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Neuropsychiatric Disease and Treatment 2017:13 889–898
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ORIGINAL RESEARCH
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/NDT.S120113
Multicenter, open-label, exploratory clinical trial
with Rhodiola rosea extract in patients suffering
from burnout symptoms
Siegfried Kasper1
Angelika Dienel2
1Universitätsklinik für Psychiatrie
und Psychotherapie, Medizinische
Universität Wien, Wien, Austria;
2Dr Willmar Schwabe GmbH & Co.
KG, Karlsruhe, Germany
Purpose: This study is the first clinical trial aiming to explore the clinical outcomes in burn-
out patients treated with Rhodiola rosea. The reported capacity of R. rosea to strengthen the
organism against stress and its good tolerability offer a promising approach in the treatment of
stress-related burnout. The aim of the treatment was to increase stress resistance, thus address-
ing the source rather than the symptoms of the syndrome and preventing subsequent diseases
associated with a history of burnout. The objective of the trial was to provide the exploratory
data required for planning future randomized trials in burnout patients in order to investigate
the clinical outcomes of treatment with R. rosea dry extract in this target group.
Methods: The study was planned as an exploratory, open-label, multicenter, single-arm trial. A
wide range of rating scales were assessed and evaluated in an exploratory data analysis to gener-
ate hypotheses regarding clinical courses and to provide a basis for the planning of subsequent
studies. A total of 118 outpatients were enrolled. A daily dose of 400 mg R. rosea extract (WS®
1375, Rosalin) was administered over 12 weeks. Clinical outcomes were assessed by the German
version of the Maslach Burnout Inventory, Burnout Screening Scales I and II, Sheehan Disability
Scale, Perceived Stress Questionnaire, Number Connection Test, Multidimensional Mood State
Questionnaire, Numerical Analogue Scales for different stress symptoms and impairment of
sexual life, Patient Sexual Function Questionnaire, and the Clinical Global Impression Scales.
Results: The majority of the outcome measures showed clear improvement over time. Several
parameters had already improved after 1 week of treatment and continued to improve further up to the
end of the study. The incidence of adverse events was low with 0.015 events per observation day.
Discussion: The trial reported here was the first to investigate clinical outcomes in patients
suffering from burnout symptoms when treated with R. rosea. During administration of the
study drug over the course of 12 weeks, a wide range of outcome measures associated with the
syndrome clearly improved.
Conclusion: The results presented provide an encouraging basis for clinical trials further
investigating the clinical outcomes of R. rosea extract in patients with the burnout syndrome.
Keywords: burnout, clinical study, Rhodiola rosea
Introduction
The burnout syndrome poses an increasing challenge to socioeconomics in the Western
world.1 This study reports an exploratory clinical trial investigating clinical outcomes
of Rhodiola rosea treatment in patients suffering from burnout symptoms.
The core indicators of the syndrome are subjective perceptions of chronic demand-
related stress with subsequent emotional exhaustion and decreased performance in work-
related or self-set tasks.1–9 Reported symptoms of burnout are manifold, comprising not
only psychiatric or mood disorders such as fatigue, cynicism, impaired sexual life, lack
Correspondence: Siegfried Kasper
Universitätsklinik für Psychiatrie und
Psychotherapie, Medizinische Universität
Wien, AKH, Währinger Gürtel 18-20,
A-1090 Wien, Austria
Tel +43 140 4003 5680
Fax +43 140 4003 0990
Email sci-biolpsy@meduniwien.ac.at
Journal name: Neuropsychiatric Disease and Treatment
Article Designation: Original Research
Year: 2017
Volume: 13
Running head verso: Kasper and Dienel
Running head recto: Rhodiola rosea extract in burnout
DOI: http://dx.doi.org/10.2147/NDT.S120113
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Kasper and Dienel
of concentration, or a generally negative attitude toward work,
but also somatic symptoms such as headaches, hypertonia,
or irritable stomach.6,9 It is also agreed that the development
of the syndrome bears a considerable risk of subsequent seri-
ous mental or somatic disorders, among which depression,
anxiety, and cardiovascular conditions are the most prevalent
indications associated with a history of burnout.3,10–13
Support in preventing and alleviating stress reactions
is offered by adaptogenic substances which are reported to
potentially enhance individual stress tolerance.14–18 R. rosea is
one of the most popular herbal medicinal plants with adapto-
genic properties.19 As in all adaptogens, the pharmacodynamic
characteristics of R. rosea include near-non-toxicity and a
nonspecific effect that increases the resistance of the organism
to adverse biochemical and physical factors.14 Unlike proper
central nervous system stimulants, R. rosea is reported to
enhance the performance without causing a subsequent
substantial decrease in work capacity and to provide mental
stimulation combined with emotional stabilization.12,18,20–22
The roots and rhizomes of R. rosea contain several
medically active compounds, that is, phenolic acids, triter-
penes, monoterpenes, flavonoids, phenylethanol derivatives,
and the phenylpropanoids such as rosavin, rosin, and rosarin.
