Content uploaded by Ion Anghelescu
Author content
All content in this area was uploaded by Ion Anghelescu on Jan 16, 2018
Content may be subject to copyright.
Content uploaded by Ion Anghelescu
Author content
All content in this area was uploaded by Ion Anghelescu on Jan 16, 2018
Content may be subject to copyright.
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=ijpc20
International Journal of Psychiatry in Clinical Practice
ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20
Stress management and the role of Rhodiola
rosea: a review
Ion-George Anghelescu, David Edwards, Erich Seifritz & Siegfried Kasper
To cite this article: Ion-George Anghelescu, David Edwards, Erich Seifritz & Siegfried Kasper
(2018): Stress management and the role of Rhodiola rosea: a review, International Journal of
Psychiatry in Clinical Practice, DOI: 10.1080/13651501.2017.1417442
To link to this article: https://doi.org/10.1080/13651501.2017.1417442
© 2018 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group.
Published online: 11 Jan 2018.
Submit your article to this journal
Article views: 17
View related articles
View Crossmark data
REVIEW ARTICLE
Stress management and the role of Rhodiola rosea: a review
Ion-George Anghelescu
a
, David Edwards
b
, Erich Seifritz
c
and Siegfried Kasper
d
a
Department of Psychiatry and Psychotherapy, Clinic Dr. Fontheim, Liebenburg, Germany;
b
Claridges Barn, Oxfordshire, UK;
c
Department of
Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland;
d
Department of Psychiatry and
Psychotherapy, Medical University of Vienna, Vienna, Austria
ABSTRACT
Objective: Stress describes the physiological reaction to threat or pressure, which manifests as physical
symptoms of exhaustion or energy loss and psychological symptoms, including irritability or tension. If
untreated, chronic stress or burnout may develop, both are areas of unmet medical need. Evidence-based
treatment and prevention measures are needed.
Methods: Prevention strategies and existing treatment options for stress-related symptoms were eval-
uated to establish criteria for an adequate pharmacological approach to stress. The authors reviewed the
literature to reach a clinically meaningful strategy for prevention and treatment of persistent stress symp-
toms and their consequences, including burnout and secondary diseases.
Results: Current medication reveals a treatment gap. Most drugs target only psychological or physical
stress symptoms. Furthermore, psychotropic medications sometimes prescribed for stress often have
unacceptable side effects and bear a risk of overtreatment. Ideally pharmacological therapy should afford
comprehensive treatment of all stress symptoms with a favourable safety profile.
Conclusions: Rhodiola rosea extract (RRE) fulfils important requirements. It is the main adaptogen
approved by the HMPC/EMA for the indication ‘stress’and influences the release of stress hormones while
boosting energy metabolism as revealed in animal literature. RRE offers comprehensive treatment of stress
symptoms and can prevent chronic stress and stress-related complications.
ARTICLE HISTORY
Received 27 October 2017
Revised 1 December 2017
Accepted 12 December 2017
KEYWORDS
Rhodiola rosea; stress;
burnout
Introduction
Stress describes the physiological reaction to environmental
threats or pressures, which can be self-driven e.g., striving for per-
fection, high ambition or external such as social pressures, exces-
sive demands or workloads. Although the body may initially adapt
to perform under stress, it soon becomes dysfunctional if stress
persists and has a too high intensity. Stress manifests itself in a
wide variety of both physical and psychological symptoms, has a
negative impact on performance and leads to absence from work.
Work-related stress occurs across all groups of society and affects
22% of the European workforce. It is a crucial factor in 50–60% of
all lost working days (Milczarek, Schneider, & Gonz
alez, 2009) with
a rising trend. In 2016, a survey of a large German health insur-
ance company revealed that over 60% of survey participants are
now more stressed than in 2013 (Techniker Krankenkasse, 2016).
The World Health Organization (WHO) has called stress ‘the health
epidemic of the 21st century’.
If stress persists and is left untreated, it can result in serious
health problems including burnout and secondary conditions, e.g.,
depression, anxiety, cardiovascular, gastrointestinal, neurological
or musculoskeletal disease or diabetes –consequently with higher
costs to the community and a higher impact on individuals’lives.
The main implications for individuals related to health impairment
are lower income and reduced quality of life. However, stress has
not only individual, but also social and economic consequences.
Organisations are affected by rising costs related to sick leave,
reduced productivity and higher staff turnover (European Agency
for Safety and Health at Work [EU-OSHA], 2014).
Methods
The authors reviewed the current literature to identify and assess
prevention strategies and treatment options for stress-related
symptoms and thus established criteria for an adequate and holistic
pharmacological approach to stress. The aim of this process was to
propose a consensus for prevention and treatment of symptoms of
persistent stress as well as for prevention of health consequences of
stress such as burnout and secondary diseases. In this review article
we have outlined current understanding of the pathophysiology of
stress and identified the areas of greatest clinical need for interven-
tion, which occurs at two stages: as a preventive treatment for a
patient with stress to avoid the development of chronic stress and
for those already suffering from persistent stress, an appropriate
therapy to avoid burnout and secondary diseases. Assessment of
prevention and treatment strategies identified some non-pharma-
cological approaches and some pharmacological approaches which
have shown limited efficacy targeting the symptoms of stress and
these are outlined below. The literature review process identified a
significant amount of data on the clinical effects of Rhodiola rosea
extract (RRE) on stress and stress-related disorders and mechanistic
studies allude to the ability of RRE to normalise stress and boost
energy levels. Thus, in the latter part of this review article we have
focused our attention on RRE as a specific pharmacological
approach to stress management.
Stress, allostatic state and allostatic (over)load
In 1936 Hans Selye postulated the so-called general adaptation
syndrome which describes the stereotyped response of an
CONTACT Ion-George Anghelescu i.anghelescu@fontheim.de Department of Psychiatry and Psychotherapy, Clinic Dr. Fontheim, 38704 Liebenburg, Germany
ß2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/Licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE, 2018
https://doi.org/10.1080/13651501.2017.1417442
organism in reaction to a stressor. This syndrome consists of three
stages. The first stage is the alarm reaction (‘fight or flight’
response) in which resources are mobilised to maintain homeosta-
sis. This has subsequently been termed as allostasis, which
describes the biological response to stressors to promote stability
through change (McEwen, 2000). Primary mediators of allostasis
include, but are not confined to, hormones of the hypothalamic-
pituitary-adrenal (HPA) axis, catecholamines and cytokines.
Restoration of allostasis leads to the second stage of resistance,
in which defence and adaptation are sustained and optimal.
However, many current stressors are persistent and can lead an
organism into stage three where the body’s capacity to withstand
them is surpassed by the consequences of exhaustion and
depleted reserves. Extreme psychological stress impacts on the
complex regulation of emotion by the brain and on human psy-
chological resilience and vulnerability to psychopathology
(Charney, 2004).
