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PSYCHIATRIC
RESEARCH
www.elsevier.com/locate/jpsychires
c,*
Abstract
Ginkgo biloba special extract EGb 761, an anti-dementia drug, enhances cognitive functioning and stabilizes mood in cognitively
impaired elderly subjects. Moreover, EGb 761 had been found to alleviate symptoms of anxiety in people with mental decline, therefore
it was now tested for clinical ecacy in younger patients suering from anxiety. One hundred and seven patients with generalized anxiety
disorder (GAD, n = 82) or adjustment disorder with anxious mood (ADWAM, n = 25) according to the diagnostic and statistical manual of mental disorders, third edition revised (DSM-III-R) were randomized to daily doses of 480 mg EGb 761, 240 mg EGb 761 or
placebo for 4 weeks. Intention-to-treat (ITT) analyses were performed on the primary outcome measure, the Hamilton rating scale for
anxiety (HAMA), and the secondary variables, the clinical global impression of change (CGI-C), the Erlangen anxiety tension and
aggression scale (EAAS), the list of complaints (B-L 0 ), and the patients global rating of change. The HAMA total scores decreased
by 14.3 (8.1), 12.1 (9.0) and 7.8 (9.2) in the high-dose EGb 761, the low-dose EGb 761 and the placebo group, respectively.
Changes were signicantly dierent from placebo for both treatment groups with p = 0.0003 (high-dose group) and p = 0.01 (low-dose).
Regression analyses revealed a doseresponse trend (p = 0.003). EGb 761 was signicantly superior to placebo on all secondary outcome measures. It was safe and well tolerated and may thus be of particular value in elderly patients with anxiety related to cognitive
decline.
2006 Elsevier Ltd. All rights reserved.
Keywords: Ginkgo biloba; EGb 761; Randomized controlled trial; Anxiety; Generalized anxiety disorder; Adjustment disorder
1. Introduction
Symptoms of anxiety, usually not in appropriate
response to a real threat, are among the frequent causes
for seeking medical help. Estimated prevalence rates for
anxiety disorders in primary care settings range from
2.5% to as much as 19% (Sansone et al., 2004; Ansseau
et al., 2004). For generalized anxiety disorder (GAD) a
prevalence of 10.3% was found in an adult primary care
*
Corresponding author. Tel.: +49 721 4005 492; fax: +49 721 4005
8492.
E-mail address: robert.hoerr@schwabe.de (R. Hoerr).
0022-3956/$ - see front matter 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jpsychires.2006.05.004
473
by EGb 761 treatment (Eckmann and Schlag, 1982). Benecial eects of EGb 761 on behavioral and psychological
symptoms of dementia (BPSD), including anxiety, have been
shown in a series of further studies (summarized in Hoerr,
2003), yet proof of ecacy in primary anxiety disorders or
anxiety in response to stressful events has been lacking.
EGb 761 showed stress-alleviating and anxiolytic-like
activity in pre-clinical studies. In a rat model EGb 761 signicantly reduced the detrimental eects of learned helplessness on a subsequent conditioned avoidance task. It
also increased the intake of novel food in a new environment in a mouse model of emotional hypophagia (Porsolt
et al., 1992). On the elevated plus maze (EPM), senescent
mice treated with EGb 761 spent signicantly more time
on the open (unsafe) arms than those treated with
drug-free vehicle only. In general, animals prefer the closed
(safe) arms. After a forced-swim task in cold water, anxiety was increased, i.e. the time spent on the open arms was
decreased, in vehicle-treated, but not in EGb 761-treated
animals (Ward et al., 2002). Mice treated with a particular
fraction of the special extract EGb 761 spent more time in
the light part of a light-dark box than control animals.
Similar eects were demonstrated for anxiolytic drugs, such
as diazepam and buspirone (Noldner and Chatterjee, personal communication). Anxiety-related hyperthermia as
observed in the remaining animals after removing mice
one by one from a cage and then replacing them, is also signicantly attenuated by the same extract fraction (Noldner
and Chatterjee, personal communication).
Using a discrimination learning task in rats, Rapin and
co-workers (1994) demonstrated that auditory perturbation (stress) during the discriminative phase of learning
decreased the percentage of correct responses and increased
the number of errors. These changes were correlated with
increases in plasma concentrations of epinephrine, norepinephrine and corticosterone. Both detrimental eects of
auditory perturbation and rises in plasma hormones were
suppressed by EGb 761. The drug eects were present
in both young and old animals. Long-term administration
of EGb 761 to rats resulted in a decreased basal corticosterone secretion and an attenuation of the related increase
in corticotropin releasing hormone (CRH) and arginine
vasopressin (AVP) gene expression (Marcilhac et al.,
1998). Under intense surgical stress CRH, ACTH and corticosterone plasma concentrations were markedly elevated
in control animals, but signicantly less so in EGb 761
treated animals. These ndings suggest that EGb 761
interferes with the regulation of the activity of the hypothalamicpituitaryadrenocortical (HPA) axis.