The latter have as yet only been found in R. rosea.23 R. rosea’s
dry extract has a long tradition as a herbal medicinal product
administered for alleviating stress-related symptoms such as
fatigue or sensation of weakness.14
Based on this knowledge, various clinical trials have
recently assessed R. rosea in subjects with stress-related condi-
tions. Edwards et al demonstrated not only a clinically relevant
improvement in subjects suffering from life-stress symptoms
after administration of R. rosea extract but also the safety of
the drug.24 Other trials evaluating the effects of R. rosea extract
in improving the physical and mental performance under
stressful conditions confirm and support these findings.25,26
Investigating the effects of R. rosea on burnout-related
symptoms, Olsson et al demonstrated the superiority of
R. rosea extract over placebo in alleviating mental fatigue as
measured by the Pines burnout scale.27 A German noninter-
ventional study conducted in 128 general practitioner (GP)
practices including 330 patients with two or more burnout
indicator symptoms, as assessed on a basic, self-rating ques-
tionnaire, also reported a considerable alleviation of these
symptoms after the administration of R. rosea extract for 8
weeks.28 Beneficial effects of R. rosea extract on emotional
instability and somatization as symptoms of mild to moderate
depression were demonstrated by Darbynian et al.29 This is of
particular interest as these symptoms – when associated with
stress – are also regarded as indicators of burnout.6,9
Both traditional knowledge and the results of these recent
studies support the use of R. rosea for stress-related symptoms
such as fatigue or lack of performance. These findings suggest
that R. rosea might also be beneficial in burnout and that
further testing of the drug in patients suffering from this
stress-related syndrome is warranted.
The trial reported here not only investigated individual
aspects of stress-related conditions and indicators of burnout
but aimed to cover as many aspects as possible, including
individual perceptions of stress and exhaustion, and to
compare these with objective assessments. Thus, a rounded
set of criteria for the evaluation of the clinical course in burn-
out was provided. This trial is therefore the first to investigate
the clinical outcomes of R. rosea treatment in patients with
predefined burnout symptoms based on numerous specific
criteria and measurements.
Objective
The trial presented in this study is the first to investigate the
clinical outcomes of the drug treatment in patients suffering
from burnout syndrome. The principal objective of the trial
was therefore to describe the therapeutic impacts as well as
the safety and tolerability of R. rosea extract applied in this
target group, thus providing exploratory data as a basis for
future randomized trials.
Methods
According to its exploratory design, which aimed to evalu-
ate the study data on a descriptive level, the trial was set
up as an open-label, single-arm, multicenter study. Control
groups and randomization were therefore unnecessary. The
trial was conducted at four centers in Vienna (Austria):
Vienna University Hospital and three GP practices. Signed
informed consent was obtained from the participants before
any trial-related action was performed. The clinical trial
number for this study is ISRCTN31235821. The clinical
trial was approved by the Ethikkommission der Medizinis-
chen Universität Wien und des AKH, Borschkegasse 8b/
E06, A-1090 Wien, Vienna, Austria, which officiated as
the responsible ethics committee. Planning, execution, and
analysis of the trial were carried out in accordance with
national regulations in Austria and the ICH Guidelines for
Good Clinical Practice (GCP).
Participants
The trial aimed to recruit 120 male and female employees or
subjects with comparable stress burdens (eg, home caring of
handicapped or demented family members) aged 30–60 years
suffering from burnout symptoms.
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Rhodiola rosea extract in burnout
Outcome measures
Since no data are available in this study-specific target popu-
lation, the following broad spectrum of outcome measures
was employed to evaluate the clinical courses in patients
suffering from burnout symptoms.
The Maslach Burnout Inventory (MBI-D),1 seven Numer-
ical Analogue Scales (NASs) of subjective stress symptoms,
one NAS to assess the “overall satisfaction with sexual life,”
the Burnout Screening Scales (BOSS I and BOSS II),30 the
Patient Sexual Function Questionnaire (PSFQ),31,32 and the
Perceived Stress Questionnaire (PSQ).33 The Clinical Global
Impressions Scale (CGI)34 were used to assess the severity of
the disorder and its change from baseline, clinical outcomes,
and the tolerability of the study medication. Mood and well-
being were measured by means of the Multidimensional
Mood State Questionnaire (MDMQ).35 These tools were all
self-rating instruments. In addition, the following objective
scales were employed: the Sheehan Disability Scale (SDS)36
to assess the negative impact of the burnout symptoms on the
patient’s work, social life, and family, and the Number Con-
nection Test (NCT)37 to assess speed of executive function.