The concepts of allostasis and allostatic load link the protective
and survival values of the acute response to stress to the adverse
consequences that result if the acute response persists and
becomes chronic (McEwen & Wingfield, 2003). An allostatic state
may result from an imbalance of the primary mediators, reflecting
excessive production of some and inadequate production of
others (McEwen, 2005). In some cases, the stress mediators them-
selves can turn on the body and cause problems. If recovery from
the acute event is not accompanied by an adequate homeostatic
response to terminate the acute adaptive response of stress medi-
ators, the deleterious effects on psychological and physiological
function termed allostatic load occur. The allostatic load is the
burden borne by a brain and body adapting to challenges, both
physiological and psychological. A sustained allostatic state may
ensue, termed allostatic overload. The tipping point for allostatic
overload will vary among individuals. It manifests as disease e.g.,
chronic hypertension and the generation of atherosclerotic pla-
ques, elevated glucocorticoids leading to insulin resistance and
increased risk for cardiovascular disease, immunosuppression or
elevation of inflammatory cytokines (see below).
Pathomechanism, symptoms and health consequences
of chronic stress
The symptoms of stress can be multiple and affect many organ
systems. The physiological stress response involves stimulation of
the autonomic nervous system (ANS) and the hormonal system,
with potentially negative impact on the cardiovascular system, the
musculoskeletal system, the immunological system and others
(Figure 1).
Fatigue and exhaustion manifest as key physical stress symp-
toms. Others can be gastrointestinal symptoms, headache, back-
ache or sexual dysfunction. Psychological and emotional
symptoms of stress include e.g., tension, irritability, anxious or
depressive mood, bad temper and the feeling of losing control.
Concomitantly, changes in cognition, including forgetfulness and
inability to concentrate may occur. Behavioural symptoms of
stress include social withdrawal, alcohol and cigarette abuse, eat-
ing disorders, proneness to mistakes and work absence (Edwards,
Heufelder, & Zimmermann, 2012; Milczarek et al., 2009).
These symptoms result from several postulated pathomechan-
isms. The HPA axis is one of the main stress response pathways.
Stress induces the release of corticotropin releasing hormone
(CRH) in the hypothalamus. This activates the pituitary gland to
release adrenocorticotropic hormone (ACTH). The latter stimulates
the release of adrenaline, noradrenaline and cortisol in the adrenal
gland. The actions of this hormone system are tightly regulated
normally to ensure that the organism can respond quickly and
adequately to stress, via negative feedback mechanisms, levels of
hormones e.g., cortisol return to normal values.
Chronic stress, however, results in persistently elevated levels
e.g., of cortisol, as demonstrated in animal and cell models.
Studies of rabbits under immobilisation stress revealed an
Figure 1. Multi-faceted symptoms of stress.
2 I.-G. ANGHELESCU ET AL.
activation of e.g., stress-activated protein kinase/Jun N-terminal
protein kinase (SAPK/JNK) (Panossian, Hambardzumyan,
Hovhanissyan, & Wikman, 2007). Previous studies, e.g., with mouse
hippocampal (HT22) cells, indicate that JNK leads to an inhibition
of glucocorticoid receptor function. This again results in a block-
ade of the negative feedback mechanism of cortisol release (see
Figure 2(A); Panossian, 2013; Panossian et al., 2007; Wang et al.,
2005). Consequently, cortisol levels in the blood remain high
which may lead to fatigue, depression, impaired cognitive per-
formance, hyperglycaemia, high blood pressure and other health
problems as a long-term consequence.
At the intracellular level, high cortisol levels impact on the
balance between trophic and atrophic factors within neurones,
thus affecting neurogenesis and brain plasticity in the hippo-
campus and frontal cortex, which results in neurodegenerative
changes involved in mood regulation (Gould & Tanapat,
1999).
Investigations with rat cells showed that the release of SAPK
leads to an increase in nitric oxide (NO) release (Guan, Buckman,
Springer, & Morrison, 1999). The latter impairs both glycolysis and
mitochondrial function which results in a decrease in adenosine
triphosphate (ATP) synthesis (see Figure 2(B); Brown, 2001; Giulivi,
1998). Low ATP levels are associated with symptoms such as loss
of energy, fatigue and exhaustion (Panossian, 2013; Panossian &
Wikman, 2009).
A role of inflammatory mechanisms involving cytokines has
also been hypothesised in chronic stress-related mental diseases,
such as depression, anxiety or dementia (Bagyinszky et al., 2017;
Kim et al., 2017).
An association between type 2 diabetes and depression has
recently been explained, to some extent, by unspecific patho-
physiological mechanisms involved in the stress response (Berge
& Riise, 2015). Chronic stress is also associated with an increased
risk of cardiovascular disease (CVD) (Bot & Kuiper, 2017; Nabi
et al., 2013). Long-term work stress accounts for an estimated
16% of male and 22% of female CVD in the EU (Houtman, 2005).
Recent studies report that the activity of the amygdala, a key
component of the brain involved in emotion and stress, is of pre-
dictive value for the incidence of acute cardiovascular events dur-
ing a median follow up period of 3.7 years among nearly 300
individuals with no prior history of CVD (Tawakol et al., 2017).
Burnout
Burnout is a stress disorder of unspecific risk stage which is char-
acterised by symptoms of mental exhaustion and physical fatigue,
Figure 2 (A) Postulated pathomechanisms of stress: persistent stress leads to a blockade of the negative feedback of cortisol. (Adapted from Panossian, 2013;
Panossian et al., 2007). (B) Postulated pathomechanisms of stress: persistent stress leads to a disruption of ATP synthesis. (Adapted from Panossian & Wikman, 2009).
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 3
cynicism or depersonalisation and reduced personal accomplish-
ment (Hochstrasser et al., 2016). It represents a risk factor not only
for psychiatric diseases such as depression and anxiety, but also
for cardiovascular, metabolic and other somatic diseases. Work-
related burnout has been associated with an increased 10-year
mortality risk (Ahola, V€
a€
an€
anen, Koskinen, Kouvonen, & Shirom,
2010). Thus, the prevention of burnout deserves special attention.
The usual non-pharmacological treatment is cognitive behav-
ioural therapy or psychotherapy and there is currently no specific
pharmacological treatment for burnout. Several biomarkers have
been tested for association with burnout, but the results are
contradictory and there are currently no established biochemical
markers which can be considered as reliable indicators for burn-
out (Danhof-Pont, van Veen, & Zitman, 2011).
Stress-vulnerability and resilience, respectively, play an import-
ant role in the predisposition for, or resistance against, burnout
and are an area of focus in stress research. The stress-vulnerability
model was first hypothesised by Zubin and Spring (1977) to iden-
tify and treat relapses of mental illness. It suggests that people
inherit a genetic predisposition to mental illness. This vulnerability
in itself is not sufficient to manifest the disorder and requires
interaction with bio-pyscho-social stressors (Goh & Agius, 2010).