In a randomized and placebo-controlled double-blind
study in 70 healthy young volunteers, Jezova and co-workers (2002) used a stress model involving a combination of
static exercise (handgrip) and mental stimuli. A single dose
of 120 mg EGb 761 signicantly attenuated the stressinduced rise in systolic and diastolic blood pressure
without aecting the heart rate. A stress-related increase
in salivary cortisol levels was observed in placebo-treated
474
disorders, obsessivecompulsive disorder, suspected dementia or severe somatic disorders were also excluded. Further
exclusion criteria were substance abuse, lack of cooperation,
inability to complete self-rating questionnaires, or treatment
with psychoactive drugs.
After general physical and neurological examination,
including laboratory tests, and a psychiatric interview,
patients were admitted to the study and underwent a
seven-day qualication period during which they received
placebo (2 lm-coated tablets t.i.d.) in a single-blind manner. Patients were eligible for randomization, if they were
compliant and if their HAMA total score did not change
by more than 7 points in either direction during the qualication period. Patients who responded to placebo treatment and those whose symptoms worsened progressively
were thus excluded.
Randomization was performed by the biometric unit of
Dr. Willmar Schwabe Pharmaceuticals. Using a validated
computer program each randomization number was assigned
to one of three treatments: high-dose EGb 761, low-dose
EGb 761 or placebo. The sealed randomization code was
stored safely and inaccessible to any person involved in the
study. Study drug was distributed to the sites in full blocks
of six successive randomization numbers. At the sites the randomization numbers, and thus the corresponding treatments,
were allocated to the patients in ascending order. This procedure ensured concealment and precluded any interference
with random treatment allocation.
During the four-week treatment period, all patients took
two lm-coated tablets t.i.d containing either 40 mg or
80 mg EGb 761 or no active drug (placebo). EGb 761
is a special extract (drugextract ratio 3567:1) of Ginkgo
biloba leaves, standardized to contain 2227% of avone
glycosides and 57% terpene lactones (ginkgolides, bilobalide). Active drug and placebo tablets were of the same size
and shape and coated with the same surface lm for identical appearance. To maintain high compliance, detailed
instructions for proper use of the study drug were provided
and repeated at every visit. Drug packages with unused
tablets were collected by the sites for compliance testing
at the end of the treatment period.
The standard instrument for the assessing of anxiety, the
Hamilton rating scale for anxiety (HAMA, CIPS, 1996) was
specied by the protocol as primary outcome measure. Secondary measures were the list of complaints (Beschwerdeliste) version B-L (CIPS, 1996), the Erlangen anxiety
tension and aggression scale (Erlanger Angst-Spannungsund Aggressivitatsskala EAAS; Junger, 1982), the clinical
global impression (CGI; CIPS, 1996) and a global self-rating
of change as perceived by the patient. The B-L and the
EAAS are self-rating instruments whereas the HAMA and
the CGI are rated by the investigators. Assessments took
place before the rst intake of the study drug (baseline),
and thereafter on days 4, 8, 15, and 29. The patients were
asked about adverse events at all visits, and laboratory tests
were done at screening and at the end of the treatment period, in order to assess safety and tolerability of the treatment.
475
Table 1
Patient characteristics at baseline, means standard deviations, n = 107
EGb 761
480 mg
EGb 761
240 mg
Placebo
12/22
47.5 11.0
170.6 8.8
77.1 15.8
30.7 5.2
27/7
14/22
47.6 12.5
170.1 9.3
70.6 12.0
29.7 5.5
25/11
15/22
46.7 13.0
171.7 7.4
73.0 11.1
29.5 5.5
30/7
Patient disposition is depicted in Fig. 1, baseline characteristics for the randomized patients are provided in Table 1.