Eligibility
The inclusion criteria were as follows: moderate degree of
burnout with an emotional exhaustion level of 1.81–2.80
and a reduced personal performance level of 3.90–4.79
according to the MBI-D, at least three perceived life
stress symptoms with a severity between 5 and 8 points as
assessed on NASs of subjective stress symptoms, a CGI
item 1 score ,4, and .5 points on the NAS for impair-
ment of sexual life.
Patients with any of the following characteristics were
excluded: Participation in other experimental drug trials within
12 weeks before enrollment, current hospitalization, risk of
suicide or item 3 of the Hamilton Rating Scale for Depression
(HAM-D)38 .2, history or evidence of substance abuse or
dependence, history of Axis I disorders according to DSM-IV,
nonmedical psychiatric treatment at least 4 weeks before the
study, intake of any prescribed psychotropic medication within
1 year before enrollment, and known hypersensitivity to R.
rosea extract or any ingredient of the drug under study.
Concomitant treatment prohibited for study participants also
included treatment for neurodegenerative diseases, centrally
acting antihypertensive medication (exception: beta-blockers
on dosage stable for at least 4 weeks), and muscle relaxants.
Laboratory tests and electrocardiogram (ECG) were
assessed for abnormalities. Existing cardiovascular, respiratory,
cerebrovascular, or metabolic disorders as well as infec-
tions, epilepsy, Parkinson’s disease, and progressive
diseases such as cancer precluded inclusion. Subjects with
generalized anxiety disorder according to module O of the
Mini International Neuropsychiatric Interview (MINI)39 or
major depression according to module A of the MINI and
having a total score $16 on the HAM-D (17-item version)
at screening were also excluded from the trial.
Intervention
The active ingredient of the preparation is a proprietary dry
ethanolic (60% w/w) extract from R. rosea roots (1.5–5:1)
(WS® 1375, Rosalin; which is the active substance of
Vitango®, manufactured by Dr Willmar Schwabe GmbH &
Co, KG, Germany). Evidence from previously conducted
clinical trials24,26,29 indicates the 400 mg/day dosage of study
medication chosen for this study to be in an effective and a
safe administration range.
After the determination of trial eligibility, the patients
were screened for inclusion and exclusion criteria on
day-2. Patients were enrolled upon meeting all the criteria,
and written informed consent was obtained from all the
patients. After the baseline visit (day 0), patients underwent
a treatment with 200 mg of R. rosea extract administered
twice daily over a treatment duration of 12 weeks. Patients
were asked to take one 200 mg tablet before breakfast and
one before lunch with a glass of water.
Regular visits were scheduled for days 0 and 7 as well
as for weeks 4 (telephone interview), 8, and 12 (termina-
tion visit). Given the comparatively long treatment duration
chosen for the trial, this schedule of visits was set in order to
allow the investigators to capture data regarding both short-
term and delayed impacts of the study medication.
All the outcome variables were measured at screening
and at week 12. BOSS I was additionally assessed at week 8,
whereas BOSS II, NASs for subjective stress symptoms,
NCT, MDMQ, and CGI were additionally assessed at day 7
and week 8.
Safety and tolerability were assessed by physical exami-
nation, vital sign measurements, 12-lead ECG, and laboratory
tests at screening and end of treatment. The patients were
asked about adverse events (AEs) and concomitant medication
at every visit. The severity and causal relationships of AEs
with the test drug were classified by the respective investiga-
tor according to standards set by ICH-GCP.
Statistical methods
The rating scales were assessed and evaluated in an explor-
atory data analysis in order to support the results of earlier
trials regarding the treatment of mental and physical symp-
toms of stress and overwork such as fatigue and exhaustion.
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Kasper and Dienel
Therefore, no hypotheses were formulated and no formal
estimation of sample size accounting for type I error rate,
power, standard deviation, and effect size was done. Because
of the exploratory characteristics of the trial, no adjustments
for multiplicity were applied.
The sample size of 120 participants was regarded as
sufficient in order to obtain primary information about the
clinical outcomes in the target group and to derive estimates
regarding variability. Calculations were based on a one-group
multivariate repeated measures design for a two-sided test, five
time points, and a descriptive significance level α=0.5. This
results in a power of 80% to detect a minimum standardized
difference of 0.5 when recruiting 120 participants – including
a 10% dropout rate.40
The absolute and relative intra-individual changes during
the time courses of the outcome parameters were evaluated.