Increased vulnerability is potentially influenced by genetic factors
and/or individual stress experience and may lead to decreased
resilience to stress. Conversely, stress overload and burnout may
be prevented by enhancing resilience. Hence, the prevention of
burnout and exhaustion by enhancement of resilience on the one
hand and by the adequate treatment of stress symptoms on the
other is very important and appears to be an area of a consider-
able unmet medical need.
Stress management strategies
Popular coping strategies, such as distraction, physical activities,
relaxation, socialising and healthy food, may be employed in order
to get out of the stressful situation with the aim of regaining
inner calm and strength. The usual form of care for work-related
chronic stress is coaching, using a cognitive-behavioural approach
whose primary aim is to reduce symptoms and improve function-
ing (Schoutens, Frings-Dresen, & Sluiter, 2016). As an alternative
non-pharmacological approach, mindfulness-based stress reduc-
tion is a clinically standardized meditation technique that has
demonstrated an effect on stress reduction in healthy people,
with benefit similar to that of standard relaxation training (Chiesa
& Serretti, 2009).
However, many modern stressors are persistent and the body’s
capacity to withstand them is surpassed by the consequences of
exhaustion and depleted reserves, leading to burnout (German
Association for Psychiatry, Psychotherapy and Psychosomatics
[DGPPN], 2012). Thus, as mentioned above, the areas of unmet
clinical need for intervention may be identified in two stages: as a
preventive treatment in a patient with stress or a lack of vitality
to avoid the development of chronic stress or exhaustion, and
secondly, as a first-line treatment when persistent stress and
exhaustion are present, to avoid burnout and secondary diseases.
It should not be the goal of a treatment strategy to make one
keep going while neglecting the signs and symptoms of exhaus-
tion, but rather to assist in coping with temporary unusual
demands, allowing for rapid readaption to normal states once the
stressful situation has subsided.
Pharmacological interventions
If stress symptoms persist, together with continuously demanding
life circumstances that cannot easily be avoided, pharmacological
intervention may become necessary to prevent serious mental
and social sequelae. However, current pharmacotherapy reveals a
treatment gap. Many herbals, vitamin combinations or prescrip-
tion medicines tend to focus only on single symptoms, rather
than comprehensively on all aspects of stress or burnout. Besides,
psychiatric prescription drugs like antidepressants, anxiolytics or
b-blockers are mostly indicated for more severe diseases, such as
depression or anxiety and there is a risk of overtreatment includ-
ing severe side effects and/or risk of dependency.
Herbal treatment options or other drugs available over-the-
counter (OTC) tend to focus either on increasing/preserving
energy reserves (treatment of physical symptoms) or on promot-
ing relaxation (treatment of psychological symptoms). For
example: those acting as energisers, including vitamins/minerals
and tonics; and those acting on mood, relaxation and sleep, such
as St. John’s wort, valerian, passion flower, lavender and antihist-
amines. An ideal pharmacological therapy should offer a compre-
hensive treatment of all relevant stress symptoms combined with
a favourable safety profile.
Figure 3. Proposed model for the mode of action of Rhodiola rosea extract (RRE): normalisation of stress hormone release and activation of ATP synthesis.
4 I.-G. ANGHELESCU ET AL.
Adaptogens
The term ‘adaptogen’is used to describe medicinal plants that
have the capacity to normalise body functions and strengthen
systems compromised by stress and are able to enhance the
‘state of non-specific resistance’of an organism to stress
described above as allostasis. The Committee on Herbal Medicinal
Products (HMPC) which is the European Medicines Agency’s
(EMA) committee responsible for compiling and assessing scien-
tific data on herbal substances, preparations and combinations
developed the reflection paper on the adaptogenic concept (EMA,
2008).
In this paper, adaptogens are defined as virtually non-toxic to
the recipient. They are non-specific in pharmacological properties
and act by increasing the resistance of an organism to a broad
spectrum of adverse biological, chemical and physical factors.
Adaptogens act as regulators with a normalising effect on the
various organ systems and their effect is the more pronounced
the deeper the pathologic changes in the organism are.
As such, adaptogens should be differentiated from traditional
herbal medicinal products of related action, such as tonics and
stimulants. The EMA has established HMPC monographs on many
herbals including some adaptogens, i.e., preparations deriving
from Eleutherococcus senticosus, Panax ginseng and Rhodiola rosea.
These monographs cover their therapeutic use and safety as regis-
tered drugs.
Rhodiola rosea extract (RRE)
Extract from the roots and rhizomes of Rhodiola rosea (RRE) is an
adaptogen that acts to increase the body’s resistance to stress,
exhaustion and fatigue. It is the main adaptogen given the indica-
tion ‘stress’by the HMPC (European Medicines Agency’s [EMA],
2011,2012). A wide variety of preclinical in vivo and ex vivo stud-
ies conducted in cell lines and animal models have elucidated
the presence of several biochemical and pharmacological stress-
reducing actions of RRE. It possesses a unique mechanism of
action: it normalises the release of stress hormones while simul-
taneously boosting energy metabolism via activation of ATP syn-
thesis in mitochondria (Figure 3; Abidov, Crendal, Grachev,
Seifulla, & Ziegenfuss, 2003; Olsson, von Sch
eele, & Panossian,
2009; Panossian et al., 2007). Blood levels of several stress media-
tors (e.g., p-SAPK/p-JNK, NO, cortisol) were assessed in rabbits
under immobilisation stress; in the animals under stress that
received placebo the levels of the above-mentioned markers
were significantly elevated while in animals which received RRE
(1 mg/kg for seven days) the stress mediators remained virtually
unchanged (Panossian et al., 2007). In other studies, rats treated
with RRE (50 mg/kg) exhibited a significantly prolonged duration
of exhaustive swimming in comparison with untreated rats.
Furthermore, RRE induced the (re)synthesis of ATP in rat mito-
chondria from skeletal muscles and stimulated recovery after exer-
cise (Abidov et al., 2003).
Table 1. Clinical studies with Rhodiola rosea extract (RRE) in subjects with stress symptoms.
Reference Study design Patient population Treatment Duration Outcome measures Results
Heldmann et al.
(2016)
Single centre, open-
label pilot study
50 healthy male and
female computer work-
ers (30–50 years)
RRE
(WS
V
R
1375; Rosalin
V
R
)
200 mg BID
12 weeks Effects on attention
and task performance
(reaction time and
error rate). Event-
related brain potentials
were measured.
Treatment led to an
increase of attention
resources under a
strong attention bur-
den (simulated multi-
tasking).
Treatment also led to
an increase in both
working speed and
working quality.
Cropley et al.
