well-performed non-
experimental descriptive studies as well as comparative
studies, correlation studies and case-studies; and IV--
evidence from expert committee reports or appraisals and/or
clinical experiences by prominent authorities.

Grade of recommendation based on the European Medicines
Agency Assessment Scale (European Medicines Agency.
Committee on Medicinal Products EMEA/HMPC/104613/2005.
Available at http://www/emea/europa/
eu/pdfs/human/hmpc/10461305en/pdf (Accessed 01/03/2009)]:
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Author:Amsterdam, Jay D.; Panossian, Alexander G.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:1USA
Date:Jun 15, 2016
Words:12853
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