Descriptive statistics were computed to describe the empirical
distributions, 95% confidence intervals for the expected
values and medians were calculated, and descriptive P-values
associated with appropriate statistical tests were presented. In
order to analyze not only the main effects but also the interac-
tion effects on various outcome variables, for example, between
time and gender, repeated measurement analysis of variance
was applied. Statistical analysis was performed by a CRO using
the SAS® statistical software package (Statistical Analysis
System; SAS Institute, Cary, NC, USA, Version 9.1.3).
The analysis was primarily based on the full analysis set
(FAS) including all participants who had received at least one
dose of R. rosea and who had had at least one post-screening
measurement on one of the rating scales (MBI-D, BOSS I+II,
NAS, PSQ, NCT, SDS, MDMQ, PSFQ, and CGI). In addi-
tion, a per-protocol (PP) analysis was performed including
those patients of the FAS without major protocol violations.
Safety variables were assessed for the safety population
which included all patients who were given study medica-
tion at least once.
Results
Participant ow
In total, 131 patients were screened and 118 patients were
finally included in the study and received the investigational
treatment at least once. The first patient was included on
July 21, 2011, and the last visit of the last patient was conducted
on October 24, 2012. One patient was lost to follow-up
without any post-baseline measurement. Thus, 117 patients
could be included in the FAS. During the treatment phase,
18 patients (15.3%) terminated the study prematurely. Major
protocol violations were observed in 49 patients; therefore, a
total of 68 patients were included in the per-protocol set (PPS).
Most of the major protocol violations were due to reduced
visit schedule compliance (n=30).
In the following, only the outcome data of the FAS are
shown since the analysis of the FAS and the PPS revealed
similar results. The disposition of patients and analysis data
sets are illustrated in Figure 1.
Demographic characteristics
The analysis of the MINI assessments showed that
4/117 patients (3.4%) reported a former episode of major
depression, 8/117 (7%) had a low suicidal risk, whereas a
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Figure 1 Disposition of patients and analysis of data sets.
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893
Rhodiola rosea extract in burnout
current panic attack, a current agoraphobia, and a current
bulimia nervosa were reported by one patient each. No further
neuropsychiatric disorders were detectable among the FAS
members. The analysis of the HAM-D showed an average
total score (± standard deviation) of 10.2±2.5 points at
screening, which indicates only mild depressive symptoms
in the FAS cohort. 40/117 patients (34.2%) had already been
treated for stress-related complaints in the past. The average
duration of stress was 2.7±3.0 years. Demographic data are
summarized in Table 1.
The overall treatment compliance evaluated according
to the number of tablets dispensed and returned in rela-
tion to the respective number of treatment days, was high.
In the FAS, the average compliance was 98.6%±6.1% with
a median of 99.4%.
Clinical outcomes
A decrease by 0.4±1.2 and 0.3±1.0 points, respectively, was
observed in the MBI-D subscales “depersonalization” and
“emotional exhaustion” between screening and week 12.
No change could be detected in the subscales “involvement”
and “personal accomplishment” (Table 2).
Figure 2 illustrates the time courses of the NASs for sub-
jective stress symptoms. All the seven items showed signifi-
cant improvement between screening and week 12, with the
greatest change occurring during the first week of treatment
(P,0.001, two-sided Wilcoxon signed-rank test, FAS, and
last observation carried forward [LOCF]). Subscores with the
most obvious change were “exhaustion,” “impaired concen-
tration,” and “somatic symptoms,” with a decrease by 3.1±2.8,
2.5±2.6, and 2.4±2.5 points, respectively, at week 12.
All subscores of the PSQ as well as the total PSQ global
score distinctly decreased between screening and end of the
intervention period. The PSQ subscores with the greatest
change after 12 weeks of administration of R. rosea were
“lack of joy,” “tension,” and “fatigue,” which improved by
2.8±4.1, 2.4±2.6, and 2.4±3.0, respectively (Table 3).
Table 4 summarizes the total average values for the
BOSS I and II assessments before and after the interven-
tion period. The global scores as well as all subscales had
improved at week 8 and also until week 12. The BOSS II
interim measurement at day 7 showed an alleviation of
symptoms (Table 4 and Figure 3).
The NAS score for Impairment of Sexual Life improved
considerably, as well as most of the items of the PSFQ.