(2015)
Open-label, rando-
mised (vs. control),
repeated measures
n¼80 mildly anxious
participants (18–35
years), with score >30
on Spielberger State-
Trait Anxiety Inventory
(STAI)
RRE
(WS
V
R
1375, Rosalin
V
R
)
200 mg BID
2 weeks STAI; Perceived Stress
Scale; Profile of Mood
States Inventory;
Milford Epworth
Sleepiness Scale; Leeds
Sleep Evaluation
Questionnaire (LSEQ);
Cognitive function
tests.
Significant reduction in
self-reported anxiety,
stress, anger, confusion
and depression;
significant improve-
ment in total mood;
no impairment in cog-
nitive performance ver-
sus control.
Edwards et al.
(2012)
Open, multicentre,
single-arm
n¼101: male (n¼33)
and female (n¼68)
outpatients (44.5 ± 7.5
years), with distinct
stress symptoms
treated in general
practice
RRE
(WS
V
R
1375, Rosalin
V
R
)
200 mg BID
4 weeks Seven Numerical
Analogue Scales (NAS)
of subjective stress
symptoms measures;
Perceived Stress
Questionnaire (PSQ);
Multidimensional
Fatigue Inventory 20
(MFI-20); Numbers
Connecting Test (NCT);
Sheehan Disability
Scale (SDS);
Multidimensional Mood
State Questionnaire
(MDMQ); Clinical Global
Impression.
All outcome variables
showed clinically rele-
vant improvement in
stress symptoms,
fatigue, quality of life,
mood, concentration,
disability, functional
impairment and overall
therapeutic effect.
Significant improve-
ments were observed
after three days of
treatment and contin-
ued for four weeks.
Darbinyan et al.
(2000)
Randomised, pla-
cebo-controlled,
double-blind, cross-
over
n¼56 healthy physi-
cians (24–35 years)
Standardised SHR-5
RRE (4.5 mg salidro-
side)
170 mg OD
32 weeks Anti-fatigue effect dur-
ing night duty using
five different tests.
Less fatigue in medical
doctors on night duty
with treatment versus
placebo after two
weeks of treatment.
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 5
RRE acts to normalise cortisol synthesis potentially through
inhibition of the SAPK pathway involved in the pathogenesis
of glucocorticoid resistance, which is also found in certain
chronic immune/inflammatory diseases and in some patients
with depression (Panossian, 2013; Panossian et al., 2007). At
the same time, through inhibition of the SAPK/JNK pathway,
RRE potentially prevents the formation of NO and the associ-
ated decline in ATP synthesis (Guan et al., 1999; Panossian &
Wikman 2009).
Stress leads to a damage of the mitochondrial function and
the excessive production of reactive oxidative species (ROS) in
mitochondria, which may cause damage e.g., to proteins, nucleic
acids, and membranes, which in turn can lead to activation of cell
death processes such as apoptosis (Zhang, Wu, Lu, Guo, & Ma,
2006). RRE may also offer potential protection against heart and
brain diseases (e.g., heart attack, stroke, depression and
Alzheimer’s disease) through anti-oxidative/anti-inflammatory
mechanisms (Lee et al., 2013; Olpe & Seifritz, 2014; Zhang et al.,
2016).
RRE products with medicinal drug status must fulfil high
pharmaceutical requirements with regard to their quality and
safety, e.g., products containing RRE WS
V
R
1375 (Rosalin
V
R
). It should
also be noted that there are many dietary supplements available
which contain Rhodiola rosea drug or extracts that do not comply
with the high standards set by the HMPC and pharmaceutical
quality requirements for registered medicinal drugs.
Clinical studies with RRE
In several clinical studies of stress, burnout and chronic fatigue,
RRE was found to be effective, safe and well tolerated.
Stress symptoms
In clinical studies, mental work capacity, attention, task perform-
ance and overall mood improved during the course of treatment
with RRE and stress and self-reported mild anxiety were reduced
(Table 1; e.g., Cropley, Banks, & Boyle, 2015; Darbinyan et al.,
2000; Edwards et al., 2012; Heldmann, Roth, Dienel, & M€
unte,
2016).
Among people suffering from life-stress symptoms, clinically
relevant improvement in stress symptoms, stress-related disabil-
ities in work, social and family life, functional impairment and
overall therapeutic effect were observed with RRE treatment over
four weeks (Figure 4; Edwards et al., 2012). In this single-arm
study, adult subjects with life-stress symptoms (n¼101) treated in
general practice received open-label RRE (200 mg, twice-daily).
Seven widely recognised questionnaires to cover various aspects
of stress symptoms and psychological well-being were employed
to assess the outcome of treatment. Invariably, all outcome varia-
bles showed significant, consistent and steady improvement in
stress symptoms, fatigue, quality of life, mood, concentration, dis-
ability, functional impairment and overall therapeutic effect. The
improvements were observed as early as after three days of treat-
ment and continued throughout the whole study duration of
28 days.
RRE has also demonstrated positive effects in the treatment of
symptoms of mild anxiety associated with stress. Among students
with self-reported anxiety and stress (n¼81) who were rando-
mised to receive either RRE or a control (no treatment), the RRE
group reported a significant reduction in self-reported anxiety,
anger, confusion, stress and vigour at 14 days and a significant
improvement in total mood as compared with the no treatment
group (Cropley et al., 2015).
The effect of RRE on neuropsychological and neurophysio-
logical measures of attention and mental resource allocation has
recently been studied (Heldmann et al., 2016). The results of this
trial of 50 healthy volunteers (aged 30–50 years) at risk for stress
symptomatology showed increased performance under multi-task-
ing conditions over the course of RRE administration for 12 weeks.
Overall, RRE had a positive influence on attention and mental
resource allocation and thus on speed and quality of performance
under conditions of high cognitive demand.
In an earlier study, the effect of RRE on healthy physicians on
night duty (n¼56) was evaluated using a combination of tests
that measured overall level of mental fatigue, involving complex
perceptive and cognitive cerebral functions, such as associative
thinking, short-term memory, calculation and ability of concentra-
tion and speed of audio-visual perception. A significant improve-
ment in these test results was observed in the RRE group during
Figure 4. Efficacy of Rhodiola rosea extract (RRE) in management of life stress symptoms. NAS: Numerical Analogue Scales-rating of symptoms from 0 (not at all) to
10 (severely impaired). (Adapted from Edwards et al., 2012).
6 I.-G. ANGHELESCU ET AL.
the two-week treatment period, suggesting that RRE can reduce
general fatigue under certain stressful conditions (Darbinyan et al.,
2000).
