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| Date: 04-15-2015 | HC# 031551-518 |
Re: Review of EGb 761® Ginkgo Extract in the Treatment of Psychiatric Disorders
Montes
P, Ruiz-Sánchez E, Rojas C, Rojas P. Ginkgo
biloba extract 761: A review of basic studies and potential clinical use in
psychiatric disorders. CNS Neurol Disord
Drug Targets. 2015;14(1):132-149.
There are many ginkgo
(Ginkgo biloba, Ginkgoaceae) leaf
extracts marketed to treat central nervous system disorders; however, most
pre-clinical and clinical research studies have analyzed a specific standardized
ginkgo extract named EGb 761® (Dr. Willmar Schwabe GmbH & Co. KG;
Karlsruhe, Germany). The authors assert that "EGb 761 has the ability to produce neuroprotection due to its chemical
composition and the synergy of its components." This review provides an
overview of EGb 761 for the treatment of psychiatric disorders such as anxiety
and depression.
EGb
761 is a well-characterized preparation, derived from a water-acetone extract
of dried green ginkgo leaves, which is processed using a standardized method to
remove lipophilic compounds and concentrate the active components as follows: 24%
flavonoid glycosides (primarily of quercetin, kaempferol, and isorhamnetin), 6%
terpenoid trilactones (3.1% ginkgolides A, B, C, J, and M; 2.9% bilobalides),
and 5-10% organic acids (kynurenic, hydroxykinurenic, and vanillic acids). [Note:
The concentration of these compounds is substantially higher in the extract
than in the raw leaf.] Although the pharmacological effects of EGb 761 have
been associated with numerous constituents, researchers have primarily focused
on these three classes of compounds which are well absorbed, extensively
metabolized, and have half-lives ranging from two to six hours. Clinical
studies indicate that the optimal therapeutic dose of EGb 761 is 120-240 mg/day.
The
most commonly reported adverse events are nausea (0.9%), headache (0.9%),
gastrointestinal disturbances (2.6%), sleep disturbances/dizziness (0.4%), and
skin reactions (0.3%). There have been four case reports of cerebral hematomas
(bleeding) associated with the consumption of ginkgo extracts (but not EGb 761)
taken alone or in conjunction with other therapies; however, systematic reviews
of randomized controlled trials (RCTs) have not detected any increased risk of
bleeding in ginkgo-treated patients or in patients taking ginkgo plus
anticoagulants. Although there is no conclusive evidence that ginkgo is
associated with an increased risk of bleeding, the authors err on the side of
caution in recommending that additional studies should be conducted to definitively
resolve the controversy regarding this potential adverse effect. No other
adverse effects have been reported.
Pharmacokinetic
studies indicate that EGb 761 does not significantly alter cytochrome P450
(CYP) drug metabolism, although effects from other ginkgo products have been
reported. In an animal model, EGb 761 enhanced the effect of diazepam, and there
has been a case report that EGb 761 augmented the sedative effect of trazodone
in a patient with Alzheimer's disease (AD). However, the results of a human
pharmacokinetic study refute the clinical relevance of these findings. Evidence
from RCTs suggests that EGb 761 may increase the efficacy and decrease the
adverse effects of other antipsychotic drugs.
The
authors review the evidence supporting four mechanisms that may account for the
neuroprotective effects of EGb 761; namely, antioxidant effects, modulation of
neurotransmission, hormonal regulation of the hypothalamic-pituitary-adrenal
axis, and upregulation of neurotrophic factors.
Stress
is a major pathogenic factor triggering psychiatric disorders, particularly
depression and anxiety. The results of nine experimental studies evaluating the
antidepressant and anxiolytic effects of EGb 761 are summarized. In RCTs, EGb
761 significantly reduced anxiety parameters in patients with generalized
anxiety disorder (n=80) or adjustment disorder with anxious mood (n=25) in a dose-dependent
manner. A single dose of EGb 761 significantly reduced blood pressure (without
affecting heart rate) in healthy subjects (n=70) exposed to stressful stimuli, and
in another study, salivary cortisol levels were significantly reduced. Based on
this evidence, the authors conclude that EGb 761 regulates the stress-induced
activation of the hypothalamic-pituitary-adrenal axis which is associated with
anxiety and depression.
Although ginkgo is
used to treat a variety of psychiatric conditions, the authors assert that
"there are more studies and a better data base for mechanisms
and clinical effects of EGb 761 related to dementia than for any other
phytopharmaceutical medicine." The authors describe nine RCTs that included a
total of 2101 patients with AD, vascular dementia, or AD plus cerebrovascular
disease. Eight trials compared a placebo to 120-240 mg/day EGb 761, while the
ninth study compared EGb 761 (240 mg/day) plus donepezil (10 mg/day) to
donepezil (10 mg/day) alone. Treatment duration ranged from 12-52 weeks, and all
of the studies measured cognitive function.
In
six of the studies, EGb 761 supplementation produced a significant improvement
(P values not reported) in cognitive function compared to placebo. Two dose-ranging
trials (120-240 mg/day) revealed no significant improvement in the EGb 761
groups. No significant difference between groups was found in the study
comparing the efficacy of EGb 761 plus donepezil to donepezil alone; however,
the incidence of adverse effects was lower in the EGb 761 plus donepezil group compared
to donepezil alone.
Systematic
reviews of the neuroprotective effects of ginkgo have produced variable
results. The authors point out that the negative 2009 Cochrane review included
all ginkgo products, while reviews restricted to EGb 761 reported positive
effects in the treatment of cognitive impairment/dementia. They summarize the
results of four relatively large clinical trials (n=400-512 in each trial)
which found that EGb 761 was more effective than placebo in treating
neuropsychiatric symptoms such as anxiety, apathy/indifference,
depression/dysphoria, irritability/mood, and sleep/nighttime behavior. The
authors conclude that EGb 761 ameliorates neuropsychiatric symptoms and thus
promotes clinical improvements in cognitive performance, activities of daily
living, and quality of life.
To
summarize, EGb 761 is a well-characterized, standardized ginkgo extract with
good tolerability and a low incidence of adverse effects that ameliorates psychiatric
disorders. "EGb 761 has demonstrated effectiveness in the treatment of
cognitive impairment and non-cognitive symptoms associated with dementia,"
and it is "particularly useful when dementia is accompanied by
neuropsychiatric symptoms such as anxiety and depression/dysphoria." The few
trials assessing the efficacy of EGb 761 in reducing the incidence of dementia
have produced variable results. The authors point out that a number of factors
(e.g., age, disease state, preparation form and dose, environmental variables,
and ethnicity) may influence the therapeutic effect of EGb 761. They also briefly
review the positive results of RCTs that evaluated the efficacy of EGb 761 in the
treatment of schizophrenia (two trials) and attention deficit disorder (one
trial).
The
authors conclude that even though the safety, tolerability, and efficacy of EGb
761 has been demonstrated in RCTs cumulatively involving thousands of patients,
additional research is still needed to determine whether EGb 761 is more
effective alone or when combined with pharmaceutical treatments.
—Heather S. Oliff,
PhD