The improvement of the “ability to have and/or maintain
an erection” was marked though not statistically sig-
nificant, while the “ability to ejaculate” and “relevance of
Table 1 Demographic data: absolute (relative) frequency and
mean ± standard deviation, FAS (N=117)
Measure Number
Female 68 (58.1%)
Male 49 (41.9%)
Age 43.7±8.0
Height (cm) 172.2±10.1
Weight (kg) 78.4±18.7
Duration of stress/stress-related complaints (years) 2.7±3.0
Prior treatment for stress-related complaints 40 (34.2%)
Family history related to study indication 22 (18.8%)
Abbreviation: FAS, full analysis set.
Table 2 MBI-D: mean ± standard deviation, median and P-value of
the two-sided Wilcoxon signed-rank test, FAS, LOCF (N=117)
Subscale Screening Week 12 Change
week 12 –
screening
P-value
Depersonalization 1.8±1.2 1.4±1.3 -0.4±1.2 ,0.001
1.6 1.2 -0.2
Emotional exhaustion 2.6±0.3 2.3±1.0 -0.3±1.0 ,0.001
2.7 2.2 -0.2
Involvement 2.1±1.3 2.0±1.3 -0.1±1.3 0.171
2.0 2.0 0.0
Personal 4.3±0.4 4.3±0.9 0.0±0.8 0.464
accomplishment 4.3 4.4 0.0
Note: High scores indicate a high burnout level, except for the subscale “personal
accomplishment” in which a lower score indicates a higher level.
Abbreviations: MBI-D, Maslach Burnout Inventory; FAS, full analysis set; LOCF,
last observation carried forward.
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Figure 2 NAS for subjective stress symptoms.
Note: N=117, mean ±95% condence interval, FAS.
Abbreviations: NAS, Numerical Analogue Scale; FAS, full analysis set.
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Kasper and Dienel
sexual functioning for current wellbeing” remained mainly
unchanged. For both the items, mild impairment had been
reported at screening (Table 5).
NCT values increased distinctly between screening and
week 12. All the three subscales of the MDMQ also showed
marked improvement from screening to week 12 (Table 6).
The global impairment score measured by the SDS
decreased from 17.8±5.8 at screening to 12.4±7.7 at week 12
(P,0.001). There was also a trend toward the reduction in
the subscore “work days lost” (1.0±2.3 vs 0.6±1.3, P=0.063)
and a significant reduction in the second subscore “days being
underproductive” (2.5±2.4 vs 1.5±1.8, P,0.001 for the two-
sided Wilcoxon signed-rank test, FAS, LOCF).
The CGI scores for therapeutic effects showed a “marked”
improvement in 49/117 (41.9%) patients after 12 weeks
of treatment, whereas the improvement of symptoms was
reported to be “moderate” in 26/117 (22.2%), and “minimal”
in 30/117 (25.6%) of the patients. In 8/117 patients (6.8%),
symptoms were rated as unchanged or worse. Comparable
results were obtained for the rating of global improve-
ment after the treatment period, which was reported to be
“very much,” “much,” or “minimally” the case in 41/117
(35.0%), 26/117 (22.2%), and 34/117 (29.1%) patients,
respectively. The mean “severity” score had significantly
dropped from 3.4±0.7 at screening to 2.4±1.1 at week 12
(P,0.001).
In addition to the overall analysis, all rating scales were
analyzed with regard to gender and age subgroups (separated
by the median) for both the FAS and PPS. In summary, all
relevant changes in outcome variables for the whole study
population could also be confirmed within each subgroup.
Safety
The participants representing the safety population were
given the investigational product between 3 and 98 days with
Table 3 PSQ: mean ± standard deviation, median, P-value of the
two-sided Wilcoxon signed-rank test, FAS, LOCF (N=117)
Subscale Screening Week
12
Change
week 12 –
screening
P-value
PSQ stress score 0.6±0.2 0.4±0.2 -0.2±0.2 ,0.001
0.6 0.4 -0.1
Fatigue 12.5±2.14 10.1±3.1 -2.4±3.0 ,0.001
13.0 10.0 -2.0
Harassment 10.1±2.3 8.6±2.6 -1.5±2.5 ,0.001
10.0 8.0 -1.0
Irritability 5.7±1.3 4.6±1.6 -1.1±1.5 ,0.001
6.0 5.0 -1.0
Lack of joy 19.3±3.7 16.5±4.6 -2.8±4.1 ,0.001
20.0 17.0 -2.0
Overload 11.6±2.6 10.2±2.9 -1.4±2.3 ,0.001
12.0 10.0 -1.0
Tension 11.7±2.1 9.3±3.0 -2.4±2.6 ,0.001
12.0 9.0 -2.0
Worries 12.9±3.1 10.7±3.3 -2.1±3.2 ,0.001
13.0 10.0 -1.0
Abbreviations: PSQ, Perceived Stress Questionnaire; FAS, full analysis set; LOCF,
last observation carried forward.