Chronic fatigue symptoms and exhaustion
Unexplained chronic fatigue is a widespread healthcare problem
that significantly affects the working population (Jackson &
Macleod, 2017) and which is often associated with stress. First-line
treatments are cognitive behavioural or graded exercise therapy
(Daniels & Loades, 2017). However, these treatments yield only
moderate effect sizes. RRE is shown to improve mental perform-
ance in people with stress-related fatigue and further to improve
all dimensions of chronic fatigue symptoms (Table 2; Lekomtseva,
Zhukova, & Tartakovsky, 2013; Olsson et al., 2009).
In a double-blind study, participants (n¼60) selected accord-
ing to diagnostic criteria for fatigue syndrome were randomised
to receive RRE (576 mg extract/day) or placebo for four weeks.
Significant effects of RRE in comparison with placebo were
observed for symptoms of fatigue (Pines burnout scale) and in
tests of attention (Connors computerised continuous performance
test II [CCPT II]). Pre- versus post-treatment cortisol responses to
awakening were significantly different in the treatment group
compared with the control group. Thus, RRE is found to exert an
anti-fatigue effect that increases mental performance, particularly
the ability to concentrate and decreases cortisol response to
awakening stress in burnout patients with fatigue syndrome
(Olsson et al., 2009).
Significant improvements in specific chronic fatigue outcomes
(e.g., multi-dimensional fatigue inventory 20 [MFI-20], recent per-
ceived stress questionnaire [PSQ-R], Sheehan disability scale
[SDS]) have been demonstrated with RRE treatment among 101
patients with chronic fatigue treated in an open-label, single-arm
study for up to eight weeks (p<.001). Furthermore, the results
of the trial supported the therapeutic effect on concomitant con-
ditions related to chronic fatigue such as mood, concentration,
quality of life and general well-being which was demonstrated
with RRE treatment (200 mg, twice-daily; Lekomtseva et al.,
2013).
Burnout symptoms
The aim of the treatment of stress and burnout with an adapto-
gen is to increase stress resistance, thus addressing the source
rather than the symptoms of the syndrome and preventing sub-
sequent diseases associated with a history of burnout. The core
indicators of burnout are subjective perceptions of chronic
demand-related stress with subsequent emotional exhaustion and
decreased performance in work-related or self-set tasks. Reported
symptoms of burnout comprise not only psychiatric or mood dis-
orders such as fatigue, cynicism, impaired sexual life, lack of con-
centration or a generally negative attitude toward work, but also
somatic symptoms such as headaches, hypertension or irritable
stomach. Treatment with RRE for eight and 12 weeks, respectively,
was accompanied by a clear improvement in burnout symptoms
(Table 3; Goyvaerts & Bruhn, 2012; Kasper & Dienel, 2017).
Investigating the effects of RRE on burnout-related symptoms,
a German non-interventional study was conducted in 128 primary
care practices and included 330 patients with two or more burn-
out indicator symptoms (exhaustion, depression, insomnia, fatigue
or drop in performance). A considerable alleviation of these symp-
toms after the administration of RRE for eight weeks was reported
based on the results of the self-rating questionnaires used in this
trial (Goyvaerts & Bruhn, 2012).
An exploratory single-arm, multi-centre study investigated the
clinical outcomes in burnout patients (n¼118) treated with RRE
Table 2. Clinical studies with Rhodiola rosea extract (RRE) in subjects with chronic fatigue.
Reference Study design Patient population Treatment Duration Outcome measures Results
Lekomtseva et al.
(2013)
Open, multicentre,
single-arm
One hundred male and
female outpatients
(18–60 years) with
chronic fatigue
symptoms
RRE
(WS
V
R
1375, Rosalin
V
R
200 mg BID
8 weeks Multidimensional Fatigue
lnventory 20 (MFI-20)
measures; three
Numerical Analogue
Scales (NAS) of chronic
fatigue symptoms;
Sheehan Disability Scale
(SDS); Number
Connecting Test (NCT);
Pittsburgh Sleep Quality
Index (PSQI); Recent
Perceived Stress
Questionnaire (PSQ-R);
Beck's Depression lnven-
tory (BDI-II); Clinical
Global Impression (CGI).
Statistically significant
improvement in all
dimensions of chronic
fatigue symptoms (MFI-
20 and NAS) from week
1–8(p<.001) and con-
comitant conditions
related to CF comorbid-
ity and general well-
being (PSQI, PSQ-R, BDI-
II, SDS and NCT).
Olsson et al.
(2009)
Randomised, placebo-
controlled, double-
blind, parallel-group
Sixty adult (20–55
years) burnout patients
experiencing difficulties
equivalent to the crite-
ria of fatigue syndrome
Proprietary SHR-5
RRE 288 mg BID
4 weeks Quality of life (SF-36
questionnaire); symp-
toms of fatigue (Pines
burnout scale); depres-
sion (Montgomery -
Asberg depression rating
scale - MADRS); atten-
tion (Conners computer-
ised continuous
performance test II -
CCPT II) and saliva
cortisol response to
awakening were
assessed on day 1 and
after 28 days of
medication.
Anti-fatigue effect that
increased mental per-
formance, particularly
the ability to concen-
trate, and decreased cor-
tisol response to
awakening stress.
Significant effects of
SHR-5 RRE in comparison
with placebo were
observed in Pines burn-
out scale and the CCPT
II indices omissions, Hit
RT SE, and variability.
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 7
(200 mg, twice-daily) over 12 weeks. The aim of the treatment
with RRE was to increase stress resistance and thus to aim at the
source rather than at the symptoms of the syndrome and to fur-
ther prevent subsequent diseases associated with a history of
burnout. A broad spectrum of rating scales was employed to
evaluate the therapeutic effect of RRE in the treatment of burnout
symptoms, such as fatigue, cynicism, difficulties to concentrate,
impaired sexual life and also somatic symptoms. A wide range of
the evaluated outcome measures improved considerably over the
course of treatment. Some of these changes were already
Table 3. Clinical studies with Rhodiola rosea extract (RRE) in subjects with burnout symptoms.
Reference Study design Patient population Treatment Duration Outcome measures Results
Kasper and Dienel
(2017)
Open, multicentre,
single-arm
n¼118 male (n¼49)
and female (n¼68)
outpatients (44 ± 8
years) with burnout
symptoms
RRE
(WS
V
R
1375, Rosalin
V
R
)
200 mg BID
12 weeks Seven Numerical
Analogue Scales (NAS) of
subjective stress symp-
toms; Burnout-Screening-
Scales BOSS I and BOSS II;
Maslach-Burnout-Inventory
(MBI); Perceived Stress
Questionnaire (PSQ);
Numbers Connecting Test
(NCT); Sheehan Disability
Scale (SDS); Clinical Global
Impression (CGI);
Multidimensional Mood
State Questionnaire
(MDMQ); Patient question-
naire for sexual function
(PSFQ); Numerical
Analogue Scales of
Subjective Stress
Symptoms (NAS).