All randomized patients had at least one examination after
baseline and could be included in the ITT analysis. The
treatment groups were comparable with respect to demographic and anthropometric data as well as severity of anxiety. The most frequent concomitant diseases were reported
for the musculoskeletal system (24%), the cardio-vascular
system (17%), the gastro-intestinal tract (15%), and metabolic functions (15%). This pattern is reected by the drugs
taken most frequently: cardiac medications, blood pressure
regulating drugs, non-steroidal anti-inammatory drugs,
and drugs for gastro-intestinal disorders. The groups were
well balanced with respect to concomitant diseases, prior
and concomitant drug intake. Seventeen patients had been
taking psychoactive drugs before enrollment: eight patients
of the placebo group (zolpidem, depot uspirilene, carbamazepine, one patient each; various herbals, ve patients),
ve patients of the low-dose EGb 761 group (doxepin,
two patients; various herbals, three patients) and four
patients of the high-dose EGb 761 group (benzodiazepines, four patients; valeriana, one patient). These treatments were discontinued before enrollment in the
Screened
109
Dropped:
Placebo Response (1)
Withdrawal of consent (1)
Randomized
107
Dropped:
Relocation (1)
Adverse Event (1)
EGb 761 480 mg
32
Completed
Placebo
37
(ITT)
Dropped:
Vacation (1)
476
Baseline
Changea
p-Value
All patients
EGb 761 480 mg
EGb 761 240 mg
Placebo
0.0003
0.01
GAD subsample
EGb 761 480 mg
EGb 761 240 mg
Placebo
0.004
0.04
ADWAM subsample
EGb 761 480 mg
EGb 761 240 mg
Placebo
n.a.
n.a.
0.04
0.16
0.002
0.006
Placebo
EGb 761 240mg
EGb 761 480mg
0
-5
-10
-15
-20
Day -7
Day -1
Day 4
Day 8
Day 15
Day 29
Fig. 2. Changes in HAMA total scores relative to baseline (day 1); means and standard errors.
EGb 761
480 mg
EGb 761
240 mg
Placebo
11 (34)
15 (47)
4 (13)
1 (3)
0 (0)
1a (3)
32 (100)
0.0001
10 (28)
14 (39)
5 (14)
7 (19)
0 (0)
0 (0)
36 (100)
0.008
5 (14)
9 (24)
9 (24)
11 (30)
3 (8)
0 (0)
37 (100)
p-values for comparisons between drug and placebo groups (U-test); ITT
analysis.
a
Severe depression in reaction to death of father.
Scale/treatment
Baseline
EAAS
EGb 761 480 mg
EGb 761 240 mg
Placebo
0.004
0.02
B-L 0
EGb 761 480 mg
EGb 761 240 mg
Placebo
0.0006
0.07
p-Value
477
478
secretion (Rapin et al., 1994; Marcilhac et al., 1998; Jezova et al., 2002; Hemmeter et al., 2001) seems to be a
feasible candidate mechanism. Central administration or
transgenic overproduction of CRH leads to increased
anxiety-like behavior in rodents (van Gaalen et al.,
2002), whereas genetic disruption of the CRH/CRHR1
system in rodents (Deussing and Wurst, 2005) or oral
administration of a CRH receptor antagonist to primates
(Habib et al., 2000) attenuates stress-related anxiety.
There is increasing evidence that elevated CRH and
overactivity of the HPA axis contribute substantially to
symptoms of depression and anxiety in humans (Strohle
and Holsboer, 2003) and that CRH-antagonistic treatment strategies may be clinically eective (Holsboer,
2001).
Whether it is appropriate to enroll patients with GAD
and ADWAM in the same study may be questioned, as
the latter is not an anxiety disorder by classication. In
fact, the etiologies appear to be dierent. However, this
does not necessarily mean that the biochemical and pathophysiological correlates of anxiety are also dierent.
Abnormal activation of the HPA axis has been found in
several disorders associated with anxiety (Strohle and
Holsboer, 2003). In subgroup analyses we found similar
baseline scores and similar dose-related eects of EGb
761 for both diagnostic groups. Statistical testing revealed
that EGb 761 was signicantly superior to placebo in the
GAD subgroup. However, testing was inappropriate for
the small ADWAM sub-sample.
EGb 761, even at a daily dose of 480 mg, was well tolerated. Adverse events were equally distributed across the
treatment groups, and laboratory tests did not reveal any
systematic changes. The clear-cut drop in systolic blood
pressure found in both treatment groups is in striking contrast to the ndings of other trials in which EGb 761 was
administered at daily doses up to 240 mg. The fact that the
size of change is exactly the same for both dosage groups
renders a high-dose eect unlikely. The nding can be better explained as a consequence of the profound relief of
anxiety and anxiety-related stress provided by EGb 761.
This also appears to be in line with the ndings by Jezova
et al. (2002) who found a lack of stress-related increase in
blood pressure.
Altogether, the results of this study suggest that EGb
761 has a specic anxiolytic eect that is dose-dependent
and signicantly exceeds the placebo eect commonly seen
in trials of psychoactive drugs. Taking into account that
anxiety in early stages of dementing disorders with perceived cognitive decline may to some extent be related to
activation of the HPA axis, as in GAD, and is reactive in
nature to some extent, as in ADWAM, it appears to be
worth considering EGb 761 for the treatment of this type
of anxiety. With its excellent tolerability, the absence of a
risk for dependence, lack of adverse impact on vigilance
and cognitive functioning (according to general experience), the drug is not only suitable for elderly patients,
but also for young people at work.
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