Table 4 BOSS I and II: total average value, mean ± standard deviation, median, P-value of the two-sided Wilcoxon signed-rank test,
FAS, LOCF (N=117)
Scale Subscale Screening Day 7 Week 8 Week 12 Change week 12 –
screening
P-value
BOSS I Profession 2.0±0.9
2.0
1.4±0.9
1.3
1.3±0.9
1.2
-0.7±1.0
-0.5
,0.001
Own person 2.5±0.9
2.5
1.6±0.9
1.5
1.5±1.0
1.4
-1.0±1.0
-0.9
,0.001
Family 2.7±1.1
2.6
1.9±1.1
1.8
1.7±1.1
1.4
-0.9±1.1
-0.6
,0.001
Friends 2.3±1.0
2.2
1.5±1.0
1.4
1.4±1.0
1.2
-0.8±1.0
-0.6
,0.001
Global score 2.3±0.8
2.3
1.6±0.8
1.4
1.4±0.9
1.3
-0.9±0.9
-0.8
,0.001
BOSS II Physical complaints 1.7±0.8
1.6
1.2±0.8
1.0
1.1±0.7
0.9
1.0±0.7
0.9
-0.7±0.8
-0.6
,0.001
Cognitive
complaints
2.3±1.0
2.2
1.7±0.9
1.6
1.5±1.0
1.3
1.4±1.0
1.2
-1.0±1.0
-0.9
,0.001
Emotional
complaints
2.2±1.1
2.1
1.5±0.9
1.4
1.3±0.9
1.1
1.2±1.0
0.9
-1.0±1.0
-0.8
,0.001
Global score 2.1±0.9
2.1
1.5±0.8
1.4
1.3±0.8
1.2
1.2±0.8
1.0
-0.9±0.8
-0.9
,0.001
Abbreviations: BOSS, Burnout Screening Scales; FAS, full analysis set; LOCF, last observation carried forward.
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Rhodiola rosea extract in burnout
a mean treatment duration of 81.3±18.0 days. A total of 145
AEs, which were either reported by the trial participants or
revealed by the investigator at scheduled visits, were observed
in 70/118 (59.3%) patients during the active treatment phase
and a subsequent 7 days risk phase. AE intensity was
predominantly rated as mild (59/145 [40.7%]) or moderate
(68/145 [46.9%]), and severe (18/145 [12.4%]). For 46/145
AEs (31.7%), a causal relationship with the investigational
product could not be excluded but was assessed as “unlikely”
in 41/46 (89.1%) cases. A causal relationship with the study
drug was rated “possible” in 5/46 (10.9%) subjects who
reported head pressure, light-headedness, nausea, feeling
irritated, and eye swelling. One serious adverse event (SAE)
occurred in a male subject who had to be hospitalized for
3 days due to urinary tract infection after cystoscopy. The
SAE was assessed as “not related” to the investigational
product and had resolved at the end of the study. Except
for this case of hospitalization, no other SAE was reported.
The calculated overall incidence of AEs per observation day
was 0.015 and was found to be low during the whole study
period. None of the safety laboratory parameters presented a
significant mean change during the course of the study. The
AEs are summarized in Table 7.
*OREDOVFRUH
'D\ :HHN :HHN6FUHHQLQJ
Figure 3 Burnout Screening Scale BOSS II.
Note: N=117, mean ±95% condence interval, FAS.
Abbreviations: FAS, full analysis set; BOSS, Burnout Screening Scales.
Table 5 Numerical Analogue Scale for “Impairment of Sexual Life” and PSFQ: number of subjects, mean ± standard deviation, median,
and P-value of the two-sided Wilcoxon signed-rank test, FAS, LOCF
Scale Item Screening Week 12 Change week 12 –
screening
P-value
NAS Impairment of sexual life 117 117 117 ,0.001
6.8±1.5 4.2±3.1 -2.6±2.8
6.3 5.0 -2.0
Thinking about sex with 116 116 116 ,0.001
interest/desire 2.7±1.5 3.3±1.4 0.6±1.3
3.0 4.0 0.0
Enjoyment of sex 115 112 112 ,0.001
2.6±1.3 3.3±1.3 0.6±1.3
3.0 4.0 0.0
Ability to become 116 114 114 ,0.001
sexually aroused 2.9±1.4 3.4±1.2 0.5±1.3
3.0 4.0 0.0
Frequency of sexual 115 113 113 ,0.001
activity 2.2±1.2 2.8±1.4 0.6±1.3
2.0 3.0 0.0
PSFQ Ability to have orgasm 116 114 114 0.005
3.0±1.3 3.3±1.2 0.3±1.1
3.0 4.0 0.0
Overall satisfaction with 113 114 112 ,0.001
sexual life 2.5±1.1 3.2±1.2 0.6±1.2
2.0 3.0 0.5
Ability to have and/or 49 49 49 0.002
maintain an erection 3.2±0.9 3.6±0.9 0.4±0.8
3.0 4.0 0.0
Ability to ejaculate 49 49 49 0.745
3.7±0.9 3.7±0.7 0.0±0.7
4.0 4.0 0.0
Relevance of sexual 117 117 117 0.609
functioning for current 3.9±1.4 3.8±1.6 -0.1±1.7
well-being 4.0 4.0 0.0
Abbreviations: PSFQ, Patient Sexual Function Questionnaire; FAS, full analysis set; LOCF, last observation carried forward; NAS, Numerical Analogue Scale.