Treatment caused a
significant and clinic-
ally relevant improve-
ment in burnout
symptoms from week
1 to week 12 (NAS,
BOSS I and II, NCT,
CGIand MDMQ).
Goyvaerts and Bruhn
(2012)
Open, multicentreand
single-arm
330 patients (>18
years) with at least
two of the following
symptoms: exhaustion,
depression, insomnia,
fatigue and drop in
performance
Proprietary SHR-5
RRE 288 mg BID
8 weeks Burnout total score. Significant improve-
ment in burnout symp-
toms total score after
4–8 weeks.
Figure 5. Intervention stages for treatment of physical/psychological stress and exhaustion. Patients with medical conditions that may result in symptoms of stress
and exhaustion such as anaemia, migraine, IBS (irritable bowel syndrome), cancer and hormonal disturbances, may also receive RRE after assessment and management
of the medical condition. ‘Control’in this context means: normal functioning in daily life.
8 I.-G. ANGHELESCU ET AL.
significant after the first week of RRE administration (Kasper &
Dienel, 2017).
The trials to date, although limited in participant numbers and
often exploratory in design, nonetheless provide promising results
and an encouraging basis for future randomised controlled trials
further investigating the clinical outcomes of RRE in patients with
high symptom load of chronic stress, chronic fatigue and burnout.
Clinical experience of sexual problems in individuals that were
predominately due to stress have been helped by RRE and recent
studies involving male and female stressed rats have confirmed
this finding (Edwards, Eltbogen, & N€
oldner, 2017; Edwards, Kumar,
&N
€
oldner, 2016). RRE has also shown encouraging data in
exploratory studies of diseases that can occur as a consequence
of stress, including depression (Darbinyan et al., 2007) and anxiety
(Bystritsky, Kerwin, & Feusner, 2008).
Safety and tolerability of RRE
RRE presents a very favourable safety profile. In clinical studies, no
serious side effects that could be attributed to RRE were reported
(e.g., Cropley et al., 2015; Edwards et al., 2012; Kasper & Dienel,
2017; Lekomtseva, Zhukova, & Wacker, 2017).
The HMPC monograph on Rhodiola rosea roots and rhizomes
states that there are no known side effects (EMA, 2012). In add-
ition, to date no drug-drug interactions have been reported for
RRE (EMA, 2012).
Treatment recommendation
RRE has the potential to close the treatment gap for clinically rele-
vant stress symptoms, which is due to its dual mode of action
providing both physical and psychological symptom relief, normal-
ising stress hormone levels and increasing energy and its excellent
safety profile. RRE potentially addresses multiple aspects in the
management of stress and burnout:
Prevention of stress symptoms from becoming chronic.
Treatment of stress symptoms.
Prevention of stress-related complications (burnout) and
secondary diseases.
Figure 5 summarises the authors’treatment recommendations
for the use of RRE in various stages of stress.
Limitations
There is still much to learn about the pathophysiology of stress,
resilience and stress vulnerability, including cellular and cerebral
network mechanisms which are the focus of current research
interests. In parallel to increasing knowledge of these phenom-
ena, additional investigations are needed to further elucidate
the impact of RRE on mechanisms that play a significant role
in stress in the human body. Clinical evidence for the effect of
RRE on stress and stress-related symptoms to date may be lim-
ited to studies of exploratory design; appropriate study popula-
tions are sometimes difficult to define. However, the studies so
far provide promising results, especially in frequently difficult to
treat populations. Further randomised controlled trials are
needed to confirm the promising results of the existing studies
with RRE in patients with symptoms of chronic stress, chronic
fatigue and burnout.
Acknowledgements
Editorial assistance was provided by H þO communications Ltd.
Disclosure statement
Ion-George Anghelescu has received consulting fees and/or hono-
raria from Schwabe, Boehringer Ingelheim, Otsuka, Janssen,
Lundbeck, Lilly, Medice, Servier and Trommsdorf (I.G. A.).
David Edwards reports honoraria and support within the last
three years from Bayer, Besins, Pfizer and Schwabe.
Erich Seifritz has received consulting fees and/or honoraria
from Schwabe, Otsuka, Janssen, Lundbeck, Eli Lilly, Servier,
Hoffmann La Roche, Vifor, Takeda, Sunovion, Pfizer, Astra Zeneca
and Angelini.
Siegfried Kasper has received grants/research support, consult-
ing fees and/or honoraria within the last three years from
Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Eli Lilly,
Janssen, KRKA-Pharma, Lundbeck, Neuraxpharm, Pfizer, Pierre
Fabre, Schwabe and Servier.
Funding
Funding for this publication was provided by Dr. Willmar Schwabe
GmbH & Co. KG.
References
Abidov, M., Crendal, F., Grachev, S., Seifulla, R., & Ziegenfuss, T.
(2003). Effect of extracts from Rhodiola rosea and Rhodiola
crenulata (Crassulaceae) roots on ATP content in mitochondria
of skeletal muscles. Bulletin of Experimental Biology and
Medicine,136, 585–587. doi:10.1023/B:BEBM.0000020211.
24779.15
Ahola, K., V€
a€
an€
anen, A., Koskinen, A., Kouvonen, A., & Shirom, A.
(2010). Burnout as a predictor of all-cause mortality among
industrial employees: A 10-year prospective register-linkage
study. Journal of Psychosomatic Research,69,51–57.
doi:10.1016/j.jpsychores.2010.01.002
Bagyinszky, E., Giau, V. V., Shim, K., Suk, K., An, S. S. A., & Kim, S.
(2017). Role of inflammatory molecules in the Alzheimer’s dis-
ease progression and diagnosis. Journal of the Neurological
Sciences,376, 242–254. doi:10.1016/j.jns.2017.03.031
Berge, L. I., & Riise, T. (2015). Comorbidity between type 2 dia-
betes and depression in the adult population: Directions of the
association and its possible pathophysiological mechanisms.
International Journal of Endocrinology,2015, 164760.
doi:10.1155/2015/164760
Bot, I., & Kuiper, J. (2017). Stressed brain, stressed heart? Lancet
(London, England),389, 770–771. doi:10.1016/S0140-
6736(17)30044-2
Brown, G. C. (2001). Regulation of mitochondrial respiration by
nitric oxide inhibition of cytochrome c oxidase. Acta Biochimica
et Biophysica Sinica,1504,46–57. doi:10.1016/S0005-
2728(00)00238-3
Bystritsky, A., Kerwin, L., & Feusner, J. D. (2008). A pilot study of
Rhodiola rosea (Rhodax) for generalized anxiety disorder (GAD).