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Discussion
Most of the outcome variables assessed in this trial demon-
strated relevant improvement over time with considerable
changes already being detectable after the first week of
R. rosea administration.
As stress-induced exhaustion is regarded as an essential
precondition to burnout development, this outcome was of
central interest in the evaluation of study assessments. The
level of “emotional exhaustion” as assessed by the MBI-D at
screening was moderate and improved clearly over the time
of the intervention. Likewise, the PSQ-assessed “fatigue”
value and the subscore “exhaustion,” as assessed by the
respective NASs, had already clearly improved by day 7 and
further decreased until the end of the intervention. Further-
more, the other subscales assessed by the NASs for subjective
stress symptoms underwent significant improvement, which
suggests an increase in coping ability and a decrease in
subjectively perceived demand after the intervention.
Mood-related results improved in a similar way with
“lack of joy” undergoing the greatest improvement among
the values assessed by PSQ. Accordingly, there was a clear
improvement of the value “loss of zest for life” as assessed
by NAS, suggesting a diminished tendency toward stress-
related depressive mood.
Overall, the data obtained by PSQ and the NASs for
subjective stress symptoms demonstrate improvement in
all the assessed values, which was most pronounced within
the first week of treatment and continued slowly afterwards.
The values most closely associated with burnout were among
those with greatest improvement. The results suggest a
development toward re-establishment of a demand–resource
balance, thus supporting the findings from earlier placebo-
controlled trials that investigated the clinical outcomes of
R. rosea treatment for stress-related symptoms25–27 and for
the symptoms of depression.29
Although the MBI-D subscale “depersonalization”
improved over time, there was no detectable improvement
in the scales “involvement” and “personal accomplishment.”
This result is in contrast to the marked improvement in the
NCT, which objectively measures executive function and
performance, and the clearly improved alertness value, as
measured by the MDMQ. The contradiction between self-
rating and objective outcome regarding “personal accom-
plishment” is in line with what is known about the essential
role of individual perception of achievement in burnout,
which often deviates from objective evaluation.5
The BOSS assessment results demonstrate that over the
12-week course of treatment the subjective perception of
different aspects of life (profession, own person, family, and
friends) as well as physical, cognitive, and emotional com-
plaints improved clearly. The average global and subvalues of
the BOSS I and the BOSS II assessments thus reflect a percep-
tion of reduced global- and aspect-related stress burdens.
Table 6 NCT and MDMQ: mean ± standard deviation, median, P-value of the two-sided Wilcoxon signed-rank test, FAS, LOCF
(N=117)
Measure/scale Screening Day 7 Week 8 Week 12 Change week 12 –
screening
P-value
NCT (time in s) 72.6±19.6 64.5±17.1 63.2±16.7 60.5±15.8 -12.1±9.2 ,0.001
68.8 60.0 59.0 57.3 -10.8
MDMQ
Alertness – 20.8±7.2 23.5±7.2 26.4±7.8 26.4±8.0 5.6±8.8 ,0.001
tiredness 20.0 24.0 27.0 26.0 5.0
Calmness – 22.3±6.6 24.5±6.3 27.3±6.8 28.2±7.4 6.0±6.8 ,0.001
restlessness 21.0 24.0 28.0 29.0 6.0
Good mood – 24.1±6.2 27.0±6.7 29.6±7.0 29.6±6.8 5.6±7.1 ,0.001
bad mood 23.0 27.0 31.0 29.0 5.0
Note: Increased scores for the MDMQ indicate an improvement of mood and wellbeing.
Abbreviations: NCT, Number Connection Test; MDMQ, Multidimensional Mood State Questionnaire; FAS, full analysis set; LOCF, last observation carried out.