Journal of Alternative and Complementary Medicine,14, 175–180.
doi:10.1089/acm.2007.7117
Charney, D. S. (2004). Psychobiological mechanisms of resilience
and vulnerability: implications for successful adaptation to
extreme stress. The American Journal of Psychiatry,161,
195–216. doi:10.1176/appi.ajp.161.2.195
Chiesa, A., & Serretti, A. (2009). Mindfulness-based stress reduction
for stress management in healthy people: A review and
meta-analysis. Journal of Alternative and Complementary
Medicine (New York, N.Y.),15, 593–600. doi:10.1089/
acm.2008.0495
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 9
Cropley, M., Banks, A. P., & Boyle, J. (2015). The effects of Rhodiola
rosea L. extract on anxiety, stress, cognition and other mood
symptoms. Phytotherapy Research,29, 1934–1939. doi:10.1002/
ptr.5486
Danhof-Pont, M. B., van Veen, T., & Zitman, F. G. (2011).
Biomarkers in burnout: A systematic review. Journal of
Psychosomatic Research,70, 505–524. doi:10.1016/j.jpsychores.
2010.10.012
Daniels, J., & Loades, M. E. (2017). A novel approach to treating
CFS and co-morbid health anxiety: A case study. Clinical
Psychology &; Psychotherapy,24, 727–736. doi:10.1002/cpp.2042
Darbinyan, V., Aslanyan, G., Amroyan, E., Gabrielyan, E.,
Malmstr€
om, C., & Panossian, A. (2007). Clinical trial of Rhodiola
rosea L. extract SHR-5 in the treatment of mild to moderate
depression. Nordic Journal of Psychiatry,61, 343–348.
doi:10.1080/08039480701643290
Darbinyan, V., Kteyan, A., Panossian, A., Gabrielian, E., Wikman, G.,
& Wagner, H. (2000). Rhodiola rosea in stress induced fatigue-a
double blind cross-over study of a standardized extract SHR-5
with a repeated low-dose regimen on the mental performance
of healthy physicians during night duty. Phytomedicine:
International Journal of Phytotherapy and Phytopharmacology,7,
365–371. doi:10.1016/S0944-7113(00)80055-0
German Association for Psychiatry, Psychotherapy and
Psychosomatics. (2012). Position paper burnout. [cited 19 May
2017]. Available from: http://www2.psychotherapeutenkammer-
berlin.de/uploads/stellungnahme_dgppn_2012.pdf
Edwards, D., Eltbogen, R., & N€
oldner, M. (2017). Stress-induced
female sexual dysfunction: Beneficial effect of the Rhodiola
rosea extract Rosalin
V
R
(WS
V
R
1375). The Journal of Sexual
Medicine 14, e196 (P-04-004). doi:10.1016/j.jsxm.2017.03.240
Edwards, D., Heufelder, A., & Zimmermann, A. (2012). Therapeutic
effects and safety of Rhodiola rosea extract WS
V
R
1375 in sub-
jects with life-stress symptoms-results of an open-label study.
Phytotherapy Research,26, 1220–1225. doi:10.1002/ptr.3712
Edwards, D., Kumar, V., & N€
oldner, M. (2016). Stress-induced sexual
dysfunction in rodents and humans: The Rhodiola rosea extract
WS
V
R
1375 shows clinical promise. The Journal of Sexual
Medicine 13, S158 (P-01-051). doi:10.1016/j.jsxm.2016.03.201
European Medicines Agency. (2008). Reflection paper on the
adaptogenic concept. Document reference. EMEA/HMPC/
102655/2007. [cited 19 May 2017]. Available from: http://www.
ema.europa.eu/docs/en_GB/document_library/Scientific_guide-
line/2009/09/WC500003646.pdf
European Medicines Agency. (2011). Community herbal mono-
graph on Rhodiola rosea L., rhizoma et radix. Document refer-
ence. EMA/HMPC/232091/2011. [cited 19 May 2017]. Available
from: www.ema.europa.eu/docs/en_GB/document_library/
Herbal_-_Community_herbal_monograph/2011/09/WC500112677.
pdf
European Medicines Agency. (2012). Committee on herbal medi-
cinal products (HMPC). Assessment report on Rhodiola rosea L.,
rhizoma et radix. Document reference. EMA/HMPC/232100/
2011. [cited 19 May 2017]. Available from: http://www.ema.eur-
opa.eu/docs/en_GB/document_library/Herbal_-_HMPC_
assessment_report/2012/05/WC500127861.pdf
European Agency for Safety and Health at Work. (2014).
Calculating the cost of work-related stress and psychosocial
risks. European Risk Observatory Literature Review. [cited 19
May 2017]. doi:10.2802/20493
Giulivi, C. (1998). Functional implications of nitric oxide produced
by mitochondria in mitochondrial metabolism. Biochemical
Journal,332, 673–679. doi:10.1042/bj3320673
Goh, C., & Agius, M. (2010). The stress-vulnerability model how
does stress impact on mental illness at the level of the brain
and what are the consequences? Psychiatria Danubina,22,
198–202.
Gould, E., & Tanapat, P. (1999). Stress and hippocampal neurogen-
esis. Biological Psychiatry,46, 1472–1479. doi:10.1016/S0006-
3223(99)00247-4
Goyvaerts, B., & Bruhn, S. (2012). Rhodiola rosea special extract
SHR-5 in burnout and fatigue syndrome. Erfahrungsheilkunde,
61,79–83. doi:10.1055/s-0031-1298676
Guan, Z., Buckman, S. Y., Springer, L. D., & Morrison, A. R. (1999).
Both p38aMAPK and JNK/SAPK pathways are important for
induction of nitric-oxide synthase by interleukin-1bin rat glom-
erular mesangial cells. Journal of Biological Chemistry,274,
36200. doi:10.1074/jbc.274.51.36200
Heldmann, M., Roth, G., Dienel, A., & M€
unte, T. F. (2016). Impact of
Rhodiola Rosea extract WS 1375 on electrophysiological corre-
lates of attention allocation in a dual task paradigm. Clinical
Neurophysiology,127, e290. doi:10.1016/j.clinph.2016.05.159
Hochstrasser, B., Br€
uhlmann, T., Cattapan, K., H€
attenschwiler, J.,
Holsboer-Trachsler, E., Kawohl, W., et al. (2016).
Therapieempfehlungen des Schweizer Expertennetzwerks Burnout
(SEB). Burnout-Behandlung Teil 1: Grundlagen[Therapy recommen-
dations of the Swiss Expert Network Burnout (SEB). Burnout treat-
ment part 1: Basics]. Swiss Medical Forum,16, 538–541.
Houtman, I. L. D. 2005. European foundation for the improvement
of living and working conditions. Work-related stress. [cited 19
May 2017]. Available from: http://eurofound.europa.eu/sites/
default/files/ef_files/pubdocs/2005/127/en/1/ef05127en.pdf
Jackson, H., & MacLeod, A. K. (2017). Well-being in chronic fatigue
syndrome: Relationship to symptoms and psychological distress.