Table 7 Adverse events during the active treatment and risk
phase: absolute (relative) frequency of subjects, safety analysis set
(SAF), N=118
Adverse event (MedDRA system
organ class)
Number of
patients (%)
Any patients with adverse event(s) 70 (59.3)
Nervous system disorders 32 (27.1)
Infections and infestations 32 (27.1)
Gastrointestinal disorders 15 (12.7)
Musculoskeletal and connective tissue disorders 9 (7.6)
Skin and subcutaneous tissue disorders 5 (4.2)
Eye disorders 4 (3.4)
Injury, poisoning and procedural complications 4 (3.4)
Note: Events that were observed in .3 subjects.
Abbreviation: MedDRA, Medical Dictionary for Regulatory Activities.
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Rhodiola rosea extract in burnout
Comparing the results of BOSS I and II with a represen-
tative normative German sample clearly shows that at the
beginning of the study the participants reported clinically
relevant psychological, physical, and psychosocial com-
plaints (global score T-values 65 and 63 for BOSS I and II,
respectively). This global score finally decreased to a normal
value after the 12-week treatment phase with R. rosea (global
T-value 54 and 53 for BOSS I and II, respectively).
Increased sexual interest and functioning as determined
by the NAS for Impairment of Sexual Life and the PSFQ are
obvious and indicate an alleviation of stress-induced impair-
ment of sex life after the intervention. These results are in
line with earlier findings on the causal relationship of life-
stress, anxiety, and depression with sexual dysfunction41,42
and support the assumption of an impairing effect of burnout
on sexual functioning.
The evaluation of therapeutic effects as assessed by
the respective CGI item before and after the intervention
period shows that at least a minimal improvement of the
disorder is reported by the vast majority of patients (105/117
or 89.7%). This suggests therapeutic efficacy of R. rosea
extract in burnout.
Despite the observed quick and distinct improvement
of most of the outcome parameters during the first week
of intervention, which might at first glance not seem to be
in accordance with what is known about the usually rather
slow process of burnout therapy, it is still in line with what
is known about the gradual development of burnout.6 In this
context, the outcomes of the PSQ and NAS assessment sug-
gest that the reduction of core values such as exhaustion,
fatigue, and subjective stress perception during the treat-
ment with R. rosea extract might be an important first step
toward a continuous alleviation of burnout symptoms, thus
inhibiting the exacerbation of the syndrome and preventing
the development of subsequent disorders such as depression
or physical illness.
The lack of a control in the trial reported here must be
considered a limitation. The results thus remain preliminary
and may not be considered confirmatory. Nevertheless, the
considerable improvements found for most of the outcome
measures reveal positive trends in burnout therapy. No symp-
tom alleviation can be expected without treatment. The trial
results are therefore important to help generate hypotheses
for further research and provide bases for confirmatory study
design, endpoints, and methodologies.43
The steady and substantial alleviation of the majority of
the burnout symptoms assessed was statistically relevant for
the variables evaluated for the FAS as early as 1 week after the
start of treatment. The consistent overall results were further
confirmed by the analyses of the PPS, subgroup analyses, and
repeated measurement analyses. The results obtained are in
line with the findings from previously conducted clinical trials
on the clinical outcomes of R. rosea in different aspects of
the burnout syndrome such as stress and depression.
The number and nature of AEs that occurred during the
trial indicate a favorable safety profile of R. rosea in patients
suffering from burnout symptoms, which is also underlined
by the remarkably high treatment compliance.
Conclusion
The trial reported here was the first to investigate clinical
outcomes in patients suffering from burnout symptoms
when treated with R. rosea. During administration of the
study drug over the course of 12 weeks, a wide range of
outcome measures associated with the syndrome clearly
improved. The consistent data obtained support the claim
that the results of this open-label exploratory study are in
line with previous findings on the alleviation of life-stress
and burnout symptoms by application of R. rosea. The results
presented therefore provide an encouraging basis for future
RCTs further investigating the clinical outcomes of R. rosea
extract in patients with the burnout syndrome.
Acknowledgments
The authors are grateful to the investigators who took part in
this trial. They thank Christine Weidl who provided support
in medical writing. All the authors contributed equally to the
preparation of the manuscript.
Disclosure
Siegfried Kasper has received grant/research support, con-
sulting fees, and/or honoraria within the last 3 years from
Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca,
Eli Lilly, Janssen, KRKA-Pharma, Lundbeck, Neuraxpharm,
Pfizer, Pierre Fabre, Schwabe, and Servier. Dr Dienel is an
employee of Dr Willmar Schwabe GmbH & Co. KG.
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