Clinical Psychology & Psychotherapy,24, 859–869. doi:10.1002/
cpp.2051
Kasper, S., & Dienel, A. (2017). Multicenter, open-label, exploratory
clinical trial with Rhodiola rosea extract in patients suffering
from burnout symptoms. Neuropsychiatric Disease and
Treatment,13, 889–898. doi:10.2147/NDT.S120113
Kim, T. K., Kim, J. E., Choi, J., Park, J. Y., Lee, J. E., Lee, E. H., …Han
P.L. (2017). Local interleukin-18 system in the basolateral amyg-
dala regulates susceptibility to chronic stress. Molecular
Neurobiology,54, 5347–5358. doi:10.1007/s12035-016-0052-7
Lee, Y., Jung, J. C., Jang, S., Kim, J., Ali, Z., Khan, I. A., & Oh, S.
(2013). Anti-inflammatory and neuroprotective effects of con-
stituents isolated from Rhodiola rosea. Evidence-Based
Complementary and Alternative Medicine,2013, 514049.
doi:10.1155/2013/514049
Lekomtseva, Y., Zhukova, I., & Tartakovsky, I. (2013). Therapy effects
and safety of Rhodiola Rosea extract WS
V
R
1375 in subjects with
symptoms of chronic fatigue. The Siberian Scientific Medical
Journal,12,73–75. doi:10.20538/1682-0363-2013-5-73-75
Lekomtseva, Y., Zhukova, I., & Wacker, A. (2017). Rhodiola rosea in
subjects with prolonged or chronic fatigue symptoms: Results
of an open-label clinical trial. Complementary Medicine Research,
24,46–52. doi:10.1159/000457918
McEwen, B. S. (2000). Allostasis and allostatic load: Implications
for neuropsychopharmacology. Neuropsychopharmacology:
Official Publication of the American College of
Neuropsychopharmacology,22, 108–124. doi:10.1016/S0893-
133X(99)00129-3
McEwen, B. S. (2005). Stressed or stressed out: What is the differ-
ence? Journal of Psychiatry & Neuroscience,30, 315–318.
McEwen, B. S., & Wingfield, J. C. (2003). The concept of allostasis
in biology and biomedicine. Hormones and Behavior,43,2–15.
doi:10.1016/S0018-506X(02)00024-7
10 I.-G. ANGHELESCU ET AL.
Milczarek, M., Schneider, E., & Gonz
alez, E. R. (2009). European Risk
observatory report. OSH in figures: stress at work –facts
and figures. [cited 19 May 2017]. Available from: https://osha.
europa.eu/en/publications/reports/TE-81-08-478-EN-C_OSH_in_
figures_stress_at_work
Nabi, H., Kivim€
aki, M., Batty, G. D., Shipley, M. J., Britton, A.,
Brunner, E. J., …Singh-Manoux A. (2013). Increased risk of cor-
onary heart disease among individuals reporting adverse impact
of stress on their health: The Whitehall II prospective cohort
study. European Heart Journal,34, 2697–2705. doi:10.1093/
eurheartj/eht216
Olpe, H. R., & Seifritz, E. 2014. Bis er uns umbringt? Wie Stress die
Gesundheit attackiert –und wie wir uns sch€
utzen k€
onnen[Until he
kills us? How stress attacks the health - and how we can protect
ourselves]. Bern, Switzerland: Verlag Hans Huber.
Olsson, E. M., von Sch
eele, B., & Panossian, A. G. (2009). A rando-
mised, double-blind, placebo-controlled, parallel-group study of
the standardised extract SHR-5 of the roots of Rhodiola rosea in
the treatment of subjects with stress-related fatigue. Planta
Medica,75, 105–112. doi:10.1055/s-0028-1088346
Panossian, A. G. (2013). Adaptogens in mental and behavioral dis-
orders. The Psychiatric Clinics of North America,36,49–64.
doi:10.1016/j.psc.2012.12.005
Panossian, A., Hambardzumyan, M., Hovhanissyan, A., & Wikman,
G. (2007). The adaptogens Rhodiola and Schizandra modify the
response to immobilization stress in rabbits by suppressing the
increase of phosphorylated stress-activated protein kinase, nitric
oxide and cortisol. Drug Target Insights,2,39–54.
Panossian, A., & Wikman, G. (2009). Evidence-based efficacy of adap-
togens in fatigue, and molecular mechanisms related to their
stress-protective activity. Current Clinical Pharmacology,4, 198–219.
doi:10.2174/157488409789375311
Schoutens, A. M., Frings-Dresen, M. H., & Sluiter, J. K. (2016).
Design of a randomized controlled trial on the effect on return
to work with coaching plus light therapy and pulsed electro-
magnetic field therapy for workers with work-related
chronic stress. BMC Public Health,16, 597. doi:10.1186/s12889-
016-3276-6
Tawakol, A., Ishai, A., Takx, R. A., Figueroa, A. L., Ali, A., Kaiser, Y.,
…Pitman R. K. (2017). Relation between resting amygdalar
activity and cardiovascular events: A longitudinal and cohort
study. Lancet,389, 834–845. doi:10.1016/S0140-6736(16)31714-7
Techniker Krankenkasse. (2016). Entspann dich, Deutschland - TK-
Stressstudie 2016 [Relax, Germany - TK Stress Study 2016]. [cited
19 May 2017]. Available from: https://www.tk.de/centaurus/serv-
let/contentblob/921466/Datei/177594/TK-Stressstudie%202016%
20Pdf%20barrierefrei.pdf
Wang, X., Wu, H., Lakdawala, V. S., Hu, F., Hanson, N. D., & Miller,
A. H. (2005). Inhibition of Jun N-terminal kinase (JNK) enhances
glucocorticoid receptor-mediated function in mouse hippocam-
pal HT22 cells. Neuropsychopharmacology,30, 242–249.
doi:10.1038/sj.npp.1300606
Zhang, X., Du, Q., Liu, C., Yang, Y., Wang, J., Duan, S., & Duan, J.
(2016). Rhodioloside ameliorates depressive behavior via up-
regulation of monoaminergic system activity and anti-inflamma-
tory effect in olfactory bulbectomized rats. International
Immunopharmacology,36, 300–304. doi:10.1016/
j.intimp.2016.05.008
Zhang, X., Wu, X. Q., Lu, S., Guo, Y. L., & Ma, X. (2006). Deficit of
mitochondria-derived ATP during oxidative stress impairs
mouse MII oocyte spindles. Cell Research,16, 841–850.
doi:10.1038/sj.cr.7310095
Zubin, J., & Spring, B. (1977). Vulnerability-a new view of schizo-
phrenia. Journal of Abnormal Psychology,86, 103–126.
doi:10.1037/0021-843X.86.2.103
INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE 11
